Merck Manual Diagnosis 17

The Merck Manual of Diagnosis and Therapy Sections
Front Matter 1. Nutritional Disorders (Chs. 1-5) 2. Endocrine / Metabolic Disorders (Chs. 6-18) 3. Gastrointestinal Disorders (Chs. 19-35) 4. Hepatic / Biliary Disorders (Chs. 36-48) 5. Musculoskeletal / Connective Tissue Disorders (Chs. 49-62) 6. Pulmonary Disorders (Chs. 63-81) 7. Ear / Nose / Throat Disorders (Chs. 82-89) 8. Ophthalmologic Disorders (Chs. 90-102) 9. Dental / Oral Disorders (Chs. 103-108) 10. Dermatologic Disorders (Chs. 109-126) 11. Hematology / Oncology (Chs. 127-145) 12. Immunology; Allergic Disorders (Chs. 146-149) 13. Infectious Diseases (Chs. 150-164) 14. Neurologic Disorders (Chs. 165-184) 15. Psychiatric Disorders (Chs. 185-196) 16. Cardiovascular Disorders (Chs. 197-213) 17. Genitourinary Disorders (Chs. 214-233) 18. Gynecology / Obstetrics (Chs. 234-254) 19. Pediatrics (Chs. 255-275) 20. Disorders Due to Physical Agents (Chs. 276-285) 21. Special Subjects (Chs. 286-297) 22. Clinical Pharmacology (Chs. 298-306) 23. Poisoning (Chs. 307-308)
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Erratum: Printed version of the 17th edition of The Merck Manual
Please note that there is an error in the dose of aqueous penicillin G in the treatment discussion of pneumococcal infections on page 1155, column 2, lin printed version of the 17th edition of The Merck Manual. The text in the first paragraph under Treatment should say "Pneumococcal meningitis or endoca requires up to 20 to 40 million U/day ...." (not 20,000 to 40,000 U/day as printed). The pediatric dose is correct as printed.
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The Merck Manual of Diagnosis and Ther

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Foreword to the Print Edition A Centennial History Guide for Readers of the Internet Edition Abbreviations and Symbols Editors and Editorial Board Consultants Contributors Editorial and Production Staff
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With this edition, The Merck Manual celebrates its 100th birthday. When the editors of the 1st Edition produced their 192-page compendium, they could not have realized the extent to which medical know would explode over the next century. The Merck Manual now fills 2,655 pages and covers countless d that were not known 100 years ago. A brief review of medical practice as reflected in The Merck Manu the past century follows in the section A Centennial History.
Although the knowledge of medicine has grown, the goal of The Merck Manual has not changed--To p useful clinical information to practicing physicians, medical students, interns, residents, nurses, pharm and other health care professionals in a concise, complete, and accurate manner. The Merck Manual continues to cover all the subjects expected in a textbook of internal medicine as well as detailed infor on pediatrics, psychiatry, obstetrics, gynecology, dermatology, pharmacology, ophthalmology, otolaryn and a number of special subjects. The Merck Manual quickly provides information that helps practition achieve optimal care. The more specialized the practice of medicine becomes, the more important suc information becomes. Specialists as well as generalists must at some time quickly access information other specialties.
The 17th edition of The Merck Manual is the culmination of an arduous but rewarding 7-year enterpris topic has been updated, and many have been completely rewritten. Topics new to this edition include disorders, prion diseases, death and dying, probabilities in clinical medicine, multiple chemical sensitiv chronic fatigue syndrome, rehabilitation, smoking cessation, and drug therapy in the elderly, among ot The members of the Editorial Board, special consultants, and contributing authors are listed on the fol pages with their affiliations. They deserve a degree of gratitude that cannot be adequately expressed h
The 17th edition of The Merck Manual is the culmination of an arduous but rewarding 7-year enterpris topic has been updated, and many have been completely rewritten. Topics new to this edition include disorders, prion diseases, death and dying, probabilities in clinical medicine, multiple chemical sensitiv chronic fatigue syndrome, rehabilitation, smoking cessation, and drug therapy in the elderly, among ot The members of the Editorial Board, special consultants, and contributing authors are listed on the fol pages with their affiliations. They deserve a degree of gratitude that cannot be adequately expressed h we know they will feel sufficiently rewarded if their efforts serve your needs.
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Mark H. Beers, M.D., and Robert Berkow, M.D
The Merck Manual of Diagnosis and Therapy

Section 12. Immunology; Allergic Disorders Chapters
146. Biology of the Immune System 147. Immunodeficiency Diseases 148. Hypersensitivity Disorders 149. Transplantation Sections Purchasing Information Home Navigation Help

Section 1. Nutritional Disorders Chapters
1. Nutrition: General Considerations 2. Malnutrition 3. Vitamin Deficiency, Dependency, and Toxicity 4. Mineral Deficiency and Toxicity 5. Obesity
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Section 13. Infectious Disorders Chapters
150. 151. 152. 153. 154. 155. 156. 157. Biology of Infectious Disease Infections in the Compromised Host Immunizations for Adults Antibacterial Drugs Antiviral Drugs Abscesses Bacteremia and Septic Shock Bacterial Diseases 158. 159. 160. 161. 162. 163. 164. Systemic Fungal Diseases Rickettsial Diseases Chlamydial Diseases Parasitic Infections Viral Diseases Human Immunodeficiency Virus Infection Sexually Transmitted Diseases

Section 2. Endocrine and Metabolic Disorders Chapters
6. Hypothalamic-Pituitary Relationships 7. Pituitary Disorders 8. Thyroid Disorders 9. Adrenal Disorders 10. Multiple Endocrine Neoplasia Syndromes 11. Polyglandular Deficiency Syndromes 12. Water, Electrolyte, Mineral, and Acid-Base Metabolism 13. Disorders of Carbohydrate Metabolism 14. The Porphyrias 15. Hyperlipidemia 16. Hypolipidemia and the Lipidoses 17. Carcinoid Tumors 18. Amyloidosis

Section 14. Neurologic Disorders Chapters
165. 166. 167. 168. 169. 170. 171. 172. 173. 174. Neurologic Approach to the Patient Neurotransmission Pain Headache Function and Dysfunction of the Cerebral Lobes Stupor and Coma Delirium and Dementia Seizure Disorders Sleep Disorders Cerebrovascular Disease 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. Trauma of the Head CNS Infections CNS Neoplasms Neuro-Ophthalmologic and Cranial Nerve Disorders Disorders of Movement Demyelinating Diseases Craniocervical Junction Abnormalities Spinal Cord Disorders Disorders of the Peripheral Nervous System Muscular Disorders

Section 3. Gastrointestinal Disorders Chapters
19. Diagnostic and Therapeutic Gastrointestinal Procedures 20. Esophageal Disorders 21. Functional Upper Gastrointestinal Complaints 22. Gastrointestinal Bleeding 23. Gastritis and Peptic Ulcer Disease 24. Bezoars and Foreign Bodies 25. Acute Abdomen and Surgical Gastroenterology 26. Pancreatitis 27. Diarrhea and Constipation 28. Gastroenteritis 29. Antibiotic-Associated Colitis 30. Malabsorption Syndromes 31. Inflammatory Bowel Diseases 32. Functional Bowel Disorders 33. Diverticular Disease 34. Tumors of the Gastrointestinal Tract 35. Anorectal Disorders

Section 15. Psychiatric Disorders Chapters
185. 186. 187. 188. 189. 190. Psychiatry in Medicine Somatoform Disorders Anxiety Disorders Dissociative Disorders Mood Disorders Suicidal Behavior 191. 192. 193. 194. 195. 196. Personality Disorders Psychosexual Disorders Schizophrenia and Related Disorders Psychiatric Emergencies Drug Use and Dependence Eating Disorders

Section 4. Hepatic and Biliary Disorders Chapters
36. Anatomy and Physiology 37. Screening and Diagnostic Evaluation 38. Clinical Features of Liver Disease 39. Fatty Liver 40. Alcoholic Liver Disease 41. Chronic Liver Disease 42. Hepatitis 43. Drugs and the Liver 44. Postoperative Liver Disorders 45. Hepatic Granulomas 46. Vascular Lesions 47. Liver Tumors 48. Extrahepatic Biliary Disorders

Section 16. Cardiovascular Disorders Chapters
197. 198. 199. 200. 201. 202. 203. 204. 205. Approach to the Cardiac Patient Diagnostic Cardiovascular Procedures Arterial Hypertension Orthostatic Hypotension and Syncope Arteriosclerosis Coronary Artery Disease Heart Failure Shock Arrhythmias 206. 207. 208. 209. 210. 211. 212. 213.
Cardiac and Respiratory Arrest and Cardiopulmonary Resus Valvular Heart Disease Endocarditis Pericardial Disease Cardiac Tumors Diseases of the Aorta and Its Branches Peripheral Vascular Disorders Athletic Heart Syndrome

Section 5. Musculoskeletal and Connective Tissue Disorders Chapters
49. Approach to the Patient with Joint Disease 50. Diffuse Connective Tissue Disease 51. Arthritis Associated with Spondylitis 52. Osteoarthritis and Neurogenic Arthropathy 53. Avascular Necrosis 54. Infections of Bones and Joints 55. Crystal-Induced Conditions 56. Tumors of Bones and Joints 57. Osteoporosis 58. Paget's Disease of Bone 59. Nonarticular Rheumatism 60. Common Foot and Ankle Disorders 61. Common Hand Disorders 62. Common Sports Injuries Sections Purchasing Information Home Navigation Help

Section 17. Genitourinary Disorders Chapters
214. 215. 216. 217. 218. 219. 220. 221. 222. 223. Clinical Evaluation of Genitourinary Disorders Urinary Incontinence Myoneurogenic Disorders Obstructive Uropathy Prostate Disease Disorders of the Penis and Scrotum Erectile Dysfunction Urinary Calculi Renal Failure Dialysis 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. Glomerular Diseases Tubulointerstitial Disease Toxic Nephropathy Urinary Tract Infections Renovascular Disease Abnormal Renal Transport Syndromes Inherited and Congenital Renal Disorders Immunologically Mediated Renal Disease Trauma to the Urinary Tract Genitourinary Cancer

Section 6. Pulmonary Disorders Chapters
63. Approach to the Pulmonary Patient 64. Pulmonary Function Testing 65. Special Procedures 66. Respiratory Failure 67. Adult Respiratory Distress Syndrome 68. Chronic Obstructive Airway Disorders 69. Acute Bronchitis 70. Bronchiectasis 71. Atelectasis 72. Pulmonary Embolism 73. Pneumonia 74. Lung Abscess 75. Occupational Lung Diseases 76. Hypersensitivity Diseases of the Lungs 77. Goodpasture's Syndrome 78. Idiopathic Interstitial Lung Diseases 79. Pulmonary Alveolar Proteinosis 80. Pleural Disorders 81. Tumors of the Lung

Section 18. Gynecology and Obstetrics Chapters
234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. Reproductive Endocrinology Menstrual Abnormalities and Abnormal Uterine Bleeding Menopause Pelvic Pain Gynecologic Inflammation and Infections Endometriosis Uterine Fibroids Gynecologic Neoplasms Breast Disorders Sexual Dysfunction in Women Medical Examination of the Rape Victim 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. Infertility Family Planning Prenatal Genetic Evaluation and Counseling Conception and Prenatal Development Normal Pregnancy, Labor, and Delivery High-Risk Pregnancy Pregnancy Complicated by Disease Abnormalities of Pregnancy Abnormalities and Complications of Labor and Delivery Postpartum Care

Section 7. Ear, Nose, and Throat Disorders Chapters
82. Approach to the Patient with Ear Problems 83. External Ear 84. Tympanic Membrane and Middle Ear 85. Inner Ear 86. Nose and Paranasal Sinuses 87. Pharynx 88. Larynx 89. Neoplasms of the Head and Neck Sections Purchasing Information Home Navigation Help

Section 19. Pediatrics Chapters
255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. Introduction Health Management in Normal Newborns, Infants, and Children Caring for Sick Children and Their Families Drug Treatment in Newborns, Infants, and Children Fluid and Electrolyte Disorders in Infants and Children Disturbances in Newborns and Infants Congenital Anomalies Developmental Problems Injuries, Poisoning, and Cardiopulmonary Resuscitation Child Abuse and Neglect Childhood Infections 266. 267. 268. 269. 270. 271. 272. 273. 274. 275. Neoplasms Cystic Fibrosis Gastrointestinal Disorders Endocrine and Metabolic Disorders Musculoskeletal and Connective Tissue Disorders Neurologic Disorders Nose and Throat Disorders Strabismus Psychiatric Conditions in Childhood and Adolescence Physical Conditions in Adolescence

Section 8. Ophthalmologic Disorders Chapters
90. Approach to the Patient with Eye Disease 91. Eye Injuries 92. Disorders of the Orbit 93. Disorders of the Lacrimal Apparatus 94. Eyelid Disorders 95. Conjunctival Disorders 96. Corneal Disorders 97. Cataract 98. Uveitis 99. Retinal Disorders 100. Glaucoma 101. Optic Nerve and Optic Pathway Disorders 102. Refractive Error

Section 20. Disorders Due to Physical Agents Chapters
276. 277. 278. 279. 280. Burns Electric Injury Radiation Reactions and Injuries Heat Disorders Cold Injury 281. 282. 283. 284. 285. Altitude Sickness Motion Sickness Medical Aspects of Air and Foreign Travel Near Drowning Injury During Diving or Work in Compressed Air

Section 9. Dental and Oral Disorders Chapters
103. Dentistry in Medicine 104. Oral Examination 105. Disorders of the Oral Region 106. Teeth and Periodontium 107. Dental Emergencies 108. Temporomandibular Disorders Sections Purchasing Information Home Navigation Help

Section 21. Special Subjects Chapters
286. 287. 288. 289. 290. 291. General Principles of Medical Genetics Syndromes of Uncertain Origin Sarcoidosis Familial Mediterranean Fever Smoking Cessation Rehabilitation 292. 293. 294. 295. 296. 297. Hyperbaric Oxygen Therapy Geriatric Medicine Care of the Dying Patient Clinical Decision Making Normal Laboratory Values Ready Reference Guides

Section 10. Dermatologic Disorders Chapters
109. 110. 111. 112. 113. 114. 115. 116. 117. Diagnostic Approach to Skin Diseases Principles of Topical Dermatologic Therapy Dermatitis Bacterial Infections of the Skin Fungal Skin Infections Parasitic Skin Infections Viral Skin Infections Disorders of Hair Follicles and Sebaceous Glands Scaling Papular Diseases 118. 119. 120. 121. 122. 123. 124. 125. 126. Inflammatory Reactions Reactions to Sunlight Bullous Diseases Disorders of Cornification Pressure Sores Pigmentation Disorders Disorders of Sweating Benign Tumors Malignant Tumors

Section 22. Clinical Pharmacology Chapters
298. 299. 300. 301. 302. Drug Input and Disposition Pharmacokinetics Pharmacodynamics Factors Affecting Drug Response Drug Toxicity 303. 304. 305. 306. Monitoring Drug Treatment Drug Therapy in the Elderly Anabolic Steroid Use Trade Names of Some Commonly Used Drugs

Section 11. Hematology and Oncology Chapters
127. 128. 129. 130. 131. 132. 133. 134. 135. 136. Anemias Iron Overload Transfusion Medicine Myeloproliferative Disorders Hemostasis and Coagulation Disorders Thrombotic Disorders Platelet Disorders Vascular Bleeding Disorders Leukopenia and Lymphocytopenia Eosinophilic Disorders 137. 138. 139. 140. 141. 142. 143. 144. 145. Histiocytic Syndromes Leukemias Lymphomas Plasma Cell Dyscrasias Disorders of the Spleen Overview of Cancer Tumor Immunology Principles of Cancer Therapy AIDS-Associated Hematologic Disorders and Malignancies

Section 23. Poisoning Chapters
307. Poisoning 308. Bites and Stings Sections Purchasing Information Home Navigation Help
The Merck Manual of Diagnosis and Therapy Corrections and Late-breaking Important Information
The Merck Manual of Diagnosis and Therapy, 17th Edition is in its second printing. The electronic vers this web site mirrors this printing. Details of printing changes are contained in the table below. Please that because the electronic version is flexible, it may contain changes not yet in print and, therefore, m slightly different from the most recent printing of the book.
Important: Please note that there is an error in the dose of aqueous penicillin G in the treatment dis of pneumococcal infections on page 1155, column 2, line 17, of the printed version of the 17th editio The Merck Manual. The text in the first paragraph under Treatment should say "Pneumococcal meni or endocarditis requires up to 20 to 40 million U/day . . ." (not 20,000 to 40,000 U/day as printed). T pediatric dose is correct as printed.
Sec. Ch. 3 13 13 23 Abb. & Sym. 2 2 9 12 32
Pg. No. Printin ing Book
Original Text ---CroTab
New Text update to discussion on flatulence update to discussion on anthrax addition of discussion on smallpox CroFab
--
---
157 1157 -162 -xiv 308 2648 --
2nd pH = hydrogen ion concentration pH = negative log of the hydrogen ion concentration 2nd -adrenergic properties, can be given orally, 2nd Conservative management is indicated for patients...total parathyroidectomy is the operation of choice. 2nd In the syndrome of familial hypocalciuric...manuevers described above is rarely needed.
113 151
-adrenergic receptor blocking properties, ca given orally, Delete two sentences.
12
151
Replace with: In the syndrome of familial hypocalciuric hypercalcemia, although parathyroid hyperplasia is consistently foun response to subtotal parathyroidectomy is unsatisfactory. Since overt clinical manifes
12
151
2nd In the syndrome of familial hypocalciuric...manuevers described above is rarely needed.
Replace with: In the syndrome of familial hypocalciuric hypercalcemia, although parathyroid hyperplasia is consistently foun response to subtotal parathyroidectomy is unsatisfactory. Since overt clinical manifes are rare in familial hypocalciuric, specific tr other than the occasional need for calcium-lowering maneuvers described abo rarely needed. However, if pancreatitis or s neonatal primary hyperparathyroidism occu parathyroidectomy is then the operation of
13
170
2nd Most physicians periodically Most physicians periodically determine determine glycosylated glycosylated hemoglobin...the -chain of Hb hemoglobin...the -chain of Hb by plasma glucose... plasma glucose... 2nd It has been shown that in hereditary amyloidosis due to transthyretin mutations, liver transplantation, which removes the site of synthesis of the mutant protein, is very effective. 2nd No treatment is needed except parenteral replacement of B12.
18
220
Add new text:...is very effective. Ultimately people with amyloidosis continue to deterio and develop terminal complications. Aggre treatment may no longer be appropriate, an should focus on relieving pain and suffering Ch. 294).
3 3
23 28
249 291
No treatment is needed except replacemen B12.
2nd These drugs should be These drugs should be discontinued if sym discontinued if symptoms persist persist > 4 days. > 4h.
30
296
2nd For an adult eating a usual For an adult eating a usual Western diet w Western diet with a daily fat daily fat intake of 50 to 150 g, fecal fat > 6g intake of 50 to 150 g, fecal fat >= abnormal. 17 mEq/day is abnormal. 2nd Other potential immunoregulatory treatments include interleukin-1 blockers,...antibody against tumor necrosis factor.
31
306
Infliximab, a monoclonal antibody that inhib tumor necrosis factor, can be given IV for moderate to severe Crohn's disease (espe fistulous disease) refractory to other treatm long-term efficacy and side effects remain determined. Other potential immunoregulat treatments include interleukin-1 blockers, a to interleukin-12, anti-CD4 antibodies, adhe molecule inhibitors, and down-regulatory cytokines. These many experimental treatm
34
330
2nd ...by infusion pump offers no advantage over systemic chemotherapy.
...by infusion pump offers no advantage ov systemic chemotherapy.
End-of-life care: Once aggressive treatme becomes inappropriate, care should focus relieving pain and suffering (see Ch. 294). (see HEPATIC DISORDERS in Ch. 251).
4 4
43 48
389 398
2nd (see HEPATIC DISORDERS in Ch. 250). 2nd Most experts remain wary of transplantation for malignancy.
Most experts remain wary of transplantatio malignancy. Once aggressive treatment be
48
398
2nd Most experts remain wary of transplantation for malignancy.
Most experts remain wary of transplantatio malignancy. Once aggressive treatment be inappropriate, care should focus on relievin and suffering (see Ch. 294).
50
422
2nd ...renal function. Although not approved for RA in the USA, cyclophosphamide also is effective...
...renal function. Although not approved for the USA, cyclophosphamide also is effectiv used less often because of greater risks of Etanercept is a tissue necrosis factor antag than can be given twice weekly (25 mg sc) patients who have had an inadequate resp one or more disease-modifying drugs. Experimental therapies (eg, interleukin-1 re antagonists) are being studied and have po but are not yet available.
52
451
2nd COX-2 inhibitors, which control COX-2 inhibitors (eg, celecoxib, rofecoxib) inflammation and decrease pain inflammation and decrease pain with fewer with far fewer side effects are gastrointestinal side effects. nearing final study. 2nd Women should be advised to consume 1000 g of elemental Ca in their daily diet,...
57
472
Women should be advised to consume 100 of elemental Ca in their daily diet,...
72
600
2nd Periodic platelet counts (in Periodic platelet counts (in patients taking patients taking heparin), together heparin--see Heparin-Induced Thrombocyt with hematocrits... in Ch. 133), together with hematocrits... 2nd Multiple oral ulcers similar to those of aphthous stomatitis 2nd Chancre (red papule rapidly developing into a painless ulcer with a serosanguinous crust), mucous patch, gumma 2nd Acute swelling 2nd Fissuring at corners of mouth often with maceration 2nd ...the vermilion border
9 9
105 752 105 752
Multiple oral aphthous ulcers; associated w penile and ocular ulcers
Chancre (red papule rapidly developing into painless ulcer with a serosanguinous crust) mucous patch, gumma; adenopathy with th two Acute swelling of allergic etiology Fissuring at corners of mouth often with maceration; common in the edentulous ...the vermillion border
9 9 9 9 9
105 752 105 752 105 753 105 753 105 753
2nd Cream-colored macules about 1 Sebaceous glands appearing as cream-col mm in diameter, benign macules about 1 mm in diameter, benign
2nd Tiny, grayish white macules with Tiny, grayish white macules with red margi red margins near orifice of orifice of parotid duct; prodrome to measle parotid duct 2nd Children should have their first routine dental examination at age 2.
106 765
Children should have their first routine den examination at age 1.
106 767
2nd For abscesses, endodontic For abscesses, a periodontal flap and root therapy, a periodontal flap and debridement are usually performed. Endod root debridement or extraction is therapy or extraction may be required.
106 767
2nd For abscesses, endodontic For abscesses, a periodontal flap and root therapy, a periodontal flap and debridement are usually performed. Endod root debridement or extraction is therapy or extraction may be required. performed. 2nd Tetracycline should not be given Delete. at bedtime because of risk of esophageal erosions. 2nd Oral finasteride, a type 2 5reductase inhibitor, is the most effective nonsurgical therapy. 2nd Although hematologic correction usually occurs within 6 wk, neural improvement may take up to 18 mo.
10
116 812
10
116 815
Oral finasteride, an inhibitor of type II 5- red is the most effective nonsurgical therapy.
11
127 868
Alternatively (less commonly), oral B12 can given in very large doses (0.5 to 2 mg/day) Although hematologic correction usually oc within 6 wk, neural improvement may take mo.
11
129 884
2nd Liver biopsy is the gold standard Liver biopsy had been the gold standard in in diagnosis. diagnosis; it now serves only to provide evi of fibrosis (cirrhosis). Gene assay is the dia test of choice. Demonstration of hepatic sid and a quantitative increase in liver content.
11
129 884
2nd First-degree relatives should be Genotypic clinical diagnosis and appropriat screened by Fe studies...13% of screening of first-degree relatives has been patients. simplified with the availability of testing for the most prevalent mutation, and H63D, a mutation; these genetic mutations account 95% of hemochromatosis cases. 2nd ...V, VII, IX... ...V, VIII, IX...
11 11
131 908
131 910- 2nd The INR is the ratio of patient PT The INR is the ratio of patient PT to contro 911 to control PT multiplied by the raised to the power of the international sen international sensitivity index... index 147 1035 2nd It also may occur in relatives of patients with common variable immunodeficiency (see above). 147 1036 2nd ...(< 2 standard deviations from mean for age of one or two IgG subclasses, but with... 157 1155 2nd Pneumococcal meningitis or endocarditis requires up to 20,000 to 40,000 U/day (for children, 250,000 to 400,000 U/kg/day in divided...
12
It also may occur in relatives of patients wit common variable immunodeficiency (see b
12
...(more than 2 standard deviations below t mean for age of one or two IgG subclasses with...
13
Pneumococcal meningitis or endocarditis r up to 20 to 40 million U/day (for children, 2 to 400,000 U/kg/day in divided...
13
157 1191 2nd Vaccines based on recombinant Vaccines based on recombinant outer-sur outer-surface protein specific to protein specific to B. burgdorferi appear to B. burgdorferi are under study. and effective; one of them is currently avail In adult populations examined so far, they appear to be safe and
13
157 1191 2nd Vaccines based on recombinant Vaccines based on recombinant outer-sur outer-surface protein specific to protein specific to B. burgdorferi appear to B. burgdorferi are under study. and effective; one of them is currently avail In adult populations examined so far, they appear to be safe and effective.
13 13
159 1234 2nd B. hensalae, a bacterial infection B. quintana, a bacterial infection recognize recognized... 162 1303 2nd ...affects mainly children in rural or suburban areas. 163 1323 2nd ...the usefulness of CSF RNA monitoring has not yet been demonstrated.
...affects mainly children in rural or suburba areas. An outbreak of West Nile encephalit occurred around New York City.
13
...the usefulness of CSF RNA monitoring h yet been demonstrated.
End-of-life care: Even with combined thera AIDS remains a terminal disease. At some relief of pain and suffering may become the of treatment, and patients may opt for hosp care (see Ch. 294).
14
166 1356 2nd No specific approved drug therapy exists, although anticholinergics (eg, benztropine) may improve cognitive function. 171 1395 2nd The patient's wishes about care should be clarified before he is incapacitated.
No specific approved drug therapy exists, a cholinergics (eg, benztropine) may improve cognitive function.
14
Disability may become so severe that aggressive--or indeed any--treatment of oth diseases is no longer warranted (see Ch. 2 and death may follow pneumonia or anothe illness. The patient's wishes about care sho clarified before he is incapacitated.
14
173 1414 2nd For other persons, stimulant drugs may help prevent sleepiness. Dosage is based on individual need.
For other persons, modafinil or stimulant dr may help prevent sleepiness. Modafinil is g a single morning dose of 200 or 400 mg po Dosage of stimulants is based on individua
14
174 1418 2nd Higher scores reflect increased Higher scores reflect increased severity of severity of the deficit; the highest deficit; the highest possible total score is 42 possible total score is 42. Aggressive treatment is not always warrant especially when the residual disabilities are profound or serious comorbidities exist. Su care is then the appropriate focus (see Ch.
14
179 1470 2nd Using dietary supplements (eg, Using dietary supplements (eg, psyllium) a psyllium) and stool softeners softeners (eg, docusate sodium) can help. (eg, docusate sodium) can help. End-of-life care: At some point, patients a to become so frail that they are bedridden, eat, and aspirate often; care then becomes supportive (Ch. 294). 183 1486 2nd Surgery to improve swallowing has limited success in patients
14
Surgery to improve swallowing has limited in patients with progressive bulbar palsy. A
14
183 1486 2nd Surgery to improve swallowing has limited success in patients with progressive bulbar palsy. 199 1642 2nd The mechanism of direct vasodilators (independent of the autonomic nervous system) is different from that of Ca blockers and ACE inhibitors (SEE TABLE 199-10):... 199 1644 2nd TABLE 199-10. 199 1645 2nd TABLE 199-10. Continued 199 1645 2nd ...usually with parenteral drugs (see TABLE 199-11), or hypertensive urgencies... 199 1645 2nd TABLE 199-11. 203 1689 2nd Usual doses are captopril 25 to 50 mg/day, enalapril and lisinopril 2.5 to 5 mg/day, and quinapril 10 mg/day. 203 1691 2nd Patients with diastolic dysfunction cannot tolerate reduced BP or plasma volume. Thus, diuretics, ACE inhibitors, and vasodilators are usually contraindicated. 203 1692 2nd ...wholly within the body, thus reducing the major complication of infection, are also being evaluated.
Surgery to improve swallowing has limited in patients with progressive bulbar palsy. A point, care becomes supportive (see Ch. 2
16
The mechanism of direct vasodilators (independent of the autonomic nervous sys different from that of Ca blockers and ACE inhibitors (SEE TABLE 199-11):...
16 16 16
TABLE 199-11. TABLE 199-11. Continued
...usually with parenteral drugs (see TABLE 199-10), or hypertensive urgencies... TABLE 199-10.
16 16
Usual doses are captopril 25 to 50 mg/day, enalapril and lisinopril 2.5 to 5 mg/day, and quinapril 10 mg/day. Adding spironolactone improves cardiac and overall function.
16
Patients with diastolic dysfunction may not reduced BP or plasma volume. Diuretics, A inhibitors, and vasodilators are usually contraindicated, but they may reduce LV m stiffness and may prove to be of value.
16
...wholly within the body, thus reducing the complication of infection, are also being ev
End-of-life care: Death is inevitable in pati with progressive disease who are not trans candidates and whose severe symptoms c be controlled. Care must focus on relief of and suffering (see Ch. 294).
16 16
205 1716 2nd The target plasma concentration The target plasma concentration is 2 to 5 m is 2 to 5 g/L.
205 1716 2nd Elimination t 1/2is 11 to 15 h, and Elimination t 1/2is 11 to 15 h, and the target the target plasma concentration concentration is 4 to 10 g/mL. is 4 to 10 g/mL.
16 16
205 1718 2nd The target plasma concentration The target plasma concentration is 0.8 to 1 is 0.8 to 1.6 mg/mL. ng/mL. 206 1746 2nd Children One-Rescuer CPR Two breaths (1-1.5 sec each) after every five cardiac Children One Rescuer CPR
Two breaths (1-1.5 sec each) after every fi cardiac compressions at 80-100/min, totalin
16
206 1746 2nd Children One-Rescuer CPR Two breaths (1-1.5 sec each) after every five cardiac compressions at 80-100/min, totaling about 7-10 breaths/min
Children One Rescuer CPR
Two breaths (1-1.5 sec each) after every fi cardiac compressions at 80-100/min, totalin about 30-40 breaths/min Children Two Rescuer CPR
16
206 1746 2nd Children Two-Rescuer CPR Two breaths (1-1.5 sec each) after every five cardiac compressions at 80-100/min, totaling about 7-10 breaths/min
Two breaths (1-1.5 sec each) after every fi cardiac compressions at 80-100/min, totalin about 30-40 breaths/min Infants One Rescuer CPR
16
206 1746 2nd Infants One-Rescuer CPR Two breaths (1-1.5 sec each) after every five cardiac compressions at 100/min, totaling about 15 breaths/min
Two breaths (1-1.5 sec each) after every fi cardiac compressions at 100/min, totaling a 40 breaths/min Infants Two Rescuer CPR
16
206 1746 2nd Infants Two-Rescuer CPR Two breaths (1-1.5 sec each) after every five cardiac compressions at 100/min, totaling about 15 breaths/min
Two breaths (1-1.5 sec each) after every fi cardiac compressions at 100/min, totaling a 40 breaths/min
17
224 1860 2nd Resistant to known therapeutic drugs
ACE inhibition for hypertension and reducti proteinuria; IVIG for rapid renal failure; corticosteroids for minimal change-like dise RPGN.
17
224 1864 2nd Therapy is not very effective and should be reserved for patients with poor prognosis. High-dose fish...Long-term nephrologic follow-up is essential.
ACE therapy is started early for hypertensio may also help normotensive patients with proteinuria >1g/day. If renal function deteri continues, fish oil can be tried. Glucocortico reserved for biopsy-proven minimal change disease. Very high initial doses are require to 3 mo in adults, 1 mo in children) and the tapered, but only long-term therapy (2 yr) is and benefits must be weighed against toxic immune globulin (IVIG) may help treat rapi functional impairment (>2 mL/min/mo). RP treated with IV pulse glucocorticoids followe oral prednisone, IV or oral cyclophosphami and/or plasmapheresis resulted in reductio plasma creatinine concentration and protei but not with reduced biopsy lesions, and di progressed after therapy was discontinued patients.
17
228 1893 2nd Treatment may not be effective in established renal amyloidosis and glomerular disease.
Treatment may not be effective in establish renal amyloidosis and glomerular disease. INTERSTITIAL CYSTITIS
17
228 1893 2nd Treatment may not be effective in established renal amyloidosis and glomerular disease.
Treatment may not be effective in establish renal amyloidosis and glomerular disease. INTERSTITIAL CYSTITIS
Interstitial cystitis (IC) is a chronic bladder d occurring primarily in women. Etiology is un The bladder wall shows inflammatory infiltr with mucosal ulceration and scarring that re smooth muscle contraction, diminished urin capacity, hematuria, and frequent, painful urination. Carcinoma in situ can mimic IC a must be ruled out.
Bladder distension may provide excellent, b transient, relief. Intravesical agents (eg, dim sulfoxide [DMSO], methylprednisolone, hep sulfate) and oral therapy with anticholinerg tricyclic antidepressants offer some relief. R augmentation cystoplasty may be undertak Very rarely, cystectomy with urinary diversi required. 18 241 1968 2nd Because radiation therapy and surgery are usually successful, chemotherapy is not used as primary treatment unless the patient presents with widely metastatic disease. 242 1982 2nd Some results are promising, but whether this approach can substantially improve survival for women who do not respond to standard-dose chemotherapy is unclear.
Patients with either metastatic disease bey regional lymph nodes or recurrent nonrese disease are treated with systemic chemoth
18
Some results are promising, but whether th approach can substantially improve surviva women who do not respond to standard-do chemotherapy is unclear.
End-of-life care: Once aggressive treatme becomes inappropriate, care should focus relieving pain and suffering (see Ch. 294).
18
254 2067 2nd If the uterus does not remain contracted with massage alone, oxytocin 10 U IM or dilute oxytocin IV drip (10 or 20 U/1000 mL of IV fluid) at 125 to 200 V/h for 1 to 2 h immediately after delivery of the placenta is given. 260 2173 2nd Prevention and Treatment
If the uterus does not remain contracted wi massage alone, oxytocin 10 U IM or dilute IV drip (10 or 20 U/1000 mL of IV fluid) at 1 200 mL/h for 1 to 2 h immediately after del the placenta is given.
19
Treatment
To help prevent diarrhea and Delete first two sentences. vomiting due to rotavirus infection, an oral vaccine, RotaShield, is available. This vaccine decreases the severity of illness and hospitalization rate in young children.
vomiting due to rotavirus infection, an oral vaccine, RotaShield, is available. This vaccine decreases the severity of illness and hospitalization rate in young children. 19 261 2220 2nd Osteogenesis imperfecta, abnormal fragility of bone,...Orthopedic care is indicated; there is no effective medical treatment.
Osteogenesis imperfecta, or "brittle-bone disease, is a defect in the production of col resulting in repeated fractures with minor tr The severity varies widely, with the neonata (congenital) type being the most severe. Fr can occur in utero and during delivery. Trau during delivery may lead to intracranial hemorrhage and stillbirth. At birth the skull and feels like a "bag of bones." Infants bor may die suddenly during the first few days weeks. Survivors develop shortened extrem and other bony deformities. Mental develop normal unless CNS injury may occur. The s are thin, translucent, and appear blue. Hea loss from ostosclerosis may occur. Orthope treatment, physiotherapy, and occupationa therapy are directed at preventing fractures increasing function. Treatment with the bisphosphonate pamidronate given IV has shown to increase bone mineral density an function and may decrease bone pain and resorption.
19
262 2255 2nd Multisensory approaches that include whole-word learning and the integration of visual, auditory, and tactual procedures to teach sounds, words, and sentences are advocated. 269 2384 2nd A normal semen has a volume of 1 to 6 mL, > 20 106 sperm/mL, of which 60% are of normal morphology and are motile (see also SPERM DISORDERS in Ch. 245).
Multisensory phonics-based approaches th include whole-word learning and the integra visual, auditory, and tactual procedures to sounds, words, and sentences are advocat
19
A normal semen has a volume of 1 to 6 mL 106 sperm/mL, of which 60% are of norma morphology and are motile (see also SPER DISORDERS in Ch. 245).
21
286 2476 2nd Also, 50 to 70% of NTDs can be Also, 50 to 70% of NTDs can be prevented prevented by maternal folic acid maternal folic acid supplementation (400 supplementation (400 mg/day) 1 mo before conception to 3 mo after concep mo before conception to 3 mo after conception. 301 2576 2nd Muscle biopsy and elevated cholecystokinin levels may be used to identify sensitive members of the patient's family. 303 2594 2nd Lithium 0.7 - 2.0 mEq/L or mmol/L 307 2638 2nd Nausea, vomiting, abdominal
22
Muscle biopsy and elevated creatine kinas may be used to identify sensitive members patient's family. Lithium 0.7 - 1.2 mEq/L or mmol/L
22 23
Nausea, vomiting, abdominal cramping, ex
23
307 2638 2nd Nausea, vomiting, abdominal cramping, excessive salivation; increased pulmonary secretion, headache, rhinorrhea, blurred vision, miosis; slurred speech, mental confusion; breathing difficulty, frothing at mouth, coma; skin absorption via inhalation or po
Nausea, vomiting, abdominal cramping, ex salivation; increased pulmonary secretion, headache, rhinorrhea, blurred vision, miosi slurred speech, mental confusion; breathin difficulty, frothing at mouth, coma; absorbe through skin, via inhalation, or orally
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Analgesic and Anti-Inflammatory | Anti-Fungal | Cardiovascular | Dermatological | Endocrinology | Gastrointestinal | Infection | Neurological | Ophth Respiratory | Vaccines
VIOXX (rofecoxib) also known as: CEOXX*.
CANCIDAS (caspofungin acetate) AGGRASTAT (tirofiban HCI) COZAAR** (losartan potassium) also known as: COSAAR**, COZAAREX**, and others. HYZAAR** (losartan potassium and hydrochlorothiazide) MEVACOR (lovastatin) also known as: LIPIVAS*, MEVINACOR*, and others. PRINIVIL (lisinopril) also known as: NOVATEC*, PRINIL*, VIVATEC*, and others. PRINZIDE (lisinopril/hydrochlorothiazide) also known as: NOVAZYD*, VIVATEC COMP.*, VIVAZID*, and others. VASERETIC (enalapril maleate & hydrochlorothiazide) also known as: CO-RENITEC*, RENACOR*, RENIDUR*, RENITEC comp.*, VASORETIC*, and others. VASOTEC (enalapril maleate) also known as: ENAPREN*, INNOVACE*, RENITEC*, RENITEN*, XANEF*, and others. ZOCOR (simvastatin) also known as: ZOCORD* and others.
PROPECIA (finasteride)
FOSAMAX (alendronate sodium)
also known as: ZOCORD* and others.
PROPECIA (finasteride)
FOSAMAX (alendronate sodium) PROSCAR (finasteride) also known as: CHIBRO-PROSCAR* and others.
PEPCID COMPLETE
CRIXIVAN (indinavir sulfate) INVANZ (ertapenem sodium) MEFOXIN (cefoxitin sodium) also known as: MEFOXITIN* and others. NOROXIN (norfloxacin) also known as: BARAZAN*, FLOXACIN*, NOROXINE*, UTINOR*, ZOROXIN*, and others. PRIMAXIN (imipenem and cilastatin sodium) also known as: TIENAM*, ZIENAM*, and others.
MAXALT (rizatriptan benzoate) SINEMET (carbidopa and levodopa) SINEMET CR (carbidopa and levodopa) also known as: CRONOMET*, SINEMET* Depot, and others.
COSOPT (dorzolamide hydrochloride-timolol maleate ophthalmic solution) TRUSOPT (dorzolamide hydrochloride) TIMOPTIC (timolol maleate) also known as: BLOCADREN*, BLOCANOL*, CHIBRO-TIMOPTOL*, TIMACAR*, TIMOFTOL*, TIMOPTOL*, and others. TIMOPTIC-XE (timolol maleate ophthalmic gel forming solution) also known as: BLOCADREN* Depot, BLOCANOL* Depot, TIMICAR* Depot, TIMOPTIC* Depot, TIMOPTOL-XE*, and others.
SINGULAIR (montelukast sodium)
COMVAX [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine] M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live) PedvaxHIB (Haemophilus b Conjugate Vaccine [Meningococcal Protein Conjugate]) PNEUMOVAX 23 (Pneumococcal Vaccine Polyvalent) Also known as: PNEUMOVAX*, PNEUMOVAX II*, PULMOVAX*, and others. RECOMBIVAX HB [Hepatitis B Vaccine (Recombinant)] Also known as: H-B-VAX* II, RECOMBIVAX* H-B, and others. VAQTA (Hepatitis A Vaccine, Inactivated) VARIVAX [Varicella Virus Vaccine Live (Oka/Merck)] *Trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, USA.
RECOMBIVAX HB [Hepatitis B Vaccine (Recombinant)] Also known as: H-B-VAX* II, RECOMBIVAX* H-B, and others. VAQTA (Hepatitis A Vaccine, Inactivated) VARIVAX [Varicella Virus Vaccine Live (Oka/Merck)] *Trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. **Trademark of E.I. du Pont de Nemours and Company, Wilmington, Delaware, USA
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Merck & Co., Inc. Plans to Establish Merck-Medco as a Separate, Publicly Traded Compa An Initial Public Offering of a Portion of the New Company Expected by Mid-2002
WHITEHOUSE STATION, N.J., Jan. 29, 2002 Merck & Co., Inc. today announced plans to establish M its pharmacy benefits management (PBM) subsidiary, as a separate, publicly traded company. Merck pla public offering of a portion of the new company by mid-2002, subject to market conditions.
Alternatives for the distribution of the remaining shares in the new company are under evaluation by Merc separation of Merck-Medco should be completed within 12 months of the initial public offering, subject to Internal Revenue Service ruling that such an event would be tax-free to shareholders and to other custom conditions.
"Mercks acquisition of Merck-Medco in 1993 has been highly successful," said Merck Chairman, Preside Raymond V. Gilmartin. As part of Merck, Merck-Medcos revenues grew from $2.2 billion in 1992 to $26 b and the number of lives covered grew from 33 million to 65 million, nearly one in four Americans. Merck-M leading pharmacy benefits manager in the country in terms of revenue, manages more than 537 million p annually, operates the worlds leading Internet pharmacy, and serves more than 1,700 clients.
"Over the past four months, Mercks management and its Board of Directors conducted a strategic review and Merck-Medcos businesses. It is clear that Merck-Medco is a much different company than it was nin and the environment in which it operates has also changed dramatically. Given the evolution of the distinc competitive environments in which Merck and Merck-Medco operate, we believe the best way to enhance of both businesses going forward is to enable each one to pursue independently its unique and focused s Gilmartin said.
Going forward, Merck expects its core pharmaceutical business to deliver double-digit earnings-per-share 2003 driven by accelerating top-line growth. For 2002, Mercks outlook for the operating earnings of its co pharmaceutical business is unchanged as a result of this transaction. On an as-reported basis, Merck ant earnings per share for 2002 will be at the same level as 2001 results. The 2002 as-reported earnings per also be affected by the benefit from the implementation of FAS 142 regarding goodwill amortization, most relates to Mercks 1993 acquisition of Merck-Medco, and the timing of the completion of the distribution o remaining shares in the company.
"This transaction will allow Merck to focus more fully on its priorities of turning cutting-edge science into b medicines and supporting them through targeted and well-executed marketing," added Mr. Gilmartin. "In a investing behind our internal pipeline, our efforts also will include a continuing, intense focus on the entire product licensing from early- to late-stage opportunities as well as targeted acquisitions. We also belie providing investors with pure plays in the pharmaceutical and PBM businesses, respectively, will allow fu both businesses."
"As a separate company, Merck-Medco will continue to provide high-quality service to its customers and w pursue strategic initiatives and competitive PBM opportunities," said Richard T. Clark, president of Merck have an experienced and talented management team and employee base, and, as a result, are well-posit continue our leadership in the PBM industry."
Merck will hold a conference call with analysts today on this announcement at 8:45 a.m., Eastern Time. In invited to listen to a live webcast of the call by visiting Mercks corporate website at www.merck.com. The available for replay on the Merck website until Feb. 5, 2002. About Merck & Co., Inc.
Merck & Co., Inc. is a leading research-driven pharmaceutical products and services company. Merck dis develops, manufactures and markets a broad range of innovative products to improve human and animal directly and through its joint ventures.
invited to listen to a live webcast of the call by visiting Mercks corporate website at www.merck.com. The available for replay on the Merck website until Feb. 5, 2002. About Merck & Co., Inc.
Merck & Co., Inc. is a leading research-driven pharmaceutical products and services company. Merck dis develops, manufactures and markets a broad range of innovative products to improve human and animal directly and through its joint ventures. About Merck-Medco
Merck-Medco is the leading provider of comprehensive, quality, affordable prescription drug care in the U Merck-Medco provides pharmaceutical care for more than 65 million nearly one in four Americans.
This press release does not constitute an offer to sell or the solicitation of an offer to buy any securities. A be made solely by means of a prospectus.
This press release contains "forward-looking statements" as that term is defined in the Private Securities Reform Act of 1995. No forward-looking statement can be guaranteed, and actual results may differ mate those projected. We undertake no obligation to publicly update any forward-looking statement, whether as new information, future events, or otherwise. Forward-looking statements in this document should be eva together with the many uncertainties that affect our businesses, particularly those mentioned in the cautio statements in Item 1 of our Form 10-K for the year ended Dec. 31, 2000, and in our periodic reports on Fo Form 8-K (if any) which we incorporate by reference. ###
MERCK'S EARNINGS PER SHARE INCREASE 8% FOR 2001, DRIVEN BY THE STRONG PERFOR FIVE KEY PRODUCTS Five Key Products Achieve Sales Growth of 26% for Full-year 2001 - ZOCOR Worldwide Sales Increase by 26% - VIOXX Worldwide Sales Increase by 18% - COZAAR/HYZAAR Worldwide Sales Increase by 11% - FOSAMAX Worldwide Sales Increase by 38% - SINGULAIR Worldwide Sales Increase by 60%
Merck Submits New Drug Application (NDA) to FDA for ARCOXIA, an Investigational COX-2 Se Medicine for the Treatment of Various Forms of Arthritis and Pain
Merck/Schering-Plough Pharmaceuticals Submits NDA to FDA for ZETIA, an Investigational Cho Absorption Inhibitor Merck-Medco Increases Volume of Prescriptions Managed by 19%
WHITEHOUSE STATION, N.J., Jan. 22, 2002 - Merck & Co., Inc. today announced that earnings per sh were $3.14, an increase of 8% over 2000. Net income grew 7% to $7,281.8 million. Sales grew 18% to $ the year.
For the fourth quarter of 2001, earnings per share were $0.81, an increase of 8% over the fourth quarter Fourth-quarter net income grew 5% to $1,860.9 million over the same period last year. Sales grew 10% i quarter of 2001 to $12.6 billion.
Merck's five key growth drivers - ZOCOR, VIOXX, COZAAR and HYZAAR*, FOSAMAX and SINGULAIR had increased sales of 20% and 26% for the fourth quarter and year, respectively, driving Merck's human performance. Overall, Merck's human health sales grew 6% for 2001. Excluding the unfavorable effect fr exchange, the company's human health sales grew by 5% and 8% for the fourth quarter and year, respec outside of the United States accounted for 37% of the company's human health sales growth for 2001. T overall sales growth also benefited from the Merck-Medco business, which increased 15% and 31% for t year, respectively.
Marketing and Administrative expenses for the fourth quarter decreased 12%, resulting in a full-year incre Total Marketing and Administrative spending for the fourth quarter is in line with spending levels in the pr 2001. The moderation of Marketing and Administrative expense growth in the fourth quarter reflects, to a the success of operational-efficiency initiatives focused on the fundamental redesign of work processes a leveraging technology to permanently reduce administrative expenses within the company's overall cost Full-year marketing expenses reflect Merck's increased resource commitment to its five key growth drive the addition of 1,000 new sales representatives in the United States in 2001 and continued refinement of and direct-selling spending mix to maximize product-sales performance. Research and Development exp $2.5 billion for 2001, a 5% increase for the year, reflecting the company's ongoing commitment to scienti
"Our five key growth drivers, which also are our five largest products, now account for 68% of Merck's wo human health sales and continue to lead Merck's income growth," said Raymond V. Gilmartin, chairman, chief executive officer. "These medicines are true breakthroughs - they offer novel approaches to disease help large, underserved patient populations and are effective, well-tolerated and convenient. The marketpotential for these medicines remains strong."
Five Key Medicines Offer Continued Growth Opportunities ZOCOR, Merck's cholesterol-modifying medicine, had another strong quarter with worldwide sales reach for the period. Total global sales for 2001 were $6.7 billion, a 26% increase over 2000. A highlight this ye was Oxford University's Heart Protection Study (HPS), the largest study ever on statins, which demonstra ZOCOR 40 mg saved lives by significantly reducing the risk of heart attack and stroke in a broad range o or at high risk for heart disease, including patients with average or below average cholesterol levels. In a
potential for these medicines remains strong."
Five Key Medicines Offer Continued Growth Opportunities ZOCOR, Merck's cholesterol-modifying medicine, had another strong quarter with worldwide sales reach for the period. Total global sales for 2001 were $6.7 billion, a 26% increase over 2000. A highlight this ye was Oxford University's Heart Protection Study (HPS), the largest study ever on statins, which demonstra ZOCOR 40 mg saved lives by significantly reducing the risk of heart attack and stroke in a broad range o or at high risk for heart disease, including patients with average or below average cholesterol levels. In a preliminary results from the study, which were presented at the American Heart Association meeting in N demonstrated that ZOCOR significantly reduced the risk of stroke and heart attacks for several distinct p with and without elevated cholesterol, including diabetes patients, stroke victims and women with or at hi heart disease. Results from HPS showed that ZOCOR 40 mg was well tolerated throughout the five-year results and the National Cholesterol Education Program changes in 2001 significantly broaden the patien considered eligible for cholesterol-control medicines.
VIOXX was the product leader in 2001 within the coxib class for new prescription volume growth in the U Pain relief and gastrointestinal safety continue to be the primary needs in the arthritis and pain market. In VIOXX was approved for relief of acute pain and pain from dysmenorrhea in 13 member states of the Eu and in Norway and Iceland. For the year, VIOXX achieved $2.6 billion in sales, an increase of 18%, with the fourth quarter.
COZAAR and HYZAAR, Merck's high-blood pressure medicines, together are the No. 1 angiotensin II an (AIIAs) worldwide despite intense competition. For the year, sales for the two products reached $1.9 billio increase of 11%, with $470 million in the fourth quarter. In the RENAAL study, which was published in Se The New England Journal of Medicine, COZAAR demonstrated that it is the first and only antihypertensiv significant reduction in End-stage Renal Disease (ESRD) in Type 2 diabetes, which continues to be a wo health concern. Merck continues to support the growth of COZAAR and HYZAAR with ongoing investme outcomes studies, LIFE and OPTIMAAL. LIFE study results will be presented at the American College of meeting in March.
Global sales of FOSAMAX, the leading product worldwide for the treatment of postmenopausal osteopor $470 million this quarter. Full-year global sales were $1.8 billion, a 38% increase over 2000. The largest osteoporosis, the National Osteoporosis Risk Assessment, found that almost half of the more than 200,0 postmenopausal women assessed in the study had low bone mass, putting them at increased risk of bon Recently published in the Journal of the American Medical Association, the study suggests that millions o aged 50 and older who have not been assessed for osteoporosis may be at increased risk of fracturing a underscoring the significant market opportunity for FOSAMAX. In 2001, FOSAMAX was launched in Japa second largest prescription drug market, under the trade name FOSAMAC by Banyu Pharmaceutical Co majority-owned Japanese affiliate. Merck licensee Teijin Limited is co-marketing FOSAMAX in Japan und name BONALON.
FOSAMAX Once Weekly, the first and only oral once-weekly treatment for osteoporosis and an excellent Merck's scientific innovation, has received rapid physician and patient acceptance since its introduction i Launched in 30 markets worldwide, the once-weekly medicine has accelerated the growth of the FOSAM extending Merck's leadership in several markets, including in the United States.
SINGULAIR, Merck's once-a-day leukotriene antagonist, remains the No. 1 prescribed asthma controller States and is the most widely used medicine of its kind. This year Banyu and Merck licensee Kyorin Pha Co., Ltd. launched SINGULAIR in Japan under the trademarks SINGULAIR and KIPRES, respectively. G SINGULAIR this quarter were $350 million. Total 2001 global sales were $1.4 billion, an increase of 60%
The company has completed its Phase III trials for the use of SINGULAIR in allergic rhinitis and plans to regulatory approval early this year. Allergic rhinitis affects more than 60 million people in the United State year.
Merck Submits New Drug Applications At its December 2001 Annual Business Briefing for securities analysts, Merck announced plans to file ap or launch 11 new medicines between 2002 and 2006. These pipeline products have the potential to offer approaches to disease treatments, help large patient populations and are effective, well tolerated and co
The company has submitted a New Drug Application (NDA) for ARCOXIA, a COX-2 selective medicine, t Food and Drug Administration (FDA) as well as to other regulatory agencies around the world. Merck see for ARCOXIA for the treatment of osteoarthritis, rheumatoid arthritis, acute pain, chronic pain and dysme (menstrual pain).
Merck/Schering-Plough Pharmaceuticals announced that it submitted an NDA to the FDA seeking appro Tablets, an investigational cholesterol absorption inhibitor, to be administered alone or with any statin for of hypercholesterolemia (elevated cholesterol levels).
Merck-Medco Increases Volume of Prescriptions Managed by 19% Merck-Medco continued its strong performance in 2001. For the year, the volume of prescriptions manag 19% to more than 537 million and drug spend increased 27% to nearly $30 billion, as a result of adding n
Merck/Schering-Plough Pharmaceuticals announced that it submitted an NDA to the FDA seeking appro Tablets, an investigational cholesterol absorption inhibitor, to be administered alone or with any statin for of hypercholesterolemia (elevated cholesterol levels).
Merck-Medco Increases Volume of Prescriptions Managed by 19% Merck-Medco continued its strong performance in 2001. For the year, the volume of prescriptions manag 19% to more than 537 million and drug spend increased 27% to nearly $30 billion, as a result of adding n such as IBM and UnitedHealth Group.
Continuing as the world's largest Internet pharmacy, merckmedco.com processed 2 million prescriptions quarter, an approximately 60 percent increase over fourth-quarter 2000. For the full year, merckmedco.co more than 7 million prescriptions, a 71% increase over 2000. The Internet pharmacy is now processing m 180,000 prescriptions per week. Its total prescription sales exceeded those of all other major online phar combined.
Merck Remains Comfortable with 2002 Earnings Per Share Estimates Calling 2002 a transition year, Merck issued a press release providing full-year 2002 financial guidance a December 11, 2001, Annual Business Briefing for securities analysts. At this meeting, the company said full-year 2002 earnings per share to be at the same level as full-year 2001 results and expects to deliver earnings per share growth in 2003. Merck remains comfortable with the guidance provided on Dec. 11. P page 8 of this news release for a breakdown of Merck's full-year 2002 financial guidance.
Investors are invited to listen to a live webcast of Merck's fourth quarter earnings conference call today a Eastern Time, by visiting Merck's corporate website at www.merck.com. The call will be available for repl Merck website until January 29, 2002.
Merck & Co., Inc. is a leading research-driven pharmaceutical products and services company. Merck dis develops, manufactures and markets a broad range of innovative products to improve human and anima directly and through its joint ventures. Merck-Medco manages pharmacy benefits for employers, insurers plan sponsors, encouraging the appropriate use of medicines and providing health management program these complementary capabilities, Merck works to improve quality of life and contain overall health-care c
This press release contains "forward-looking statements" as that term is defined in the Private Securities Reform Act of 1995. No forward-looking statement can be guaranteed, and actual results may differ mate those projected. We undertake no obligation to publicly update any forward-looking statement, whether as a result of new information, future otherwise. Forward-looking statements in this document should be evaluated together with the many unc affect our businesses, particularly those mentioned in the cautionary statements in Item 1 of our Form 10 year ended Dec. 31, 2000, and in our periodic reports on Form 10-Q and Form 8-K (if any) which we inco reference.
*COZAAR and HYZAAR are registered trademarks of E.I. DuPont de Nemours & Company, Wilmington, DE, USA.
The following tables show the financial results for Merck & Co., Inc. and subsidiaries for the quarter and n ended September 30, 2001, compared with the corresponding periods of the prior year.
(In Millions Except Earnings per Common Share Quarter Ended December 31 2001 2000
Sales Costs, Expenses and Other Materials and production
$12,558.0
$11,467.3
6,570.6 7,642.4
Marketing and administrative Research and development Equity income from affiliates Other (income) expense, net Income Before Taxes Taxes on Income Net Income Basic Earnings per Common Share Earnings per Common Share Assuming Dilution Average Shares Outstanding Average Shares Outstanding Assuming Dilution
1,555.4 716.4 (128.2) 113.5 2,658.5 797.6 1,860.9 $0.82 $0.81 2,274.0 2,301.0
1,774.1 662.4 (145.5 94.6 2,511.1 746.7 1,764.4 $0.77 $0.75 2,304.8 2,355.8
* The increase in materials and production costs for the three months ended December 31, 2001, is primarily driven by growth in the Merck-Medco busin
(In Millions Except Earnings per Common Shar 12 Months Ended December 31 2001 2000
Sales Costs, Expenses and Other Materials and production
$47,715.7
$40,363.2
22,443.5 28,976.5
Marketing and administrative Research and development Equity income from affiliates Other (income) expense, net
6,224.4 2,456.4 (685.9) 341.7
6,167.7 2,343.8 (764.9 349.0
Income Before Taxes Taxes on Income Net Income Basic Earnings per Common Share Earnings per Common Share Assuming Dilution Average Shares Outstanding Average Shares Outstanding Assuming Dilution
10,402.6 3,120.8 7,281.8 $3.18 $3.14 2,288.3 2,322.3
9824.1 3,002.4 6,821.7 $2.96 $2.90 2,306.9 2,353.2
* The increase in materials and production costs for the twelve months ended December 31, 2001, is primarily driven by growth in the Merck-Medco bus
Merck Financial Guidance Worldwide (WW) gross sales will be driven by Merck's five key growth drivers. Sales forecasts for those products are as follows: Product ZOCOR COXIBS (VIOXX & ARCOXIA) COZAAR & HYZAAR FOSAMAX SINGULAIR 2002 ($billions) $7.1 - 7.4 $2.8 - 3.1 $2.2 - 2.5 $2.0 - 2.3 $1.6 - 1.8
As expected, combined WW sales of VASOTEC, PEPCID, MEVACOR and PRINIVIL, all of which had U.S. market exclusivity ending between 2 2002, should decline in total to approximately $1.8 to $2.0 billion.
Under an agreement with AstraZeneca (AZN), Merck receives supply payments at predetermined rates on the U.S. sales of certain products by notably PRILOSEC and NEXIUM. The U.S. product patent on PRILOSEC expired in 2001. Accordingly, Merck anticipates that the total supply paym Company receives from AZN will decline in 2002. Marketing and administrative expense for 2002 is estimated to grow in the low single digits over the full year 2001 expense. Research and development expense is estimated to be $2.9 billion in 2002 Other P&L Components Merck-Medco sales in 2002 are estimated to range from $29 to $30 billion.
The growth rate of Merck-Medco will moderate the company's gross margin. In addition, in 2002, the strong growth rate of COZAAR, for which M profits in North America with DuPont, will have a slight negative impact on the human health overall gross margin. As a result, the total company gro estimated to be 37%.
Other P&L Components Merck-Medco sales in 2002 are estimated to range from $29 to $30 billion.
The growth rate of Merck-Medco will moderate the company's gross margin. In addition, in 2002, the strong growth rate of COZAAR, for which M profits in North America with DuPont, will have a slight negative impact on the human health overall gross margin. As a result, the total company gro estimated to be 37%. The company's 2002 tax rate is estimated to be approximately 30.0% to 30.5%, which is consistent with the full year 2001 rate of 30.0%. 2002 will include the benefit of FAS 142 implementation regarding goodwill amortization.
Merck anticipates full-year 2002 earnings per share consistent with 2001 full-year results. To achieve this result, it would be reasonable to anticipate an e share growth rate in the second half of 2002 moderately better than the growth rate in the first half of 2002. The company expects to deliver double-digit share growth in 2003. ###
Welcome!
The cascade of knowledge flowing from biotechnology and the unraveling of the human genom name only two recent developments - is far too complex for any single company to handle alon why Merck looks outside for insight and innovation. And that's why Merck recently has stepped pace of the search for such ventures.
Merck has a long history as a successful partner -- for example, among the five products that a drivers of growth, Fosamax and Cozaar/Hyzaar came to Merck via license agreements. We be 'win-win' arrangements with benefits accruing to both parties in an equitable manner. Once a l product enters Merck's pipeline, we bring the breadth of Merck's resources, talent and experie getting the product to market and then optimizing its success in markets worldwide.
Currently, Merck's focus is to supplement our existing franchises with complementary external arrangements and to bring the best science into areas where we do not currently have produc includes not only early-stage research collaborations leading to a compound for development, innovative arrangements involving products that are either established or in later stages of dev To contact Licensing, click here.
This Web site contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. more>>
WELCOME TO THE MERCK NEWSROOM This site is designed to provide members of the media with quick and easy access to information about M you will find press releases, policy statements, executive speeches, executive profiles, and information ab products, research and development and corporate citizenship.
Merck & Co., Inc. Plans to Establish Merck-Medco as a Separate, Publicly Traded Compa An Initial Public Offering of a Portion of the New Company Expected by Mid-2002
WHITEHOUSE STATION, N.J., Jan. 29, 2002 Merck & Co., Inc. today announced plans to establish M its pharmacy benefits management (PBM) subsidiary, as a separate, publicly traded company. Merck pla public offering of a portion of the new company by mid-2002, subject to market conditions.
Merck's Earning Per Share Increase 8% for 2001, Driven by the Strong Performance of Five Key Five Key Products Achieve Sales Growth of 26% for Full-year 2001 - ZOCOR Worldwide Sales Increase by 26% - VIOXX Worldwide Sales Increase by 18% - COZAAR/HYZAAR Worldwide Sales Increase by 11% - FOSAMAX Worldwide Sales Increase by 38% - SINGULAIR Worldwide Sales Increase by 60%
Merck Submits New Drug Application (NDA) to FDA for ARCOXIA, an Investigational COX-2 Sel Medicine for the Treatment of Various Forms of Arthritis and Pain
Merck/Schering-Plough Pharmaceuticals Submits NDA to FDA for ZETIA, an Investigational Cho Absorption Inhibitor Merck-Medco Increases Volume of Prescriptions Managed by 19%
WHITEHOUSE STATION, N.J., Jan. 22, 2002 - Merck & Co., Inc. today announced that earnings per sha were $3.14, an increase of 8% over 2000. Net income grew 7% to $7,281.8 million. Sales grew 18% to $4 the year.
Merck's Ability to Deliver Breakthrough Medicines Provides Opportunities for Significant Growth Over the Long Term Merck Expects to File or Launch 11 New Medicines and Vaccines Between 2002-2006 Regulatory Filings Planned in 2002 for Allergic Rhinitis Indication for Singulair and for Ezetimibe Planned in 2003 for Zetia/Zocor Combination Tablet Merck Announces New Pipeline Candidates
Company Continues to See Benefits from Operational Efficiency While Increasing Investments in and Development
Planned in 2003 for Zetia/Zocor Combination Tablet Merck Announces New Pipeline Candidates
Company Continues to See Benefits from Operational Efficiency While Increasing Investments in and Development
WHITEHOUSE STATION, N.J., Dec. 11, 2001 - Focusing on its strong scientific track record and ability t breakthrough medicines, Merck & Co., Inc. today updated some 300 securities analysts at its Annual Bus Briefing. The meeting highlighted the current performance and future potential of Merck's key products an strength of its research pipeline, with 11 new medicines and vaccines expected to be filed or launched be and 2006. Eight of the 11 pipeline products have the potential to become what Merck calls "breakthrough that offer novel approaches to disease treatments; help large patient populations; and are convenient, we and effective.
Merck Announces First Quarter Dividend
WHITEHOUSE STATION, N.J., Nov. 27, 2001 - The Board of Directors of Merck & Co., Inc., meeting tod a quarterly dividend of 35 cents a share on the company's common stock for the first quarter of 2002.
11.30.01 Raymond V. Gilmartin Chairman, President and Chief Executive Officer Merck & Co., Inc.
Meeting the Challenge of Pharmaceutical Innovation in an Environment of Rising R&D Co

Tufts Center for the Study of Drug and Development Raymond V. Gilmartin
10.01.01
Merck Research Laboratories Groundbreaking Ceremony

Boston, Massachusetts Raymond V. Gilmartin
06.25.01
United Nations General Assembly Special Session on HIV/AIDS

Roundtable on Prevention and Care New York, New York Raymond V. Gilmartin
06.01.01
Ballydine 25th Anniversary Luncheon

Clonmel, Ireland Raymond V. Gilmartin
05.16.01
Committee for Economic Development: Corporate Citizenship Award

New York Waldorf Astoria Raymond V. Gilmartin
05.14.01
"Sustainable Development and the New Economy"

OECD Forum 2001 Paris, France Raymond V. Gilmartin
04.24.01
Merck & Co., Inc. Annual Meeting of Stockholders
Whitehouse Station, NJ Discusses Merck's Strategy for Growth and the Company's overall performance in 2000. 04.05.01
"Sustaining America's Prosperity"
National Innovation Summit San Diego, CA In his opening remarks at the National Innovation Summit, convened by the Council on Competitiveness, Mr. Gilmartin discusses the need to expand America's innovative capacity to ensure our ability to compete at a high level for the long term. Mr. Gilmartin is chairman of the Council on Competitiveness. 02.08.01
"Realizing the Promise of Biomedical Discovery"

BioVision: World Life Science Forum Lyon, France Discusses issues concerning access to medicines around the world.
02.02.01
Health Affairs/Academy for Health Services Research First National Health Policy Conference
Washington, D.C.
01.29.01
The Globalization of AIDS

World Economic Forum 2001 Davos, Switzerland
11.17.00
The 2nd Annual National Congress on the Future of Genomics, Biotechnology and Pharmaceuticals in Medical Care
Arlington, VA
10.16.00
Committee for Economic Development

New York Helmsley Hotel
04.25.00

Whitehouse Station, NJ
01.31.00
"Laying the foundation for global health - the GAVI initiative"

01.29.00
"Doing well by doing good: corporate responsibility as corporate strategy"

01.19.00
Chief Executives Club of Boston

Boston, MA
12.09.99
1999 Business Briefing
12.09.99
1999 Business Briefing

10.12.99
Building Another Century of Discovery

Dedication Ceremony at Rahway
04.27.99

04.20.99
"Medicare and Prescription Drugs"

Opinion piece published in the Wall Street Journal
03.21.99
Leadership Roles in Society: Perspectives for Today and Tomorrow

American Medical Association National Leadership Development Conference
03.01.99
The Health Care Question and Market Solutions

The Economic Club of Detroit
01.30.99
The Role of the Health Care Industry in Global Health

Speeches | Biography | Annual Report | Philanthropy
"We are on the brink of discovery and development on so many therapeutic fronts that this has to be one of the most exciting and challenging times in the history of Merck Research Laboratories."
Edward Scolnick, M.D. President of Merck Research Laboratories and Executive Vice President, Science and Technology
Welcome to Merck Research Laboratories (MRL). We've created this site to help you learn about our work and our people, as well as our research philosophy, culture, and values. Equally important is the information we've included to help you explore career opportunities at MRL that match your background, experience, and goals. Medicines discovered and developed by Merck scientists save and improve countless lives around the globe. Thanks to the people behind the life-enhancing discoveries of MRL, we rank among the world's most innovative institutions in the medical sciences. Our environment is designed to help bring out the best in medicine for people everywhere. Visit Our Research to learn more about MRL and opportunities for you within it. Submit your resume to be considered for positions at MRL's U.S. sites.
Financial Information is Available in Acrobat PDF format Available in Acrobat PDF format
Statements on business and policy by Merck Chairman Raymond V. It's all about Merck! Review an annual report, understand the Merck Gilmartin. mission, and find answers to your company questions. Our mission includes providing: superior products, superior work environments, and a superior rate of return. Learn more about our mission and values. The latest information for Merck stockholders: Annual Reports and Learn about Merck's philanthropic outreach around the world. Proxy Statements. Find answers to some of the most common questions in our FAQ area. Locate information about our company, our products, and other related topics.
Revision date: 09/25/2001 I.
OVERVIEW OF COMPANY
A. Where is your corporate headquarters? Whitehouse Station, NJ, USA. B. Can you provide a brief description of the Company?
Merck is a worldwide research-intensive company that discovers and develops, manufactures a markets human and animal health products and services.
The Merck-Medco Managed Care Division manages pharmacy benefits for more than 65 million Americans. C. Can you provide information on the Company's major business areas? Research Discovers and develops human and animal health products at eight major research centers United States, Europe, and Japan.
Manufacturing Chemical processing, drug formulation, and packaging operations are carried out in 31 plan United States, Europe, Central and South America, the Far East, and the Pacific Rim.
Product marketing Products are sold in the United States, Europe, Central and South America, the Middle East East, and the Pacific Rim.
Services marketing The Merck-Medco Managed Care Division manages pharmacy benefits for more than 65 mi Americans, encouraging the appropriate use of medicines and providing disease-managem programs. D. Can you provide a list of the Company's principal products? Yes, click here. II.
MERCK AND THE INTERNET

A. L ink to www.merck.com If you would like to link to our site follow these instructions.
II.
MERCK AND THE INTERNET

A. L ink to www.merck.com If you would like to link to our site follow these instructions. B. What are cookies, and why are they utilized on the Merck web site?
Cookies are a technology that enables web sites to store small bits of information on your comp and then ask for that information back at a later time.
The Merck web site utilizes cookies to more accurately track how many people use the web site are also utilized for limited applications which help to deliver selected information to the approp audiences. Cookies do not store personal information about web site users without their consen
In most cases, a site's usage of cookies is completely invisible to web users. However, some pe may opt to enable a feature in their browser software which notifies them when cookies are bein exchanged. If you have enabled this feature, we apologize for any inconvenience such notificat cause you, and assure you that Merck's usage of cookie technology is for the internal reporting site usage levels. III.
ANNUAL REPORT
A. How can I get a copy of your most recent Annual Report? The 2000 Merck Annual Report is here. If you would like a printed version you may call 1-800-CALL-MRK (United States and Canada only).
IV.
FINANCIAL INFORMATION
A. What were the Company's total sales in 2000? Sales in 2000 were valued at $40.36 billion. B. What was the Company's net income in 2000? Net income in 2000 was valued at $6.821 billion. C. How can I obtain additional earnings information?
The most recently reported earnings for Merck are available by calling 1-800-CALL-MRK (1-800-225-5675, United States and Canada only). Through this number you can hear a record summary of major news developments at the Company, including quarterly sales and earnings You may also use this service to request copies of our new releases as well as copies of financ reports by either fax or mail. This service is free-of-charge 24 hours a day, seven days a week. D. What was the Company's total R&D (research and development) budget in 2000? Merck spent approximately $2.3 billion on research and development in 2000. E. Does Merck have a direct purchase plan?
Yes. Effective February 1, 1997 non-stockholders now have the ability to purchase Merck stock
D. What was the Company's total R&D (research and development) budget in 2000? Merck spent approximately $2.3 billion on research and development in 2000. E. Does Merck have a direct purchase plan?
Yes. Effective February 1, 1997 non-stockholders now have the ability to purchase Merck stock from the company. The new Merck Stock Investment Plan replaces the Dividend Reinvestment Cash Payment Plan that was available only to current registered Merck stockholders. To obtain complete enrollment kit including a prospectus describing the New Plan please call 1-800-831-8 (United States and Canada only). F. Does Merck have a dividend investment plan?
One of the features of the New Merck Stock Investment Plan is dividend reinvestment. Through Plan you can elect to have your quarterly dividends automatically reinvested to purchase additio shares of Merck common stock. If you are currently a registered stockholder and wish to enroll Merck Stock Investment Plan, please provide your name and mailing address, or call Merck Sto Services at 1-800-613-2104 (United States and Canada only). If you are not a registered stockh please refer to previous question.
G. Can I make automatic monthly investments to the Merck Stock Investment Plan throug checking or savings account?
Yes. One of the features of the Merck Stock Investment Plan is Automatic Cash Withdrawal and Investment (ACH). Through the plan you can elect to have money automatically withdrawn from checking or savings account each month and invested in your plan account. In order to participa please call Merck Stockholder Services at 1-800-613-2104 (United States and Canada only) to an Account Election Form. H. Can I have my Merck quarterly dividend directly deposited to my checking or savings account?
Yes. Your Merck quarterly dividend can be automatically deposited to either your checking or sa account by calling 1-800-613-2104 (United States and Canada only) and requesting an enrollm be sent to you. V.
HUMAN RESOURCES
A. How can I obtain information on employment opportunities such as internships, sales, research positions? For more information on professional and college opportunities, contact us at: Merck & Co., Inc. One Merck Drive P.O. Box 100 WS 1F-55 (Source Code: Internet) Whitehouse Station, NJ 08889-0100 ATTN: Employment Opportunities
We recommend you go to the Career Opportunities section of our web site to obtain additiona
P.O. Box 100 WS 1F-55 (Source Code: Internet) Whitehouse Station, NJ 08889-0100 ATTN: Employment Opportunities
We recommend you go to the Career Opportunities section of our web site to obtain additiona information. B. T o whom should I address my rsum?
It is against company policy to provide employee information. Please see the Career Opportun section of our web site for information on submitting your rsum. VI.
THE MERCK INDEX

A. What is The Merck Index?
The Merck Index is a a one-volume encyclopedia of chemicals, drugs and biologicals that conta than 10,000 monographs. Each monograph in this authoritative reference source is a concise description of a single substance or a small group of closely related compounds.
Compounds included:
human and veterinary drugs biotech drugs and monoclonal antibodies biologicals and natural products plants and herbal medicines nutraceuticals and cosmeceuticals agricultural chemicals industrial chemicals laboratory reagents and catalysts dyes, colors and indicators environmentally significant substances
Information provided:
chemical, common and generic names trademarks and associated companies CAS Registry Numbers chemical structures molecular formulae and weights physical and toxicity data therapeutic and commercial uses scientific and patent literature references capsule statements identifying compound classes and scientific significance
In addition, there are Name, Formula, CAS Registry Number and Therapeutic Category/Biologic Activity indices. The collection of supplementary tables contains physical, chemical and biomed and listings of pharmaceutical company names, locations and experimental drug codes. The Or Name Reactions section contains over 400 reactions featuring descriptions, literature reference graphical depictions.
Send your questions, comments and suggestions about the contents of The Merck Index to the staff via E-mail: Merck_index@merck.com or Fax: 1-732-594-1187. U. How can I order a print version of The Merck Index?
The most recent edition of The Merck Index (Thirteenth Edition, 2001) can be ordered by calling 1-800-819-9546 ext. 759 within the continental United States, or by faxing the Merck Publishing at 1-732-750-2735. Price: $60.00. You may also mail your order to:
The most recent edition of The Merck Index (Thirteenth Edition, 2001) can be ordered by calling 1-800-819-9546 ext. 759 within the continental United States, or by faxing the Merck Publishing at 1-732-750-2735. Price: $60.00. You may also mail your order to: Merck Publishing Group Merck & Co., Inc. One Merck Drive P.O. Box 2000 WBD-120 Rahway, NJ 07065 USA Whether you fax or mail your order, please be sure to include the following information: Your full name Your complete street address
Note: A post office box (PO Box number) is not sufficient
Your city and state (and country, if applicable) Any postal (ZIP) codes V. Is there a CD-ROM version of The Merck Index?
The CD-ROM version of The Merck Index, Thirteenth Edition is co-published by Merck & Co., In CambridgeSoft. This electronic version of The Merck Index contains the text and structures of th monographs, the supplementary tables section and the Organic Name Reactions section. This is available for Microsoft Windows and features powerful text and substructure searching to exploring the contents. W. How can I order the CD-ROM version of The Merck Index? CambridgeSoft products and services may be purchased by contacting: CambridgeSoft 100 Cambridge Park Drive Cambridge, MA 02140 USA ChemStore.Com (the online store) 800-315-7300 (US & Canada) 617-588-9300 (Local & International) info@cambridgesoft.com (sales department E-mail) X. Is there a web accessible version of The Merck Index?
The web accessible version of the Thirteenth Edition will be available in January of 2002. Subsc will be available through CambridgeSoft. For subscription information contact: CambridgeSoft 100 Cambridge Park Drive Cambridge, MA 02140 USA ChemStore.Com (the online store)
CambridgeSoft 100 Cambridge Park Drive Cambridge, MA 02140 USA ChemStore.Com (the online store) 800-315-7300 (US & Canada) 617-588-9300 (Local & International) info@cambridgesoft.com (sales department E-mail) Y. Is there an on-line version of The Merck Index?
The following licensed vendors (all fee-based) provide on-line access to The Merck Index Onlin 1. DIALOG The Dialog Corporation 2440 El Camino Real Mountain View, CA 94040 Tel: 1-800-3-DIALOG 2. Questel Orbit, Inc. 8000 Westpark Drive Suite 130 McLean, VA 22102 Tel: 1-800-456-7248 3. STN International Chemical Abstract Service 2540 Olentangy River Road Columbus, OH 43202 Tel: 1-800-848-6533 VII.
THE MERCK MANUALS

A. What is The Merck Manual?
The Merck Manual is the most widely used medical text in the world. Written by over 300 exper covers all but the most obscure disorders. In addition to describing symptoms, common clinical procedures, laboratory tests, and virtually all the disorders that a general internist might encoun Manual deals with problems of pregnancy and delivery; common and serious disorders of neon infants, and children; genetics; drug dependency; psychiatric disorders; and many disorders cov other specialties. The Manual also contains information about special circumstances, such as d emergencies, reactions and injuries caused by radiation exposure, and problems encountered i deep-sea diving. Current therapy is presented for each disorder and supplemented with a sepa section on clinical pharmacology. B. How can I order a print version of The Merck Manual? Purchasing information for The Merck Manual 17th Edition is available here. C. Is The Merck Manual on-line? The Merck Manual is available on-line.
Purchasing information for The Merck Manual 17th Edition is available here. C. Is The Merck Manual on-line? The Merck Manual is available on-line. D. Is there a CD-ROM version of The Merck Manual?
Currently, there is a CD-ROM version of The Merck Manual available. The disc is titled The Mer Manual Illustrated and also includes The Merck Manual of Geriatrics and hundreds of additiona images. Both books are extensively cross linked. The disc also includes Merriam-Webster's Me Dictionary, electronic edition, price: $95.00. To order, contact Medifor, Inc. - at http://www.medi or e-mail info@medifor.com or call 1-800-366-3710 E. What is The Merck Manual of Medical Information--Home Edition?
The Merck Manual of Medical Information--Home Edition is an all new book that is based on Th Manual. While The Merck Manual provides medical information to health care professionals, Th Edition was written for patients, their families, and all non-health care professionals interested in learning more about illnesses, their diagnosis, and their treatment. Written by over 200 experts, all but the most obscure disorders and contains almost all the information included in the profes version, written in plain English
F. How can I order a print version of The Merck Manual of Medical Information--Home Edi
Purchasing information for The Merck Manual of Medical Information--Home Edition is available G. Is The Merck Manual of Medical Information--Home Edition on-line? The Home Edition is available on-line. H. Is there a CD-ROM version of The Home Edition?
Currently, there is a CD-ROM version of The Home Edition available. The disc is titled The Merc Manual of Medical Information--Home Edition; price $39.95. To order, contact McGraw Hill at http://www.pbg.mcgraw-hill.com or call 1-800-2-MCGRAW (1-800-262-4729). VIII.
THE MERCK MANUAL OF GERIATRICS

A. What is The Merck Manual of Geriatrics?
The Merck Manual of Geriatrics is the most widely used textbook of geriatric medicine. It discus medical care of the elderly with detailed attention to how physiology changes with age, the uniq diseases present in the elderly, and the special considerations of treating disease in elderly per Entire chapters cover medication use in the elderly, legal issues related to medical care, the demographics of aging, institutional care, home care, hospice care, and death and dying. Altho book was written mostly for doctors and nurses, it may be useful to many other health professio to some older persons and their families seeking information about their medical conditions. B. How can I order a print version of The Merck Manual of Geriatrics?
diseases present in the elderly, and the special considerations of treating disease in elderly per Entire chapters cover medication use in the elderly, legal issues related to medical care, the demographics of aging, institutional care, home care, hospice care, and death and dying. Altho book was written mostly for doctors and nurses, it may be useful to many other health professio to some older persons and their families seeking information about their medical conditions. B. How can I order a print version of The Merck Manual of Geriatrics?
The most recent edition of The Merck Manual of Geriatrics, Third Edition, can be ordered by ca 1-800-819-9454 within the continental United States. Price: $32.50. You may also mail your order to: Merck Publishing Group Merck & Co., Inc. PO Box 2000 WBD-120 Rahway, NJ 07065 USA Whether you fax or mail your order, please be sure to include the following information: Your full name Your complete street address (Note: A post office box (PO Box number) is not sufficient) Your city and state (and country, if applicable) Any postal (ZIP) codes C. Is The Merck Manual of Geriatrics on-line? The Merck Manual of Geriatrics, Third Edition is available on-line. D. Is there a CD-ROM version of The Merck Manual of Geriatrics?
The Merck Manual of Geriatrics (2nd Edition) is available on CD-ROM combined with the regula Manual from Medifor, Inc. (1-800-366-3710). It works on both Macintosh and PCs. The 3rd Edit The Merck Manual of Geriatrics will be available on CD-ROM soon. IX.
THE MERCK VETERINARY MANUAL

A. What is The Merck Veterinary Manual?
Since 1955, veterinary professionals have depended on The Merck Veterinary Manual for comprehensive, relevant information on all aspects of animal healthcare. The 8th edition is com redesigned and contains 500 additional pages, more than 50 new or expanded topics, and a ne user-friendly format.
It covers topics such as emergency medicine and critical care, treatment of exotic animals, such caged birds, fish, reptiles, ostriches and llamas as well as topics ranging from gastrointestinal a musculoskeletal disorders of small animals to respiratory disease of cattle and horses. B. Is there an electronic version of The Merck Veterinary Manual?
Yes. Now, this comprehensive reference is available as an easy-to-navigate, dual platform (PC
caged birds, fish, reptiles, ostriches and llamas as well as topics ranging from gastrointestinal a musculoskeletal disorders of small animals to respiratory disease of cattle and horses. B. Is there an electronic version of The Merck Veterinary Manual?
Yes. Now, this comprehensive reference is available as an easy-to-navigate, dual platform (PC compatible), fully searchable CD-ROM with a user-friendly format containing all the information printed book, plus valuable features to further enhance it use. The custom search engine of the edition of The Merck Veterinary Manual, allows you to search by keyword, subjects or tables. To frequently referred to, can be bookmarked for future reference. The CD-ROM is generously illus and contains original anatomical artwork and hundreds of clinical and diagnostic photos of num disease states.
C. How can I order either the print or electronic version of The Merck Veterinary Manual?
The most recent edition of The Merck Veterinary Manual (Eighth Edition, 1998) may be ordered calling 1-800-839-4440 within the continental United States, or by faxing the Merck Publishing G 1-732-750-2735. You may also mail your order to: Merck Publishing Group Merck & Co., Inc. P.O. Box 2000 WBD-120 Rahway, NJ 07065 USA Whether you fax or mail your order, please be sure to include the following information: Your full name Your complete street address (NOTE: A post office box (PO Box) number is not sufficient.) Your city and state (and country, if applicable) Any postal (ZIP) codes
X.
EMPLOYEE CONTACTS
A. I am interested in working for Merck. Can you provide me the name of the individual I s contact?
It is against company policy to provide employee information. Please see the Career Opportun section of our web site for information on contacting our Human Resources department. B. I am trying to reach a Merck employee via Internet email. Can you help me?
The format for a Merck employee's Internet email address is FirstName_LastName@Merck.C the particular employee you are attempting to reach has Internet email, he or she will receive yo message. However, note that not all Merck employees have access to Internet email, and at thi Merck does not publish a list of which employees have access and which do not.
Revision date: 09/25/2001
the particular employee you are attempting to reach has Internet email, he or she will receive yo message. However, note that not all Merck employees have access to Internet email, and at thi Merck does not publish a list of which employees have access and which do not.
Explore this comprehensive, yet easy to understand information to learn more about your health. Celebrate the progress in medicine monthly with new quizzes. According to research, large doses of vitamins (including vitamin C) do not prevent or cure The February topic is Respiratory Health with our featured topic the common cold. Lung Cancer.
Merck & Co., Inc. Plans to Establish Merck-M Separate, Publicly Traded Company
Merck's Earning Per Share Increase 8% for the Strong Performance of Five Key Product
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NEW Careers site launched! Visit The Merck Manual 17th edition the world's most widely used medical text and also discover other Merck publications. Also, The Merck Manual of Geriatrics, Third Edition is now online! Merck markets a broad range of innovative products.
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As you take a walk through the following pages, you will learn more about m that make up Merck. Take a look at all of our areas, as your education, skills to a variety of positions throughout the company. Research Sales & Marketing Pharmacy Manufacturing Engineering Finance Information Services Corporate
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The work we do at Merck requires talented and driven individuals who are lo passion to a career. Thats why our recruiting efforts take us all over the worl students and recent graduates like you who are learning from distinguished f developments in science, technology, marketing, public relations, business a finance. Mercks future lies in this next generation and Mercks future could So come with me, as I give you the tour of University Recruiting.
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Q. What happens to my resume after I submit it online?
A. Your resume will be included in our candidate tracking system. If you pos your resume will be reviewed by the hiring group to determine if your bac will be notified in writing when your resume has been received. If you pos not apply for a particular job, your resume will simply be added to the gen For future job openings, Merck hiring managers will be able to search for if your background matches their job requirements.
Q. Can I send you my resume via mail or fax?
A. For the fastest and most effective way to get considered for employment resume through our online resource within Merck.com. This will allow you and submit your resume for specific opportunities and future searches. H prefer to use email, you can send your resumes to merckcareers@alexu you can also fax your resume to 1-888-568-0844. Finally, if you prefer to can send it to the following address: Merck & Co., Inc P.O. Box 3058 Scranton, PA 18505
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Erratum: Printed version of the 17th edition of The Merck Manual
Please note that there is an error in the dose of aqueous penicillin G in the treatment discussion of pneumococcal infections on page 1155, column 2, lin printed version of the 17th edition of The Merck Manual. The text in the first paragraph under Treatment should say "Pneumococcal meningitis or endoca requires up to 20 to 40 million U/day ...." (not 20,000 to 40,000 U/day as printed). The pediatric dose is correct as printed.
The Merck Manual of Medical Information

Home Edition
The Merck Manual of Geriatrics

Third Edition
The Merck Manual of Diagnosis and Therap

Seventeenth Edition
The Merck Manual is celebrating its with the publication of the 17th Edit The Merck Manual of Medical Information--Home The third edition of The Merck Manual of Geriatrics was published Merck Manual is used by more med Edition was published for the first time in professionals worldwide than any o in Fall of 2000. This new edition has been redesigned and September 1997. This edition uses everyday medical textbook and has been con features a unique interdisciplinary approach that specifically language to present information about diseases, addresses the challenges facing geriatric care. It includes published longer than any other En diagnosis, prevention, and treatment. To search information on nursing care, pharmacy issues, discussions of the language general medical textbook the sections of The Home Edition that are best drugs for the elderly, and new or extensively revised chapters pleased to provide the new 17th Ed currently online, please use the general site-wide on dementia, Alzheimer's disease, rehabilitation, respiratory web site free of charge for your unli search facility at the top of the page. failure, and managed care. We are pleased to provide the new 3rd Edition on this web site free of charge for your unlimited use.
The Merck Index Providing data and descriptions of chemicals, drugs, and biologicals, this single volume encyclopedia contains over 10,000 monographs. Subject matter includes: human and veterinary drugs, biologicals and natural products, agricultural chemicals, industrial and laboratory chemicals, and environmentally significant compounds.
The Merck Veterinary Manual
Addressing the the medical concerns of companion, food, and zoo animals, this manual is a veritable source of information for veterinary medicine. Chapters that cover particular disease entities include brief discussions of etiology, transmission and pathogenesis, clinical findings and lesions, diagnosis, treatment, control and prevention.
The Merck Manual of Diagnosis and Therapy Seventeenth Edition Centennial Edition Home
Editors Mark H. Beers, M.D., and Robert Berkow, M.D.
Senior Assistant Editors Robert M. Bogin, M.D., and Andrew J. Fletcher, M.B., B.Chir.
Editorial Board Philip K. Bondy, M.D.; Preston V. Dilts, Jr., M.D.; Douglas A. Drossman, M.D.; L. Jack Faling, Eugene P. Frenkel, M.D.; Glen O. Gabbard, M.D.; Robert A. Hoekelman, M.D.; Gerald L. Mandel Fred Plum, M.D.; G. Victor Rossi, Ph.D.; Paul H. Tanser, M.D., F.R.C.P.(C)
Editorial and Production Staff Keryn A.G. Lane, Executive Editor | Susan T. Schindler, Senior Staff Editor | Julie Kostecky, Staff Sandra J. Masse, Staff Editor | Debra G. Share, Production Editor | Roger I. Schreck, M.D., Contributing Editor | Lorraine B. Kilmer, Design | Susan Thomas, Ph.D., In Diane C. Zenker, Textbook Production Coordinator | Dorothy A. Bailey, Medical Textbook Coordin Diane Cosner-Bobrin, Executive Assistant | Gary Zelko, Publisher | Pamela J. Barnes, Advertising and Promotional Supervisor
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Copyright 1999 by Merck & Co., Inc. All rights reserved.
Merck is dedicated to providing reliable, easy-to-use medical information. That is why Merck ha published The Merck Manual for 100 years on a not-for-profit basis. This book has become the most widely used general medical text and is now published in 14 languages. In 1990, we publi The Merck Manual of Geriatrics (updated in 2000 with the 3rd edition), in keeping with Merck's commitment to providing excellent information on care for the elderly. In 1997, we published Th Merck Manual of Medical Information--Home Edition, providing medical information in everyday language.
The Merck Manuals are available for purchase in a variety of electronic editions, but we are del to make the 17th edition of The Merck Manual available on our web site free of charge. This boo Centennial Edition--was published in April 1999. Merck also provides The Merck Manual of Med Information--Home Edition on our web site free as well. Please use these books as often as you
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The Migraine site now has a quarterly newsletter called "Heads Up on Migraine". Read information about Migraines from interviews with top physicians a people in the Migraine field. Check out the 10 Ten Things to Tell Your Doctor if you or someone you love suffers from Migraine. Read a Migraine suffers experience in the Testimonial section...Tell us about your Migraine experience, and your testimonial may be chosen and posted anonymously! Premiere the Tranquility Zone, a new dimension in web technology. You can design your personal "get-away" zone by choosing soothing images and mu a Tranquil scene. Test your knowledge of Migraines with new quiz questions.
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Webcast from the Fifth International Congress on Drug Therapy in HIV Infection Click to listen to the lectures and see the speakers slides: Drug Resistance and Viral Responses to Therapy Global Trials with Twice-Daily Indinavir/Ritonavir Achieving Convenience and Durability with Indinavir/Ritonavir Penetration of HIV-1 Protease Inhibitors into CSF & Semen
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Front Matter Topics
A Centennial History
During the past 100 years, advances in medical information, technology, diagnosis, and treatment hav occurred at an accelerating rate that is both amazing and challenging. The Merck Manual has always attempted to present the best of clinical practice, and with the publication of this Centennial Edition, w resist looking back at earlier editions, noting changes in the practice of medicine during the past centu celebrating the development of The Manual--the oldest continuously published general medical textbo English language.
The 1st Edition, published in 1899 under the title Merck's Manual of the Materia Medica, was a 192-pa based on the United States Pharmacopoeia. Part I (entitled Materia Medica) listed in alphabetical orde agent then thought to be of therapeutic value (from absinthin, a tonic, to zinc valerianate, for nervous afflictions), with a description of each agent's properties and doses. The second part of the book, entit Therapeutic Indications, listed in alphabetical order symptoms, signs, disorders, and diseases; each w followed by a list of all known treatments with a brief explanation of their use. In the third part, drugs w classified "according to their physiologic actions," which included several categories not generally cons today, such as "alteratives," "amenogogues," "discutients," and "resolvents," which date back to Galen all of the drugs listed have been replaced by more effective remedies, but some, such as atropine, dig chloral hydrate, codeine, and quinidine, are still used today. The use of drugs that we recognize mostl poisons today, such as arsenic and strychnine, was surprisingly common. However, anyone reading th current edition of The Merck Manual would recognize that we still use a number of poisons, especially treating cancer.
In an essay reviewing the 1st Edition of The Manual1, Dr. Harold J. Morowitz noted that the 1st Edition extraordinary number of treatments of little or no value for most diseases. For example, after noting 75 treatments for diphtheria and 96 for gonorrhea, none of which was effective, he commented that ". . . t natural feeling that it is better to do something than to do nothing" and that "the less a disease was understood, the larger the number of treatments available." These tendencies exist in medical therapy
In an essay reviewing the 1st Edition of The Manual1, Dr. Harold J. Morowitz noted that the 1st Edition extraordinary number of treatments of little or no value for most diseases. For example, after noting 75 treatments for diphtheria and 96 for gonorrhea, none of which was effective, he commented that ". . . t natural feeling that it is better to do something than to do nothing" and that "the less a disease was understood, the larger the number of treatments available." These tendencies exist in medical therapy Observing that bacteriology, organic chemistry, and biochemistry were new disciplines in 1899 and tha physicians regarded themselves as highly trained medical scientists dedicated to relieving human suff Morowitz cautioned against too readily scoffing at our predecessors; 100 years from now, the informat this Centennial Edition may look quite primitive.
We have no direct information about the development of The Merck Manual, 1st Edition, but the forew clearly expressed the intent: ". . . to meet a need which every general practitioner has often experience Memory is treacherous. It is particularly so with those who have much to do and more to think of. Whe best remedy is wanted, to meet indications in cases that are a little out of the usual run, it is difficult, a sometimes impossible, to recall the whole array of available remedies so as to pick out the best. . . . B mere reminder is all he needs, to make him at once master of the situation and enable him to prescrib what his judgement tells him is needed for the occasion." The intent of The Manual to provide clinically relevant material to meet the needs of practicing physicians has remained the same to this day.
The Merck Manual was an immediate success, and the 2nd Edition (1901) evolved quickly in response advances in information and the changing needs of practicing physicians. In the 2nd Edition, brief defi were added under the name of each condition, and aspirin was mentioned for the first time, only 2 yea its introduction by Bayer.
Subsequent editions reflected the march of medical progress. The 3rd Edition (1905) discussed adren vasoconstrictor for the first time and noted that scurvy was "due to improper and insufficient diet." By 1 war-delayed 5th Edition required nearly 600 pages. It expanded on popularly received hints for bedsid diagnosis. Urinalysis was given 21 pages; a discussion about taking blood pressures (a new diagnosti procedure) and a table of blood pressures were added. Arsphenamine and salversan joined the syphil armamentarium as galenic medicine was fading from practice.
In the 6th Edition (1934), Dr. Bernard Fantus, Professor of Therapeutics at the University of Illinois Co Medicine and the first to implement blood banking, became the first person to have his name mentione Manual. Because of phenomenal advances in the biological sciences and organic chemistry, the 6th E became a completely new book with 1379 pages. Issued under a new title, The Merck Manual of Ther and Materia Medica, it was three times as thick as its predecessor and covered many more diseases, arranged alphabetically, with definitions, etiology, diagnosis (including laboratory findings as well as cli symptoms and signs), and therapy, with copious prescriptions. Some of its concepts are now archaic-t endorsement of roentgen therapy for many skin conditions and the belief that pregnant women should travel. That edition called the automobile "a potent cause of abortion"; considering the state of roads a time, perhaps it was right. But the deficiency diseases (eg, pellagra, beriberi) were explained, and diab was recognized as a deficiency in pancreatic insulin secretion. Acidosis, shock, psychopathology, subcutaneous and intravenous drugs, the composition of foods, and a table of vitamins were among th medical advances introduced. However, there were still no antibiotics, and infections were a leading ca death. There was also surprisingly little information about neoplasms. Gastric cancer, leukemias, and Hodgkin's disease were discussed, but lengthy discussions of "colon stasis" and intestinal obstruction even mention bowel neoplasms. A grateful acknowledgement to the authors and publishers of a numb other medical texts also appeared, suggesting that The Manual was composed by summarizing mater other books.
In the 7th Edition (1940), Dr. M. R. Dinkelspiel (an ophthalmologist) was identified as the editor for this 6th Edition. Dr. Fantus' assistance was acknowledged again, and the help and advice received from le specialists in various fields were cited to fortify the dependability of the 1436 pages to which The Manu
other medical texts also appeared, suggesting that The Manual was composed by summarizing mater other books.
In the 7th Edition (1940), Dr. M. R. Dinkelspiel (an ophthalmologist) was identified as the editor for this 6th Edition. Dr. Fantus' assistance was acknowledged again, and the help and advice received from le specialists in various fields were cited to fortify the dependability of the 1436 pages to which The Manu grown. Again, there was little discussion of neoplasms. Coronary occlusion was discussed as occurrin sleep or at rest, not with exertion. New topics included allergy, circulatory failure, granulocytopenias, ro ray sickness, and obesity. Organic mercurials were proposed to treat edema, and the importance of so retention in the pathogenesis of edema was recognized. The theory of intrinsic and extrinsic factors in pernicious anemia was explained, and physostigmine and pilocarpine were recommended for glaucom so were leeches, applied to the temples). Some sulfonamides were now in use, but there were still no drugs to treat hypertension. Under malaria, ways to decrease the expense of quinine therapy were dis For the first time, an index was provided.
World War II delayed publication of the 8th Edition until 1950. Unprecedented advances in medicine a required a completely new Manual-new in form and philosophy as well as in content. Dr. Charles E. Ly may be considered the father of the modern Merck Manual, took over as editor and effected the overh title changed to its present one, The Merck Manual of Diagnosis and Therapy; the alphabetical listing diseases was replaced by organization into 20 special fields of medicine (suggesting how specialized American medicine had become); and discussions of marvelous new drugs replaced the old materia m To treat infections, there were sulfonamides, penicillin, streptomycin, dihydrostreptomycin, chlortetracy and chloramphenicol. The dramatic effects of corticosteroids in arthritis were described. Diphtheria an toxoid and pertussis vaccine were used for routine pediatric immunization, but no vaccine was yet ava German measles (although the devastating effects of this disease on the fetus were appreciated).
Dr. Lyght introduced the dictionary-like thumb tabs between sections of the book and listed the editoria of the 9th Edition, which consisted of four members. The chapter on bedside procedures conveyed str concern for the patient's comfort and welfare, including details of bathing a patient in bed. If the patien became so matted as to require cutting, securing a signed consent was advised. A chapter on the con the doctor's bag attested that house calls were still the order of the day. For the first time, a small grou physician-editors did not have to ransack leading textbooks for material to be digested, reorganized, a dictated to a battery of secretaries, because outside authors were recruited to provide text. Dr. Lyght commented, "These authorities helped greatly. To a man, however, they wrote too long and each in hi style and pattern. Much editing was necessary to achieve brevity, clarity, and consistency without alter factual content." To Dr. Lyght's relief, nearly every author expressed thanks for making his contribution "better." Authors received modest honoraria and served anonymously.
Dr. Lyght guided the growth and revisions of The Manual through the 11th Edition (1966). Despite his for brevity, The Manual grew to a size that could be accommodated only by a kangaroo's pocket. The Edition (1972) was produced under the supervision of Dr. David Holvey, with much assistance from Dr Talbott (formerly Professor and Chairman, Department of Medicine, the State University of New York a Buffalo, and Editor of The Journal of the American Medical Association), who acted as consulting edito Holvey died in an accident, and Dr. Robert Berkow became the editor of the 13th Edition, again produ Dr. Talbott's assistance. The number of outside authors increased to about 250, mostly from the Unite and a distinguished editorial board of 12 members actively participated in developing the book, selecti authors, and reviewing manuscripts. Authors' names were listed for the first time.
The 13th Edition (1977) required enormous effort to include within the confines of a smallish handbook remarkable amount of new information on physiology, immunology, and pharmacology. New sections added, old sections were enlarged, and the physical dimensions of the book were increased. The cont double that of the 12th Edition. Controlling the size of The Manual continued to challenge the editors a advances in enzymology, molecular and cellular biology, genetic engineering, and diagnostic and surg procedures poured out of research laboratories and were incorporated into clinical practice.
The 13th Edition (1977) required enormous effort to include within the confines of a smallish handbook remarkable amount of new information on physiology, immunology, and pharmacology. New sections added, old sections were enlarged, and the physical dimensions of the book were increased. The cont double that of the 12th Edition. Controlling the size of The Manual continued to challenge the editors a advances in enzymology, molecular and cellular biology, genetic engineering, and diagnostic and surg procedures poured out of research laboratories and were incorporated into clinical practice.
Subsequent editions have changed in other ways as well. The 16th Edition of The Merck Manual was in several CD-ROM versions and was made accessible on the Internet at no charge. Foreign language versions of The Merck Manual are also playing a larger role. German and Spanish language editions h been available since the 1950s, but the 16th Edition was available in 14 languages other than English Altogether, almost 2 million copies of the 16th Edition were sold, and we believe The Merck Manual is most widely used general medical text in the world. Foreign translations of the 17th Edition and electro versions are already underway.
The Centennial (17th) Edition required a concerted effort by many people and would not have been po without the aid of a Co-Editor, Dr. Mark H. Beers, and two Senior Assistant Editors, Drs. Robert M. Bo Andrew Fletcher. Keryn Lane, Executive Editor, has overseen an extraordinary group of editors and st with all editions since the 13th, the process began with an internal analysis of the previous edition, eve though it had received highly favorable reviews and outstanding reader acceptance. Sections of the 16 Edition were then sent to outside experts who had nothing to do with its preparation, to solicit their can criticism. Published reviews and letters from readers were analyzed. Next, the Editorial Board met to c reviews and critiques and to plan the 17th Edition. Distinguished special consultants were enlisted to p additional expertise. Then, 290 authors with outstanding qualifications, experience, and knowledge we engaged. Their manuscripts were painstakingly edited by our staff to retain every valuable morsel of knowledge while eliminating unneeded, although often elegant, words. Each manuscript was then revi an Editorial Board member or a consultant. In many cases, additional special reviewers were invited to comment. Every mention of a drug and its dosage was reviewed by outside pharmacy consultants. Th objective of all the reviews was to ensure accurate, adequate, and relevant coverage of each subject, simple, clean exposition. The authors then reworked, modified, and polished their manuscripts. Almos the manuscripts were revised at least 6 times; 15 to 20 revisions were not uncommon. We believe tha other medical text undergoes as many reviews and revisions as does The Merck Manual.
The 1st Edition of The Merck Manual began with a note to its readers saying, "Physicians are earnestl requested to communicate . . . any suggestions that may tend to improve this book for its Second Edit Whatever the publishers can do to make Merck's Manual of still greater service to the medical profess be gladly undertaken and promptly performed for all subsequent editions." The note went on to explain any physician who proposed improvements would be rendering "valuable service" to the entire profess invitation has been extended to readers in every succeeding edition of The Merck Manual.
1Harold
J. Morowitz, "The Merck of Time," Hospital Practice, December 1976.

Front Matter Topics
Guide for Readers of the Internet Edition

Chapters are numbered serially from the beginning to the end of the book. Readers will find many cross-references to other sections and chapters throughout the text.
Titles of sections are listed on the Sections page, essentially a table of contents. Clicking on a Section bring up its own table of contents, listing chapters. Clicking on a chapter will reveal the first topic in tha chapter.
Abbreviations and symbols, used throughout the text as essential space savers, are shown in Front Abbreviations and Symbols. Other abbreviations in the text are expanded at first mention in the chapte
Section 21, Special Subjects, has discussions on genetics, smoking cessation, rehabilitation, geriatri medicine, care of the dying patient, and clinical decision making, among others. There are also referen tables in laboratory medicine.
Laboratory values in the book are given in conventional units. In most cases, however, SI units follow parentheses.
Drugs are designated in the text by generic (nonproprietary) names. In the last chapter of the Clinical Pharmacology section, many of the drugs mentioned in the book are listed alphabetically, with each ge term followed by one or more trade names.
Laboratory values in the book are given in conventional units. In most cases, however, SI units follow parentheses.
Drugs are designated in the text by generic (nonproprietary) names. In the last chapter of the Clinical Pharmacology section, many of the drugs mentioned in the book are listed alphabetically, with each ge term followed by one or more trade names.
Important: The authors, reviewers, and editors of this book have made extensive efforts to ensure tha treatments, drugs, and dosage regimens are accurate and conform to the standards accepted at the ti publication. However, constant changes in information resulting from continuing research and clinical experience, reasonable differences in opinions among authorities, unique aspects of individual clinical situations, and the possibility of human error in preparing such an extensive text require that the reade exercise individual judgment when making a clinical decision and, if necessary, consult and compare information from other sources. In particular, the reader is advised to check the product information pr by the manufacturer of a drug product before prescribing or administering it, especially if the drug is un or is used infrequently.

Front Matter Topics
Abbreviations and Symbols
The following abbreviations are used throughout the text; other abbreviations are expanded at first me the chapter or subchapter.
ACE ACTH ADH AIDS ALT AST ATP BCG
angiotensin converting enzyme adrenocorticotropic hormone antidiuretic hormone acquired immunodeficiency syndrome alanine aminotransferase (formerly SGPT) aspartate aminotransferase (formerly SGOT) adenosine triphosphate bacille Calmette-Gurin
Mg mg MI MIC min mIU mL mm
magnesium milligram myocardial infarction minimum inhibitory concentration minute milli-international unit milliliter millimeter
BCG bid BMR BP BSA BUN C Ca cAMP CBC cGy Ch. Ci CK Cl cm CNS CO2 COPD CPR CSF CT cu D&C dL DNA DTP D/W ECF
bacille Calmette-Gurin 2 times a day basal metabolic rate blood pressure body surface area blood urea nitrogen Celsius; centigrade; complement calcium cyclic adenosine monophosphate complete blood count centigray chapter curie creatine kinase chloride; chlorine centimeter central nervous system carbon dioxide chronic obstructive pulmonary disease cardiopulmonary resuscitation cerebrospinal fluid computed tomography cubic dilation and curettage deciliter (= 100 mL) deoxyribonucleic acid diphtheria-tetanus-pertussis (toxoids/vaccine) dextrose in water extracellular fluid
mm mmol mo mol wt MRI N Na NaCl ng nm nmol O2 OTC oz P
millimeter millimole month molecular weight
mOsm milliosmole magnetic resonance imaging sodium sodium chloride nanogram (= millimicrogram) nanometer (= millimicron) nanomole oxygen
nitrogen; normal (strength of solutio
NSAID nonsteroidal anti-inflammatory drug
over-the-counter (pharmaceuticals) ounce phosphorus; pressure
PACO2 alveolar carbon dioxide partial pres
PaCO2 arterial carbon dioxide partial press PAO2 PaO2 PAS PCO2 pg pH PMN po PO2 PPD alveolar oxygen partial pressure arterial oxygen partial pressure periodic acid-Schiff carbon dioxide partial pressure (or tension) picogram (= micromicrogram) negative log of the hydrogen ion concentration polymorphonuclear leukocyte orally
oxygen partial pressure (or tension
purified protein derivative (tubercul
ECF ECG EEG ENT ERCP ESR F FDA ft FUO Gy g GFR GI G6PD GU h Hb HCl HCO 3 Hct Hg HIV HLA Hz ICF ICU IM INR IPPB
extracellular fluid electrocardiogram electroencephalogram ear, nose, and throat endoscopic retrograde cholangiopancreatography erythrocyte sedimentation rate Fahrenheit U.S. Food and Drug Administration foot; feet (measure) fever of unknown origin gray gram glomerular filtration rate gastrointestinal glucose-6-phosphate dehydrogenase genitourinary hour hemoglobin hydrochloric acid; hydrochloride bicarbonate hematocrit mercury human immunodeficiency virus human leukocyte antigen hertz (cycles/second) intracellular fluid intensive care unit intramuscular(ly) international normalized ratio intermittent positive pressure breathing
PPD ppm prn q qid RA RBC RNA SaO2 SBE sc sec SI SIDS SLE soln sp gr sq STS TB tid TPN U URI UTI WBC WHO wk wt yr
purified protein derivative (tubercul parts per million as needed every 4 times a day rheumatoid arthritis red blood cell ribonucleic acid arterial oxygen saturation subacute bacterial endocarditis subcutaneous(ly) second International System of Units sudden infant death syndrome systemic lupus erythematosus solution specific gravity square serologic test(s) for syphilis tuberculosis 3 times a day total parenteral nutrition unit upper respiratory infection urinary tract infection white blood cell World Health Organization week weight year micro-; micron
IgA, etc immunoglobulin A, etc
IPPB IU IV IVU K kcal kg L lb LDH M m m2 MCH MCHC mCi MCV mEq
intermittent positive pressure breathing international unit intravenous(ly) intravenous urography potassium kilocalorie (food calorie) kilogram liter pound lactic dehydrogenase molar meter square meter mean corpuscular hemoglobin mean corpuscular hemoglobin concentration millicurie mean corpuscular volume milliequivalent
Ci g L m mol m / < > <= >= ~=
micro-; micron microcurie microgram microliter micrometer (= micron) micromole millimicron (= nanometer) per less than more than equal to or less than equal to or more than approximately equal to plus or minus section
Osm micro-osmole

Front Matter Topics
Editors
MARK H. BEERS, M.D. ROBERT BERKOW, M.D.
Senior Assistant Editors

ROBERT M. BOGIN, M.D. ANDREW J. FLETCHER, M.B., B.Chir.
Editorial Board
Philip K. Bondy, M.D. Preston V. Dilts, Jr., M.D. Douglas A. Drossman, M.D. L. Jack Faling, M.D. Eugene P. Frenkel, M.D. Glen O. Gabbard, M.D. Robert A. Hoekelman, M.D. Gerald L. Mandell, M.D. Fred Plum, M.D. G. Victor Rossi, Ph.D. Paul H. Tanser, M.D., F.R.C.P.(C)

Front Matter Topics
Consultants
JAMES C. BALLENGER, M.D. Chairman and Professor, Department of Psychiatry and Behavioral Sciences, and Director, Institut Psychiatry, Medical University of South Carolina Psychiatric Disorders WILLIAM M. BENNETT, M.D. Professor of Medicine and Pharmacology, Oregon Health Sciences University Genitourinary Disorders JOSEPH W. BERKOW, M.D. Assistant Professor of Ophthalmology, Johns Hopkins University
WILLIAM M. BENNETT, M.D. Professor of Medicine and Pharmacology, Oregon Health Sciences University Genitourinary Disorders JOSEPH W. BERKOW, M.D. Assistant Professor of Ophthalmology, Johns Hopkins University Ophthalmologic Disorders INA LEE STILE CALLIGARO, Pharm.D. Associate Professor and Clinical Pharmacist, Pediatrics, and Chairperson, Department of Pharmacy Practice, Temple University Pediatric Pharmaceutical Preparations and Dosages RALPH E. CUTLER, M.D. Professor of Medicine and Pharmacology, Loma Linda University; Chief of Nephrology, Pettis Memorial VA Medical Center Genitourinary Disorders MARK V. DAHL, M.D. Professor and Chairman, Department of Dermatology, University of Minnesota Dermatologic Disorders GEORGE E. DOWNS, Pharm.D. Professor of Clinical Pharmacy and Dean, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia Pharmaceutical Preparations and Dosages EDWARD J. FINE, M.D. Associate Professor of Neurology, State University of New York at Buffalo Neurologic Disorders
SUSAN HENDRIX, D.O. Assistant Professor of Obstetrics and Gynecology and Director, Women's Health Initiative, Wayne University/Hutzel Hospital Gynecology and Obstetrics CHARLES S. HOUSTON, M.D. Professor of Medicine (Emeritus), University of Vermont Disorders Due to Physical Agents PETER LAIBSON, M.D. Director, Corneal Service, Wills Eye Hospital Ophthalmologic Disorders JOS J. LLINAS, M.D. Clinical Professor of Psychiatry, College of Medicine, University of Florida; Medical Director, Meridian Behavioral Health Care, Gainesville Psychiatric Disorders MORTIMER LORBER, D.M.D., M.D. Associate Professor of Physiology and Biophysics, Georgetown University Dental and Oral Disorders JOANNE LYNN, M.D.
MORTIMER LORBER, D.M.D., M.D. Associate Professor of Physiology and Biophysics, Georgetown University Dental and Oral Disorders JOANNE LYNN, M.D. Professor of Health Care Sciences and Medicine, The George Washington University; Director, The Center to Improve Care of the Dying Special Subjects BRUCE C. PATON, M.D. Clinical Professor of Surgery, University of Colorado Health Sciences Center Disorders Due to Physical Agents HAL B. RICHERSON, M.D. Professor of Internal Medicine (Emeritus), University of Iowa Immunology; Allergic Disorders ROBERT J. RUBEN, M.D. Chairman, Otolaryngology, Albert Einstein College of Medicine, Montefiore Medical Center Ear, Nose, and Throat Disorders H. RALPH SCHUMACHER, JR., M.D. Professor of Medicine, The University of Pennsylvania; Director, Arthritis-Immunology Center, VA Medical Center, Philadelphia Musculoskeletal and Connective Tissue Disorders RUTH W. SCHWARTZ, M.D. Professor of Obstetrics and Gynecology, University of Rochester Gynecology and Obstetrics WARREN R. SELMAN, M.D. Professor of Neurological Surgery and Vice Chairman, Department of Neurological Surgery, Case Reserve University and University Hospitals of Cleveland Neurologic Disorders ROBERT A. SINKIN, M.D. Associate Professor of Pediatrics, University of Rochester; Medical Director NICU, Children's Hospital at Strong Pediatrics
Reviewers for Selected Chapters

Sarah Atkinson, M.D. Robert N. Butler, M.D. Andrea Calabrese, Pharm.D. Steven Frucht, M.D. Terry Fulmer, Ph.D., R.N. Mateel Graham, M.D. Cynthia Harden, M.D. Kurt Hirschhorn, M.D. Philip Landrigan, M.D., M.Sc. Frank W. LoGerfo, M.D. John S. Macdonald, M.D. James V. Mackell, M.D. Donald E. Mock, Ph.D. Pekka Mooar, M.D. Richard Moon, M.D. David R. Nalin, M.D.
John C. Nemiah, M.D. Robert Ratcheson, M.D. Henry Rosenberg, M.D. Findley E. Russell, M.D., Ph. George L. Spaeth, M.D. Margaret A. Winker, M.D. Virgil Wooten, M.D. Vincent Zarro, M.D.
Andrea Calabrese, Pharm.D. Steven Frucht, M.D. Terry Fulmer, Ph.D., R.N. Mateel Graham, M.D. Cynthia Harden, M.D. Kurt Hirschhorn, M.D. Jonathan Jay, M.D.
John S. Macdonald, M.D. James V. Mackell, M.D. Donald E. Mock, Ph.D. Pekka Mooar, M.D. Richard Moon, M.D. David R. Nalin, M.D.
Henry Rosenberg, M.D. Findley E. Russell, M.D., Ph. George L. Spaeth, M.D. Margaret A. Winker, M.D. Virgil Wooten, M.D. Vincent Zarro, M.D.

Front Matter Topics
Contributors
HAGOP S. AKISKAL, M.D. Professor of Psychiatry and Director of the International Mood Center, University of California at San Diego Mood Disorders KATHERINE A. ALBERT, M.D., Ph.D. Assistant Professor of Neurology and Neuroscience in Psychiatry, The New York Hospital-Cornell Medical Center Sleep Disorders JAMES K. ALEXANDER, M.D.
KATHERINE A. ALBERT, M.D., Ph.D. Assistant Professor of Neurology and Neuroscience in Psychiatry, The New York Hospital-Cornell Medical Center Sleep Disorders JAMES K. ALEXANDER, M.D. Professor of Medicine, Baylor College of Medicine Pulmonary Embolism CHLOE G. ALEXSON, M.D. Professor of Pediatrics, University of Rochester Congenital Heart Disease TERRY D. ALLEN, M.D. Professor of Urology, The University of Texas Southwestern Medical Center at Dallas Intersex States
ROY D. ALTMAN, M.D. Professor of Medicine and Chief of Rheumatology and Immunology, University of Miami; Director o Clinical Research, Geriatric Research, Education, and Clinical Center, Miami VA Medical Center Paget's Disease of Bone
KARL E. ANDERSON, M.D. Professor of Preventive Medicine and Community Health, Internal Medicine and Pharmacology an Toxicology, The University of Texas Medical Branch at Galveston The Porphyrias GERALD ANDRIOLE, M.D. Professor of Urologic Surgery, Washington University Myoneurogenic Disorders; Prostate Disease BRIAN R. APATOFF, M.D., Ph.D. Director, Multiple Sclerosis Clinical Care and Research Center, Department of Neurology and Neuroscience, The New York Hospital-Cornell Medical Center Demyelinating Diseases JACOB V. ARANDA, M.D., Ph.D. Professor of Pediatrics, Pharmacology and Therapeutics, McGill University; Director, Perinatal and Developmental Pharmacology Research, The Lady Davis Institute-Jewish General Hospital Drug Treatment in Newborns, Infants, and Children NOEL A. ARMENAKAS, M.D. Clinical Assistant Professor, Cornell University Medical College; Attending Surgeon, Lenox Hill Hospital and The New York Hospital-Cornell Medical Center Trauma to the Urinary Tract ROBERT C. ASHTON, JR., M.D. Fellow in Cardiothoracic Surgery, Columbia Presbyterian Medical Center Diagnostic Cardiovascular Procedures (Invasive Procedures) ZUHAIR K. BALLAS, M.D. Professor of Internal Medicine, University of Iowa Biology of the Immune System
ROBERT C. ASHTON, JR., M.D. Fellow in Cardiothoracic Surgery, Columbia Presbyterian Medical Center Diagnostic Cardiovascular Procedures (Invasive Procedures) ZUHAIR K. BALLAS, M.D. Professor of Internal Medicine, University of Iowa Biology of the Immune System
MARK BALLOW, M.D. Professor of Pediatrics, State University of New York at Buffalo; Chief of Allergy/Immunology and P Rheumatology, The Children's Hospital of Buffalo Immunologic Status of the Fetus and Newborn
NEIL BARG, M.D. Associate Professor of Medicine, University of Michigan; Assistant Chief of Infectious Disease, Dep of Veterans Affairs Medical Center, Ann Arbor Pseudomonas Infections; Campylobacter Infections; Noncholera Vibrio Infections JOHN G. BARTLETT, M.D. Professor of Medicine and Chief, Division of Infectious Diseases, Johns Hopkins University Pneumonia; Lung Abscess NIR BARZILAI, M.D. Associate Professor of Medicine, Albert Einstein College of Medicine Disorders of Carbohydrate Metabolism MARK H. BEERS, M.D. Editor, The Merck Manuals; Associate Clinical Professor of Medicine, Allegheny University of the Health Sciences Syndromes of Uncertain Origin
JAMES R. BERENSON, M.D. Chief of Medical Oncology, West Los Angeles VA Medical Center; Professor of Medicine, Universi California at Los Angeles Plasma Cell Dyscrasias ROBERT BERKOW, M.D. Editor, The Merck Manuals; Clinical Professor of Medicine and Psychiatry, Allegheny University of the Health Sciences Psychiatry in Medicine; Somatoform Disorders; Placebos
RICHARD W. BESDINE, M.D. Professor of Medicine, University of Connecticut Health Center School of Medicine; Director, UCon Center on Aging Geriatric Medicine DON C. BIENFANG, M.D. Assistant Professor of Ophthalmology, Harvard University Optic Nerve and Optic Pathway Disorders; Neuro-ophthalmologic and Cranial Nerve Disorders JOHN H. BLAND, M.D. Professor of Medicine-Rheumatology (Emeritus), University of Vermont College of Medicine
Assistant Professor of Ophthalmology, Harvard University Optic Nerve and Optic Pathway Disorders; Neuro-ophthalmologic and Cranial Nerve Disorders JOHN H. BLAND, M.D. Professor of Medicine-Rheumatology (Emeritus), University of Vermont College of Medicine Osteoarthritis and Neurogenic Arthropathy M. DONALD BLAUFOX, M.D., Ph.D. Professor of Nuclear Medicine and Medicine and Chairman of Nuclear Medicine, Albert Einstein College of Medicine and Montefiore Medical Center Radiation Reactions and Injuries RODNEY BLUESTONE, M.B., F.R.C.P. Clinical Professor of Medicine, University of California at Los Angeles Diffuse Connective Tissue Disease PHILIP K. BONDY, M.D. Professor of Medicine (Emeritus), Yale University Adrenal Disorders; Polyglandular Deficiency Syndromes LAURENCE A. BOXER, M.D. Professor of Pediatrics and Director, Pediatric Hematology, University of Michigan Leukopenia and Lymphocytopenia THOMAS G. BOYCE, M.D. Fellow in Pediatric Infectious Diseases, Vanderbilt University Gastroenteritis LEWIS E. BRAVERMAN, M.D. Visiting Professor of Medicine, Harvard Medical School; Senior Physician, Brigham and Women's Thyroid Disorders PETER C. BRAZY, M.D. Professor of Medicine, University of Wisconsin at Madison Abnormal Renal Transport Syndromes; Anomalies in Kidney Transport DICK D. BRIGGS, JR., M.D. Emeritus Professor and Eminent Scholar, Chair in Pulmonary Diseases, Department of Medicine, University of Alabama at Birmingham Special Procedures (Pulmonary)
GEORGE R. BROWN, M.D. Associate Chairman of Psychiatry, East Tennessee State University; Chief of Psychiatry, James H VA Medical Center Psychosexual Disorders MARILYN R. BROWN, M.D. Professor of Pediatrics, Gastroenterology and Nutrition, University of Rochester Obesity (Pediatric) MICHAEL F. BRYSON, M.D. Clinical Associate Professor of Pediatrics, University of Rochester Growth and Physical Development; Psychomotor and Intellectual Development
Professor of Pediatrics, Gastroenterology and Nutrition, University of Rochester Obesity (Pediatric) MICHAEL F. BRYSON, M.D. Clinical Associate Professor of Pediatrics, University of Rochester Growth and Physical Development; Psychomotor and Intellectual Development
ROGER J. BULGER, M.D. Clinical Professor of Medicine, Georgetown and George Washington Universities; President and C Executive Officer, Association of Academic Health Centers Rat-Bite Fever
JOHN F. BURKE, M.D. Helen Andrus Benedict Professor of Surgery (Emeritus), Harvard University; Chief of Trauma Serv (Emeritus), Massachusetts General Hospital Burns HILARY CAIN, M.D. Assistant Professor, Yale University School of Medicine; Director, Medical Intensive Care Unit, VA Connecticut Healthcare System, West Haven Campus Special Procedures (Pulmonary)
RONALD W. F. CAMPBELL, M.B., Ch.B., F.R.C.P., F.E.S.C. (Deceased) British Heart Foundation Professor of Cardiology, University of Newcastle upon Tyne; Honorary Co Cardiologist, Freeman Hospital Arrhythmias DAVID PAUL CARBONE, M.D., Ph.D. Associate Professor of Medicine and Cell Biology, Vanderbilt University Tumor Immunology
GEORGE S. CEMBROWSKI, M.D., Ph.D. Associate Professor of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alber Canada Normal Laboratory Values
DANIEL J. COBAUGH, Pharm.D. Assistant Professor of Emergency Medicine, University of Rochester; Director, Finger Lakes Regio Poison and Drug Information Center Poisoning (Pediatric) ALAN S. COHEN, M.D. Distinguished Professor of Medicine, Boston University Amyloidosis ROBERT B. COHEN, D.M.D. Senior Tutor, Harvard School of Dental Medicine Oral Examination; Disorders of the Oral Region; Teeth and Periodontium; Dental Emergencies; Temporomandibular Disorders
SIDNEY COHEN, M.D. Richard Laylord Evans Professor of Medicine and Chairman, Department of Medicine, and Assista President, Temple University Esophageal Disorders
Temporomandibular Disorders
SIDNEY COHEN, M.D. Richard Laylord Evans Professor of Medicine and Chairman, Department of Medicine, and Assista President, Temple University Esophageal Disorders NANANDA F. COL, M.D. Assistant Professor of Medicine, Tufts University School of Medicine and New England Medical Center Clinical Decision Making JULES CONSTANT, M.D. Clinical Associate Professor of Medicine, State University of New York at Buffalo Valvular Heart Disease
EUGENE L. COODLEY, M.D., M.A.C.P. Professor of Medicine, University of California at Irvine; Chief of Internal Medicine, VA Medical Cen Long Beach Normal Laboratory Values MARY ANN COOPER, M.D. Associate Professor of Emergency Medicine, University of Illinois at Chicago Electric Injury
LARRY J. COPELAND, M.D. Professor and Chairman of Obstetrics and Gynecology, Ohio State University; Chief of Staff, Jame Cancer Hospital Gynecologic Neoplasms JOHN K. CRANE, M.D., Ph.D. Assistant Professor of Medicine, State University of New York at Buffalo Enterobacteriaceae Infections; Haemophilus Infections; Brucellosis; Tularemia RICARDO CRUCIANI, M.D., Ph.D. Senior Clinical Associate in Neurology and Psychiatry, The New York Hospital-Cornell Medical Center Neurotransmission EMMETT T. CUNNINGHAM, JR., M.D., Ph.D., M.P.H. Assistant Professor and Codirector, Uveitis Service, and Director, Ocular Immunology Laboratory, Francis I. Proctor Foundation, University of California at San Francisco Uveitis BARRY CUSACK, M.D. Chief of Gerontology and Geriatric Medicine, VA Medical Center, Boise Drug Therapy in the Elderly DREW C. CUTLER, M.D. Assistant Professor of Pediatrics, Loma Linda University Inherited and Congenital Renal Disorders
RALPH E. CUTLER, M.D. Professor of Medicine and Pharmacology, Loma Linda University; Chief of Nephrology, Pettis Mem
DREW C. CUTLER, M.D. Assistant Professor of Pediatrics, Loma Linda University Inherited and Congenital Renal Disorders
RALPH E. CUTLER, M.D. Professor of Medicine and Pharmacology, Loma Linda University; Chief of Nephrology, Pettis Mem Medical Center Clinical Evaluation of Genitourinary Disorders; Obstructive Uropathy; Renal Failure; Glomerular Dis Tubulointerstitial Disease; Urinary Tract Infections; Renovascular Disease JOHANNA P. DAILY, M.D. Instructor, Harvard University; Associate Physician, Brigham and Women's Hospital Antiviral Drugs DAVID C. DALE, M.D. Professor of Medicine, University of Washington Infections in the Compromised Host PATRICIA A. DALY, M.D. Instructor in Medicine, Harvard University Multiple Endocrine Neoplasia Syndromes
ANNE L. DAVIS, M.D. Associate Professor of Clinical Medicine, New York University; Attending Physician, Bellevue Hosp Bronchiectasis; Atelectasis NORMAN L. DEAN, M.D. Geriatrician-Pulmonologist, Health Services Division, North Carolina Department of Corrections Near Drowning
RONALD DEE, M.D. Associate Clinical Professor of Surgery, Albert Einstein College of Medicine; Associate Attending S St. Joseph's Medical Center, Stamford Varicose Veins
DEEPINDER KAUR DHALIWAL, M.D. Chief of Refractive Surgery and Assistant Professor of Ophthalmology, Eye and Ear Institute, Univ Pittsburgh Refractive Error RICHARD D. DIAMOND, M.D. Professor of Medicine and Research Professor of Biochemistry, Boston University Nocardiosis; Actinomycosis; Systemic Fungal Diseases
PRESTON V. DILTS, JR., M.D. Professor of Obstetrics and Gynecology (Emeritus), University of Missouri at Kansas City Conception and Prenatal Development; Normal Pregnancy, Labor, and Delivery; High-Risk Pregna Pregnancy Complicated by Disease; Abnormalities of Pregnancy; Abnormalities and Complications Labor and Delivery; Postpartum Care
EUGENE P. DiMAGNO, M.D. Professor of Medicine, Mayo Medical School; Consultant in Gastroenterology and Internal Medicin
Conception and Prenatal Development; Normal Pregnancy, Labor, and Delivery; High-Risk Pregna Pregnancy Complicated by Disease; Abnormalities of Pregnancy; Abnormalities and Complications Labor and Delivery; Postpartum Care
EUGENE P. DiMAGNO, M.D. Professor of Medicine, Mayo Medical School; Consultant in Gastroenterology and Internal Medicin Director of Gastroenterology Research Unit, Mayo Clinic Pancreatic Tumors
GEORGE E. DOWNS, Pharm.D. Professor of Clinical Pharmacy and Dean, Philadelphia College of Pharmacy, University of the Scie Philadelphia Trade Names of Some Commonly Used Drugs
DOUGLAS A. DROSSMAN, M.D. Professor of Medicine and Psychiatry, University of North Carolina at Chapel Hill Diagnostic and Therapeutic Gastrointestinal Procedures; Functional Upper Gastrointestinal Compl CATHERINE DuBEAU, M.D. Assistant Professor of Medicine, Harvard University Urinary Incontinence CAROLYN P. DUKARM, M.D. Senior Instructor in Pediatrics, University of Rochester Physical Conditions in Adolescence FELTON J. EARLS, M.D. Professor of Child Psychiatry, Harvard University Childhood Psychoses; Childhood Depression DAVID EIDELBERG, M.D. Director, Movement Disorders Center, North Shore University Hospital Disorders of Movement SHERMAN ELIAS, M.D. Professor and Head, Department of Obstetrics and Gynecology, University of Illinois at Chicago Prenatal Genetic Evaluation and Counseling ELLIOT F. ELLIS, M.D. Professor of Pediatrics (Emeritus), State University of New York at Buffalo Asthma
E. DALE EVERETT, M.D. Professor of Medicine and Director, Infectious Diseases Division, University of Missouri Health Scie Center Bacterial Infections of the Skin; Abscesses L. JACK FALING, M.D. Clinical Professor of Medicine, Boston University; Associate Chief of Medicine, Boston VA Medical Center Adult Respiratory Distress Syndrome ELIZABETH M. FAULCONER, M.D. Director, Adult Inpatient Unit, Chestnut Lodge Hospital
L. JACK FALING, M.D. Clinical Professor of Medicine, Boston University; Associate Chief of Medicine, Boston VA Medical Center Adult Respiratory Distress Syndrome ELIZABETH M. FAULCONER, M.D. Director, Adult Inpatient Unit, Chestnut Lodge Hospital Psychiatric Emergencies
HARVEY FEIGENBAUM, M.D. Distinguished Professor of Medicine and Director of Echocardiography Laboratories, Krannert Insti Cardiology, Indiana University Echocardiography ANDREW FEIGIN, M.D. Assistant Professor of Neurology, New York University; Attending Neurologist, North Shore University Hospital Disorders of Movement DONALD I. FEINSTEIN, M.D., M.A.C.P. Professor of Medicine, University of Southern California Hemostasis and Coagulation Disorders ROBERT FEKETY, M.D. Professor (Emeritus) of Internal Medicine, University of Michigan Bacterial Diseases (Caused by Gram-Positive Cocci) WAYNE S. FENTON, M.D. Director of Research, Chestnut Lodge Hospital Schizophrenia and Related Disorders; Psychiatric Emergencies STEPHEN FINN, M.D. Fellow, Department of Gastroenterology, University of Virginia-Health Sciences Center Gastritis and Peptic Ulcer Disease
MICHAEL R. FOLEY, M.D. Clinical Associate Professor, University of Arizona; Director, Obstetric Intensive Care and Associat Director, Maternal-Fetal Medicine, Good Samaritan Regional Medical Center Drugs in Pregnancy CHIN-TO FONG, M.D. Assistant Professor of Pediatrics, Genetics, and Oncology, University of Rochester Genetic Abnormalities of Carbohydrate Metabolism; Anomalies in Amino Acid Metabolism
JEFFERY M. FOWLER, M.D. Division Director of Gynecologic Oncology and Associate Professor of Obstetrics and Gynecology, James Cancer Hospital and Research Institute, Ohio State University Gynecologic Neoplasms NOBLE O. FOWLER, M.D. Professor of Medicine (Emeritus), University of Cincinnati Pericardial Disease HOWARD R. FOYE, JR., M.D.
NOBLE O. FOWLER, M.D. Professor of Medicine (Emeritus), University of Cincinnati Pericardial Disease
HOWARD R. FOYE, JR., M.D. Clinical Associate Professor of Pediatrics, University of Rochester; Associate Attending Pediatricia Strong Memorial Hospital Behavioral Problems STEVEN D. FREEDMAN, M.D. Assistant Professor of Medicine, Harvard University Pancreatitis
EUGENE P. FRENKEL, M.D. Professor of Internal Medicine and Radiology, Patsy R. and Raymond D. Nasher Distinguished Ch Cancer Research, and A. Kenneth Pye Professorship in Cancer Research, Division of Hematology-Oncology, Department of Medicine, The University of Texas Southwestern Medical Ce Dallas Anemias; Iron Overload; Principles of Cancer Therapy
LOREN FRIEDMAN, M.D. Assistant Professor of Health Care Sciences, The George Washington University; Associate Medic Director, Hospice of Northern Virginia Care of the Dying Patient STEVEN M. FRUCHTMAN, M.D. Director, Stem Cell Transplant Program, Mount Sinai Hospital, New York Myeloproliferative Disorders ROBERT H. GELBER, M.D. Clinical Professor of Medicine and Dermatology, University of California at San Francisco Leprosy MICHAEL C. GELFAND, M.D. Clinical Associate Professor of Medicine, Georgetown University Immunologically Mediated Renal Disease JAMES N. GEORGE, M.D. Professor of Medicine and Chief of Hematology-Oncology Section, University of Oklahoma Platelet Disorders; Vascular Bleeding Disorders RAY W. GIFFORD, JR., M.D. Professor of Internal Medicine, Ohio State University; Consultant, Cleveland Clinic Foundation Arterial Hypertension ROBERT GINSBURG, M.D. Professor of Medicine, University of Colorado Peripheral Vascular Disorders; Arteriovenous Fistula
LINDA GIUDICE, M.D., Ph.D. Professor of Gynecology and Obstetrics and Chief of Reproductive Endocrinology and Infertility, S
ROBERT GINSBURG, M.D. Professor of Medicine, University of Colorado Peripheral Vascular Disorders; Arteriovenous Fistula
LINDA GIUDICE, M.D., Ph.D. Professor of Gynecology and Obstetrics and Chief of Reproductive Endocrinology and Infertility, S University; Director, Center for Research on Women's Health and Reproductive Medicine Reproductive Endocrinology; Menstrual Abnormalities and Abnormal Uterine Bleeding; Endometrio Infertility
BARRY STEVEN GOLD, M.D. Assistant Professor of Medicine, Johns Hopkins University; Assistant Professor of Medicine, Unive Maryland Bites and Stings STEPHEN E. GOLDFINGER, M.D. Associate Professor of Medicine and Faculty Dean for Continuing Education, Harvard University Familial Mediterranean Fever
M. JAY GOODKIND, M.D. Clinical Associate Professor of Medicine, The University of Pennsylvania; Chief (Retired), Departm Cardiology, Mercer Medical Center Cardiac Tumors FRANK ANTHONY GRECO, M.D. Medical Director, The Sarah Cannon-Minnie Pearl Cancer Center, Nashville Overview of Cancer
JOHN H. GREIST, M.D. Clinical Professor of Psychiatry, University of Wisconsin; Distinguished Senior Scientist, Dean Fou for Health, Research and Education Anxiety Disorders RICHARD L. GUERRANT, M.D. Thomas H. Hunter Professor of International Medicine, University of Virginia Enterobacteriaceae Infections; Haemophilus Infections; Brucellosis; Tularemia
JOHN G. GUNDERSON, M.D. Professor of Psychiatry, Harvard University; Director, Outpatient Personality Disorder Services, Mc Hospital Personality Disorders
JUDITH G. HALL, M.D. Professor and Head of Pediatrics, University of British Columbia; Head of Pediatrics, British Colum Children's Hospital Chromosomal Abnormalities; General Principles of Medical Genetics JOHN W. HALLETT, JR., M.D. Professor of Surgery, Mayo Clinic and Mayo Medical School Diseases of the Aorta and Its Branches; Peripheral Vascular Disorders
ROBERT W. HAMILTON, M.D. Professor of Medicine, Medical College of Ohio; Medical Director of Hemodialysis Unit, Medical Co
JOHN W. HALLETT, JR., M.D. Professor of Surgery, Mayo Clinic and Mayo Medical School Diseases of the Aorta and Its Branches; Peripheral Vascular Disorders
ROBERT W. HAMILTON, M.D. Professor of Medicine, Medical College of Ohio; Medical Director of Hemodialysis Unit, Medical Co Hospitals Dialysis
PAUL G. ST. J. HAMMOND, M.B., D.Phil., F.R.C.P.(C) Associate Professor of Medicine, Loma Linda University; Chief, Nephrology Section, Pettis Memor Medical Center Glomerular Diseases LAURENCE A. HARKER, M.D. Blomeyer Professor of Medicine and Director of Hematology and Oncology, Emory University Thrombotic Disorders
JOAN K. HARROLD, M.D. Adjunct Assistant Professor, The Center to Improve Care of the Dying, The George Washington U Medical Director, Hospice of Lancaster County Care of the Dying Patient DANIEL H. HECHTMAN, M.D. Assistant Professor of Surgery, University of Pittsburgh; Attending Surgeon, Children's Hospital of Pittsburgh Diagnostic Cardiovascular Procedures (Invasive Procedures) I. CRAIG HENDERSON, M.D. Adjunct Professor of Medicine, University of California at San Francisco Breast Disorders
SUSAN HENDRIX, D.O. Assistant Professor of Obstetrics and Gynecology and Director, Women's Health Initiative, Wayne University/Hutzel Hospital Menopause; Pelvic Pain; Gynecologic Inflammation and Infections; Uterine Fibroids; Medical Exam of the Rape Victim BASIL I. HIRSCHOWITZ, M.D. Professor of Medicine and Physiology, University of Alabama in Birmingham Peptic Ulcer Disease; Gastroesophageal Reflux Disease (Pediatric) CHRISTOPHER H. HODGMAN, M.D. Professor of Psychiatry and Pediatrics, University of Rochester Adolescent Psychiatric Conditions; Suicide in Children and Adolescents ROBERT A. HOEKELMAN, M.D. Professor and Chairman of Pediatrics (Emeritus), University of Rochester Introduction (Pediatrics); Pinworm Infection PAUL D. HOEPRICH, M.D. Professor of Medicine (Emeritus), University of California at Davis Erysipelothricosis; Listeriosis
Professor and Chairman of Pediatrics (Emeritus), University of Rochester Introduction (Pediatrics); Pinworm Infection PAUL D. HOEPRICH, M.D. Professor of Medicine (Emeritus), University of California at Davis Erysipelothricosis; Listeriosis WAUN KI HONG, M.D. American Cancer Society Clinical Research Professor; Professor and Chairman of Thoracic/Head Neck Oncology, The University of Texas, M. D. Anderson Cancer Center Tumors of the Lung CHARLES S. HOUSTON, M.D. Professor of Medicine (Emeritus), University of Vermont Heat Disorders; Cold Injury; Altitude Sickness WILLIAM C. HULBERT, M.D. Associate Professor of Urology and Pediatrics, University of Rochester Renal and Genitourinary Defects
DANIEL A. HUSSAR, Ph.D. Remington Professor of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences i Philadelphia Drug Interactions HAROLD L. ISRAEL, M.D. (Deceased) Professor of Medicine (Emeritus), Thomas Jefferson University Sarcoidosis
MASAYOSHI ITOH, M.D. Associate Professor of Clinical Rehabilitation Medicine, New York University; Consultant, Goldwate Memorial Hospital Rehabilitation
MICHAEL JACEWICZ, M.D. Associate Professor of Neurology, University of Tennessee Neurologic Approach to the Patient; CNS Infections; Neuro-ophthalmologic and Cranial Nerve Diso
GEORGE GEE JACKSON, M.D. Professor of Medicine (Emeritus), University of Illinois at Chicago; Clinical Professor of Medicine, U of Utah Respiratory Viral Diseases
HARRY S. JACOB, M.D., F.A.A.A.S. Clark Professor of Medicine, University of Minnesota; President of American Society of Hematolog (1998-1999) Disorders of the Spleen
JAMES W. JEFFERSON, M.D. Clinical Professor of Psychiatry, University of Wisconsin; Distinguished Senior Scientist, Dean Fou for Health, Research and Education Anxiety Disorders NICHOLAS JOSPE, M.D.
JAMES W. JEFFERSON, M.D. Clinical Professor of Psychiatry, University of Wisconsin; Distinguished Senior Scientist, Dean Fou for Health, Research and Education Anxiety Disorders NICHOLAS JOSPE, M.D. Associate Professor of Pediatrics, University of Rochester Endocrine and Metabolic Disorders (Pediatric)
BURK JUBELT, M.D. Chairman and Professor of Neurology and Professor of Microbiology/Immunology and Neuroscien University of New York Health Science Center at Syracuse Slow Virus Infections
FRAN E. KAISER, M.D. Adjunct Professor of Medicine, St. Louis University; Senior Regional Medical Director, Merck & Co Erectile Dysfunction HAROLD S. KAPLAN, M.D. Professor and Director of Clinical Pathology and Director, Transfusion Medicine, The University of Texas Southwestern Medical Center at Dallas Transfusion Medicine KARL D. KAPPUS, Ph.D. Epidemiologist, Center for Infectious Diseases, Centers for Disease Control and Prevention Rabies EDWARD A. KAUFMAN, M.D. Vice President and National Medical Director, SmithKline Beecham Clinical Laboratories Normal Laboratory Values
DONALD KAYE, M.D. President and CEO and Professor of Medicine, Allegheny University of the Health Sciences; President and CEO, Allegheny University Hospitals, E Antibacterial Drugs KENNETH M. KAYE, M.D. Assistant Professor of Medicine, Harvard University Viral Diseases (Introduction; Herpesvirus Infections) MICHAEL J. KEATING, M.B. Professor of Medicine, The University of Texas, M. D. Anderson Cancer Center Leukemias GREGORY F. KEENAN, M.D. Assistant Professor of Pediatrics and Medicine, The University of Pennsylvania Musculoskeletal and Connective Tissue Disorders (Pediatric); Sydenham's Chorea FADLO R. KHURI, M.D. Assistant Professor of Medicine, The University of Texas, M. D. Anderson Cancer Center Tumors of the Lung
FADLO R. KHURI, M.D. Assistant Professor of Medicine, The University of Texas, M. D. Anderson Cancer Center Tumors of the Lung
THOMAS KILLIP, M.D. Professor of Medicine, Albert Einstein College of Medicine; Director, Heart Institute, Beth Israel Me Center Coronary Artery Disease; Heart Failure
ERIC P. KINDWALL, M.D. Associate Professor (Emeritus), Department of Plastic and Reconstructive Surgery and Departmen Pharmacology and Toxicology, Medical College of Wisconsin Hyperbaric Oxygen Therapy TALMADGE E. KING, JR., M.D. Director, Interstitial Lung Disease, National Jewish Medical and Research Center Idiopathic Interstitial Diseases of the Lungs; Pulmonary Alveolar Proteinosis HAROLD KLEINERT, M.D. Clinical Professor of Surgery, University of Louisville Common Hand Disorders RICHARD P. KLUFT, M.D. Clinical Professor of Psychiatry, Temple University Dissociative Disorders
ARTHUR E. KOPELMAN, M.D. Professor of Pediatrics, East Carolina University School of Medicine Perinatal Physiology; Caring for Sick Children and Their Families; Disturbances in Newborns and I Gastrointestinal Defects DAVID N. KORONES, M.D. Assistant Professor of Pediatrics, University of Rochester Neoplasms (Pediatric) JOHN N. KRIEGER, M.D. Professor of Urology, University of Washington Disorders of the Penis and Scrotum DOUGLAS R. LABAR, M.D., Ph.D. Director, Comprehensive Epilepsy Center, The New York Hospital-Cornell Medical Center Seizure Disorders JULES Y.T. LAM, M.D., F.R.C.P.(C) Associate Professor of Medicine, University of Montreal; Cardiologist, Montreal Heart Institute Arteriosclerosis
LEWIS LANDSBERG, M.D. Irving S. Cutter Professor and Chairman, Department of Medicine, Northwestern University Medica Multiple Endocrine Neoplasia Syndromes
Cardiologist, Montreal Heart Institute Arteriosclerosis
LEWIS LANDSBERG, M.D. Irving S. Cutter Professor and Chairman, Department of Medicine, Northwestern University Medica Multiple Endocrine Neoplasia Syndromes EDWARD H. LANPHIER, M.D. Senior Scientist (Emeritus), Department of Preventive Medicine, University of Wisconsin at Madison Injury During Diving or Work in Compressed Air
RUTH A. LAWRENCE, M.D. Professor of Pediatrics and of Obstetrics and Gynecology, University of Rochester; Adjunct Profes Public Health, University at Albany Initial Care; Infant Nutrition; Drugs in Lactating Mothers; Poisoning (Pediatric) MATHEW H. M. LEE, M.D. The Howard A. Rusk Professor of Rehabilitation Medicine, New York University; Medical Director, Institute Rehabilitation
HARVEY LEMONT, D.P.M. Professor and Chairman, Department of Medicine, Pennsylvania College of Podiatric Medicine; Director, Laboratory of Podiatric Pathology, Philadelph Common Foot and Ankle Disorders
JOSEPH R. LENTINO, M.D., Ph.D. Professor of Medicine, Loyola University of Chicago; Chief, Section of Infectious Diseases, Hines V Hospital Anthrax; Clostridial Infections BARRY LEVINSON, M.D. Assistant Professor of Medicine, The University of Texas Southwestern Medical Center at Dallas AIDS-Associated Hematologic Disorders and Malignancies DANIEL LEVINSON, M.D. Associate Professor of Family and Community Medicine, University of Arizona; Staff Psychiatrist, LaFrontera Mental Health Center Medical Aspects of Air and Foreign Travel ROBERT I. LEVY, M.D. Senior Vice President for Science and Technology, American Home Products Hyperlipidemia; Hypolipidemia and the Lipidoses
JAMES L. LEWIS, III, M.D. Assistant Professor of Medicine and Director, Nephrology Fellowship Training Program, University Alabama at Birmingham Water, Electrolyte, Mineral, and Acid-Base Metabolism
LAWRENCE M. LICHTENSTEIN, M.D., Ph.D. Professor of Medicine, Johns Hopkins University; Director, Johns Hopkins Asthma and Allergy Cen Hypersensitivity Disorders
Alabama at Birmingham Water, Electrolyte, Mineral, and Acid-Base Metabolism
LAWRENCE M. LICHTENSTEIN, M.D., Ph.D. Professor of Medicine, Johns Hopkins University; Director, Johns Hopkins Asthma and Allergy Cen Hypersensitivity Disorders
HAROLD I. LIEF, M.D. Professor of Psychiatry (Emeritus), The University of Pennsylvania; Honorary Staff, Pennsylvania H Psychosexual Disorders (Sexual Dysfunctions); Sexual Dysfunction in Women GREGORY S. LIPTAK, M.D. Associate Professor of Pediatrics, University of Rochester The Chronically Disabled Child JEFFREY M. LIPTON, M.D., Ph.D. Chief of Pediatrics, Hematology/Oncology, The Mount Sinai School of Medicine Histiocytic Syndromes ELLIOT M. LIVSTONE, M.D. Attending Physician, Sarasota Memorial Hospital Tumors of the Gastrointestinal Tract MORTIMER LORBER, D.M.D., M.D. Associate Professor of Physiology and Biophysics, Georgetown University Dentistry in Medicine ROBERT G. LOUDON, M.B., Ch.B. Professor of Medicine (Emeritus), University of Cincinnati Approach to the Pulmonary Patient
FRANK E. LUCENTE, M.D. Professor and Chairman, Department of Otolaryngology, State University of New York Health Scie Center at Brooklyn Ear, Nose, and Throat Disorders; Motion Sickness
JOANNE LYNN, M.D. Professor of Health Care Sciences and Medicine, The George Washington University; Director, Th to Improve Care of the Dying Care of the Dying Patient
MAREN L. MAHAWALD, M.D. Professor of Medicine, University of Minnesota; Chief of Rheumatology Section, Minneapolis VA M Center Infections of Bones and Joints LOIS A. MAIMAN, Ph.D. Senior Investigator, Prevention Research Branch, National Institute of Child and Human Development Compliance (Pediatric) STEPHEN E. MALAWISTA, M.D. Professor of Medicine, Department of Internal Medicine, Yale University Lyme Disease
National Institute of Child and Human Development Compliance (Pediatric) STEPHEN E. MALAWISTA, M.D. Professor of Medicine, Department of Internal Medicine, Yale University Lyme Disease JOHN J. MARINI, M.D. Professor of Medicine, University of Minnesota; Academic Chief of Medicine and Director of Pulmonary/Critical Care, Regions Hospital Respiratory Failure ALFONSE T. MASI, M.D., Dr.P.H. Professor of Medicine and Epidemiology, University of Illinois Nonarticular Rheumatism
RICHARD G. MASSON, M.D. Associate Professor of Medicine, University of Massachusetts; Chief of Pulmonary Medicine and C Care, Framingham Campus, Metrowest Medical Center Pulmonary Function Testing
MICHAEL A. MATTHAY, M.D. Professor of Medicine and Anesthesia and Senior Associate of Cardiovascular Research Institute, University of California at San Francisco Shock RICHARD A. MATTHAY, M.D. Professor and Associate Director, Pulmonary and Critical Care Section, Yale University Special Procedures (Pulmonary) ELIZABETH R. McANARNEY, M.D Professor and Chair of Pediatrics, University of Rochester Physical Conditions in Adolescence DANIEL J. McCARTY, M.D. Will and Cava Ross Professor of Medicine (Emeritus-active), Medical College of Wisconsin Crystal-Induced Conditions F. LELAND McCLURE, Ph.D., D.A.B.F.T. Technical Manager of Operations Steering Team, SmithKline Beecham Clinical Laboratories Normal Laboratory Values J. ALLEN McCUTCHAN, M.D. Professor of Medicine, Division of Infectious Disease, University of California at San Diego Human Immunodeficiency Virus Infection; Sexually Transmitted Diseases
GERALYN M. MENY, M.D. Assistant Professor and Associate Director of Transfusion Medicine, The University of Texas South Medical Center at Dallas Transfusion Medicine
GERALYN M. MENY, M.D. Assistant Professor and Associate Director of Transfusion Medicine, The University of Texas South Medical Center at Dallas Transfusion Medicine
CAROLE M. MEYERS, M.D. Clinical Assistant Professor of Obstetrics and Gynecology, University of Maryland; Director, Geneti Center, Mercy Medical Center, Baltimore Prenatal Genetic Evaluation and Counseling GABE MIRKIN, M.D. Associate Clinical Professor of Pediatrics, Georgetown University Common Sports Injuries
DANIEL R. MISHELL, JR., M.D. Lyle G. McNeile Professor and Chairman, Department of Obstetrics and Gynecology, University of Southern California Family Planning JOHN P. MORGAN, M.D. Professor of Pharmacology, City University of New York; Adjunct Professor of Pharmacology, The Sinai School of Medicine Drug Use and Dependence
W.K.C. MORGAN, M.D. Professor of Medicine, The University of Western Ontario; Chest Diseases Service, London Health Sciences Centre, University Campus, London, Ontario, Canada Occupational Lung Diseases JOS L. MUOZ, M.D. Associate Professor of Pediatrics and Chief of Pediatric Infectious Diseases, New York Medical College; Attending Physician, Westchester Medical Center Urinary Tract Infection (Pediatric) GARY J. MYERS, M.D. Professor of Pediatrics and Neurology, University of Rochester Birth Trauma; Neonatal Seizure Disorders; Congenital Anomalies (Introduction; Musculoskeletal Abnormalities) DOUGLAS B. NELSON, M.D. Assistant Professor of Medicine, University of Minnesota VA Medical Center Extrahepatic Biliary Disorders DAVID H. NEUSTADT, M.D., M.A.C.R. Clinical Professor of Medicine, University of Louisville Common Hand Disorders JOHN D. NORANTE, M.D. Associate Professor of Otolaryngologic Surgery, University of Rochester Adenoid Hypertrophy; Nose and Throat Disorders (Pediatric) ROBERT A. NOZIK, M.D. Clinical Professor, University of California at San Francisco and Proctor Foundation
JOHN D. NORANTE, M.D. Associate Professor of Otolaryngologic Surgery, University of Rochester Adenoid Hypertrophy; Nose and Throat Disorders (Pediatric) ROBERT A. NOZIK, M.D. Clinical Professor, University of California at San Francisco and Proctor Foundation Uveitis
KEVIN OLDEN, M.D. Assistant Professor of Medicine and Psychiatry, Mayo Medical School; Division of Gastroenterolog Clinic, Scottsdale Functional Bowel Disorders
ROBERT E. OLSON, M.D., Ph.D. Professor of Pediatrics, University of South Florida Nutrition: General Considerations; Malnutrition; Vitamin Deficiency, Dependency, and Toxicity; Min Deficiency and Toxicity
RAYMOND F. ORZECHOWSKI, Ph.D. Professor of Pharmacology and Toxicology, Philadelphia College of Pharmacy, University of the S in Philadelphia Pharmacodynamics
STEPHEN E. OSHRIN, Ph.D. Professor and Chairman, Department of Speech and Hearing Sciences, University of Southern Mis Measurement of Hearing in Children
BOSCO PAES, M.D. Professor, Department of Pediatrics, Neonatal Division, McMaster University; Director of Neonatolo Joseph's Hospital, Hamilton, Ontario, Canada Cardiopulmonary Resuscitation (Pediatric) HERBERT PATRICK, M.D. Clinical Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University Sarcoidosis
STEPHEN G. PAUKER, M.D. Sara Murray Jordan Professor of Medicine and Associate Physician-in-Chief, Department of Medic New England Medical Center Clinical Decision Making LAWRENCE L. PELLETIER, JR., M.D. Professor of Internal Medicine, University of Kansas School of Medicine at Wichita Endocarditis PETER L. PERINE, M.D. Professor of Epidemiology and Medicine, University of Washington Endemic Treponematoses; Relapsing Fever; Leptospirosis HART PETERSON, M.D. Professor of Neurology in Pediatrics (Emeritus), Cornell University Cerebral Palsy Syndromes
Endemic Treponematoses; Relapsing Fever; Leptospirosis HART PETERSON, M.D. Professor of Neurology in Pediatrics (Emeritus), Cornell University Cerebral Palsy Syndromes DAVID J. PETRON, M.D. Assistant Professor of Family Medicine and Orthopedics and Team Physician, University of Utah Anabolic Steroid Use
THOMAS L. PETTY, M.D. Professor of Medicine, University of Colorado Health Sciences Center; Professor of Medicine, Rus University Smoking Cessation DALE L. PHELPS, M.D. Professor of Pediatrics and Ophthalmology, Children's Hospital at Strong and University of Rochester Retinopathy of Prematurity SIDNEY F. PHILLIPS, M.D. Professor of Medicine, Mayo Medical School; Consultant, Mayo Clinic Diarrhea and Constipation
MICHAEL E. PICHICHERO, M.D. Professor of Microbiology and Immunology and Professor of Pediatrics and Medicine, University of Rochester Childhood Immunizations NATHANIEL F. PIERCE, M.D. Professor of Medicine and International Health, Johns Hopkins University Cholera WILLY F. PIESSENS, M.D. Professor of Tropical Public Health and Associate Professor of Medicine, Harvard University Parasitic Infections
FRED PLUM, M.D. University Professor and Chairman of Neurology (Emeritus), Cornell University; Attending Neurolog New York Hospital-Cornell Medical Center Neurotransmission; Function and Dysfunction of the Cerebral Lobes; Stupor and Coma; Delirium a Dementia; Trauma of the Head; Spinal Cord Injury RUSSELL K. PORTENOY, M.D. Chairman, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center Pain
CAROL S. PORTLOCK, M.D. Associate Professor, Cornell University; Attending Physician, Memorial Sloan-Kettering Cancer Ce Lymphomas
JOEL D. POSNER, M.D. Professor of Medicine and Chief, Division of Geriatric and Rehabilitation Medicine, Allegheny Unive
CAROL S. PORTLOCK, M.D. Associate Professor, Cornell University; Attending Physician, Memorial Sloan-Kettering Cancer Ce Lymphomas
JOEL D. POSNER, M.D. Professor of Medicine and Chief, Division of Geriatric and Rehabilitation Medicine, Allegheny Unive the Health Sciences Prevention of Coronary Artery Disease
GLENN M. PREMINGER, M.D. Professor of Urologic Surgery and Director, Comprehensive Kidney Stone Center, Duke University Urinary Calculi DOUGLAS J. PRITCHARD, M.D. Professor of Orthopedics and Oncology, Mayo Clinic Tumors of Bones and Joints
WILLIAM PULSINELLI, M.D., Ph.D. Semmes-Murphey Professor and Chairman, Department of Neurology, University of Tennessee H Sciences Center at Memphis Cerebrovascular Disease RONALD RABINOWITZ, M.D. Professor of Urology and Pediatrics and Chief of Pediatric Urology, University of Rochester Renal and Genitourinary Defects
STEVEN B. RAFFIN, M.D. Clinical Associate Professor of Medicine, University of California at San Francisco; Senior Medical Health Net Bezoars and Foreign Bodies
MOBEEN H. RATHORE, M.D. Associate Professor and Chief, Infectious Diseases/Immunology, Department of Pediatrics and As Chairman for Research and Academic Affairs, University of Florida Health Science Center/Jackson Diphtheria; Pertussis; Occult Bacteremia; Acute Infectious Gastroenteritis; Periorbital and Orbital C Acute Epiglottitis; Bacterial Tracheitis ROBERT W. REBAR, M.D. Professor and Director, Department of Obstetrics and Gynecology, University of Cincinnati Hypothalamic-Pituitary Relationships; Pituitary Disorders JEFFREY B. REICH, M.D. Assistant Professor of Neurology, Cornell University Headache
NEIL M. RESNICK, M.D. Associate Professor of Medicine, Harvard University; Chief of Gerontology and Director, Continenc Center, Brigham and Women's Hospital Urinary Incontinence HAL B. RICHERSON, M.D. Professor of Internal Medicine (Emeritus), University of Iowa
Associate Professor of Medicine, Harvard University; Chief of Gerontology and Director, Continenc Center, Brigham and Women's Hospital Urinary Incontinence HAL B. RICHERSON, M.D. Professor of Internal Medicine (Emeritus), University of Iowa Hypersensitivity Diseases of the Lungs
MELVIN I. ROAT, M.D. Clinical Associate Professor of Ophthalmology, University of Maryland Approach to the Patient With Eye Disease; Eye Injuries; Disorders of the Orbit; Disorders of the La Apparatus; Eyelid Disorders; Conjunctival Disorders; Corneal Disorders; Cataract; Congenital Eye Strabismus
KENNETH B. ROBERTS, M.D. Professor of Pediatrics, University of North Carolina; Director, Pediatric Teaching Program, Moses Health System Fluid and Electrolyte Disorders in Infants and Children WILLIAM O. ROBERTSON, M.D. Professor of Pediatrics, University of Washington; Medical Director, Washington Poison Center Poisoning
ROBERT M. ROGERS, M.D. Professor of Medicine and Anesthesiology, Division of Pulmonary/Critical Care Medicine, Departm Medicine, University of Pittsburgh Cardiac and Respiratory Arrest and Cardiopulmonary Resuscitation STACIE L. ROPKA, M.S. Senior Research Specialist, State University of New York Health Science Center at Syracuse Slow Virus Infections
BERYL J. ROSENSTEIN, M.D. Professor of Pediatrics, Johns Hopkins University; Director of Cystic Fibrosis Center, Johns Hopkin Hospital Cystic Fibrosis ROBERT J. RUBEN, M.D. Chairman, Otolaryngology, Albert Einstein College of Medicine, Montefiore Medical Center Hearing Deficits in Children
FRED H. RUBIN, M.D. Clinical Professor of Medicine, University of Pittsburgh; Chairman, Department of Medicine, Shady Hospital Immunizations for Adults
MICHAEL RUBIN, M.D. Associate Professor of Clinical Neurology, Cornell University; Director of Neuromuscular Service, T York Hospital-Cornell Medical Center Spinal Cord Disorders; Disorders of the Peripheral Nervous System PAUL S. RUSSELL, M.D. John Homans Professor of Surgery, Harvard University; Visiting Surgeon, Massachusetts General
MICHAEL RUBIN, M.D. Associate Professor of Clinical Neurology, Cornell University; Director of Neuromuscular Service, T York Hospital-Cornell Medical Center Spinal Cord Disorders; Disorders of the Peripheral Nervous System PAUL S. RUSSELL, M.D. John Homans Professor of Surgery, Harvard University; Visiting Surgeon, Massachusetts General Transplantation
DAVID B. SACHAR, M.D. The Dr. Burrill B. Crohn Professor of Medicine and Director, Division of Gastroenterology, The Mou School of Medicine Antibiotic-Associated Colitis; Inflammatory Bowel Diseases OLLE JANE Z. SAHLER, M.D. Professor of Pediatrics, Psychiatry, and Medical Humanities, University of Rochester Failure to Thrive; Recurrent Abdominal Pain
JAY P. SANFORD, M.D. (Deceased) Professor of Medicine, The University of Texas Southwestern Medical Center at Dallas Plague; Meliodosis; Cat-Scratch Disease; Chlamydial Diseases; Arbovirus and Arenavirus Disease
JAMES W. SAYRE, M.D. Clinical Professor of Pediatrics, University of Rochester and Children's Hospital at Strong Health Supervision of the Well Child; Common Feeding and Gastrointestinal Problems; Child Abus Neglect
KURT SCHAPIRA, M.D., F.R.C.P., F.R.C.Psych. Honorary Senior Research Associate, Department of Psychiatry, University of Newcastle upon Tyn England; Consultant Psychiatrist (Emeritus), Royal Victoria Infirmary Suicidal Behavior
I. HERBERT SCHEINBERG, M.D. Senior Lecturer in Medicine, College of Physicians and Surgeons, Columbia University; Senior Res Associate, St. Luke's-Roosevelt Institute for Health Sciences Mineral Deficiency and Toxicity (Copper)
ALBERT P. SCHEINER, M.D. Professor of Pediatrics (Emeritus), Division of Developmental and Behavioral Pediatrics, University Massachusetts Medical School Mental Retardation ROBERT T. SCHOOLEY, M.D. Head, Infectious Diseases Division, University of Colorado Health Sciences Center Infectious Mononucleosis GEORGE E. SCHREINER, M.D., F.R.C.P.S. Distinguished Professor of Medicine, Georgetown University Toxic Nephropathy
H. RALPH SCHUMACHER, JR., M.D. Professor of Medicine, The University of Pennsylvania; Director, Arthritis-Immunology Center, VA M Center Approach to the Patient With Joint Disease; Diffuse Connective Tissue Disease; Avascular Necros
Toxic Nephropathy
H. RALPH SCHUMACHER, JR., M.D. Professor of Medicine, The University of Pennsylvania; Director, Arthritis-Immunology Center, VA M Center Approach to the Patient With Joint Disease; Diffuse Connective Tissue Disease; Avascular Necros RONALD W. SCHWORM, Ph.D. Educational Diagnostician/Consultant, The Reading and Learning Disorders Center, Rochester Learning Disorders DAVID W. SELDIN, M.D. Section Head, Nuclear Medicine, Lahey Clinic, Burlington, Massachusetts Diagnostic Cardiovascular Procedures (Noninvasive Procedures)
ELDON A. SHAFFER, M.D., F.R.C.P.(C), F.A.C.P., F.A.C.G. Professor and Head, Department of Medicine, University of Calgary, Calgary, Alberta, Canada Screening and Diagnostic Evaluation of the Liver and Biliary System; Fatty Liver; Alcoholic Liver D Chronic Liver Disease; Vascular Lesions of the Liver WILLIAM R. SHAPIRO, M.D. Chairman, Division of Neurology, Barrow Neurological Institute/St. Joseph's Hospital, Phoenix CNS Neoplasms
JEROME B. SIMON, M.D., F.R.C.P.(C) Professor of Medicine, Queen's University, Kingston, Ontario, Canada Anatomy and Physiology; Clinical Features of Liver Disease; Hepatitis; Drugs and the Liver; Posto Liver Disorders; Hepatic Granulomas; Liver Tumors
LEE S. SIMON, M.D. Associate Professor of Medicine, Harvard University; Director of Graduate Medical Education, Beth Deaconess Medical Center Osteoporosis
GORDON L. SNIDER, M.D. Professor of Medicine and Vice Chairman, Department of Medicine, Boston University; Chief of Me Service, VA Medical Center, Boston Chronic Obstructive Pulmonary Disease; Acute Bronchitis; Pleural Disorders NORMAN SOHN, M.D. Clinical Assistant Professor of Surgery, Cornell University Anorectal Cancer; Anorectal Disorders P. FREDERICK SPARLING, M.D. Professor and Chairman, Department of Medicine, University of North Carolina, Chapel Hill Bacterial Diseases (Caused by Gram-Negative, Aerobic Cocci)
GABRIEL SPERGEL, M.D. Clinical Associate Professor of Medicine, Cornell University and Downstate Medical Center, State University of New York; Chief of Endocrino
University of North Carolina, Chapel Hill Bacterial Diseases (Caused by Gram-Negative, Aerobic Cocci)
GABRIEL SPERGEL, M.D. Clinical Associate Professor of Medicine, Cornell University and Downstate Medical Center, State University of New York; Chief of Endocrino New York Community Hospital of Brooklyn Pheochromocytoma
WILLIAM W. STEAD, M.D. Professor of Medicine, University of Arkansas College of Medicine; Director, Tuberculosis Program Arkansas Department of Health Tuberculosis SCOTT STEIDL, M.D., D.M.A. Assistant Professor, Department of Ophthalmology, University of Maryland Retinal Disorders
E. RICHARD STIEHM, M.D. Professor of Pediatrics and Chief, Division of Pediatric Immunology/Allergy/Rheumatology, Univers California at Los Angeles Immunodeficiency Diseases
MATTHEW J. STILLER, M.D. Associate Clinical Professor of Dermatology, College of Physicians and Surgeons, Columbia Unive Director, Clinical Pharmacology, Columbia Presbyterian Medical Center Dermatologic Disorders; Herpes Gestationis; Pruritic Urticarial Papules and Plaques of Pregnancy; Impetigo and Ecthyma
LARRY STRAUSBAUGH, M.D. Professor of Medicine, Oregon Health Sciences University; Staff Physician, Portland VA Medical C Antimicrobial Chemoprophylaxis JOERG-PATRICK STBGEN, M.D. Assistant Professor of Neurology and Neuroscience, The New York Hospital-Cornell Medical Center Craniocervical Junction Abnormalities; Muscular Disorders ALBERT J. STUNKARD, M.D. Professor of Psychiatry, The University of Pennsylvania Obesity; Eating Disorders
MICHAEL J. SULLIVAN, M.D., F.R.C.P.(C) Associate Clinical Professor of Medicine, McMaster University; Staff Cardiologist, St. Joseph's Hos Hamilton, Ontario, Canada Cardiopulmonary Resuscitation (Pediatric) DAVID A. SWANSON, M.D. Professor and Chairman, Department of Urology, The University of Texas, M. D. Anderson Cancer Center Genitourinary Cancer JAN PETER SZIDON, M.D. Professor of Medicine, Section of Pulmonary Medicine, Rush University
Professor and Chairman, Department of Urology, The University of Texas, M. D. Anderson Cancer Center Genitourinary Cancer JAN PETER SZIDON, M.D. Professor of Medicine, Section of Pulmonary Medicine, Rush University Goodpasture's Syndrome; Cor Pulmonale
PAUL H. TANSER, M.D., F.R.C.P.(C) Professor of Medicine, McMaster University; Senior Cardiologist, St. Joseph's Hospital, Hamilton, O Canada Approach to the Cardiac Patient; Cardiomyopathy
JOAN B. TARLOFF, Ph.D. Associate Professor of Pharmacology and Toxicology, Philadelphia College of Pharmacy, Universi Sciences in Philadelphia Drug Toxicity ANNETTE KATRIEN TEREBUH, M.D. Assistant Professor, Thomas Jefferson University; Attending Surgeon, Wills Eye Hospital Glaucoma JOSIP TEREBUH, M.D. Eye Physician and Surgeon, Mary Rutan Hospital, Bellefontaine, Ohio Glaucoma
RONALD G. TOMPKINS, M.D., Sc.D. John F. Burke Professor of Surgery, Harvard University; Visiting Surgeon, Massachusetts General Gastrointestinal Bleeding; Acute Abdomen and Surgical Gastroenterology; Diverticular Disease; M Diverticulum; Burns
COURTNEY M. TOWNSEND, JR., M.D. Professor and John Woods Harris Distinguished Chairman, Department of Surgery, The University Texas Medical Branch at Galveston Carcinoid Tumors THOMAS N. TOZER, Ph.D. Professor of Biopharmaceutical Sciences and Pharmaceutical Chemistry (Emeritus), University of California at San Francisco Drug Input and Disposition; Pharmacokinetics; Monitoring Drug Treatment ALLAN TUNKEL, M.D., Ph.D. Associate Professor of Medicine, Allegheny University of the Health Sciences Biology of Infectious Disease
ELISE W. VAN DER JAGT, M.D., M.P.H. Associate Professor of Pediatrics and Critical Care, Children's Hospital at Strong and University of Rochester Injuries (Pediatric) JACK A. VENNES, M.D. Professor of Medicine (Retired), University of Minnesota Extrahepatic Biliary Disorders
Injuries (Pediatric) JACK A. VENNES, M.D. Professor of Medicine (Retired), University of Minnesota Extrahepatic Biliary Disorders ELLIOT S. VESELL, M.D., Sc.D. Evan Pugh Professor and Chair, Department of Pharmacology, Pennsylvania State University Pharmacogenetics ROBERT E. VESTAL, M.D. Professor of Medicine and Adjunct Professor of Pharmacology, University of Washington; Director, Mountain States Medical Research Institute, Boise Drug Therapy in the Elderly LILLI A. VISNAPUU, M.D. Director of National Quality Assurance, SmithKline Beecham Clinical Laboratories Normal Laboratory Values JACOB WALFISH, M.D. Assistant Clinical Professor of Medicine, The Mount Sinai School of Medicine Antibiotic-Associated Colitis; Inflammatory Bowel Diseases WENDY WATSON, M.D. Clinical Associate Professor of Pediatrics, University of Rochester Neonatal Infections; Viral Infections (Pediatric) WILLIAM C. WATSON, M.D., Ph.D., F.R.C.P. Professor (Emeritus), University of Western Ontario, London, Ontario, Canada Malabsorption Syndromes
MAX HARRY WEIL, M.D., Ph.D. Distinguished University Professor and President, Institute of Critical Care Medicine, Palm Springs Research Professor of Surgery and Clinical Professor of Anesthesiology, University of Southern California Bacteremia and Septic Shock JOHN M. WEILER, M.D. Professor of Internal Medicine, University of Iowa Biology of the Immune System
GEOFFREY A. WEINBERG, M.D. Associate Professor of Pediatrics, University of Rochester; Director, Pediatric HIV Program, Childre Hospital at Strong Human Immunodeficiency Virus Infection in Children; Miscellaneous Infections
CLAUDE E. WELCH, M.D. (Deceased) Clinical Professor of Surgery (Emeritus), Harvard University; Senior Surgeon, Massachusetts Gene Hospital Acute Abdomen and Surgical Gastroenterology; Diverticular Disease
NANETTE K. WENGER, M.D. Professor of Medicine (Cardiology), Emory University School of Medicine; Director, Cardiac Clinics Memorial Hospital
Clinical Professor of Surgery (Emeritus), Harvard University; Senior Surgeon, Massachusetts Gene Hospital Acute Abdomen and Surgical Gastroenterology; Diverticular Disease
NANETTE K. WENGER, M.D. Professor of Medicine (Cardiology), Emory University School of Medicine; Director, Cardiac Clinics Memorial Hospital Orthostatic Hypotension and Syncope; Athletic Heart Syndrome
THEODORE E. WOODWARD, M.D., M.A.C.P. Professor of Medicine (Emeritus), University of Maryland; Physician, VA Maryland Health Care Sys Rickettsial Diseases VERNA WRIGHT, M.D., F.R.C.P.(Deceased) Professor of Rheumatology (Emeritus), University of Leeds, England Arthritis Associated With Spondylitis DOROTHEA ZUCKER-FRANKLIN, M.D. Professor of Medicine, Department of Medicine, New York University Eosinophilic Disorders
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Front Matter Topics
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Section 12. Immunology; Allergic Disorders Chapter 146. Biology Of The Immune System Topics
[General] T Cells And Cellular Immunity B Cells And Humoral Immunity The Complement System Resolution Of An Immune Response
[General]
Nonspecific (Innate) Immunity
The immune system is a network of interacting cellular and soluble components. Its function is to distin entities within the body as "self" or "nonself" and to eliminate those that are nonself. Microorganisms a principal nonself entities, but neoplasms, transplants, and certain foreign substances (eg, some toxins also important. To accomplish its tasks, the immune system has evolved two mechanisms: nonspecific immunity and specific immunity, which are linked to and influence each other.
This type of immunity is older phylogenetically, is present at birth, does not require a previous encount the offending substance, and does not develop memory. Innate immunity includes barriers, such as th and chemical protection, such as gastric acid. There are two cellular components: (1) the phagocytic whose function is to ingest and digest invading microorganisms, and (2) natural killer (NK) cells, whose function is to kill some tumors, microorganisms, and virally infected cells (see below). The soluble components consist of complement proteins, acute phase reactants, and cytokines.
Phagocytes include neutrophils and monocytes (in the blood) and macrophages (in the tissues). Wide distributed, macrophages are strategically situated at the interfaces of tissues with blood or cavitary sp eg, alveolar macrophages (lungs), Kupffer cells (liver sinusoids), synovial cells (joint cavities), perivasc microglial cells (lining of CNS), mesangial phagocytes (kidneys).
Cytokines are nonimmunoglobulin polypeptides secreted by monocytes and lymphocytes in response interaction with a specific antigen (Ag), a nonspecific Ag, or a nonspecific soluble stimulus (eg, endoto other cytokines). Cytokines affect the magnitude of inflammatory or immune responses. Although secr cytokines may be triggered by the interaction of a lymphocyte with its specific Ag, cytokines are not Ag-specific; thus, they bridge innate and adaptive immunities.
Cytokines are nonimmunoglobulin polypeptides secreted by monocytes and lymphocytes in response interaction with a specific antigen (Ag), a nonspecific Ag, or a nonspecific soluble stimulus (eg, endoto other cytokines). Cytokines affect the magnitude of inflammatory or immune responses. Although secr cytokines may be triggered by the interaction of a lymphocyte with its specific Ag, cytokines are not Ag-specific; thus, they bridge innate and adaptive immunities.
Specific (Adaptive) Immunity
Specific immunity has the hallmarks of learning, adaptability, and memory. The cellular component is t lymphocyte, and immunoglobulins (Igs) are the soluble component.
Lymphocytes are divided into two subsets: thymus-derived (T cell) and bone marrow-derived (B cell). Lymphocytes are clonally distributed; each clone specializes in recognizing a specific Ag by means of receptor. Because the number of Ags is potentially limitless, this specialization would seem to place an burden on the immune system. The dilemma of providing an infinite number of unique clones is solved ability of the lymphocyte's Ag-receptor genes to combine in potentially limitless arrangements.
The function of the Ag receptor on B cells is mediated by surface immunoglobulins (sIgs). After B c soluble Ag through their sIg, a series of events (eg, proliferation, differentiation) culminates in secretio that is the specific antibody (Ab) for that Ag. The current belief is that the Ab repertoire of an organism exposure to Ag is due to Abs generated during B-cell maturation through Ig gene rearrangements. To understand the nature of Ig gene arrangement, one must understand Ig structure (see also Antibody S below).
Igs are composed of two heavy and two light chains, each with constant and variable domains. Ag is b the variable domain. At the gene level, the C region is coded for by the C-region genes; the V region (f light chains) by the V- and J-region genes and (for the heavy chains) by the V-, D-, and J-region genes gene segments are not situated in a continuum on the chromosome, but rather are discontinuous and juxtaposed during B-cell maturation. Thus, to synthesize a heavy chain, one of several D segments (a are identified) joins to one of 6 J segments. This cluster then joins to one of several hundred (possibly thousands) of V-region gene segments to make a complete transcriptional unit for an Ig heavy chain.
Depending on which particular segment of each gene region is used, a vast number of Ig molecules w varying specificities is possible. The potential for diversity is enlarged further by addition of random nu at the joining sites (between the V, D, and J regions), by somatic point mutations, and by inaccuracies joining of the various segments.
T cells do not have sIg but recognize Ag by their principal recognition tool, the T-cell receptor (TCR), other accessory adhesion molecules. Genes that encode the TCR belong to the Ig-gene superfamily; the Ig genes, they are subject to recombination, thus giving rise to a large number of T-cell clones, eac specific Ag responsiveness.
The Ag-binding portion of the TCR consists of two chains (either or ); each has a constant and a varia domain. Unlike Ig, which exists independently on the B-cell surface, the TCR is associated with the CD molecule; the whole unit is called the TCR/CD3 complex. Although TCR chains are subject to gene rearrangement and are variable, CD3 chains (consisting of at least five chains) are invariable and are Ag-specific. Some anti-CD3 Abs activate T cells directly, thus bypassing the requirement for Ag. Thus, important for the transduction of the activation signal through the lymphocyte membrane.
Lymphocytes can be further divided into subsets either by function or by surface markers. Lymphocyte have been identified by combinations of certain molecules on their surfaces. These surface markers h been designated clusters of differentiation (CD). To date, 166 CD have been identified. Up-to-date information on CD antigens can be found on the worldwide web (http://www.ncbi.nlm.nih.gov/prow).
important for the transduction of the activation signal through the lymphocyte membrane.
Lymphocytes can be further divided into subsets either by function or by surface markers. Lymphocyte have been identified by combinations of certain molecules on their surfaces. These surface markers h been designated clusters of differentiation (CD). To date, 166 CD have been identified. Up-to-date information on CD antigens can be found on the worldwide web (http://www.ncbi.nlm.nih.gov/prow).
Major Histocompatibility Complex
The ability of the immune system to differentiate self from nonself is determined largely by products of major histocompatibility complex (MHC) whose genes are on chromosome 6, belong to the Ig gene superfamily, and are subject to recombination. Class I MHC products consist of HLA-A, -B, and -C; th a wide distribution and are present on the surface of all nucleated cells and on platelets.Class II MHC consist of HLA-D, -DR, -DP, and -DQ; they have a more limited distribution on B cells, macrophages, d cells, Langerhans' cells, and activated (but not resting) T cells.
B cells can respond to soluble Ag, but T cells rarely do so and recognize Ag only when embedded with MHC; T cells therefore recognize MHC/Ag complex. The mechanism by which Ag is processed and as with MHC before it is presented to the T cells is accomplished by antigen-presenting cells (APCs)--e Langerhans' cells, monocytes, macrophages, follicular dendritic cells, and B cells. Although the nuanc not fully understood, it appears that to be processed, Ag must be unfolded, degraded, and fragmented exogenous processing, Ag undergoes endocytosis and degradation in lysosomes, is associated with c MHC products, and is transported to the cell surface. By endogenous processing, Ag is produced intra (eg, by viral infection) and undergoes degradation outside the lysosomes in organelles called proteoso The resulting peptides are transported to the rough endoplasmic reticulum (RER) by transporter protei in the RER, these peptides are associated with class I MHC products before transport to the cell surfa important to know whether Ag is associated with class I or II MHC, because the CD4 and CD8 molecu as accessory adhesion molecules by binding to class II or I, respectively. Engagement of the TCR with MHC/Ag complex may not be sufficient for induction of T-cell activation. A coactivation signal needs to present; this second signal is mediated by engaging CD28 on the T-cell surface with CD80 or CD86 on APC. Absence of the CD28/CD80-CD86 interaction may render the T cell anergic or tolerant (see Fig.
Cytokines
Although intimate cell contact is necessary for optimal T-cell responses, T cells and monocytes secret cytokines, which can influence close or distant events. Cytokines interact with specific cell surface rece and may act in an autocrine or paracrine manner.
Cytokines can be divided into several groups, which include interferons (IFNs-, , and ), tumor necrosis (TNF- and ), interleukins (IL-1 to IL-8), transforming growth factors, and the hematopoietic colony-stim factors (CSF). For the major cytokines, their cellular sources, and major effects, see Table 146-1.
Although the various cytokines and their effects are usually listed separately, it is important to rememb cytokines act in concert, in tandem, or in conflict in a given immune response; eg, IL-1 can induce the secretion of IL-2. IL-2, IL-4, and IL-6 can synergize in generating cytotoxic T lymphocytes. IL-4 and IFN counteract each other's effects in the induction of class II expression on B cells and in the induction of secretion.
The simultaneous orchestration of several responses and the redundancy of the immune system is pe best illustrated by the structure of some of the interleukin receptors. The IL-2 receptor is made up of th chains: , , and . Expression of all three chains results in the high-affinity IL-2 receptor; expression of th chains results only in an intermediate-affinity IL-2 receptor, whereas the chain represents only a low-a receptor. It has recently been shown that mutations or deletion of the IL-2 receptor chain are the mole
The simultaneous orchestration of several responses and the redundancy of the immune system is pe best illustrated by the structure of some of the interleukin receptors. The IL-2 receptor is made up of th chains: , , and . Expression of all three chains results in the high-affinity IL-2 receptor; expression of th chains results only in an intermediate-affinity IL-2 receptor, whereas the chain represents only a low-a receptor. It has recently been shown that mutations or deletion of the IL-2 receptor chain are the mole basis of X-linked severe combined immunodeficiency (SCID). Interestingly, mutations in the or chains IL-2 receptor do not result in SCID (at least in animal models). This apparent discrepancy arises becau chain of the IL-2 receptor is also part of the receptor complex for IL-4, IL-7, IL-9, and IL-15; this chain referred to as the common chain (c). The IL-15 receptor shares the and c chains with the IL-2 recepto chain of the IL-13 receptor is identical to the chain of the IL-4 receptor. IL-3, IL-5, and GM-CSF recept have an identical chain.
A new family of cytokines is the aptly named chemokines; chemokines induce chemotaxis and migra leukocyte subsets. There are four subsets of chemokines, which are defined by the number of interven amino acids between the first two cysteine residues in the molecule. Some of the receptors on chemo may serve as the coreceptors for entry of HIV into monocytes/macrophages.

Section 12. Immunology; Allergic Disorders Chapter 148. Hypersensitivity Disorders Topics
[General] Disorders With Type I Hypersensitivity Reactions Disorders With Type II Hypersensitivity Reactions Disorders With Type III Hypersensitivity Reactions Disorders With Type IV Hypersensitivity Reactions
[General]
Hypersensitivity refers to pathologic processes that result from immunologically specific interactions be antigens (exogenous or endogenous) and humoral antibodies or sensitized lymphocytes. This definitio excludes those disorders in which demonstrated antibodies have no known pathophysiologic significan the antibody to heart tissue that follows heart surgery or MI), even though their presence may have dia value.
Any classification of hypersensitivity will be oversimplified. Some are based on the time required for sy or skin test reactions to appear after exposure to an antigen (eg, immediate and delayed hypersensitiv the type of antigen (eg, drug reactions), or on the nature of organ involvement. Moreover, classification take into account that more than one type of immune response may be occurring or that more than on may be necessary to produce immunologic injury.
The Gell and Coombs Classification
This classification of reactions, consisting of four types, is widely used despite limitations, because it is most satisfactory.
Type I are reactions in which antigens (allergens) combine with specific IgE antibodies that are bound membrane receptors on tissue mast cells and blood basophils. The antigen-antibody reaction causes release of potent vasoactive and inflammatory mediators, which may be preformed (eg, histamine, tryp newly generated from membrane lipids (eg, the leukotrienes and prostaglandins). Over hours, mast ce basophils also release proinflammatory cytokines (eg, interleukin-4 and interleukin-13). The mediators vasodilation, increased capillary permeability, glandular hypersecretion, smooth muscle spasm, and tis infiltration with eosinophils and other inflammatory cells.
Type II are cytotoxic reactions resulting when antibody reacts with antigenic components of a cell or ti
newly generated from membrane lipids (eg, the leukotrienes and prostaglandins). Over hours, mast ce basophils also release proinflammatory cytokines (eg, interleukin-4 and interleukin-13). The mediators vasodilation, increased capillary permeability, glandular hypersecretion, smooth muscle spasm, and tis infiltration with eosinophils and other inflammatory cells.
Type II are cytotoxic reactions resulting when antibody reacts with antigenic components of a cell or ti elements or with antigen or hapten that is coupled to a cell or tissue.
The antigen-antibody reaction may activate certain cytotoxic cells (killer T cells or macrophages) to pro antibody-dependent cell-mediated cytotoxicity. It usually involves complement activation and may caus opsonic adherence through coating of the cell with antibody; the reaction develops by activation of complement components through C3 (with consequent phagocytosis of the cell), or by activation of the complement system with consequent cytolysis or tissue damage.
Type III are immune complex (IC) reactions resulting from deposition of soluble circulating antigen-ant ICs in vessels or tissue. The ICs activate complement and thus initiate a sequence of events that resu polymorphonuclear cell migration and release of lysosomal proteolytic enzymes and permeability facto tissues, thereby producing acute inflammation. Consequences of IC formation depend in part on the re proportions of antigen and antibody in the IC. With an excess of antibody, the ICs rapidly precipitate w antigen is located (eg, within the joints in RA) or are phagocytosed by macrophages and thus do no ha With a slight excess of antigen, the ICs tend to be more soluble and may cause systemic reactions by deposited in various tissues.
Type IV are cellular, cell-mediated, delayed, or tuberculin-type hypersensitivity reactions caused by se T lymphocytes after contact with a specific antigen.
Circulating antibodies are not involved in nor are they necessary for development of tissue injury. Tran delayed hypersensitivity from sensitized to nonsensitized persons can occur with peripheral lymphocyt not with serum.
Sensitized T lymphocytes that are triggered or activated by contact with a specific antigen may cause immunologic injury by a direct toxic effect or through the release of soluble substances (lymphokines). culture, activated T lymphocytes destroy target cells after sensitization by direct contact. Cytokines rel from activated T lymphocytes include several factors that affect the activity of macrophages, neutroph lymphoid killer cells (see Table 146-1).

Section 12. Immunology; Allergic Disorders Chapter 147. Immunodeficiency Diseases Topics
[General] Primary And Secondary Immunodeficiencies Specific Immunodeficiencies
[General]
Immunodeficiency diseases: A group of diverse conditions caused by one or more immune system de characterized clinically by increased susceptibility to infections with consequent severe, acute, recurre chronic disease.
An immunodeficiency disorder should be considered in anyone with infections that are unusually frequ severe, and resistant; without a symptom-free interval; from an unusual organism; or with unexpected severe complications. Since immunodeficiency disorders are relatively uncommon, other disorders lea recurrent infection should be considered first (see Table 147-1). If these disorders can be excluded, a host defense should be suspected.

Section 12. Immunology; Allergic Disorders Chapter 149. Transplantation Topics
[General] Immunobiology Of Rejection Kidney Transplantation Liver Transplantation Heart Transplantation Lung And Heart-Lung Transplantation Pancreas Transplantation Bone Marrow Transplantation Transplantation Of Other Organs And Tissues
[General]
(See also Corneal Transplantation in Ch. 96.)
Transplantation: The transfer of living cells, tissues, or organs from a donor to a recipient, with the inte maintaining the functional integrity of the transplanted material in the recipient.
Since the first successful kidney transplantation more than 40 yr ago, great expansion of transplantatio treating end-stage organ failure has occurred. Projected survival rates are improved (see Table 149-1) many organs are now transplanted. This expansion is attributed to new, more selective immunosuppre improved measures for detecting preexisting immunity to given donors; better patient selection; earlier intervention; improved surgical technique; earlier and more accurate detection of rejection episodes; a better understanding of rejection.
However, transplantation is still somewhat limited, mainly because of rejection, which can destroy the soon after transplantation except in special circumstances (eg, most grafts of cornea and cartilage and transplants between identical twins). Slower, chronic rejection has also emerged as a significant factor long-term survival and functional status of transplanted organs. Limitations in the availability of human organs also continue to be important.
Transplants are categorized by site and genetic relationship between the donor and recipient. An orth tissue or organ graft is transferred to an anatomically normal recipient site (eg, in a heart transplant). T to an anatomically abnormal site is called heterotopic (eg, transplantation of a kidney into the iliac fos recipient). An autograft is the transfer of one's own tissue from one location to another (eg, a bone gra stabilize a fracture). A syngeneic graft (isograft) is a graft between identical twins; an allograft (hom is a graft between genetically dissimilar members of the same species. Xenografts (heterografts) are
Transplants are categorized by site and genetic relationship between the donor and recipient. An orth tissue or organ graft is transferred to an anatomically normal recipient site (eg, in a heart transplant). T to an anatomically abnormal site is called heterotopic (eg, transplantation of a kidney into the iliac fos recipient). An autograft is the transfer of one's own tissue from one location to another (eg, a bone gra stabilize a fracture). A syngeneic graft (isograft) is a graft between identical twins; an allograft (hom is a graft between genetically dissimilar members of the same species. Xenografts (heterografts) are transplants between members of different species. Xenografts in general are confined to fixed, nonvia material, eg, porcine heart valves. Improved immunosuppression may allow for successful organ xeno help overcome the current critical shortage of donors.
With rare exceptions, transplants are allografts from either living relatives (and occasionally unrelated individuals) or cadaveric donors. Living donors are used mainly in kidney and bone marrow transplanta segmental liver, pancreas, and lung transplants are increasingly being donated by the recipients' living relatives. Acceptance of the concept of brain death has increased the use and demand for cadaveric o making it common to procure many organs from a single donor. Nevertheless, the need for organs far the number available from relatives of patients, and the number of patients waiting for organ transplan continues to grow (see Table 149-2).
Section 1. Nutritional Disorders Chapter 1. Nutrition: General Consideration Topics

[General] Nutrition In Clinical Medicine Nutritional Support Nutrient-Drug Interactions Food Additives And Contaminants
[General]
Nutrition is the science of food and its relationship to health.
The nutritional sciences deal with the nature and distribution of nutrients in food, their metabolic effect the consequences of inadequate food intake. Nutrients are chemical compounds in foods that are abs and used to promote health. Some nutrients are essential because they cannot be synthesized by the and thus must be derived from the diet. Essential nutrients include vitamins, minerals, amino acids, fa and some carbohydrate as a source of energy. Nonessential nutrients are those that the body can syn from other compounds, although they may also be derived from the diet. Nutrients are generally divide macronutrients and micronutrients.
Macronutrients
Macronutrients constitute the bulk of the diet and supply energy as well as essential nutrients needed growth, maintenance, and activity. Carbohydrates, fats (including essential fatty acids), proteins, macrominerals, and water are macronutrients. Carbohydrates are converted to glucose and other monosaccharides; fats, to fatty acids and glycerol; and proteins, to peptides and amino acids. These macronutrients are interchangeable as sources of energy; fats yield 9 kcal/g; proteins and carbohydra 4 kcal/g. Ethanol, not usually considered a nutrient, yields 7 kcal/g.
Carbohydrates and fat spare tissue protein. Unless sufficient nonprotein calories are available from eit dietary sources or tissue stores (particularly of fat), protein cannot be used efficiently for tissue mainte replacement, or growth, and considerably more dietary protein is required for positive nitrogen balance
Essential amino acids (EAAs) are the components of proteins that make them essential in the diet. O amino acids in proteins, 9 are essential, ie, required in the diet because they cannot be synthesized in
Carbohydrates and fat spare tissue protein. Unless sufficient nonprotein calories are available from eit dietary sources or tissue stores (particularly of fat), protein cannot be used efficiently for tissue mainte replacement, or growth, and considerably more dietary protein is required for positive nitrogen balance
Essential amino acids (EAAs) are the components of proteins that make them essential in the diet. O amino acids in proteins, 9 are essential, ie, required in the diet because they cannot be synthesized in body. Eight EAAs are required by all humans. Infants require one more, histidine.
The recommended dietary allowance (RDA) for protein decreases from 2.2 g/kg in 3-mo-old infants to in 5-yr-old children and to 0.8 g/kg in adults. The requirement for dietary protein correlates with the gro which varies at different times in the life cycle. The different protein requirements are reflected in the requirements for EAAs (see Table 1-1). The total amount of EAAs required by infants (715 mg/kg/day) represents 32% of their total protein requirement; the 231 mg/kg/day required by children aged 10 to 1 represents 20%, and the 86 mg/kg/day required by adults represents 11%.
The amino acid composition of proteins varies widely. The extent to which a protein matches the amin composition of animal tissues determines its biologic value (BV). A perfect match is egg protein, with a 100. Animal proteins in milk and meat have a high BV (~90), whereas proteins in cereal and vegetable lower BV (~40), and some derived proteins, such as gelatin, which lack tryptophan and valine, have a The complementarity among different proteins in the diet determines the overall BV of the diet. The RD protein assumes that the average mixed diet has a BV of 70.
Essential fatty acids (EFAs) are required in amounts equaling 6 to 10% of fat intake (equivalent to 5 g/day). They include -6 (n-6) fatty acids--linoleic acid (cis-9,12-octadecadienoic acid) and arachidonic (cis-5,8,11,14-eicosatetraenoic acid)--and -6 (n-3) fatty acids--linolenic acid (cis-9,12,15-octadecatrien acid), cis-5,8,11,14,17-eicosapentaenoic acid, and cis-4,7,10,13,16,19-docosahexaenoic acid. EFAs m provided by the diet: Vegetable oils provide linoleic acid and linolenic acid, and marine fish oils provide eicosapentaenoic acid and docosahexaenoic acid. However, some EFAs can be made from others. Fo example, the body can make arachidonic acid from linoleic acid, and eicosapentaenoic acid and docosahexaenoic acid can be partially synthesized from linolenic acid, although fish oil is a more effici source. EFAs are required for the formation of a variety of eicosanoids, including prostaglandins, thromboxanes, prostacyclins, and leukotrienes (see also Essential Fatty Acid Deficiency in Ch. 2). -3 F acids appear to play a role in decreasing the risk of coronary artery disease (see Dietary Modification 202). All EFAs are polyunsaturated fatty acids (PUFAs), but not all PUFAs are EFAs.
The macrominerals--sodium, chloride, potassium, calcium, phosphorus, and magnesium--are require gram quantities per day by humans (see Table 1-2). Water is also considered a macronutrient becaus required in amounts of 1 mL/kcal of energy expended, or about 2500 mL/day (see Water and Sodium Metabolism in Ch. 12).
Micronutrients
Vitamins, which are classified as water-or fat-soluble, and trace minerals are micronutrients (see Table Water-soluble vitamins are vitamin C (ascorbic acid) and eight members of the vitamin B complex--t (vitamin B1), riboflavin (vitamin B 2 ), niacin, pyridoxine (vitamin B6), folic acid, cobalamin (vitamin B12), and pantothenic acid. Fat-soluble vitamins include retinol (vitamin A), cholecalciferol and ergocalcife (vitamin D), -tocopherol (vitamin E), and phylloquinone and menaquinone (vitamin K). Only vitamins A B12 are stored to any significant extent in the body.
Essential trace minerals include iron, iodine, fluorine, zinc, chromium, selenium, manganese, molybd and copper. Except for fluorine and chromium, each of these minerals is incorporated into enzymes or hormones required in metabolism. Fluoride forms a compound with calcium (CaF2), which stabilizes th
(vitamin D), -tocopherol (vitamin E), and phylloquinone and menaquinone (vitamin K). Only vitamins A B12 are stored to any significant extent in the body.
Essential trace minerals include iron, iodine, fluorine, zinc, chromium, selenium, manganese, molybd and copper. Except for fluorine and chromium, each of these minerals is incorporated into enzymes or hormones required in metabolism. Fluoride forms a compound with calcium (CaF2), which stabilizes th mineral matrix in bones and teeth and prevents tooth decay. Except for iron and zinc, micromineral deficiencies are uncommon in clinical practice in industrialized countries (see Chs. 3 and 4).
Other trace minerals implicated in animal nutrition (ie, aluminum, arsenic, boron, cobalt, nickel, silicon, vanadium) have not been established as being required by humans. All trace minerals are toxic at high and some (arsenic, nickel, and chromium) have been implicated as causes of cancer. In the body, lea cadmium, barium, and strontium are toxic, but gold and silver are inert as components of teeth.
Other Dietary Substances
The daily human diet contains as many as 100,000 chemical substances (eg, 1 cup of coffee contains Of these, only 300 can be classified as nutrients, and 45 as essential nutrients. However, many of the substances are useful. For example, food additives (eg, preservatives, emulsifiers, antioxidants, and stabilizers) improve production, processing, storage, and packaging of foods. Trace components (eg, flavors, odors, colors, phytochemicals, and many other natural products) improve the appearance, tas stability of food.
Fiber, which occurs in various forms (eg, cellulose, hemicellulose, pectin, and gums), is also useful. Di components of dietary fiber act in different ways, depending on their structure and solubility. Fiber imp mobility and aids in the prevention of constipation and the management of diverticular disease (see Ch and 33). Foods rich in soluble fiber reduce the postprandial rise in blood glucose and are sometimes p the management of diabetes mellitus (see Ch. 13). Fruits and vegetables rich in guar gums and pectin reduce plasma cholesterol by enhancing hepatic cholesterol conversion to bile acids. Fiber is thought increase the elimination of cancer-causing substances produced by the bacteria in the large intestine. Epidemiologic evidence strongly supports an association between colon cancer and low fiber intake an beneficial effect of fiber in functional bowel disorders, appendicitis, Crohn's disease, obesity, varicose and hemorrhoids, but the mechanism remains obscure.
The typical Western diet is low in fiber (about 12 g/day) because of a high intake of highly refined whe and a low intake of fruits and vegetables. Increasing fiber intake to about 30 g/day by consuming more vegetables, and fruits is generally recommended.
Nutritional Requirements
The objective of a proper diet is to achieve and maintain a desirable body composition and a high pote physical and mental work. The daily dietary requirements for essential nutrients, including energy sour depend on age, sex, height, weight, and metabolic and physical activity. The Food and Nutrition Board National Academy of Sciences/National Research Council and the US Department of Agriculture (USD periodically review the scientific literature on human requirements for the 45 essential nutrients. Every Food and Nutrition Board issues the recommended dietary allowances (RDAs), which are computed to the needs of all healthy persons, with a significant safety factor (see Table 1-3). For vitamins and mine about which less is known, safe and adequate daily dietary intakes have been estimated (see Table 1
For good health, body composition must be kept within reasonable limits. This requires balancing ener intake with energy expenditure. If energy intake exceeds expenditure or expenditure decreases, body
periodically review the scientific literature on human requirements for the 45 essential nutrients. Every Food and Nutrition Board issues the recommended dietary allowances (RDAs), which are computed to the needs of all healthy persons, with a significant safety factor (see Table 1-3). For vitamins and mine about which less is known, safe and adequate daily dietary intakes have been estimated (see Table 1
For good health, body composition must be kept within reasonable limits. This requires balancing ener intake with energy expenditure. If energy intake exceeds expenditure or expenditure decreases, body increases, resulting in obesity (see Ch. 5). Conversely, if energy intake is less than expenditure, weigh Body weight standards corrected for height (see Table 1-5) and body mass index, which equals weigh kilograms) divided by the square of the height (in meters), are used as guides for desirable body comp (see below).
Diets for pregnant women are discussed under Prenatal Care in Ch. 249, and diets for infants under In Nutrition in Ch. 256.
Nutritional Information for the Public
Originally, the USDA proposed the Basic Four Food Groups (dairy products, meat and protein-rich veg cereals and breads, fruits and vegetables) as a guide to a balanced diet. In 1992, the USDA proposed Food Guide Pyramid (see Fig. 1-1) as a better guide. In the pyramid, the intake of cereals was increas 4 servings to 6 to 11 servings), fruits and vegetables were split into 2 groups (with 2 to 4 and 3 to 5 se respectively), the intake of dairy and meat products was maintained (at 2 to 3 servings), and a group o oils, and sweets was created (to be used "sparingly"). The number of recommended servings varies, depending on a person's energy needs, which can vary from 1600 to > 2400 calories/day.
The new food guide recommends reducing fat intake to about 30% of calories and increasing the intak fruits, vegetables, and cereals. Its purpose is to supply essential nutrients as part of a healthy diet. Tow end, the Department of Health and Human Science of the USDA has developed general nutritional gu that complement the Food Guide Pyramid.
Section 1. Nutritional Disorders Chapter 4. Mineral Deficiency And Toxicity Topics

[General] Iron Iodine Fluorine Zinc Chromium Selenium Manganese Molybdenum Copper
[General]
Six macrominerals are required by humans in amounts varying from 0.3 to 2.0 g/day (see Ch. 14). Fou them (sodium, potassium, calcium, and magnesium) are cations, and two (phosphate and chloride) ar accompanying anions.
Nine trace minerals (microminerals) are required by humans in small amounts (micrograms to milligram day): iron, iodine, fluorine, zinc, chromium, selenium, manganese, molybdenum, and copper. (For sou dietary requirements, see Tables 1-2, 1-3, and 1-4.) Except for fluorine and chromium, each of these m is a component of an enzyme or endocrine system. All trace minerals are toxic at high levels, and som (arsenic, nickel, and chromium) have been implicated in carcinogenesis.
Except for deficiencies of iron, zinc, and iodine, mineral deficiencies do not often develop spontaneous adults on ordinary diets; however, infants are more vulnerable because of their rapid growth and varia intake. The use of synthetic diets for the treatment of inborn errors of metabolism and the developmen parenteral nutrition and renal dialysis, all of which present iatrogenic risks, demonstrate the nutritional importance of trace minerals. Toxicity can result from the excess intake of trace minerals--for example "health foods" touted as a source of protection against chronic diseases. Sometimes mineral deficienc toxicity is caused by hereditary diseases.

Section 1. Nutritional Disorders Chapter 2. Malnutrition Topics
[General] Starvation Protein-Energy Malnutrition Carnitine Deficiency Essential Fatty Acid Deficiency
[General]
Malnutrition results from imbalance between the body's needs and the intake of nutrients, which can le syndromes of deficiency, dependency, toxicity, or obesity. Malnutrition includes undernutrition, in whic nutrients are undersupplied, and overnutrition, in which nutrients are oversupplied. Undernutrition ca from inadequate intake; malabsorption; abnormal systemic loss of nutrients due to diarrhea, hemorrha failure, or excessive sweating; infection; or addiction to drugs. Overnutrition can result from overeatin insufficient exercise; overprescription of therapeutic diets, including parenteral nutrition; excess intake vitamins, particularly pyridoxine (vitamin B6), niacin, and vitamins A and D; and excess intake of trace minerals. See also discussions of obesity in Ch. 5, vitamin and mineral deficiency and toxicity in Chs. and eating disorders in Ch. 196.
Malnutrition (undernutrition and overnutrition) develops in stages, which usually require considerable t First, nutrient levels in blood and/or tissues change, followed by intracellular changes in biochemical fu and structure. Ultimately, symptoms and signs appear; morbidity and mortality can result (see Fig. 2-1
Early Detection
The key to early detection is awareness that persons in certain circumstances have a high risk of undernutrition (see Table 2-1) or overnutrition (see Table 2-2). Undernutrition is associated with pover social deprivation, occurring among the poor, including some immigrants arriving from developing cou The risk of undernutrition is also greater at certain times in a person's life, ie, infancy, early childhood, adolescence, pregnancy and lactation, and old age. Overnutrition is associated with a sedentary lifesty the continuous availability of food in more affluent countries. Persons in the following circumstances may be at risk of malnutrition.
Infancy and childhood: Because of the high demand for energy and essential nutrients, infants and c
adolescence, pregnancy and lactation, and old age. Overnutrition is associated with a sedentary lifesty the continuous availability of food in more affluent countries. Persons in the following circumstances may be at risk of malnutrition.
Infancy and childhood: Because of the high demand for energy and essential nutrients, infants and c are at particular risk of undernutrition. Protein-energy malnutrition in children consuming inadequate a of protein, calories, and other nutrients is a particularly severe form of undernutrition that retards grow development (see below). Hemorrhagic disease of the newborn, a life-threatening disorder, is due to inadequate vitamin K (see Vitamin K Deficiency in Ch. 3). Deficiencies of iron, folic acid, vitamin C, co zinc, and vitamin A may occur in inadequately fed infants and children. In adolescence, nutritional requirements increase because the growth rate increases. Anorexia nervosa, a form of starvation, ma adolescent girls (see Ch. 196).
Pregnancy and lactation: Requirements for all nutrients are increased during pregnancy and lactatio Aberrations of diet, including pica (the consumption of nonnutritive substances, such as clay and charc common in pregnancy (see Iron-Deficiency Anemia in Ch. 127). Anemia due to folic acid deficiency is in pregnant women, especially those who have taken oral contraceptives. Folic acid supplements are n recommended for pregnant women to prevent neural tube defects (spina bifida) in their children. An exclusively breastfed infant can develop vitamin B 12 deficiency if the mother is a vegan. An alcoholic m may have a handicapped and stunted child with fetal alcohol syndrome, which is due to the effects of and malnutrition on fetal development (see Fetal Alcohol Syndrome in Ch. 260).
Old age: A diminished sense of taste and smell, loneliness, physical and mental handicaps, immobility chronic illness can militate against adequate dietary intake in the elderly. Absorption is reduced, possib contributing to iron deficiency, osteoporosis (also related to calcium deficiency), and osteomalacia due of vitamin D and absence of exposure to sunshine (see Vitamin D Deficiency and Dependency in Ch.
With aging--independent of disease or dietary deficiency--there is progressive loss of lean body mass, amounting to about 10 kg in men and 5 kg in women. It accounts for the decrease in BMR, total body skeletal mass, and height and for the increase in mean body fat (as a percentage of body weight) from 20 to 30% in men and from 27 to 40% in women. These changes and a reduction in physical activity re lower energy and protein requirements compared with those of younger adults.
Chronic disease: In patients with chronic disease, malabsorption states (including those resulting from surgery) tend to impair the absorption of fat-soluble vitamins, vitamin B12, calcium, and iron. Liver dise impairs the storage of vitamins A and B 12 and interferes with the metabolism of protein and energy so Patients with kidney disease, including those on dialysis, are prone to develop deficiencies of protein, vitamin D. Some patients with cancer and many with AIDS have anorexia, which complicates treatmen patients receiving long-term home parenteral nutrition (see Parenteral Nutrition in Ch. 1)--most commo total or near-total resection of the gut--vitamin and trace mineral deficiencies must be especially guard against. A physician should ensure that biotin, vitamin K, selenium, molybdenum, manganese, and zin adequately supplied.
Vegetarian diets: The most common form of vegetarianism is ovo-lacto vegetarianism, in which meat are eschewed but eggs and dairy products are eaten. Iron deficiency is the only risk. Ovo-lacto vegeta tend to live longer and to develop fewer chronic disabling conditions than their meat-eating peers. How their lifestyle usually includes regular exercise and abstention from alcohol and tobacco, which may co to their better health. Vegans consume no animal products and are susceptible to vitamin B12 deficien Yeast extracts and oriental-style fermented foods provide this vitamin. Intake of calcium, iron, and zinc tends to be low. A fruitarian diet, which consists solely of fruit, is deficient in protein, salt, and many micronutrients and is not recommended.
their lifestyle usually includes regular exercise and abstention from alcohol and tobacco, which may co to their better health. Vegans consume no animal products and are susceptible to vitamin B12 deficien Yeast extracts and oriental-style fermented foods provide this vitamin. Intake of calcium, iron, and zinc tends to be low. A fruitarian diet, which consists solely of fruit, is deficient in protein, salt, and many micronutrients and is not recommended.
Fad diets: Many commercial diets are claimed to enhance well-being or reduce weight. A physician sh alert to early evidence of nutrient deficiency or toxicity in patients adhering to them. Such diets have re frank vitamin, mineral, and protein deficiency states and cardiac, renal, and metabolic disorders as we some deaths. Very low calorie diets (< 400 kcal/day) cannot sustain health for long. Some trace miner supplements have induced toxicity.
Alcohol or drug dependency: Patients with alcohol or drug problems are notoriously unreliable when questioned about their eating habits, so making judicious inquiries of relatives or acquaintances may b necessary. Addiction leads to a disturbance of lifestyle in which adequate nourishment is neglected. Absorption and metabolism of nutrients are also impaired. High levels of alcohol are poisonous and ca tissue injury, particularly of the GI tract, liver, pancreas, brain, and peripheral nervous system. Beer dr who continue to consume food may gain weight, but alcoholics who consume >= 1 quart of hard liquor lose weight and become undernourished. Drug addicts are usually emaciated. Alcoholism is the most cause of thiamine deficiency in the USA and may lead to deficiencies of magnesium, zinc, and other v (see Thiamine Deficiency and Dependency in Ch. 3).
Diagnosis
The diagnosis of malnutrition is based on results of the medical and diet history, physical examination, selected laboratory tests (see Appraisal of Nutritional Status in Ch. 1). Results are compared with norm weight for height, body mass index (BMI), dietary intake, physical findings, and plasma levels of nutrie nutrient-dependent substances, such as hemoglobin, thyroid hormones, transferrin, and albumin.
History: A history of poor appetite, GI disturbance, and recent sizable weight loss suggests the possib malnutrition. A history of bleeding may indicate iron deficiency. Chronic use of alcohol, cocaine, heroin immunosuppressants, or certain antibiotics and anticonvulsants raises questions about the adequacy vitamin and mineral nutrition. A diet history may reveal food faddism, lack of variety, or inadequate or excessive intake of energy and essential nutrients.
Physical examination: Significant changes in body composition and organ function may suggest mal as a cause. The skin should be examined for dryness, scaliness, atrophy, petechiae, and ecchymoses the mouth for angular stomatitis, glossitis, swollen or bleeding gums, and decayed teeth. Depigmentat the hair and spooned nails point to malnutrition. The musculature should be examined for size, streng tenderness. A neurologic examination may detect disorientation, an abnormal gait, altered reflexes, an sensory or motor neuron abnormalities. Painful bones and joints, osteopenia, and distortions in the sh size of bones (eg, rachitic rosary) may indicate current or past malnutrition.
Anthropometric measurements are essential to diagnosis. Table 1-5 lists desirable body weight ranges threshold weight for obesity (20% above the average desirable weight). Nutritional status can be class the basis of BMI (see Table 2-3). The triceps skinfold (TSF) estimates the amount of body fat within 20 is therefore useful in determining the body's energy stores. Based on the midarm muscle area, an app measure of lean body mass, muscle mass may be classified as adequate, marginal, depleted, or wast Table 2-4).
Laboratory tests: A CBC and measurement of certain plasma proteins that reflect the adequacy of am acid nutrition (albumin, prealbumin, and transferrin) aid in the diagnosis of malnutrition, as does meas of plasma lipids and related lipoproteins (see Table 1-6). Abnormal electrolyte levels may point to a mi deficiency or a defect in ion homeostasis. Fat- and water-soluble vitamins can be measured in plasma
measure of lean body mass, muscle mass may be classified as adequate, marginal, depleted, or wast Table 2-4).
Laboratory tests: A CBC and measurement of certain plasma proteins that reflect the adequacy of am acid nutrition (albumin, prealbumin, and transferrin) aid in the diagnosis of malnutrition, as does meas of plasma lipids and related lipoproteins (see Table 1-6). Abnormal electrolyte levels may point to a mi deficiency or a defect in ion homeostasis. Fat- and water-soluble vitamins can be measured in plasma urine. Skin tests using antigens are used to evaluate cell-mediated immunity. Various imaging techniq (x-ray, CT, and MRI) may be helpful.
Surgical procedures place additional stress on undernourished persons. Indicators of malnutrition hav used to develop a prognostic nutritional index (PNI), a linear predictive model of increased morbidity a mortality after surgical procedures. The formula for PNI uses serum albumin (A) in g/dL, TSF in mm, s transferrin (TFN) in mg/dL, and delayed hypersensitivity (DH) response (0 to 2), measured by leukocyt migration inhibition, transformation, and cytotoxicity tests.
For example, a well-nourished patient with A = 4.8, TSF = 14, TFN = 250, and DH = 2 has a PNI of 15 152.2, or a 5.8% chance of complications. A malnourished patient with abnormal indexes (A = 2.8, TS TFN = 180, and DH = 1) has a PNI of 158 - 95.3, or a 62.7% chance of complications.

Section 1. Nutritional Disorders Chapter 5. Obesity Topics
[General]
[General]
Obesity: The excessive accumulation of body fat.
Traditionally, obesity has been defined as a body weight of > 30% above ideal or desirable weight on s height-weight tables (see Table 1-5). Now, it is usually defined in terms of the body mass index (BMI)(in kilograms) divided by the square of the height (in meters).
Epidemiology
The prevalence of obesity in the USA is high and rising higher. In the past decade, the overall prevale from 25 to 33%, an increase of 1/3. Prevalence varies significantly by sex, age, socioeconomic status, race (see also Obesity in Ch. 275). Prevalence is 35% among women and 31% among men, and it mo doubles between the ages of 20 and 55. Among women, obesity is strongly associated with socioecon status, being twice as common among those with lower socioeconomic status as it is among those wit status. Although prevalence among black and white men does not differ significantly, obesity is far mo common among black than among white women, affecting 60% of middle-aged black women compare 33% of white women.
Etiology
In one sense, the cause of obesity is simple--expending less energy than is consumed. But in another is elusive, involving the regulation of body weight, primarily body fat. How this regulation is achieved is fully understood.
Weight is regulated with great precision. For example, during a lifetime, the average person consumes 60 million kcal. A gain or loss of 20 lb, representing 72,000 kcal, involves an error of no more than 0.0 Regulation of body weight is believed to occur not only in persons of normal weight but also among ma obese persons, in whom obesity is attributed to an elevation in the set point around which weight is reg The determinants of obesity can be divided into the genetic, the environmental, and the regulatory.
Weight is regulated with great precision. For example, during a lifetime, the average person consumes 60 million kcal. A gain or loss of 20 lb, representing 72,000 kcal, involves an error of no more than 0.0 Regulation of body weight is believed to occur not only in persons of normal weight but also among ma obese persons, in whom obesity is attributed to an elevation in the set point around which weight is reg The determinants of obesity can be divided into the genetic, the environmental, and the regulatory.
Genetic determinants: Recent discoveries have helped explain how genes may determine obesity an they may influence the regulation of body weight. For example, mutations in the ob gene have led to m obesity in mice. Cloning the ob gene led to the identification of leptin, a protein coded by this gene; lep produced in adipose tissue cells and acts to control body fat. The existence of leptin supports the idea body weight is regulated, because leptin serves as a signal between adipose tissue and the areas of t that control energy metabolism, which influences body weight.
The extent of genetic influences on human obesity has been assessed by twin, adoption, and family s the first studies, of twins, the heritability of the BMI was estimated to be very high, about 80%, and this still frequently cited. The results of adoption and family studies, however, agree on a heritability of abo which is generally viewed as more reasonable than that of the twin studies. Genetic influences may be important in determining regional fat distribution than total body fat, particularly the critical visceral fat d (see below).
Environmental determinants: The fact that genetic influences account for only 33% of the variation i weight means that the environment exerts an enormous influence. This influence is dramatically illustr the marked increase in the prevalence of obesity in the past decade.
Socioeconomic status is an important influence on obesity, particularly among women. The negative correlation between socioeconomic status and obesity reflects an underlying cause. Longitudinal studi shown that growing up with lower socioeconomic status is a powerful risk factor for obesity. Socioecon factors are major influences on both energy intake and energy expenditure.
A large food intake is associated with obesity. For many years, it was believed that obscure metaboli disturbances caused obesity and that food intake was normal. However, the doubly labeled water met using stable isotopes of hydrogen and oxygen, shows that obese persons have a large energy expend which requires in turn a large food intake. Furthermore, this large food intake usually includes a large f intake, which independently predisposes to obesity.
A sedentary lifestyle, so prevalent in Western societies, is another major environmental influence pro obesity. Physical activity not only expends energy but also helps control food intake. Animal studies su that physical inactivity contributes to obesity by a paradoxical effect on food intake. Although food inta increases as energy expenditure increases, food intake may not decrease proportionately when physic activity falls below a minimum level; restricting activity may actually increase food intake for some peo
Regulatory determinants: Pregnancy is a major determinant of obesity in some women. Although m women weigh only a little bit more a year after delivery, about 15% weigh 20 lb more with each pregna
An increase in fat cells and adipose tissue mass during infancy and childhood--and for some sever obese persons, even during adulthood--predisposes to obesity. This increase can result in five times a fat cells in obese persons as in persons of normal weight. Dieting reduces only fat cell size, not fat cel number. As a result, persons with hypercellular adipose tissue can reduce to a normal weight only by m depleting the lipid content of each cell. Such depletion and the associated events at the cell membran set a biologic limit on their ability to lose weight and may explain their difficulty in reducing to a normal
Brain damage caused by a tumor (especially craniopharyngioma) or an infection (particularly affecting hypothalamus) leads to obesity in a very small number of persons. Whatever the other determinants o
number. As a result, persons with hypercellular adipose tissue can reduce to a normal weight only by m depleting the lipid content of each cell. Such depletion and the associated events at the cell membran set a biologic limit on their ability to lose weight and may explain their difficulty in reducing to a normal
Brain damage caused by a tumor (especially craniopharyngioma) or an infection (particularly affecting hypothalamus) leads to obesity in a very small number of persons. Whatever the other determinants o obesity, the final common pathway to caloric balance lies in behavior mediated by the CNS.
Drugs have recently been added to the list of determinants of obesity because of the increased use o pharmacotherapy. Weight gain can be produced by steroid hormones and four major classes of psych drugs--traditional antidepressants (tricyclics, tetracyclics, monoamine oxidase inhibitors), benzodiazep lithium, and antipsychotic drugs. Limiting the use of drug treatment to prevent weight gain may presen serious therapeutic dilemma.
Endocrine factors have been traditionally viewed as important determinants of obesity. Hyperinsulinis pancreatic neoplasms, hypercortisolism from Cushing's syndrome, the ovarian dysfunction of polycyst syndrome, and hypothyroidism have all been implicated in some cases of obesity, but endocrine deter affect only a very small number of obese persons.
Psychologic factors, once viewed as important determinants of obesity, are now believed to be limite to two deviant eating patterns. Binge eating disorder is characterized by the consumption of large am food in a short time with a subjective sense of loss of control during the binge and distress after it (see 196). Unlike patients with bulimia nervosa, these patients do not engage in compensatory behaviors, s vomiting; thus their binges contribute to excessive caloric intake. Binge eating disorder is believed to o 10 to 20% of persons entering weight reduction programs. The night-eating syndrome consists of mo anorexia, evening hyperphagia, and insomnia. It occurs in about 10% of persons seeking treatment fo
Symptoms and Signs
The symptoms and signs of obesity consist of the immediate consequences of the large adipose tissu Prominent among them is sleep apnea, a seriously underdiagnosed disorder, characterized by mome during sleep when breathing ceases, as often as hundreds of times a night (see Sleep Apnea Syndrom Ch. 173).
In the obesity-hypoventilation syndrome (pickwickian syndrome), impairment of breathing leads to hypercapnia, a reduced effect of CO2 in stimulating respiration, hypoxia, cor pulmonale, and a risk of premature death.
Obesity may lead to orthopedic disturbances of weight-bearing and non-weight-bearing joints. Skin dis are particularly common; increased sweat and skin secretions, trapped in thick folds of skin, produce a medium conducive to fungal and bacterial growth and infections.
The level of general psychopathology, as assessed by psychologic tests, does not differ between pers are obese and those who are not. However, for some young women in upper and middle socioeconom groups, psychologic problems are linked to obesity. The current view is that the intense prejudice and discrimination to which obese persons are subjected is the source of these problems. In addition to the disorders noted above, these problems include disparagement of body image, a condition in which pe feel that their body is grotesque and loathsome. These women believe that others view them with host contempt, which makes them self-conscious and impairs social functioning.
Diagnosis
disorders noted above, these problems include disparagement of body image, a condition in which pe feel that their body is grotesque and loathsome. These women believe that others view them with host contempt, which makes them self-conscious and impairs social functioning.
Diagnosis
Obesity represents one end of a distribution curve of body fat, with no physiologically defined cutoff po practical purposes, the eyeball test is sufficient: If a person looks fat, the person is fat. For a more qua measure of obesity, BMI is used, with obesity arbitrarily defined as a BMI of > 27.8 for men and > 27.3 women.
Some special distributions of body fat are important in the diagnosis of certain disorders--for example, buffalo hump of hyperadrenocorticism and the peculiar accumulation of fluid in hypothyroidism.
Recognizing the significance of body fat distribution, particularly of the visceral fat depot, has measura advanced the understanding of obesity. Clinically, this distribution is assessed by the waist/hip ratio, w high-risk upper body obesity defined as a ratio of > 1.0 for men and > 0.8 for women. Risk, however, is proportional to the size of the ratio, independent of sex; the greater mortality and morbidity of men is a of their greater waist/hip ratio.
Complications
The deleterious consequences of obesity are considerable. Recent estimates attribute 280,000 deaths in the USA to "overnutrition," making it second only to cigarette smoking as a cause of death.
Many of the metabolic disorders of obesity are believed to be caused by abdominal visceral fat, which an increased concentration of free fatty acids in the portal vein and, consequently, to decreased hepat clearance, insulin resistance, hyperinsulinemia, and hypertension. This sequence of events leads to d dyslipidemias, and, ultimately, coronary artery disease.
The complications of obesity highlight a paradox. Most of the persons receiving treatment for obesity a women, who are far less likely to suffer from its complications than are men. Men who need treatment receiving it.
Prognosis and Treatment
The prognosis for obesity is poor; untreated, it tends to progress. With most forms of treatment, weigh lost, but most persons return to their pretreatment weight within 5 yr.
In recent years, the goals and methods of the treatment of obesity have changed radically as a result o developments. The first is evidence that a modest weight loss, 10% or perhaps even 5% of body weig sufficient to control, or at least improve, most complications of obesity. Therefore, there is no reason to the traditional goal of attaining an ideal body weight, which is so seldom attained and, if attained, is so maintained. The "10% solution" has become the goal of most treatment programs.
The second development, derived from the poor maintenance of weight loss during treatment, is a mo a goal of weight loss to one of weight management, achieving the best weight possible in the context o health. Weight management programs can be divided into three major categories.
Do-it-yourself programs are the resource for most obese persons who seek help. A physician may h
a goal of weight loss to one of weight management, achieving the best weight possible in the context o health. Weight management programs can be divided into three major categories.
Do-it-yourself programs are the resource for most obese persons who seek help. A physician may h obese patients by becoming familiar with these programs. They include self-help groups, such as Ove Anonymous and Take Off Pounds Sensibly (TOPS); community-based and work-site programs; books magazine articles; and weight loss products, such as meal replacement formulas.
Nonclinical programs are popular commercial enterprises that have a structure created by a parent c and weekly meetings conducted by variably trained counselors, supplemented by instructional and gui materials prepared in consultation with health care professionals. These programs usually provide no than 1 yr of treatment, and their costs vary from approximately $12/wk for Weight Watchers to $3,000/ treatment in some programs. The effectiveness of commercial programs is hard to evaluate because t publish few statistics and have high dropout rates. Nevertheless, their ready availability has made them popular. Physicians can assist patients by helping them select programs with sensible low-fat diets an emphasis on physical activity.
Clinical programs are provided by licensed health care professionals, often as part of a commercial w loss enterprise but also in solo or group private practice.
Weight management programs make use of four modalities: diet and nutritional counseling, behavior t drugs, and surgery.
Diet: Traditional dieting is now rarely prescribed; long-term habit change is emphasized instead. Most programs teach clients how to make safe, sensible, and gradual changes in eating patterns. Changes increased intake of complex carbohydrates (fruits, vegetables, breads, cereals, and pasta) and decrea intake of fats and simple carbohydrates. Very low calorie diets, providing 400 to 800 kcal/day, have de popularity, as it has become apparent how rapidly patients regain the large amounts of weight they ha
Behavior therapy: The basis of most nonclinical (commercial) weight loss programs is behavior thera based on behavioral analysis, which considers the behavior to be changed, its antecedents, and its consequences. The primary behavior to be changed is eating, with efforts to slow the rate of eating. N effort to change the antecedents of eating, ranging from relatively remote ones (eg, shopping for food) immediate ones (eg, too readily available high-calorie snacks in the home). The third step is reinforcin behaviors. Self-monitoring, with detailed record keeping, is used to determine which behaviors should modified and reinforced. Nutrition education is increasingly important in these programs, as are measu increase physical activity. Cognitive therapy is being applied to overcome the self-defeating, maladapt attitudes toward weight reduction common among obese persons and to provide training in relapse pr for the usual lapses experienced in any program of weight management.
Drugs: The many benefits of even modest weight loss and the difficulty in maintaining weight loss hav rekindled interest in the pharmacotherapy of obesity, especially since the newer drugs have less poten abuse than those used in the 1970s. However, the recent discovery of widespread valvular heart disea patients who received fenfluramine alone or in combination with phentermine (often referred to as fenhas cast a pall over drug therapy for obesity. Fenfluramine should no longer be used, and what effect unfortunate disclosure will have on the prescription of appetite suppressant drugs is unclear. Sibutram recently been approved as an appetite suppressant, but experience with it is limited. Over-the-counter are generally harmless, questionably effective, and best avoided.
Surgery: For persons with very severe obesity (BMI > 40) and those with less severe obesity and seri life-threatening complications, surgical procedures are the treatment of choice. They can result in large losses that are usually well maintained for > 5 yr. The most common operations--vertical banded gastr
unfortunate disclosure will have on the prescription of appetite suppressant drugs is unclear. Sibutram recently been approved as an appetite suppressant, but experience with it is limited. Over-the-counter are generally harmless, questionably effective, and best avoided.
Surgery: For persons with very severe obesity (BMI > 40) and those with less severe obesity and seri life-threatening complications, surgical procedures are the treatment of choice. They can result in large losses that are usually well maintained for > 5 yr. The most common operations--vertical banded gastr and gastric bypass--radically reduce stomach volume by creating a gastric pouch of no more than 25 m volume.
Weight loss after surgery is rapid at first, slowing gradually over a period of 2 yr. It is directly proportion extent of obesity and usually varies between 40 and 60 kg. The weight loss is accompanied by marked improvement in medical complications as well as in mood, self-esteem, body image, activity levels, an interpersonal and vocational effectiveness. In experienced hands, preoperative and operative mortality usually < 1% and operative complications < 10%.
Section 1. Nutritional Disorders Chapter 3. Vitamin Deficiency, Dependency, And T Topics

[General] Vitamin A Deficiency Vitamin A Toxicity Vitamin D Deficiency And Dependency Vitamin D Toxicity Vitamin E Deficiency Vitamin E Toxicity Vitamin K Deficiency Vitamin K Toxicity Thiamine Deficiency And Dependency Riboflavin Deficiency Niacin Deficiency Vitamin B6 Deficiency And Dependency Vitamin B6 Toxicity Biotin Deficiency And Dependency Pantothenic Acid Deficiency Vitamin C Deficiency
[General]
In technologically advanced societies, vitamin deficiency results mainly from poverty, food faddism, mi drugs (see Nutrient-Drug Interactions in Ch. 1), chronic alcoholism, or prolonged parenteral feeding.
Vitamin dependency results from a genetic defect in the metabolism of the vitamin or in the binding of vitamin-related coenzyme to its apoenzyme. In some instances, vitamin doses as high as 1000 times t recommended dietary allowance (RDA) improve the function of the altered metabolic pathway. Person vitamin dependency have been identified for vitamin D, thiamine, niacin, vitamin B6, biotin, and vitamin (see Table 1-2). Vitamin B12 deficiency and folic acid deficiency are discussed under Megaloblastic M Anemias in Ch. 127.
Megavitamin therapy is a cause of vitamin toxicity (hypervitaminosis) for vitamins A, D, E, C, and B 6 , f and for folic acid (folate). Sources, usual therapeutic dosages, and dietary requirements are listed in Tables 1-2, 1-3, and 1-4.
Section 13. Infectious Diseases Chapter 150. Biology Of Infectious Disease Topics
[General] Host Defense Mechanisms Pathogenesis Of Infection Manifestations Of Infection
[General]
A healthy person lives in harmony with the microbial flora that help protect from invasion by pathogens microorganisms that have the capacity to cause disease. Microorganisms colonize body sites by a phenomenon known as tissue tropism, in which some tissues are colonized but others are not. The mi flora comprises normal resident flora, which is found consistently and promptly reestablishes itself if disturbed, and transient flora, which may colonize the host for hours to weeks but does not permanen establish itself. Bacteria and fungi account for most of the commensal and symbiotic flora.
Species that make up the normal flora are influenced by many factors (eg, diet, hygiene, sanitary cond air pollution). For example, lactobacilli are common intestinal commensal organisms found in people w high intake of dairy products; Hemophilus influenzae colonize the tracheobronchial tree in patients with
Pathogens occasionally are part of the normal flora. Organisms in normal flora can cause disease, esp in patients whose defense barriers are disrupted.

Section 13. Infectious Diseases Chapter 158. Systemic Fungal Diseases (Systemic Mycoses) Topics
[General] Histoplasmosis Coccidioidomycosis Blastomycosis Paracoccidioidomycosis Sporotrichosis Cryptococcosis Systemic Candidiasis Aspergillosis Mucormycosis Mycetoma Chromomycosis And Phaeohyphomycosis Other Fungal Opportunists
[General]
General Diagnostic Principles
The major systemic mycoses are discussed in this chapter. Dermatophytoses and other skin infections discussed in Ch. 113; pulmonary disorders caused by hypersensitivity to fungi are discussed in Ch. 76 those with pleural involvement in Ch. 80; fungal diseases affecting the GU system can be found in Ch
Many of the causative fungi are opportunists and are not usually pathogenic unless they enter a comp host (see also Ch. 151). Opportunistic fungal infections are particularly likely to occur in patients during with corticosteroids, immunosuppressants, or antimetabolites; such infections also tend to occur in pat with AIDS, azotemia, diabetes mellitus, bronchiectasis, emphysema, TB, lymphoma, leukemia, or burn Candidiasis, aspergillosis, mucormycosis (phycomycosis), nocardiosis, and cryptococcosis are typical opportunistic infections. (Nocardiosis is discussed in Ch. 157.) In immunocompetent patients, dissemi mycoses with pneumonia and septicemia are rare. Lung lesions may develop slowly in such patients. mycoses affecting severely immunocompromised patients often have acute or subacute presentations rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination.
Fungal diseases occurring as primary infections may have a typical geographic distribution. For examp the USA, coccidioidomycosis is virtually confined to the Southwest; histoplasmosis occurs primarily in and Midwest; blastomycosis is restricted to North America and Africa; and paracoccidioidomycosis, so
mycoses affecting severely immunocompromised patients often have acute or subacute presentations rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination.
Fungal diseases occurring as primary infections may have a typical geographic distribution. For examp the USA, coccidioidomycosis is virtually confined to the Southwest; histoplasmosis occurs primarily in and Midwest; blastomycosis is restricted to North America and Africa; and paracoccidioidomycosis, so called South American blastomycosis, is confined to that continent. However, travelers can develop di some time after becoming infected and returning from such endemic areas.
In immunocompetent patients, systemic mycoses typically have a chronic course. Months or even yea elapse before medical attention is sought or a diagnosis is made. Symptoms are rarely intense in such mycoses, but fever, chills, night sweats, anorexia, weight loss, malaise, and depression may occur.
When a fungus disseminates from a primary focus in the lung, the manifestations may be characterist example, cryptococcosis usually presents as a chronic meningitis, progressive disseminated histoplas generalized involvement of the reticuloendothelial system (liver, spleen, bone marrow), and blastomyc single or multiple skin lesions.
Immunoserologic tests are available for many systemic mycoses, but few provide definitive diagnoses themselves. Among the most useful assays are those that measure specific antigenic products of orga most notably Cryptococcus neoformans and, more recently, Histoplasma capsulatum. Some tests, suc complement fixation assays for anti-coccidioidal antibodies, are specific and do not require proof of ris levels and thus can provide invaluable confirmatory evidence for diagnosis as well as an indication of t relative risk of extrapulmonary dissemination. In chronic meningitis, a positive complement fixation for anti-coccidioidal antibodies in CSF often provides the only definite diagnostic indication of the need fo aggressive antifungal therapy. Most tests for antifungal antibodies, however, are of limited usefulness. have low sensitivity and/or specificity, and because measurement of high or rising antibody titers takes time, it is unhelpful in guiding initial therapy.
Diagnoses are usually confirmed by isolating causative fungi from sputum, urine, blood, bone marrow, specimens from infected tissues. The clinical significance of positive sputum cultures may be difficult t interpret for commensal organisms (eg, Candida albicans) or for those that are prevalent in the environ (eg, Aspergillus sp). Therefore, an etiologic role can be established with certainty only by confirmation invasion.
In contrast to viral and bacterial diseases, fungal infections often can be diagnosed histopathologically high degree of reliability based on distinctive morphologic characteristics of invading fungi rather than specific antibody products. However, definitive identification may be difficult, especially if few organism visible, so that histopathologic diagnoses should be confirmed by cultures whenever possible. Assessm the activity of the infection is based on cultures from many different sites, fever, leukocyte counts, clini laboratory parameters related to specific involved organs (eg, liver function tests), and immunoserolog in certain mycoses.
General Therapeutic Principles
Drugs for systemic antifungal treatment include amphotericin B, various azole derivatives, and flucytos addition to antifungal chemotherapy and general medical care, surgery may be needed to clear certain localized infections. Drug choices for specific systemic fungal infections appear in Table 158-1.
Amphotericin B: Despite its high toxicity, amphotericin B remains the standard therapy for most life-threatening systemic mycoses. For chronic mycoses, treatment usually is started with >= 0.3 mg IV gradual daily increases of >= 0.1 mg/kg until the desired peak dose is reached (usually 0.4 mg/kg to 1 in a single dose, but generally not exceeding 50 mg daily). If patients tolerate the acute toxic effects of more concentrated infusions, daily IV doses can be changed gradually to a more convenient alternate
localized infections. Drug choices for specific systemic fungal infections appear in Table 158-1.
Amphotericin B: Despite its high toxicity, amphotericin B remains the standard therapy for most life-threatening systemic mycoses. For chronic mycoses, treatment usually is started with >= 0.3 mg IV gradual daily increases of >= 0.1 mg/kg until the desired peak dose is reached (usually 0.4 mg/kg to 1 in a single dose, but generally not exceeding 50 mg daily). If patients tolerate the acute toxic effects of more concentrated infusions, daily IV doses can be changed gradually to a more convenient alternate schedule using double the peak daily dose. Extended courses of treatment also may be adjusted to le frequent and more convenient dosing schedules (eg, 3 times weekly). For acute, life-threatening myco amphotericin B is started using the desired peak dose (0.6 to 1.0 mg/kg/day) if tolerated. For certain ra progressive opportunistic mycoses (eg, invasive aspergillosis), peak doses as high as 1.5 mg/kg/day h sometimes been used, usually divided between two or three separate IV infusions.
The standard formulation, colloidal amphotericin B deoxycholate, must always be administered in 5% because salts (including saline and KCl) can precipitate the drug. It is usually administered over 2 to 3 although more rapid infusions over 20 to 60 min are safe in most patients. Reactions are usually mild, some patients may experience chills, fever, nausea, vomiting, anorexia, headache, and, occasionally, hypotension. Premedication with acetaminophen or aspirin is often used. The minority of patients who severe fever, nausea, vomiting, or hypotension may get relief using bolus IV injections of 25 to 50 mg hydrocortisone; it may then be mixed in subsequent IV infusions to prevent or minimize reactions. In m cases, hydrocortisone can be tapered and ultimately omitted during extended therapy. Severe chills an can be relieved or prevented by meperidine, 50 to 75 mg IV. Chemical thrombophlebitis may also occu
Intrathecal amphotericin B injections are sometimes used in treating chronic meningitis, usually via dir intracisternal injection or with a subcutaneous Ommaya-type reservoir connected to an intraventricular catheter. Headache, nausea, and vomiting may occur but may be reduced by adding dexamethasone intrathecal injection. Lumbar intrathecal injections are seldom used because of erratic penetration to th involved areas of the brain and potentially severe local inflammatory effects, which may lead to adhes arachnoiditis. At the time of injection, 10 mL or more of CSF is withdrawn into a syringe containing amphotericin B diluted in 5% D/W to 0.2 mg/mL. Doses of 0.05 to 0.5 mg are then injected slowly, ove or more. Most often, doses are gradually increased as tolerated, peaking with a regimen of 0.5 mg 3 ti weekly.
Renal functional impairment is the major toxic risk of amphotericin B therapy. Serum creatinine and BU should be monitored before and at regular intervals during treatment. Amphotericin B is unique among nephrotoxic antimicrobial drugs in that it is not eliminated appreciably via the kidneys. Thus, amphoter does not accumulate in increasing amounts as renal failure worsens, and the dose should not be redu moderate abnormalities in renal function. However, in patients who begin therapy with normal renal fu amphotericin B dosages should be reduced if serum creatinine rises to more than 3.0 to 3.5 mg/dL (26 mol/L) or BUN to more than 50 mg/dL (18 mmol Urea/L). Acute nephrotoxicity can be reduced by IV with saline before amphotericin B infusions. Mild to moderate renal function abnormalities induced by amphotericin generally resolve gradually after completion of therapy. Permanent damage primarily occ those patients who receive prolonged courses of therapy. (For example, 75% of those who receive tot of amphotericin B > 4 g develop permanent renal functional deficits.) In any patient whose renal functi severely compromised before or during amphotericin B therapy, ultimate decisions on IV amphotericin dosages must involve weighing the severity of the systemic mycosis and the potential efficacy of altern antifungal drugs against the risk of renal impairment. Besides renal toxicity, amphotericin B frequently suppression of bone marrow function manifested primarily by anemia. Hepatotoxicity or other untowar are unusual.
Recently, several lipid vehicles have been evaluated in efforts to reduce the toxic manifestations of amphotericin B while maintaining therapeutic efficacy. Although these preparations differ in compositio toxicity, and clearance from serum, they all concentrate deposition of amphotericin in the liver, spleen, lungs and cause less nephrotoxicity than standard amphotericin B deoxycholate. Higher doses of the l preparations can then be administered safely. Three preparations are available in Europe but only one
Recently, several lipid vehicles have been evaluated in efforts to reduce the toxic manifestations of amphotericin B while maintaining therapeutic efficacy. Although these preparations differ in compositio toxicity, and clearance from serum, they all concentrate deposition of amphotericin in the liver, spleen, lungs and cause less nephrotoxicity than standard amphotericin B deoxycholate. Higher doses of the l preparations can then be administered safely. Three preparations are available in Europe but only one been licensed in the USA. The latter, amphotericin B lipid complex, is limited to use only for invasive aspergillosis that is either unresponsive to colloidal amphotericin B or cannot be safely treated with ad doses of the standard preparation because of abnormal renal function. Trials are in progress in patien various mycoses to define relative safety and efficacy of this lipid complex preparation as well as that amphotericin B colloidal dispersion, a liposomal amphotericin B preparation, and liposome-encapsulat nystatin (another polyene antifungal related to amphotericin B). Some investigators also have used mi amphotericin B with Intralipid, but this seems less useful. Preparations have not been standardized, so may vary, and nephrotoxicity has not been appreciably or consistently reduced.
Antifungal azoles: These drugs are not nephrotoxic and can be administered orally. They have made treatment of chronic mycoses in an outpatient setting easier. The first such oral drug, ketoconazole, h largely been supplanted by newer, more effective, less toxic triazole derivatives such as fluconazole a itraconazole.
Fluconazole is water-soluble and is absorbed almost completely after an oral dose. It is excreted larg unchanged in urine and has a half-life > 24 h, facilitating use in single daily doses. It has high penetrat CSF (>= 70% of serum levels) and has been especially useful for the treatment of cryptococcal and coccidioidal meningitis (see below). It also provides an effective, less toxic alternative to amphotericin treatment of candidemia in non-neutropenic patients. Although it was originally approved for the treatm systemic mycoses in 200 to 400 mg daily doses, doses as high as 800 mg/day may be needed for som seriously ill patients with certain mycoses (see below), and daily doses of >= 1000 mg have been give limited trials without apparent undue toxicity.
Candida cruzii is typically fluconazole-resistant, and Candida (Torulopsis) glabrata is generally less se than C. albicans. Other fluconazole-resistant Candida sp have been increasingly emerging recently in to repeated widespread use for the treatment and prevention of candidiasis and other mycoses. So fa resistant Candida isolates appear sensitive to itraconazole, but some are not. Of special concern are r fluconazole-resistant Candida in non-AIDS patients never previously treated with azoles. Restraint is s recommended to avoid indiscriminate fluconazole use when other therapy would be effective for mucocutaneous candidiasis.
GI discomfort and skin rash are the most common side effects. More severe toxicity is unusual, but flu use has been associated with hepatic necrosis, Stevens-Johnson syndrome, anaphylaxis, alopecia, an congenital anomalies after use beyond the 1st trimester of pregnancy. Interactions with other drugs oc often with fluconazole than with ketoconazole or itraconazole. However, fluconazole sometimes cause elevated serum levels of cyclosporine, rifabutin, phenytoin, warfarin-type oral anticoagulants, sulfonylu drugs such as tolbutamide, or zidovudine. Rifampin may lower fluconazole blood levels.
Itraconazole has become the standard treatment for lymphocutaneous sporotrichosis as well as mild moderately severe histoplasmosis, blastomycosis, or paracoccidioidomycosis. It also has proven effec mild cases of invasive aspergillosis, some cases of coccidioidomycosis, and certain types of chromom Because of its high lipid solubility and protein binding, itraconazole blood levels tend to be low, but tiss levels are generally high. Drug levels are negligible in urine or CSF. Itraconazole has been used succe to clear some types of fungal meningitis, although it is not the drug of choice.
Itraconazole, like ketoconazole, requires an acid pH for absorption, so that blood levels may vary after administration. Acidic drinks (eg, cola, acidic fruit juices) or food may improve absorption. However, ab may be lowered if itraconazole is taken with any prescription or OTC drugs used to lower gastric acidit
levels are generally high. Drug levels are negligible in urine or CSF. Itraconazole has been used succe to clear some types of fungal meningitis, although it is not the drug of choice.
Itraconazole, like ketoconazole, requires an acid pH for absorption, so that blood levels may vary after administration. Acidic drinks (eg, cola, acidic fruit juices) or food may improve absorption. However, ab may be lowered if itraconazole is taken with any prescription or OTC drugs used to lower gastric acidit Several drugs may decrease serum itraconazole concentrations, including rifampin, rifabutin, didanosi phenytoin, and carbamazepine. Itraconazole also inhibits metabolic degradation of other drugs, causin level elevations with potentially serious consequences. Serious, even fatal cardiac arrhythmias may oc itraconazole is used with cisapride or some antihistamines, such as terfenadine, astemizole, and perh loratadine. Rhabdomyolysis has been associated with itraconazole-induced elevations in blood levels cyclosporine or cholesterol-reducing drugs such as lovastatin or simvastatin. Blood level elevations of tacrolimus, oral anticoagulants, or oral hypoglycemic drugs also may occur when these drugs are used itraconazole.
In doses of up to 400 mg/day, the main side effects are GI-related, but a few men have reported impo and higher doses may cause hypokalemia, hypertension, and edema. Other reported side effects inclu allergic rash, hepatitis, and hallucinations.
Flucytosine: Flucytosine, a nucleic acid analog, is water-soluble and well absorbed after oral adminis Preexisting or emerging resistance to the drug is common, so that it is almost always used with anothe antifungal drug, usually amphotericin B. Flucytosine combined with amphotericin B is primarily used to cryptococcosis but has also proven valuable for some cases of disseminated candidiasis, other yeast infections, and severe invasive aspergillosis. Occasionally, flucytosine alone has improved (but probab completely cured) some cases of chromomycosis. Flucytosine has also been used in combination with antifungal azoles in recent trials. This latter combination has yielded promising preliminary results in cryptococcosis and some cases of other mycoses but remains experimental.
The usual dose (150 mg/kg/day po in 4 divided doses) leads to high drug levels in serum, urine, and C Because flucytosine is primarily cleared by the kidneys, blood levels tend to rise to toxic ranges as nephrotoxicity develops during concomitant use with amphotericin B, particularly when the latter is use doses > 0.4 mg/kg/day. Reversible hepatic dysfunction may also occur. Flucytosine serum concentrati should be monitored and the dosage adjusted to keep serum concentrations within a range of about 4 g/mL to reduce risks of thrombocytopenia and leukopenia. Flucytosine concentrations often become during early phases of amphotericin B nephrotoxicity, when creatinine clearance rises significantly with major elevation in serum creatinine values. Therefore, especially if timely blood levels cannot be obtai prudent to begin therapy with a lower dose (100 mg/kg/day), then adjust doses downward using the no in the package insert according to any further declines in renal function.
Section 13. Infectious Diseases Chapter 151. Infections In The Compromised H Topics
[General]
[General]
Infections in patients whose host defense mechanisms are compromised range from minor to fatal and are caused by organisms that normally reside on body surfaces. In the hospital setting, they frequently from colonization by antibiotic-resistant organisms and from use of catheters and mechanical devices. Nosocomial infections in the newborn are discussed under Neonatal Infections in Ch. 260. Opportunis infections in AIDS are discussed in Ch. 163.
Host defense mechanisms--physiologic, anatomic, or immunologic--may be altered or breached by dis trauma or by procedures or agents used for diagnosis or therapy. Infections in this setting, often called opportunistic infections, occur if antimicrobial therapy alters the normal relationship between host and or if host defense mechanisms have been altered by age, burns, neoplasms, metabolic disorders, irrad foreign bodies, immunosuppressive or cytotoxic drugs, corticosteroids, or diagnostic or therapeutic instrumentation.
The underlying alteration predisposes the patient to infections from endogenous microflora that are nonpathogenic or from ordinarily harmless, saprophytic organisms acquired by contact with other patie hospital personnel, or equipment. These organisms may be bacteria, fungi, viruses, or other parasites precise character of the host's altered defenses determines which organisms are likely to be involved. organisms are often resistant to multiple antibiotics.
Drug Therapy and Impaired Host Defense Mechanisms
Antibiotics alter the normal microflora of the skin, mucous membranes, and GI tract and may result in colonization by new organisms. Colonization is harmless unless followed by superinfection, which refe invasion by indigenous or environmental organisms resistant to the administered antibiotic. Factors predisposing to superinfection include extremes of age, debilitating diseases, and prolonged treatmen antibiotics, especially broad-spectrum ones. Superinfections usually appear on the 4th or 5th day of th and may convert a benign, self-limited disease into a serious, prolonged, or even fatal one. The diagno superinfection by a normally commensal organism is certain only when the organism is recovered from CSF, or body cavity fluid.
predisposing to superinfection include extremes of age, debilitating diseases, and prolonged treatmen antibiotics, especially broad-spectrum ones. Superinfections usually appear on the 4th or 5th day of th and may convert a benign, self-limited disease into a serious, prolonged, or even fatal one. The diagno superinfection by a normally commensal organism is certain only when the organism is recovered from CSF, or body cavity fluid.
Cytotoxic drugs enhance the susceptibility to infection through leukopenia and thrombocytopenia; dep of the immune response, particularly cell-mediated immunity; and altered inflammatory response. Mos opportunistic infections result from the leukopenia.
Corticosteroids alter many aspects of host defenses; one of the most important is inhibition of the mov neutrophils, monocytes, and lymphocytes into the inflammatory exudate. Corticosteroids may reactiva quiescent pulmonary TB, histoplasmosis, coccidioidomycosis, and blastomycosis. Patients receiving corticosteroid treatment (especially in high dose) for RA, ulcerative colitis, asthma, sarcoidosis, SLE, pemphigus, or Cushing's syndrome have increased susceptibility to infection from usual and unusual b and tend to develop infections with Aspergillus, Candida, Cryptococcus, Mucor, or Nocardia.
Nosocomial (Hospital-Acquired) Infections
These infections are acquired from the hospital environment or personnel (eg, inadequately sterilized equipment or insufficient hand washing). They usually occur when a susceptible patient has a portal fo infection from altered anatomic barriers (see below) or has been given broad-spectrum antibiotics. The commonly due to Staphylococcus, Enterobacter, Klebsiella, Serratia, Pseudomonas, Proteus, Acineto Aspergillus, or Candida.
Alterations of Anatomic Barriers
Patients with extensive burns or those undergoing diagnostic or therapeutic procedures that breach no anatomic barriers to infection (eg, tracheostomy, inhalation therapy, urinary tract instrumentation, indw urethral or IV catheter placement, surgery, and surgical prostheses application) are vulnerable to infec endogenous or exogenous antibiotic-resistant organisms. Gram-negative bacteria, particularly Pseudo and Serratia, and other multiply resistant organisms, alone or in combination with staphylococci, cause tissue infections and bacteremia in severely burned patients. Significant bacteriuria develops in patien indwelling urethral catheters, increasing the risk of cystitis, pyelonephritis, and bacteremia with gram-n bacilli. Sepsis from IV catheter sites, due to staphylococci, gram-negative bacilli, or Candida, may cau suppuration or severe and sometimes fatal systemic infections. Patients with endotracheal tubes or tracheostomies and others who require repeated tracheal suctioning or inhalation therapy with equipm containing a reservoir of nebulization fluid may develop bronchopulmonary infection, usually with noso gram-negative organisms.
Impaired Cellular or Humoral Host Defense Mechanisms
Neoplastic and immunodeficiency diseases such as leukemia, aplastic anemia, Hodgkin's disease, my and HIV infection are characterized by selective defects in host resistance. Patients with hypogammaglobulinemia, myeloma, macroglobulinemia, or chronic lymphocytic leukemia tend to have deficient humoral immune mechanisms and to develop pneumococcal and Haemophilus pneumonia ( Pneumonia in the Compromised Host in Ch. 73) and bacteremia. Patients with neutropenia due to leu intensive immunosuppressive therapy, or irradiation frequently develop gram-negative bacteremia from infections acquired through the mucous membranes or secondary to pneumonia (see Ch. 135). Sever immunosuppressed patients and those with Hodgkin's disease and HIV tend to have depressed cellula immune mechanisms; serious infections with mycobacteria, Aspergillus, Candida, Cryptococcus, Histo Mucor, Nocardia, or Staphylococcus are frequent. Herpes zoster, cytomegalovirus, Pneumocystis, and
Pneumonia in the Compromised Host in Ch. 73) and bacteremia. Patients with neutropenia due to leu intensive immunosuppressive therapy, or irradiation frequently develop gram-negative bacteremia from infections acquired through the mucous membranes or secondary to pneumonia (see Ch. 135). Sever immunosuppressed patients and those with Hodgkin's disease and HIV tend to have depressed cellula immune mechanisms; serious infections with mycobacteria, Aspergillus, Candida, Cryptococcus, Histo Mucor, Nocardia, or Staphylococcus are frequent. Herpes zoster, cytomegalovirus, Pneumocystis, and Toxoplasma infections also occur. AIDS often leads to infections caused by atypical mycobacteria, her simplex, Giardia, Cryptosporidia, Isospora, and many others. (AIDS is discussed in Ch. 163, and other immunodeficiency diseases are discussed in Ch. 147.)
Prophylaxis
Awareness of the patterns of infection that occur in the compromised host helps in early recognition of infections and initiation of appropriate therapy. Awareness of the specific site of breached defense, the defense system that has been weakened or lost, and the characteristics of organisms prevalent in a p institution, based on continuous hospital surveillance, is also helpful.
Antibiotic prophylaxis (see also Antimicrobial Chemoprophylaxis in Ch. 153) is indicated for some conditions, including rheumatic fever and bacterial endocarditis, TB exposure, recurrent UTIs and otitis bacterial infections in granulocytopenic patients, and some types of Neisseria infections. Prophylaxis w antibiotics is also indicated after vaginal or abdominal hysterectomy; colonic, rectal, cardiac, joint, or v surgery; prostatectomy in patients with previous UTIs; and pneumocystis in AIDS patients (see Pneum Caused by Pneumocystis Carinii in Ch. 73). However, use of broad-spectrum antibiotics, massive dos antibiotic, or prophylactic use of systemic antibiotics may ultimately result in infection with resistant bac Patients receiving antibiotics should be watched for signs of superinfection.
The hematopoietic growth factors, granulocyte colony-stimulating factor and granulocyte-macropha colony-stimulating factor, can accelerate hematopoietic recovery after chemotherapy. They are useful preventing infections from agents that cause transient neutropenia. Their broader use to prevent or tre infections is under investigation.
Active or passive immunization helps prevent some types of infections. Active immunization can pre influenza, Haemophilus influenzae type b, meningococcal, and pneumococcal infections. Pneumococc vaccination is effective for chronically ill, asplenic, and elderly patients and those with sickle cell and H disease. Hepatitis B vaccine should be given to patients who repeatedly receive blood products as we medical and nursing personnel and others at risk. Passive immunization can prevent or ameliorate her zoster, hepatitis A and B, measles, and cytomegalovirus infection in selected immunosuppressed patie Severe hypogammaglobulinemia requires maintenance with immune globulin.
Barriers help control and prevent infection. Strict asepsis should be maintained in diagnostic and ther manipulative procedures. Attendants should wear sterile gloves during endotracheal or tracheostomy suctioning, and suction catheters should be sterile, disposable, and used only once. Masks, tubing, ne jars, and other respiratory therapy equipment connected directly to a patient's airway should be steriliz steam or gas before use and should be changed daily. When steam or gas sterilization is not possible equipment should be disinfected with a 2% glutaraldehyde or 2% acetic acid wash, followed by thorou rinsing and drying. Alternatively, nebulization of 0.25% acetic acid through the equipment, followed by thorough rinsing, is usually satisfactory for daily cleaning of a ventilator that is in use. Care should be t ensure that the gas jets have been completely cleaned.
Urethral catheters must be connected to closed sterile drainage bags and the system kept closed. IV c should be inserted securely, covered with a sterile protective dressing, and removed after 48 to 72 h o first sign of phlebitis. An ointment of neomycin, polymyxin B, and bacitracin or an iodine ointment (eg, povidone-iodine), applied daily to the cannulation site and the emerging catheter, may help prevent inf
ensure that the gas jets have been completely cleaned.
Urethral catheters must be connected to closed sterile drainage bags and the system kept closed. IV c should be inserted securely, covered with a sterile protective dressing, and removed after 48 to 72 h o first sign of phlebitis. An ointment of neomycin, polymyxin B, and bacitracin or an iodine ointment (eg, povidone-iodine), applied daily to the cannulation site and the emerging catheter, may help prevent inf Thrombophlebitis usually responds to catheter withdrawal and local application of hot compresses, bu antibiotic therapy for specifically identified or presumed causative organisms may be necessary.
Treatment
Opportunistic infections are difficult to treat once established because the organisms tend to be resista most commonly used antibiotics. Short-term therapy tends to merely suppress infection temporarily un underlying condition can be corrected (eg, urethral or IV catheters removed or tracheostomy closed); t treatment often must be longer than usual. Cultures and possibly tissue biopsy should be performed b starting or altering antibiotics, but therapy may need to be started while awaiting laboratory results on of clinical-bacteriologic diagnosis and knowledge of the organisms known to be prevalent in a particula institution and their presumptive sensitivity. If possible, corticosteroid dosage and immunosuppressive chemotherapy should be reduced while treating opportunistic infections. Patients with severe agranulo who have documented infection may benefit from granulocyte transfusions.
Further details of treatment appear in discussions of specific underlying disorders elsewhere in The M

Section 13. Infectious Diseases Chapter 159. Rickettsial Diseases Topics
[General] Epidemic Typhus Murine (Endemic) Typhus Scrub Typhus Rocky Mountain Spotted Fever Ehrlichiosis Eastern Tick-Borne Rickettsioses Rickettsialpox Q Fever Bartonellosis
[General]
Rickettsioses comprise four groups: typhus--epidemic typhus, Brill-Zinsser disease, murine (endemic) and scrub typhus; spotted fever--Rocky Mountain spotted fever, Eastern tick-borne rickettsiosis, and rickettsialpox; Q fever; and trench fever. Ehrlichiosis is caused by Ehrlichia, a rickettsia-like bacteria transmitted to humans by ticks.
Rickettsial diseases (rickettsioses): Various illnesses caused by rickettsiae and manifested by sudden course of fever of one to several weeks, headache, malaise, prostration, peripheral vasculitis, and, in m cases, a characteristic rash.
Most members of the order Rickettsiales are obligate intracellular pleomorphic coccobacilli. They are t bacteria as they have metabolic enzymes and cell walls, use O2, and are susceptible to antibiotics, alth they require living cells for growth. Most rickettsiae are maintained in nature by a cycle involving an an reservoir and an insect vector (usually an arthropod) that infects humans. Because many rickettsiae a localized to certain geographic areas, a knowledge of where the patient lives or has recently traveled o helps in diagnosis.
Some rickettsiae multiply at the site of an arthropod attachment and produce a local lesion (eschar). T penetrate the skin or mucous membranes and multiply in the endothelial cells of small blood vessels, c a vasculitis consisting of endothelial proliferation, perivascular infiltration, and thrombosis. The endova causes the rash, encephalitic signs, and gangrene of skin and tissues.
Differential Diagnosis of Rickettsial Diseas
Some rickettsiae multiply at the site of an arthropod attachment and produce a local lesion (eschar). T penetrate the skin or mucous membranes and multiply in the endothelial cells of small blood vessels, c a vasculitis consisting of endothelial proliferation, perivascular infiltration, and thrombosis. The endova causes the rash, encephalitic signs, and gangrene of skin and tissues.
Differential Diagnosis of Rickettsial Diseas
Differentiating rickettsioses from other acute infectious diseases is difficult during the first several days the rash appears. A history of louse or flea infestation or tick bite in known endemic areas of rickettsio helpful. Any seriously ill patient who lives in or near a wooded area and has unexplained fever, headac prostration, with or without a history of tick contact, should be suspected of having Rocky Mountain sp fever (RMSF).
In meningococcemia, the rash may be pink, macular, maculopapular, or petechial in the subacute form petechially confluent or ecchymotic in the fulminant form; it resembles RMSF or epidemic typhus. The meningococcal rash develops rapidly in acute disease and, when ecchymotic, usually is tender on palp the rickettsial rash usually appears on about the 4th febrile day and gradually becomes petechial over days. In rubeola, the rash begins on the face, spreads to the trunk and arms, and soon becomes confluent; thus may be confused with rubeola. The rash of rubella usually remains discrete. Postauricular lymph and lack of toxicity favor rubella.
In murine typhus, which is milder than RMSF or epidemic typhus, the rash is nonpurpuric, nonconfluen less extensive; renal and vascular complications are uncommon. However, differentiating RMSF from typhus may be difficult, and specific serologic testing may be required. Treatment should not be delaye this distinction is made.
Epidemic louse-borne typhus causes all the profound physiologic and pathologic abnormalities of RMS including peripheral vascular collapse, shock, cyanosis, ecchymotic skin necrosis, digital gangrene, az renal failure, delirium, and coma. The rash of epidemic typhus usually appears first over the axillary fo trunk; later it spreads peripherally, rarely involving the palms, soles, and face.
Local eschars occur in patients with scrub typhus, rickettsialpox, and, occasionally, the spotted fevers. epidemiologic history often helps in differentiation. The rash in rickettsialpox is vesicular; in tick-borne is often obviously maculopapular. In Q fever, a rash is unusual; in trench fever, sparse. In ulcerogland tularemia (associated with an eschar) and other forms of tularemia, there is no exanthem. Lyme disea which the characteristic erythema chronicum migrans rash often occurs, should also be considered.
Rickettsialpox is mild; usually an initial eschar occurs at the point of the mite attachment, and the rash form of vesicles with surrounding erythema, is sparse. Because similar oral lesions occur in varicella, i be ruled out.
Patients with scrub typhus have all the clinical and pathologic manifestations of RMSF and epidemic ty however, scrub typhus occurs in different geographic areas, particularly in Malaya and northern Thaila Frequently, an eschar develops with satellite adenopathy.
Laboratory tests: Serologic tests, isolation and identification of Rickettsia rickettsii from blood or tissu identification of the agent in skin or other tissues by immunofluorescence help confirm the diagnosis, particularly in RMSF. To be useful, serologic tests require three serum samples, taken during the 1st, 4th to 6th wk of illness. Polymerase chain reaction is useful in early identification of specific rickettsial acids.
Laboratory tests: Serologic tests, isolation and identification of Rickettsia rickettsii from blood or tissu identification of the agent in skin or other tissues by immunofluorescence help confirm the diagnosis, particularly in RMSF. To be useful, serologic tests require three serum samples, taken during the 1st, 4th to 6th wk of illness. Polymerase chain reaction is useful in early identification of specific rickettsial acids.
Complement fixation reaction: The serologic patterns of RMSF and typhus are distinctive in specific rickettsial antigens. Spotted fever and typhus group rickettsiae have two types of complement fixation antigens; the soluble fraction is common to all members of the group, whereas purified fractions are m specific for individual rickettsiae. Various spotted fevers (eg, RMSF, rickettsialpox, fivre boutonneuse Asian tick-borne rickettsiosis, Queensland tick typhus) may be distinguished by type-specific washed rickettsial-body antigen. Antibodies in response to a primary infection of RMSF and typhus are usually type. CF antibodies appear in patients during the 2nd and 3rd wk of these illnesses and later in those with antibiotics within the first 3 to 5 days of illness. Under these circumstances, a later convalescent s should be taken at 4 to 6 wk. In Brill-Zinsser disease, type 7S antibodies appear rapidly after several d illness. Q-fever antigens are specifically diagnostic. In acute infections, antibodies to phase 2 antigens phase 1 antibodies indicate chronic infection (eg, hepatitis, endocarditis).
Other serologic tests: Using purer antigens, other serologic tests for rickettsioses not only distinguish between specific infections but also help determine the type of immunoglobulin in acute (IgM) and late recurrent (IgG) illnesses, such as Brill-Zinsser disease. CF tests are useful for routine diagnosis; micro agglutination, indirect fluorescent antibody (IFA), and hemagglutination reactions are valuable for iden and are becoming standard. IFA and CF tests help confirm trench fever. R. akari shares a common an with other members of the spotted fever group but can be differentiated by demonstration of a rising ti specific CF antibodies. R. conorii, R. sibirica, and R. australis share a common antigen with R. ricketts akari but are differentiated by CF and mouse toxin neutralization tests as well as by cross-immunity te guinea pigs.
Immunofluorescence techniques have been used to detect R. rickettsii and R. prowazekii in tissues of embryos, guinea pigs, and vector ticks. Identifiable rickettsiae have been seen in skin lesions of patien RMSF as early as the 4th day of illness or as late as the 10th day. Rickettsiae may be stained by IFA technique in formalin-fixed tissues.
Isolation and identification: Isolation of an organism is rarely needed except for epidemiologic reaso when attempted, blood should be taken early from febrile patients with spotted or typhus fever before treatment. Isolation of causative rickettsia by inoculation of guinea pigs, mice, or embryo yolk sacs has generally been replaced with various tissue culture techniques.
Treatment of Rickettsial Diseases
All rickettsioses require specific chemotherapy and supportive care. Measures advisable for all infectio described here; variations are described below for ehrlichiosis, rickettsialpox, Q fever, and trench feve
Symptoms and signs are promptly alleviated if therapy begins early, when the rash first appears. Since untreated patients with RMSF may become moribund or die before definitive serologic data are availab treatment should begin as soon as a presumptive diagnosis is made. Obvious clinical improvement is noted within 36 to 48 h, with defervescence in 2 to 3 days. In scrub typhus, the response is even more dramatic.
Tetracyclines and chloramphenicol are specifically effective; they are rickettsiostatic, not rickettsicidal. regimens include an initial oral dose of tetracycline 25 mg/kg or chloramphenicol 50 mg/kg. Subseque
treatment should begin as soon as a presumptive diagnosis is made. Obvious clinical improvement is noted within 36 to 48 h, with defervescence in 2 to 3 days. In scrub typhus, the response is even more dramatic.
Tetracyclines and chloramphenicol are specifically effective; they are rickettsiostatic, not rickettsicidal. regimens include an initial oral dose of tetracycline 25 mg/kg or chloramphenicol 50 mg/kg. Subseque doses of the same amount are divided equally and given at 6- to 8-h intervals until the patient improve has been afebrile for about 24 h. IV preparations are used in those too ill to take oral medication.
In patients first treated during the later stages, improvement is slower and fever is of longer duration. P seriously ill with a rickettsial disease of the typhus and spotted fever group often have circulatory colla oliguria, anuria, azotemia, anemia, hyponatremia, hypochloremia, edema, and coma. In mildly and mo ill patients, these alterations are absent, making management less complicated. Critically ill patients w first seen late in the course of severe illness may be given large doses of corticosteroids in combinatio specific antibiotics for about 3 days.
Severely ill patients with RMSF and epidemic typhus may have a marked increase in capillary permea later stages; IV fluids should be given cautiously to avoid worsening pulmonary and cerebral edema. H is not recommended in patients with disseminated intravascular coagulation. (See also Chs. 131 and 1

Section 13. Infectious Diseases Chapter 152. Immunizations For Adults Topics
[General]
[General]
Immunobiologic agents used in the USA for adults contain antigens (eg, vaccines, toxoids) or antibodi immune globulins, antitoxins). Immune globulins and antitoxins available in the USA are listed in Table Use of immune globulins, antitoxins, and nonroutine vaccines (eg, rabies vaccine) are discussed unde disorders elsewhere in The Manual. Immunizations for infants and children are discussed under Child Immunizations in Ch. 256.
A toxoid is a modified bacterial toxin that has been rendered nontoxic but retains the ability to stimula formation of antibodies. A vaccine, a suspension of whole (live or inactivated) or fractionated bacteria viruses that have been rendered nonpathogenic, is given to induce an immune response and prevent Although the development and widespread use of vaccines is a major public health triumph, vaccines risks as well as benefits. Even though no vaccine is entirely safe or completely effective, their use as d is strongly supported by their benefit-to-risk ratio.
Vaccines should always be given exactly as recommended on the package insert; however, the interv between a series of doses may be lengthened without losing efficacy. Live-microbial vaccines should n given simultaneously with immune globulin; ideally, such vaccines should be given 2 wk before or 6 to after the immune globulins. Live vaccines usually should not be given to immunocompromised or preg patients. Table 152-2 lists licensed vaccines available in the USA. Vaccines against HIV, Lyme diseas various other pathogens are currently under study.
Routine Immunizations
Immunizations to be considered for all adults are listed in Table 152-3.
Measles, mumps, and rubella attenuated live viruses are combined into one vaccine that is routinely all children in their 2nd yr of life. However, some adults have never received this vaccine and did not b infected with these diseases in youth. Some who received the vaccine have not maintained a high tite antibodies and may be at risk. Generally, people born before 1956 are considered immune by virtue o infection. Those born after 1956 should receive the combined vaccine if their immune status is uncerta
Measles, mumps, and rubella attenuated live viruses are combined into one vaccine that is routinely all children in their 2nd yr of life. However, some adults have never received this vaccine and did not b infected with these diseases in youth. Some who received the vaccine have not maintained a high tite antibodies and may be at risk. Generally, people born before 1956 are considered immune by virtue o infection. Those born after 1956 should receive the combined vaccine if their immune status is uncerta they are likely to become exposed. Although these vaccines can be given separately, the combined fo preferred because a person who needs one vaccine probably needs all three, and revaccination poses particular risk.
Tetanus toxoid is combined with diphtheria toxoid in tetanus and diphtheria toxoids adsorbed (Td). Although tetanus is rare, it has a high mortality rate. Since 1/3 of cases result from only minor injuries, universal vaccination remains necessary. Adults who missed the primary series of three tetanus inject childhood should receive an initial dose, followed by a 2nd dose 1 mo later, and a 3rd dose 6 mo later Thereafter, a booster of q 10 yr maintains lifelong immunity (all doses 0.5 mL IM). Alternatively, some authorities recommend a single booster at age 50 because of excellent long-term protection from the p immunization.
Hepatitis B (HB) vaccine is recommended as a one-time series of three or four injections, but a perso known exposure may be revaccinated if the antibody titer is low. Candidates for vaccination include an risk for exposure to the virus through blood or sexual contact, including health care workers, mortuary patients receiving frequent transfusions or hemodialysis, IV drug users, homosexual males, and sex p of known HB carriers. Additionally, anyone not previously infected who is exposed to the virus (eg, a n an inadvertent needlestick injury) should be vaccinated.
Influenza A virus undergoes antigenic drift each year, requiring annual revaccination with the new stra Because outbreaks usually begin in early or midwinter, the vaccine should be given in the fall. It is recommended for those at high risk for serious sequelae, including anyone > 65 yr; residents of extend facilities; and patients with chronic cardiovascular or pulmonary disease, metabolic disorders, renal fai hemoglobinopathies, immunosuppression, or HIV infection. Health care workers and anyone desiring symptoms should also be vaccinated. During influenza outbreaks in extended-care facilities, amantadi rimantadine can be prescribed regardless of vaccination status.
Pneumococcal pneumonia vaccine is a polyvalent preparation containing antigens from the 23 most of the 83 subtypes of pneumococcus. Its overall efficacy in preventing bacteremia in adults has been r to be 56 to 81%, but this rate is somewhat lower in debilitated elderly people. It should be given to any high risk for pneumococcal pneumonia or its complications, including patients at risk for influenza complications and those with functional asplenia, alcoholism, hematologic malignancy, or CSF leak. T vaccine may be given simultaneously with the influenza A vaccine but at a different site (eg, the oppos deltoid muscle). One immunization is recommended for lifetime protection, although revaccination q 6 should be considered for high-risk patients.
Varicella vaccine contains live, attenuated virus. It is indicated for young adults not previously infecte especially health care workers and close contacts of immunocompromised persons. It produces detec varicella antibodies in 97% of recipients and reduces the likelihood of clinical illness by 70% after expo immune globulins, including varicella-zoster immune globulin, should be given within 5 mo before or 2 vaccination. This vaccine may be given concomitantly with measles-mumps-rubella. Recipients should salicylates for 6 wk because of the possibility of Reye's syndrome.
Immunizations for Travelers

Immunizations may be required for travel through various regions where infectious diseases not seen
Immunizations for Travelers

Immunizations may be required for travel through various regions where infectious diseases not seen USA are endemic. The Centers for Disease Control and Prevention (Atlanta, GA 30333) can provide information; a telephone service (404-332-4559) is available to medical practitioners and travelers 24

Section 13. Infectious Diseases Chapter 160. Chlamydial Diseases Topics
[General]
[General]
The chlamydiae are nonmotile, obligate intracellular parasites. Although originally considered viruses b they multiply in the cytoplasm of host cells, they are now considered to be bacteria because they conta DNA and RNA, have a cell wall chemically similar to that of gram-negative bacteria, possess ribosome grow well in the yolk sacs of embryonated eggs.
In the genus Chlamydia, three species are recognized: C. psittaci, which causes psittacosis; C. pneum which causes chlamydial pneumonia; and C. trachomatis, which includes 15 serotypes and causes ma conditions. Serotypes A, B, Ba, and C cause trachoma and inclusion conjunctivitis; D through K cause transmitted diseases. L1 and L 2 cause lymphogranuloma venereum, and L3 causes mouse pneumonit
C. trachomatis is the most common cause of sexually transmitted diseases in the USA, including nongonococcal urethritis and epididymitis in men; cervicitis, urethritis, and pelvic inflammatory disease women; Reiter's syndrome; and neonatal conjunctivitis and pneumonia acquired through maternal transmission. C. trachomatis has been implicated in 20% of adults with pharyngitis.
C. pneumoniae (previously called TWAR), originally considered a serotype of C. psittaci, is accepted species and can cause pneumonia, especially in children and young adults. The percent of community-acquired pneumonia due to C. pneumoniae ranges from 6 to 19% in various studies. It ma clinically indistinguishable from pneumonia caused by Mycoplasma pneumoniae. Although chlamydial pneumonia is uncommon in children < 5 yr of age in some studies, it accounts for 6 to 9% of pneumon in other studies. No seasonal variations in occurrence have been observed. The organism has been fo atheromatous lesions, and infection is associated with increased risk of coronary artery disease. Caus not been established and therapeutic trials are in progress. C. psittaci infects many animals, but human infection is closely related to contact with birds.
Psittacosis and chlamydial pneumonia are discussed in Ch. 73; lymphogranuloma venereum and uret Ch. 164; epididymitis, in Ch. 219; Reiter's syndrome, in Ch. 51; neonatal conjunctivitis and neonatal pneumonia, under Neonatal Infections in Ch. 260; and trachoma and inclusion conjunctivitis, in Ch. 95
C. psittaci infects many animals, but human infection is closely related to contact with birds.
Psittacosis and chlamydial pneumonia are discussed in Ch. 73; lymphogranuloma venereum and uret Ch. 164; epididymitis, in Ch. 219; Reiter's syndrome, in Ch. 51; neonatal conjunctivitis and neonatal pneumonia, under Neonatal Infections in Ch. 260; and trachoma and inclusion conjunctivitis, in Ch. 95
Chlamydiae can be isolated using tissue cultures. Direct fluorescent antibody and enzyme immunoass demonstrate chlamydiae. Serologic tests may be used to exclude Chlamydia in a low-prevalence popu
Treatment is with tetracyclines, macrolides, and some fluoroquinolones. Therapy for >= 2 wk may redu recrudescences.

Section 13. Infectious Diseases Chapter 153. Antibacterial Drugs Topics
[General] -Lactam Antibiotics Aminoglycosides Macrolides, Lincomycin, And Clindamycin Tetracyclines Miscellaneous Antibiotics Quinolones Polypeptides Sulfonamides Trimethoprim-Sulfamethoxazole Antimicrobial Chemoprophylaxis
[General]
Selection of an Antibacterial Drug
Antibacterial, antirickettsial, and antifungal drugs are derived from bacteria or molds (the antibiotics) or novo synthesis. Antibiotics act on organisms by inhibiting cell wall synthesis and activating enzymes th destroy the cell wall, increasing cell membrane permeability, interfering with protein synthesis, and inte with nucleic acid metabolism.
Although etiology can often be inferred from symptoms, cultures and antibiotic sensitivities are essenti properly selecting a drug to treat most serious infections. Although it may be necessary to begin treatm critically ill patients before culture and sensitivity studies are completed, culture specimens should alw taken before therapy is begun.
Generally, drugs active in vitro are therapeutically effective. However, in vitro sensitivity of an organism antibiotic may not be a true index of the drug's clinical effectiveness, since efficacy depends in part on pharmacology of the drug (absorption, distribution, concentration in fluids and tissues, protein binding, of excretion or metabolism), the presence of drug interactions or of inhibiting substances, and host de mechanisms. The nature and gravity of the illness, the toxicity of the drug, the patient's history of hypersensitivity or other serious reaction, and the cost of the drug must also be considered.
Penicillins, cephalosporins, vancomycin, aminoglycosides, quinolones, and polymyxins are generally considered bactericidal (ie, they kill bacteria). Erythromycin, tetracyclines, chloramphenicol, clindamyc
pharmacology of the drug (absorption, distribution, concentration in fluids and tissues, protein binding, of excretion or metabolism), the presence of drug interactions or of inhibiting substances, and host de mechanisms. The nature and gravity of the illness, the toxicity of the drug, the patient's history of hypersensitivity or other serious reaction, and the cost of the drug must also be considered.
Penicillins, cephalosporins, vancomycin, aminoglycosides, quinolones, and polymyxins are generally considered bactericidal (ie, they kill bacteria). Erythromycin, tetracyclines, chloramphenicol, clindamyc lincomycin, clarithromycin, azithromycin, and sulfonamides are generally bacteriostatic (ie, they slow b growth). However, bactericidal drugs may be bacteriostatic against certain microorganisms and vice ve
In most infections, including pneumococcal pneumonia and UTI, there seems to be no advantage of bactericidal over bacteriostatic drugs. However, bactericidal activity seems to be necessary in infection which host defense mechanisms are at least partially lacking at the local site or systemically, eg, endo meningitis, serious staphylococcal infections, and serious gram-negative bacillary infection in neutrope patients.
Combinations of antibiotics are often necessary in serious infections, especially before the infecting organism's susceptibility pattern is known. Combinations are also frequently required in mixed infection are superior to single drugs in treating infections, in which resistance of the microorganism tends to de when only one drug is used (eg, TB). Combinations that rely on synergistic effects are required to trea enterococcal endocarditis, for which an aminoglycoside must be added to penicillin or vancomycin to p adequate bactericidal activity for cure. Combinations also seem to be important in leukopenic patients serious Pseudomonas aeruginosa infection; an aminoglycoside (eg, tobramycin) plus an antipseudom penicillin (eg, ticarcillin) may give better results than either agent alone.
Administration: Parenteral administration, preferably IV, is usually mandatory in severe infection; ora preparations are often used for maintenance once the infection is under control. Therapy should be co until objective evidence shows that systemic infection has been absent for several days (eg, absence leukocytosis, and abnormal laboratory findings).
Doses of antibiotics excreted mainly in the urine must be adjusted when given to patients with impaire function. Such patients may tolerate the usual doses for the first 24 h, but subsequent doses must be or the intervals between them prolonged. Monitoring and adjustment are also important in infants (see Neonatal Infections in Ch. 260) and the elderly.
Direct toxicity or hypersensitivity may produce undesirable effects with any antibiotic and can involve m organ systems. Adverse reactions do not always require stopping treatment, especially if the offending the only one effective. The severity and type of reactions, their expected course, the possibility of influ them by proper management, and the gravity of the infection must be considered. Complications of chemotherapy appear in Table 153-1.
Organisms may develop resistance to any drug, either rapidly or after long or repeated courses of the Resistance is avoided by controlling infections promptly. Inadequate doses promote the development resistance; thereafter, even greatly increased doses may fail to control the infection.
Misuses of chemotherapy: Antibacterial drugs are often used without a valid indication (such as for v illness) or are used improperly. The most frequent misuse is probably in the treatment of fever that doe appear to be due to bacterial infection. Without strong evidence of bacterial invasion, antibiotic therapy be delayed, if possible, until clinical and laboratory studies confirm the infection.
Common misuses and errors include choosing an ineffective antibiotic, giving inadequate or excessive treating nonbacterial infections such as uncomplicated viral disease, using an improper route of admin continuing use after bacterial resistance has developed, continuing in the presence of a serious toxic o reaction, prematurely stopping effective therapy, using improper combinations of chemotherapeutic dr
be delayed, if possible, until clinical and laboratory studies confirm the infection.
Common misuses and errors include choosing an ineffective antibiotic, giving inadequate or excessive treating nonbacterial infections such as uncomplicated viral disease, using an improper route of admin continuing use after bacterial resistance has developed, continuing in the presence of a serious toxic o reaction, prematurely stopping effective therapy, using improper combinations of chemotherapeutic dr relying on chemotherapy or prophylaxis to the exclusion of surgical intervention (eg, drainage of localiz infection and removal of a foreign body).

Section 13. Infectious Diseases Chapter 161. Parasitic Infections Topics
[General] Extraintestinal Protozoa Infections With Free-Living Amebas Intestinal Protozoa Nematode (Roundworm) Infections Trematode (Fluke) Infections Cestodes (Tapeworms)
[General]
(See also Creeping Eruption in Ch. 114, Trichomoniasis in Ch. 164, and Pinworm Infestation in Ch. 26
Parasitic infections are common in Africa, Asia, and Central and South America but are relatively rare elsewhere. Persons from industrialized countries traveling to endemic areas often can reduce risk by f strict rules for eating and bathing and taking simple measures to minimize exposure. Casual visitors fr endemic countries are not likely to spread parasitic diseases, because the environmental requirement vectors, or intermediary hosts needed for transmission of many parasitic infections often are not prese industrialized countries. However, transmission of imported infections may occur via the fecal-oral rout blood transfusions or organ transplants, or by a suitable local vector.
The latest recommendations to prevent certain parasitic infections may be obtained from the Centers Disease Control and Prevention (CDC) in Atlanta. Advice about treating unfamiliar infections may be a from major medical or public health centers. Several drugs not commercially available in the USA can obtained when necessary from the Parasitic Diseases Branch of the CDC.
Laboratory Diagnosis of Parasitic Infections

Methods for the diagnosis of specific infections are summarized in Table 161-1.
Many protozoa and the eggs of some helminths are shed sporadically. Routine detection of intestinal o parasites requires examination of at least three stool specimens, preferably collected every other day consecutive days.
Freshly passed stools uncontaminated with urine, water, dirt, or disinfectants should be sent to the exa laboratory within 1 h, particularly if they are unformed or diarrheal (ie, likely to contain motile trophozoi
Many protozoa and the eggs of some helminths are shed sporadically. Routine detection of intestinal o parasites requires examination of at least three stool specimens, preferably collected every other day consecutive days.
Freshly passed stools uncontaminated with urine, water, dirt, or disinfectants should be sent to the exa laboratory within 1 h, particularly if they are unformed or diarrheal (ie, likely to contain motile trophozoi Formed stools may be refrigerated (but not frozen) if not examined immediately and need not be kept while in transit. If possible, portions of fresh stools should be emulsified in fixative to preserve GI proto Thin fecal smears preserved in Schaudinn's fixative are also useful. If necessary, stool samples can b concentrated by the formalin-ether, zinc flotation, sugar-coverslip, or Baerman techniques. Anal swabs demonstrate pinworm or tapeworm eggs. Antibiotics, x-ray contrast material, purgatives, and antacids detection of ova and parasites for several weeks.
Sigmoidoscopy should be considered when routine stool examinations are negative in patients suspec amebiasis or schistosomiasis. Sigmoidoscopic specimens should be collected with a curet or a Volkm spoon (cotton swabs are not suitable) and processed immediately for microscopy. If giardiasis or strongyloidiasis is suspected in patients with a negative stool examination, duodenal aspirates or string may be performed. Small-bowel biopsies may be necessary for the diagnosis of such infections as cryptosporidiosis.

Section 13. Infectious Diseases Chapter 154. Antiviral Drugs Topics
[General] Antiviral Drugs For HIV Infection
[General]
The development of drugs against HIV has resulted in a dramatic expansion of new antiviral chemothe drugs. The applications of some of these drugs are being evaluated for other viral infections such as h B virus (HBV). Other advances include development of drugs with improved bioavailability for common infections such as herpes simplex virus (HSV) and varicella-zoster virus (VZV).
Chemotherapeutic intervention can occur before or at the time of viral particle attachment to host cell membranes, during uncoating of viral nucleic acids, by inhibiting a cellular receptor or factor required f replication, or by blocking specific virus-coded enzymes and proteins produced in the host cells that ar essential for viral replication but not for normal host cell metabolism.
Idoxuridine
Idoxuridine (IDU) acts by irreversibly replacing thymidine in newly synthesized DNA and producing an abnormal and essentially nonfunctional DNA molecule. The drug acts on viral and host cell DNA and i toxic to host cells. Because of its high systemic toxicity, IDU has been limited to topical therapy of herp simplex keratoconjunctivitis. Two topical ophthalmic preparations are available. One drop of a 0.1% so instilled conjunctivally q 1 h during waking hours and q 2 h at night. Treatment should be continued for days after complete healing to lessen the chance of recurrence. IDU may cause irritation, pain, pruritu inflammation or edema of the eyelids; rare allergic reactions and photophobia have also been reported
Vidarabine
Vidarabine (adenine arabinoside, ara-A) interferes with viral DNA synthesis and is effective in the treat HSV infections. Vidarabine appears less susceptible to the development of drug-resistant viral strains IDU, and IDU-resistant infections often respond to vidarabine. Ophthalmic preparations of vidarabine a effective for acute keratoconjunctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2.
Vidarabine (adenine arabinoside, ara-A) interferes with viral DNA synthesis and is effective in the treat HSV infections. Vidarabine appears less susceptible to the development of drug-resistant viral strains IDU, and IDU-resistant infections often respond to vidarabine. Ophthalmic preparations of vidarabine a effective for acute keratoconjunctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2. ophthalmic ointment is instilled 1 cm inside the lower conjunctival sac of the affected eye 5 times/day w awake (q 3 h). Treatment should be continued for 5 to 7 days after complete healing to prevent recurre Possible adverse effects include tearing, irritation, pain, photophobia, and superficial punctate keratitis
Trifluridine
Trifluridine (trifluorothymidine), a thymidine analog, interferes with DNA synthesis and is effective in tre primary keratoconjunctivitis and recurrent keratitis caused by HSV-1 and HSV-2. Trifluridine is as effec vidarabine and may be effective in patients who have not responded to IDU or vidarabine. The marrow-suppressive effect of trifluridine precludes systemic use. Trifluridine has been used to treat acyclovir-resistant cutaneous HSV in immunocompromised patients with variable success. One drop o ophthalmic solution should be instilled into the affected eye q 2 h while the patient is awake. The maxi recommended dose is 9 drops/day until the corneal ulcer has reepithelialized, then 5 drops/day (1 dro while awake) for 7 days. If the condition does not improve in 7 days, another drug should be used. Adv effects include burning or stinging in the eye and palpebral edema; less frequently, punctate keratopat hypersensitivity reactions develop.
Acyclovir
Acyclovir is a purine nucleoside analog with activity against herpes viruses (in order of potency): HSVHSV-2, VZV, Epstein-Barr virus (EBV). It has minimal activity against cytomegalovirus (CMV). Viral thy kinase converts acyclovir into acyclovir monophosphate, which is further converted by cellular enzyme active triphosphate compound that competitively inhibits deoxyguanosine triphosphate for viral DNA polymerase. This active compound, when incorporated into viral DNA, terminates synthesis. Immunocompromised patients who require prolonged treatment may develop resistance via a mutatio viral thymidine kinase.
Oral acyclovir is effective for primary and recurrent genital HSV (see also Genital Herpes in Ch. 164). I primary genital HSV, oral acyclovir 400 mg po tid or 200 mg po q 6 h for 10 days shortens the clinical c reduces pain, and decreases viral shedding. For episodic recurrences, acyclovir 200 mg q 4 h should started at first sign of infection. Suppression is more efficacious and should be considered if a patient more than six outbreaks of genital HSV a year, with titration of 200 mg 2 to 5 times a day, 400 mg bid, mg daily. Adverse effects are infrequent with oral administration, but nausea, vomiting, diarrhea, head and rashes have been reported. Dose should be adjusted for renal insufficiency. Immunocompromised patients who have frequent outbreaks may require higher doses to overcome partial thymidine kinase mutations. If patients are resistant to acyclovir, alternatives such as foscarnet may be tried.
IV acyclovir is indicated when a higher serum level of drug is required, as in herpes encephalitis. In clin trials, acyclovir 10 mg/kg IV q 8 h has been more effective than vidarabine for herpes encephalitis. It re mortality and improves functional capacity of survivors. As with vidarabine, the best response is in you patients who begin therapy before onset of coma. In neonatal herpes infections, acyclovir 30 mg/kg/da divided q 8 h for 10 to 14 days is more effective than vidarabine and requires less fluid for administrati Adverse effects include phlebitis, rash, and neurotoxicity resulting in lethargy, confusion, seizures, or c
Depending on extent of disease and host immune status, either IV or oral acyclovir is effective in prima varicella. It reduces complications of varicella in immunocompromised patients and pregnant women.
mortality and improves functional capacity of survivors. As with vidarabine, the best response is in you patients who begin therapy before onset of coma. In neonatal herpes infections, acyclovir 30 mg/kg/da divided q 8 h for 10 to 14 days is more effective than vidarabine and requires less fluid for administrati Adverse effects include phlebitis, rash, and neurotoxicity resulting in lethargy, confusion, seizures, or c
Depending on extent of disease and host immune status, either IV or oral acyclovir is effective in prima varicella. It reduces complications of varicella in immunocompromised patients and pregnant women. immunocompetent adults, oral acyclovir may reduce duration of fever and vesicles. For herpes zoster, po 5 times/day has been shown to reduce the time to healing of lesions and, particularly in older patien prevalence of postherpetic neuralgia. Acyclovir is also effective in reducing complications of herpes zo ophthalmicus.
Famciclovir
Famciclovir is a pro-drug of the active antiviral penciclovir. It inhibits HSV-1, HSV-2, and VZV. It has m activity against EBV and minimal activity against CMV. In addition, it reduces HBV viral load in patients chronic HBV and is undergoing further study for this application. Famciclovir is 77% bioavailable and is converted to penciclovir in the intestine and liver. Penciclovir is phosphorylated by the viral thymidine k a monophosphate form, which is converted to penciclovir triphosphate by cellular kinases, which in tur viral DNA polymerase. Famciclovir is as effective as acyclovir in the treatment of genital herpes and he zoster and is more bioavailable. Strains resistant to acyclovir will also be resistant to famciclovir.
For primary genital HSV, the dosage is 250 mg po tid for 5 days or, for episodic treatment, 125 mg po days. Treatment must be initiated immediately. Suppressive dose is 250 mg po daily. For herpes zoste famciclovir 500 mg po tid decreased healing time and, in older patients, reduced duration of postherpe neuralgia compared with placebo. Treatment should be started within 72 h. Adverse effects are similar with oral acyclovir (see above).
Penciclovir
Penciclovir is a guanosine analog that is phosphorylated; it competitively inhibits HSV-1 and HSV-2 vir polymerase. Penciclovir 1% cream is used to treat recurrent orolabial HSV in adults. In clinical trials, p reduced in 3.5 days with penciclovir vs. 4.1 days with placebo if applied within 1 h of recurrent HSV an repeatedly applied every 2 h while awake. Acyclovir-resistant strains are cross-resistant, and adverse did not occur more often in the treatment group as compared with placebo.
Valacyclovir
Valacyclovir is the hydrochloride salt of l-valyl ester of acyclovir. It is active against HSV-1, HSV-2, and is modestly active against EBV and minimally active against CMV. Valacyclovir is converted to acyclov first-pass intestinal and hepatic metabolism; the bioavailability of acyclovir after conversion is 54%, wh three to five times higher than that of oral acyclovir.
Valacyclovir is effective in treating and suppressing genital herpes. Valacyclovir and acyclovir equally r healing time and length of episode compared with placebo when used within 24 h of initial symptoms. dosage for primary genital HSV is 1 g po bid for 10 days; for recurrent genital HSV, 500 mg po bid for Suppressive therapy is more efficacious and should be considered if a patient has more than six outbr year; the dose is titrated to 500 mg po bid or daily.
Early treatment of herpes zoster with valacyclovir demonstrated improvement in healing time and, in o
healing time and length of episode compared with placebo when used within 24 h of initial symptoms. dosage for primary genital HSV is 1 g po bid for 10 days; for recurrent genital HSV, 500 mg po bid for Suppressive therapy is more efficacious and should be considered if a patient has more than six outbr year; the dose is titrated to 500 mg po bid or daily.
Early treatment of herpes zoster with valacyclovir demonstrated improvement in healing time and, in o patients, duration of postherpetic neuralgia. Valacyclovir 1 g po tid for 7 days was shown to be modera superior to acyclovir (800 mg 5 times/day) for decreasing postherpetic neuralgia. Adverse effects are s those of acyclovir (see above). Very high doses of valacyclovir given to AIDS patients (8 g daily) may c thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome.
Ganciclovir
Ganciclovir is a nucleoside analog of 2-deoxyguanosine that differs from acyclovir by an additional hydroxymethyl group on the side chain. It has in vitro activity against all herpes viruses, including CMV Ganciclovir is primarily used in patients with HIV and CMV retinitis. Ganciclovir inhibits viral DNA synth competitive inhibition of viral DNA polymerase and is incorporated into viral DNA as DNA chain termin phosphorylated by viral thymidine kinase of HSV or VZV and by a kinase unique to CMV. Mutations in viral enzymes results in resistance (eg, HSV resistant to acyclovir is cross-resistant to ganciclovir). Its adverse effect is bone marrow suppression, particularly neutropenia. Severe neutropenia, ie, < 500/L requires bone marrow stimulation with granulocyte colony-stimulating factor or granulocyte-macrophag colony-stimulating factor or discontinuation if indicated. Less common adverse effects include anemia fever, azotemia, liver function abnormalities, nausea, and vomiting.
Oral ganciclovir has very low bioavailability (about 6 to 9%). At the standard dose of 1 g po tid, time to progression of CMV retinitis after an IV induction course is prolonged. The oral formulation is convenie reduces risks associated with indwelling catheters, but patients who have vision-threatening diseases the IV formula for maintenance (see below). Most patients with CMV retinitis will relapse on suppressiv therapy and should be reinduced with the IV formulation; if reinduction fails, another drug is required. O ganciclovir for primary prophylaxis of CMV disease may be beneficial in selected patients, although ad effects and the formulation, which requires 12 capsules/day, limit its usefulness. Oral ganciclovir is als prophylaxis to prevent CMV infection in some transplant recipients during the initial profound immune suppressive period.
For CMV infection, patients are initially treated with 10 mg/kg/day IV in 2 divided doses for 2 to 3 wk an require suppressive therapy to prolong time to relapse at 5 mg/kg/day. Oral ganciclovir can also be us suppressive therapy.
IV ganciclovir with immune globulin has reduced mortality of CMV pneumonitis in bone marrow transp patients; nevertheless, a significant mortality rate remains.
Intravitreal injections of ganciclovir 400 g, administered through the pars plana, are used for patients CMV retinitis who are resistant to IV ganciclovir or who cannot tolerate the IV formula. Compared with ganciclovir, a twice-weekly induction period, followed by weekly intravitreal injections, controls retinitis well. Potential complications include vitreous hemorrhage, retinal detachment, cystoid macular edema endophthalmitis, cataract formation, and possible retinal toxicity.
Alternatively for CMV retinitis, an intraocular device can be implanted every 6 mo through the pars pla the vitreous cavity, where it releases ganciclovir at a constant rate. Stabilization of retinitis is similar to IV ganciclovir; in addition, the progression of retinitis is significantly delayed. Implants may be benefici patients resistant to IV ganciclovir because high local concentrations can often overcome resistance. Nevertheless, systemic therapy is needed to prevent retinitis in the contralateral eye and to decrease r
Alternatively for CMV retinitis, an intraocular device can be implanted every 6 mo through the pars pla the vitreous cavity, where it releases ganciclovir at a constant rate. Stabilization of retinitis is similar to IV ganciclovir; in addition, the progression of retinitis is significantly delayed. Implants may be benefici patients resistant to IV ganciclovir because high local concentrations can often overcome resistance. Nevertheless, systemic therapy is needed to prevent retinitis in the contralateral eye and to decrease r extraocular CMV disease. Short-term complications of hemorrhage, retinal detachment, and developm disease in the contralateral eye must be weighed against the benefit of implants.
Foscarnet
Foscarnet is an organic analog of inorganic pyrophosphate. It selectively inhibits virus-specific DNA polymerase and reverse transcriptase. It is not phosphorylated by viral thymidine kinase and therefore against acyclovir-resistant HSV/VZV strains. In addition, ganciclovir-resistant CMV should be sensitive foscarnet. Foscarnet also inhibits HSV-1, HSV-2, human herpes virus 6, EBV, and VZV. Foscarnet's e similar to that of ganciclovir for treating and delaying progression of CMV retinitis, with a different adve effect profile; in addition, it has some anti-HIV activity.
For treatment of CMV retinitis in HIV disease, an induction with 60 mg/kg tid or 90 mg/kg IV bid for 2 w followed by maintenance of 90 to 120 mg/kg IV daily. The higher maintenance dose may slow time to Combination therapy of ganciclovir with foscarnet for CMV in HIV prolongs therapeutic effect and dela progression, although the combined adverse effects are severe and more frequent than with monothe Foscarnet has also been used for CMV disease in other immunocompromised patients.
Intravitreal foscarnet has been used in patients with contraindications to other regimens. Doses betwe and 2400 g have been used with an induction period of twice a week for 3 wk, followed by weekly inje Potential adverse effects include direct retinal toxicity, intravitreal bleeding, and endophthalmitis. Adve effects of IV foscarnet are significant and include nephrotoxicity, symptomatic hypocalcemia, hypomagnesemia, phosphatemia, hypokalemia, and CNS effects.
Ribavirin
Ribavirin is a guanosine analog that inhibits the replication of many RNA and DNA viruses. Its exact mechanism of action is undefined, but it appears to inhibit messenger RNA formation. Ribavirin exhibi inhibitory activity in vitro against respiratory syncytial virus (RSV), influenza A and B, HSV-1, HSV-2, a other viruses. Its use is considered in high-risk infants, young children, and immunocompromised adul severe lower respiratory tract infection due to RSV. The aerosolized drug needs to be initiated within th few days of infection. Aerosolized ribavirin may have some activity against influenza A, influenza B, an parainfluenza, but its role in treatment is not defined. Ribavirin is mutagenic to mammalian cells in cult appropriate measures to protect health care workers from the aerosolized drug are necessary. Advers of aerosolized ribavirin include worsening of respiratory status.
IV ribavirin decreases mortality in severe Lassa fever. Some data and early human studies demonstra IV ribavirin is effective in reducing morbidity and mortality of hantavirus pulmonary syndrome. A signifi adverse effect of the IV formula is hemolysis.
Amantadine and Rimantadine
Both drugs are used primarily for influenza A prophylaxis and treatment. They inhibit penetration or un of the virus, thus blocking the early stage of virus-host interaction. They should be used within 48 h of
Amantadine and Rimantadine
Both drugs are used primarily for influenza A prophylaxis and treatment. They inhibit penetration or un of the virus, thus blocking the early stage of virus-host interaction. They should be used within 48 h of influenza A illness to decrease severity and duration of symptoms. They are also indicated for prophyl unvaccinated patients or health care workers during outbreaks or for patients in whom the vaccine is contraindicated or ineffective. These drugs will not interfere with the development of immunity from the vaccine.
Prophylactic dosage of amantadine for ages 14 to 64 yr is 100 mg po bid for the duration of the epidem until immunity from the vaccine develops (typically 2 wk after administration). For patients >= 65 yr of a dose is 100 mg/day. When used for treatment of influenza A, the dose is the same; however, resistanc these drugs rapidly emerges, so treatment should be discontinued as soon as clinically warranted, ie, days of treatment or 1 to 2 days after symptoms resolve. Amantadine is excreted renally, and dosage adjusted for the elderly and for patients with renal impairment. Rimantadine is primarily metabolized in liver. The dose of rimantadine is 100 mg po bid for ages 14 to 64 yr or 100 to 200 mg for patients > 64
Adverse effects, which are more common with amantadine, primarily affect the CNS, including nervou insomnia, light-headedness, dizziness, slurred speech, ataxia, inability to concentrate, hallucinations, a depression, but anorexia, nausea, and constipation may also occur. Adverse effects usually develop w h after starting the drug and often resolve during continued use.
Cidofovir
Cidofovir (cytosine; HPMPC) is a nucleotide analog and, in contrast to nucleoside analogs, contains a phosphonate group that does not require virus-dependent phosphorylation. Cellular enzymes convert to the active diphosphate form, which has a long intracellular half-life. Cidofovir has inhibitory in vitro a against a broad spectrum of viruses, including HSV-1, HSV-2, VZV, CMV, EBV, adenovirus, human papillomavirus (HPV), and human polyomavirus. It is used to treat CMV retinitis in patients with HIV. In therapy for CMV retinitis in HIV-infected patients consists of IV treatment 5 mg/kg once weekly for 2 w maintenance therapy every other week. Efficacy is similar to ganciclovir or foscarnet. Significant adver effects include renal failure, heralded by proteinuria, which is prevented by use of probenecid. Howeve adverse effects of probenecid, including rash, headache, and fever, may be significant enough to prev use.
Topical cidofovir is used for mucocutaneous herpes simplex unresponsive to oral or IV acyclovir. Spec intravitreal formulations of cidofovir (20-g injections) have been used for patients with resistant CMV as salvage therapy, although significant potential adverse effects include iritis and hypotony despite probenecid.
Oligonucleotides
These antisense molecules contain oligodeoxynucleotide structures complementary to gene sequence target virus. Phosphorothioate oligonucleotides that are complementary to viral RNA have demonstrat inhibition of viral replication in cell cultures. ISIS 2922 is a phosphorothioate oligonucleotide with poten antiviral activity against CMV; it is complementary to the RNA of region 2 of the immediate early transc unit of CMV and inhibits protein synthesis. It is being studied as an intravitreal treatment for CMV retin Adverse effects include vitreitis and retinal pigment epithelial stippling.
These antisense molecules contain oligodeoxynucleotide structures complementary to gene sequence target virus. Phosphorothioate oligonucleotides that are complementary to viral RNA have demonstrat inhibition of viral replication in cell cultures. ISIS 2922 is a phosphorothioate oligonucleotide with poten antiviral activity against CMV; it is complementary to the RNA of region 2 of the immediate early transc unit of CMV and inhibits protein synthesis. It is being studied as an intravitreal treatment for CMV retin Adverse effects include vitreitis and retinal pigment epithelial stippling.
Immune Globulins
Hyperimmune CMV immunoglobulin has attenuated CMV disease associated with kidney transplantat has not proved useful in preventing CMV disease in HIV-infected persons. A human monoclonal anticytomegalovirus antibody may be useful as adjunctive therapy with foscarnet or ganciclovir for trea CMV retinitis.
Interferons
Interferons are natural cellular products released from infected host cells in response to viral or other f nucleic acids. They are detectable as early as 2 h after infection. Their complex mechanism of action h been fully established, but interferon selectively blocks translation and transcription of viral RNA, stopp replication without disturbing normal host cell function.
A recombinant form of endogenous interferon- is being studied in selected patients with hairy cell leuk Kaposi's sarcoma, human papillomavirus, and respiratory viruses. It is used primarily for hepatitis B an Patients with active HBV or hepatitis C virus (HCV) with detectable viral loads and abnormal liver funct may benefit from therapy.
In patients with HBV who fit appropriate criteria, 2.5 to 5 million U sc or IM for 4 to 6 mo can induce cle of HBV DNA and the hepatitis B e antigen (HBeAg) from serum and improve liver function test abnorm and liver histology in 25 to 40% of patients. For chronic delta hepatitis, higher doses in the range of 9 t million U 3 times/wk are required, and relapse is very common. For HCV, 3 to 6 mo of 3 to 6 million U times/wk for 6 to 12 mo typically decreases HCV RNA level and improves liver function tests and liver in 10 to 25%. Adverse effects include fever, chills, weakness, and myalgia typically starting 7 to 12 h a injection and lasting up to 12 h. The lower dose used in HCV leads to less severe adverse effects, alth worsening of hepatitis has been reported. Addition of ribavirin to interferon for HCV shows promise.

Section 13. Infectious Diseases Chapter 162. Viral Diseases Topics
[General] Respiratory Viral Diseases Herpesvirus Infections Central Nervous System Viral Diseases Arbovirus And Arenavirus Diseases Smallpox
[General]
Viruses are the smallest of parasites; they are completely dependent on cells (bacterial, plant, or anim reproduce. Viruses are composed of an outer cover of protein and sometimes lipid, and a nucleic acid RNA or DNA. In many cases, this core penetrates susceptible cells and initiates the infection.
Viruses range from 0.02 to 0.3 ; too small for light microscopy but visible using electron microscopy. can be identified by biophysical and biochemical methods. Like most other parasites, viruses stimulate antibody production.
Several hundred different viruses infect humans. Because many have been only recently recognized, clinical effects are not fully understood. Many viruses infect hosts without producing symptoms; nevert because of their wide and sometimes universal prevalence, they create important medical and public h problems.
Viruses that primarily infect humans are spread mainly via respiratory and enteric excretions. These vi (see Table 162-1) are found worldwide, but their spread is limited by inborn resistance, prior immunizin infections or vaccines, sanitary and other public health control measures, and prophylactic antiviral dru
Zoonotic viruses pursue their biologic cycles chiefly in animals; humans are secondary or accidental h These viruses (see Table 162-2) are limited to areas and environments able to support their nonhuma cycles of infection (vertebrates or arthropods or both).
Some viruses have oncogenic properties. Human T-cell lymphotropic virus type 1 (a retrovirus) is asso with human leukemia and lymphoma. Epstein-Barr virus has been associated with malignancies such nasopharyngeal carcinoma (see Ch. 87), Burkitt's lymphoma (see Ch. 139), Hodgkin's disease, and lymphomas in immunosuppressed organ transplant recipients (see Ch. 149). Kaposi's sarcoma-assoc virus is associated with Kaposi's sarcoma (see Ch. 126), primary effusion lymphomas, and Castleman
Some viruses have oncogenic properties. Human T-cell lymphotropic virus type 1 (a retrovirus) is asso with human leukemia and lymphoma. Epstein-Barr virus has been associated with malignancies such nasopharyngeal carcinoma (see Ch. 87), Burkitt's lymphoma (see Ch. 139), Hodgkin's disease, and lymphomas in immunosuppressed organ transplant recipients (see Ch. 149). Kaposi's sarcoma-assoc virus is associated with Kaposi's sarcoma (see Ch. 126), primary effusion lymphomas, and Castleman disease (a lymphoproliferative disorder).
Slow viral diseases are characterized by prolonged incubations and cause some chronic degenerative diseases, including subacute sclerosing panencephalitis (measles virus), progressive rubella panence progressive multifocal leukoencephalopathy (JC virus), and Creutzfeldt-Jakob disease (a prion disease Slow Virus Infections, below, and Subacute Sclerosing Panencephalitis and Progressive Rubella Panencephalitis in Ch. 265.)
Latency--a quiescent infection by a virus--permits recurrent infection despite immune responses and fa person-to-person spread. Herpesviruses exhibit latency.
Diagnosis
Only a few viral diseases can be diagnosed clinically or epidemiologically (eg, by well-known viral syndromes--see Measles, Rubella, Roseola Infantum, Erythema Infectiosum, and Chickenpox under V Infections in Ch. 265). Diagnosis usually requires testing. Serologic examination during acute and convalescent stages is sensitive and specific but slow; more rapid diagnosis can sometimes be made culture, polymerase chain reaction, or viral antigen tests. Histopathology can sometimes be helpful. Sp diagnostic procedures are described elsewhere in The Manual. Many state health laboratories and the for Disease Control and Prevention offer diagnostic help.
Prophylaxis and Treatment
Effective vaccines in general use for active immunity include influenza, measles, mumps, poliomyelitis rubella, hepatitis A, hepatitis B, varicella, and yellow fever. An effective adenovirus vaccine is available used only in high-risk groups, such as military recruits. Immune globulins are also available for passive immune prophylaxis (see also Ch. 152 and Childhood Immunizations in Ch. 256).
Effective therapeutic or prophylactic drugs against some viruses are available: amantadine or rimantad influenza A; acyclovir, valacyclovir, and famciclovir for herpes simplex or varicella-zoster infections; ga foscarnet, and cidofovir for cytomegalovirus infections; and reverse transcriptase inhibitors, protease i and others for HIV. Currently, the use of interferon is limited to hepatitis B and C and human papilloma (See also Ch. 154.)

Section 13. Infectious Diseases Chapter 155. Abscesses Topics
[General] Intra-Abdominal Abscesses Prostatic Abscesses Head And Neck Abscesses Pyomyositis
[General]
Pathogenesis
Abscesses: Collections of pus in tissues, organs, or confined spaces, usually caused by bacterial infec
The organisms that form abscesses are myriad; many are also discussed elsewhere in The Manual. In particular, anorectal abscesses are discussed in Ch. 35; hand abscesses, in Ch. 61; lung abscesses, 74; cutaneous abscesses, in Ch. 112; mixed anaerobic infections, in Ch. 157; and brain and spinal co abscesses, in Chs. 176 and 182, respectively.
Organisms causing an abscess may enter the tissue by direct implantation (eg, penetrating trauma wit contaminated object); spread from an established, contiguous infection; dissemination via lymphatic o hematogenous routes from a distant site; or migration from a location where they are resident flora into adjacent, normally sterile area because of disruption of natural barriers (eg, perforation of an abdomin causing an intra-abdominal abscess).
Predisposing factors to abscess formation include impaired host defense mechanisms (eg, abnormal l function); the presence of foreign bodies; obstruction to normal drainage of the urinary, biliary, or resp tracts; tissue ischemia or necrosis; hematoma or excessive fluid accumulation in tissue; and trauma.
Abscesses may begin as cellulitis (see Ch. 112). Separation of cellular elements by fluid or space crea cellular necrosis from another cause provides an area where leukocytes can accumulate and form an Progressive dissection by pus or the necrosis of surrounding cells expands the abscess. Highly vascul connective tissue may then invade and surround the necrotic tissue, leukocytes, and debris to wall off abscess and limit further spread.
Symptoms, Signs, and Complications
cellular necrosis from another cause provides an area where leukocytes can accumulate and form an Progressive dissection by pus or the necrosis of surrounding cells expands the abscess. Highly vascul connective tissue may then invade and surround the necrotic tissue, leukocytes, and debris to wall off abscess and limit further spread.
The symptoms and signs of cutaneous and subcutaneous abscesses are heat, swelling, tenderness, a redness over the affected site. Fever may occur, especially with surrounding cellulitis. For deep absce local pain and tenderness with systemic symptoms, especially fever, as well as anorexia, weight loss, fatigue are typical. The predominant manifestation of some abscesses is abnormal organ function, eg, hemiplegia with a brain abscess.
Complications of abscesses include bacteremia, with spread of infection to distant sites; rupture into a tissue; bleeding from vessels eroded by inflammation; impaired function of a vital organ; and inanition systemic effects of anorexia and a catabolic state.
Treatment
Healing usually requires surgical drainage of the contents. Rupture of the abscess may result in spont drainage, sometimes associated with the formation of chronic draining sinuses. Without spontaneous surgical drainage, an abscess occasionally resolves slowly after proteolytic digestion of the pus produc thin, sterile fluid that is resorbed into the bloodstream. Incomplete resorption leaves a cystic loculation fibrous wall, where calcium salts sometimes precipitate to form a calcified mass.
Systemic antimicrobial drugs active against the responsible organisms are indicated for deep-seated in but are often ineffective without concurrent drainage. Adequate drainage consists of thoroughly remov necrotic tissue, and debris. To prevent reformation of the abscess, elimination of dead space by packi gauze or by placing drains may be necessary. Predisposing conditions, eg, obstruction or the presenc foreign body, require correction if possible. Gram stains and cultures followed by susceptibility studies isolates obtained from the abscess provide a guide to antimicrobial therapy.
Section 13. Infectious Diseases Chapter 163. Human Immunodeficiency Virus Infe Topics
[General]
[General]
Human immunodeficiency virus infection: Infection caused by one of two related retroviruses (HIV-1 an HIV-2) resulting in a wide range of clinical manifestations varying from asymptomatic carrier states to s debilitating and fatal disorders related to defective cell-mediated immunity.
Some retroviruses are oncogenic, and others have pathologic effects that alter normal cell function or cell death. Of the retroviruses known to infect humans, human T-cell lymphotrophic virus (HTLV) types are associated with lymphoid neoplasms and neurologic disease and less commonly with severe immunosuppression, whereas HIV causes immunosuppression but does not appear to cause neoplas directly.
HTLV-I and HTLV-II are both lymphotropic and oncogenic, type C retroviruses, causing adult T-cell leukemia/lymphomas in < 5% of infected persons. Expansion of CD4+ T (helper) lymphocytes in the tis and circulation leads to leukemia, diffuse lymphadenopathy, hepatosplenomegaly, and skin lesions. M patients appear to be immunosuppressed and some are subject to the same opportunistic infections a with advanced HIV infections. HTLV-I is also neurotropic, causing a progressive myelopathy (tropical s paraparesis or HTLV-associated myelopathy [HAM]) in < 1% of carriers. A few cases of myelopathy ha described in HTLV-II carriers. Clinically, HAM is a progressive spastic paraparesis with weakness, stiff numbness, dysesthesias of the legs, and urinary frequency and incontinence presenting within the firs after infection. (See also Tropical Spastic Paraparesis/HTLV-I-associated Myelopathy in Ch. 162.)
HTLV-I is transmitted sexually and through blood, but most infections appear to be transmitted vertica mother to child by breastfeeding. The patterns of disease and seroprevalence for HTLV-I suggest that widely, but not homogeneously, distributed. For example, high levels of HTLV-I are present in southern and the Caribbean and among IV drug users and prostitutes in some U.S. cities.
The human retrovirus that has had the greatest social and medical impact is HIV-1, which was identifie 1984 as the cause of a widespread epidemic of severe immunosuppression called acquired immunodeficiency syndrome (AIDS). AIDS is a disorder of cell-mediated immunity characterized by opportunistic infections, malignancies,
The human retrovirus that has had the greatest social and medical impact is HIV-1, which was identifie 1984 as the cause of a widespread epidemic of severe immunosuppression called acquired immunodeficiency syndrome (AIDS).
AIDS is a disorder of cell-mediated immunity characterized by opportunistic infections, malignancies, neurologic dysfunction, and a variety of other syndromes. AIDS is the most severe manifestation of a s of HIV-related conditions (see Symptoms and Signs, below). The risk that an untreated person infecte HIV will develop AIDS is estimated to be 1 to 2%/yr in the first several years after infection and about 5 thereafter. The cumulative risk is about 50% in the first decade. Almost all untreated HIV-infected pers eventually develop AIDS. Some long-term sequelae of HIV infection (eg, other malignancies and chron neurologic diseases) may not yet have been elucidated.
AIDS was initially defined by the development of serious opportunistic infections and/or certain second cancers, such as Kaposi's sarcoma and non-Hodgkin's lymphoma, known to be associated with defec cell-mediated immunity. The Centers for Disease Control and Prevention's 1993 definition categorizes adolescents and adults as asymptomatic (A), symptomatic with conditions attributable to HIV (B), and AIDS (C); see Tables 163-1 and 163-2. HIV patients are also categorized by CD4+ lymphocyte counts cells/L (1), 200 to 499 cells/L (2), < 200 cells/L (3). Many patients first become aware of their HIV i when diagnosed with a life-threatening opportunistic infection or malignancy without having experience preceding chronic symptoms.
Transmission
HIV transmission requires contact with body fluids containing infected cells or plasma. HIV may be pre any fluid or exudate that contains plasma or lymphocytes, specifically blood, semen, vaginal secretion milk, saliva, or wound exudates. Although theoretically possible, transmission by saliva or droplet nucl produced by coughing or sneezing is extremely rare, if it occurs. HIV is not transmitted by casual conta even by the close nonsexual contact that occurs at work, school, or home. The most common means transmission is direct transfer of bodily fluids either through sharing contaminated needles or sexual re
Sexual practices involving no exposure to bodily fluids are safe. Other practices, such as fellatio and cunnilingus appear to be relatively, but not absolutely, safe. The greatest risk is through genital interco especially anal-receptive intercourse. Sexual practices producing mucosal trauma before or during inte increase the risk. Use of latex, but not natural membrane, condoms or vaginal barriers decreases but eliminate risk. Oil-based lubricants decrease the protection provided by latex condoms because they d them.
Infected cells or free virions can reach target cells in a new host via blood transfusion, accidental injec mucous membrane exposure. The role of mucous membrane inflammation is illustrated by the effect o sexually transmitted diseases (STDs) on susceptibility to HIV infection. HIV transmission is definitely in by chancroid and may be more likely in the presence of herpes, syphilis, trichomoniasis, and possibly STDs.
Transmission of HIV by needle-stick injury, estimated at about 1/300 incidents, is much less frequent transmission of hepatitis B, presumably because of the relatively lower number of HIV virions in the blo most infected patients. Risk of HIV transmission appears to be increased by deep wounds or injection such as when hollow-bore needles containing blood penetrate the skin.
Risk of HIV transmission from infected medical personnel who observe good techniques to uninfect patients is very small but is less clear. Transmission from a single dentist to at least six of his patients been documented. However, extensive investigations of patients cared for by other HIV-infected physi and surgeons have failed to uncover other cases. The means of transmission of HIV from the dentist t
such as when hollow-bore needles containing blood penetrate the skin.
Risk of HIV transmission from infected medical personnel who observe good techniques to uninfect patients is very small but is less clear. Transmission from a single dentist to at least six of his patients been documented. However, extensive investigations of patients cared for by other HIV-infected physi and surgeons have failed to uncover other cases. The means of transmission of HIV from the dentist t patients is not understood and remains a troubling, but apparently unique, episode. Procedures or situ from which HIV-infected medical personnel should be excluded have not been clearly identified. Trans of HIV during medical care is a potential problem if transfused blood is not screened or medical instrum are not adequately sterilized.
Use of enzyme-linked immunosorbent assay (ELISA) (see below) to screen blood donors has vastly the risk of acquiring HIV by transfusion. However, persons in the early stages of HIV infection, who ha yet mounted an antibody response, may have transiently negative ELISA and Western blot results wh yielding positive results for HIV p24 antigen in plasma. These persons may account for the very low, b continuing, risk of transfusion-associated HIV infection (estimated at between 1/10,000 and 1/100,000 transfused). Currently mandated screening for both antibody and p24 antigen may further reduce this
Pathogenesis
Two closely related retroviruses, HIV-1 and HIV-2, have been identified as causing AIDS in different geographic regions. HIV-1 causes most cases of AIDS in the Western Hemisphere, Europe, Asia, and South, and East Africa; HIV-2 is the principal agent of AIDS in West Africa and appears less virulent th HIV-1. In certain areas of West Africa, both organisms are prevalent.
All retroviruses contain an enzyme called reverse transcriptase that converts viral RNA into a proviral D copy that becomes integrated into the host cell DNA. These integrated proviruses are duplicated by no cellular genes each time the cell divides. Thus, all progeny of the originally infected cell will contain the retroviral DNA. The proviral HIV DNA is both transcribed to RNA and translated to proteins to produce hundreds of copies of the infectious virus. Critical to the final step in the life cycle of HIV is another enz HIV protease. This enzyme converts immature, noninfectious HIV to its infectious form by splitting cruc proteins so they can rearrange within the virus after it has budded from an infected human cell.
HIV infects a major subset of T lymphocytes defined phenotypically by the T4 or CD4 transmembrane glycoprotein and functionally as helper/inducer cells. HIV also infects nonlymphoid cells, such as macrophages, microglial cells, and various endothelial and epithelial cells. Dendritic cells in the lymph can bind HIV at the cell surface but are not invaded. As a result of HIV infection, the numbers and func T cells, B cells, natural killer cells, and monocytes-macrophages are disturbed. Despite abnormalities other than CD4+ lymphocytes, much of the immunologic dysfunction in AIDS appears to be explained of the helper function of these lymphocytes, which is critical to cell-mediated immunity (see Ch. 146).
The best predictors of onset of the serious opportunistic infections that define AIDS (see Table 163-1 the total number of circulating CD4 + lymphocytes (CD4 count) and the level of HIV RNA in plasma (vir The CD4 count is the product of the WBC count, the percentage of lymphocytes in the WBCs, and th percentage of lymphocytes that bear the CD4 marker. Normal counts are about 750 250 cells/L, bu are usually reduced by about 40 to 50% early in HIV infection. Vulnerability to opportunistic infections increases markedly when CD4 lymphocyte levels are < 200/L. Other evidence of decreased cell-med immunity is loss of delayed hypersensitivity to intradermally injected antigens such as the PPD skin tes The viral load (number of HIV-1 RNA copies in 1 mL of plasma) provides a useful predictor of future c course and measure of responses to antiretroviral therapy. Levels of HIV-1 RNA increase with advanc immunosuppression, but high levels also predict the future rates of decline in CD4 counts, even in pat without symptoms or evidence of severe immunosuppression (> 500 CD4 cells/L). The risk of progre AIDS or death appears to increase about 50% for every threefold increase in plasma viral RNA.
immunity is loss of delayed hypersensitivity to intradermally injected antigens such as the PPD skin tes The viral load (number of HIV-1 RNA copies in 1 mL of plasma) provides a useful predictor of future c course and measure of responses to antiretroviral therapy. Levels of HIV-1 RNA increase with advanc immunosuppression, but high levels also predict the future rates of decline in CD4 counts, even in pat without symptoms or evidence of severe immunosuppression (> 500 CD4 cells/L). The risk of progre AIDS or death appears to increase about 50% for every threefold increase in plasma viral RNA.
Suppressor/cytotoxic CD8+ lymphocytes appear to be functionally normal and increased in number in infection, which may contribute further to immunosuppression and results in reduction of the CD4:CD8 (normally 2:1) to < 1. Because other viral infections (eg, CMV, Epstein-Barr virus, influenza, hepatitis B produce transient reductions in the CD4:CD8 ratio, decreased ratios are not specific.
Concepts of how HIV disrupts the immune system have been radically changed by the discovery of hig of both production and removal of HIV, as revealed by the rapid reduction of plasma HIV RNA during t with potent antiretroviral drugs. The median turnover time of HIV RNA in plasma (time taken for half of virions to be replaced) is estimated to be less than a day, corresponding in moderate to heavy HIV infe a turnover of about 108 to 109 virions/day. This rapid viral replication provides many opportunities for m and thereby the possibility for rapid emergence of viral mutants resistant to antiretroviral drugs. For inf CD4 cells, the half-life is slower (about 2 days). It appears that newly infected CD4 cells contribute > 9 plasma RNA; after about 2 days of viral replication, these cells die. Thus, even asymptomatic patients constantly destroying their CD4 cells at rates determined by the level of plasma RNA. During effective therapy, plasma HIV RNA levels fall within days and reach lower plateaus or become undetectable wit weeks or months. These insights and a host of powerful new antiretroviral drugs have radically change approach to antiretroviral therapy (see below).
The relationship of RNA in plasma to levels in lymph nodes and the brain is under intense investigatio because the effect of treatment on these reservoirs of HIV in the body is unclear. Even when combina therapy reduces plasma HIV RNA to unmeasurable levels, virus remains detectable in lymph nodes fo years. CSF levels of HIV RNA in patients treated effectively with drugs such as nucleoside analog reve transcriptase inhibitors (eg, zidovudine or stavudine) are usually unmeasurable and may reflect levels brain, but this is not yet proven. Targeting HIV in these reservoirs may be a crucial step in eliminating infection in individual patients.
The pattern of loss of CD4+ lymphocytes proceeds in three phases and at rates that vary from patie patient. Within the first months of infection, circulating CD4+ cell numbers drop rapidly. A prolonged pe slower decline may be followed by another more rapid decline in the 1- to 2-yr period before AIDS dev Variation in lymphocyte depletion rates over time and between persons appears to correlate with level RNA in plasma. The mechanisms underlying cell destruction are not fully understood, however.
Humoral immunity is also affected. Hyperplasia of B (antibody-producing) lymphocytes in lymph node causes lymphadenopathy and increased secretion of antibodies, leading to hyperglobulinemia. Produc antibodies to previously encountered antigens persists; however, response to new antigens is defectiv sometimes absent. Thus, total antibody levels (especially IgG and IgA) may be elevated and titers of antibodies to specific agents (eg, cytomegalovirus) unusually high, but response to immunizations incr declines as CD4 counts decline.
The measurable immunologic abnormalities in AIDS include anergy (demonstrated by lack of delaye hypersensitivity responses to intradermal injection of common antigens; eg, tetanus, mumps, Candida albicans), poor T-cell proliferative responses to mitogens and antigens, polyclonal hypergammaglobuli elevated plasma immune complex levels, diminished antibody responses to both recall and new antige decreased natural killer function, and increased levels of markers of immune activation such as 1-thym acid-labile interferon, neopterin, and 2-microglobulin.
hypersensitivity responses to intradermal injection of common antigens; eg, tetanus, mumps, Candida albicans), poor T-cell proliferative responses to mitogens and antigens, polyclonal hypergammaglobuli elevated plasma immune complex levels, diminished antibody responses to both recall and new antige decreased natural killer function, and increased levels of markers of immune activation such as 1-thym acid-labile interferon, neopterin, and 2-microglobulin.
Opportunistic infections: Patterns of specific opportunistic infections vary geographically, among ris and as a result of medical interventions. In the USA and Europe, > 90% of AIDS patients with Kaposi's sarcoma are homosexual or bisexual men, probably because they are co-infected with human herpesv newly identified viral cofactor (with HIV) for Kaposi's sarcoma. Toxoplasmosis and TB are more comm tropical areas where the prevalence of latent infections with Toxoplasma gondii and Mycobacterium tuberculosis in the general population is high. Even in developed countries where background levels o low, HIV has caused increased rates and atypical presentations of TB. Widespread use of effective prophylaxis against such agents as Pneumocystis carinii and Mycobacterium avium complex has redu risk of these infections in developed countries.
Epidemiology
Since AIDS was first recognized in 1981 when cases of Pneumocystis carinii pneumonia and Kaposi's sarcoma were reported in homosexual men in California and New York, > 581,000 cases and 357,000 have been reported through December 1996 in the USA. Over 30 million HIV infections and 10 million cases are estimated worldwide.
Two epidemiologic patterns of HIV transmission are recognized. In the USA and Europe (type 1), transmission is primarily homosexual or via blood. Most patients are 20- to 49-yr-old men in high-risk g (eg, homosexual or bisexual men, IV drug users who share needles, and recipients of transfused bloo blood components who sometimes transmit HIV to women heterosexually). In the USA, women are an increasing proportion (about 20%) of all AIDS cases.
Among persons with hemophilia and other bleeding disorders, AIDS has become the leading cause of Before 1985, the risk of HIV infection among hemophiliacs correlated with large requirements for facto concentrates and the origin of their plasma products in the USA. The wide distribution of commercial p products originating in the USA resulted in a high rate of HIV infection, even in recipients from areas n initially affected by the epidemic. In most of Europe, where clotting factor material was collected from populations with lower risk of HIV infection, fewer hemophiliacs were infected. However, routine use o screened and heat-treated blood or bioengineered treatments for hemophilia has subsequently elimina risk of infection.
In Africa, South America, and Southern Asia (type 2), transmission is primarily heterosexual. In the men and women are nearly equally affected. Mixtures of the two patterns have been found in countrie as Brazil and Thailand. Typically, diseases follow routes of transportation and trade to cities and secon rural areas.
The continuing spread of HIV in developing countries with minimal resources with which to manage th epidemic has grave implications. The spread of two distinct serogroups of HIV-1 in Thailand is illustrat about 1990, parallel epidemics of heterosexually transmitted (genotype A) and needle-transmitted (ge B) HIV rapidly infected female prostitutes and their clients and IV opiate users who shared needles.
Infection of large numbers of women of childbearing age has led to a substantial number of pediatric AIDS (see Human Immunodeficiency Virus Infection in Children under Viral Infections in Ch. 265). HIV transmitted transplacentally or perinatally. The virus has been found in breast milk, and breastfeeding been implicated in transmission. In addition, groups of newborns and children have become infected f repeated use of inadequately sterilized needles.
Infection of large numbers of women of childbearing age has led to a substantial number of pediatric AIDS (see Human Immunodeficiency Virus Infection in Children under Viral Infections in Ch. 265). HIV transmitted transplacentally or perinatally. The virus has been found in breast milk, and breastfeeding been implicated in transmission. In addition, groups of newborns and children have become infected f repeated use of inadequately sterilized needles.
Symptoms and Signs
HIV causes a broad spectrum of clinical problems, which may mimic other diseases. Immediately after infection and for a prolonged period (more than several months in a small number of persons), there is antibody-negative carrier state. During this time, the virus reproduces rapidly until the immune system to react and/or targets are exhausted. HIV RNA or HIV p24 (capsid) antigen is detectable in plasma, e when no antibody to HIV is detectable. Within 1 to 4 wk after infection, some patients develop acute r syndrome or primary HIV infection with fever, malaise, rash, arthralgias, and generalized lymphaden usually lasting 3 to 14 days, followed within days to 3 mo by seroconversion for antibody to HIV. Acute retroviral syndrome is frequently misdiagnosed as a febrile upper respiratory illness ("flu") or mononuc Subsequently, these acute manifestations disappear (although lymphadenopathy usually persists) and become antibody-positive, asymptomatic HIV carriers. Some of these patients develop mild, remitt symptoms and signs that do not meet the definition of AIDS (eg, thrush, zoster, diarrhea, fatigue, feve Leukopenia is common and anemia and immune-mediated thrombocytopenia may also occur.
Neurologic symptoms: Neurologic symptoms are common and may be the first manifestation of AID Symptoms may be due to direct effects of HIV, opportunistic infections, neoplasms, or vascular compl They include acute aseptic meningitis; peripheral neuropathies of several types; encephalopathy with focal motor, sensory, or gait deficits; and cognitive dysfunction progressing to dementia (see Non-Alzh Dementias in Ch. 171).
Peripheral neuropathy may cause painful dysesthesias, moderate distal sensory loss (stocking-glove distribution), depressed ankle reflexes, distal weakness, and atrophy and can occur in varying degrees Guillain-Barr syndrome or cytomegalovirus (CMV) polyradiculopathy may present as ascending paral Myopathy similar to polymyositis may complicate AIDS or zidovudine therapy.
Aseptic meningitis may cause headache, fever, and photophobia and may be associated with a CSF mononuclear pleocytosis. Transient aseptic meningitis may accompany primary HIV infection.
Subacute encephalitis may be caused by HIV, CMV, or both. Neuropathology at autopsy may reveal collections of microglial cells without other inflammatory infiltrates in gray matter. Intranuclear and intracytoplasmic inclusions of CMV are associated with the nodules in cases of CMV encephalitis. Sm poorly defined foci of perivenular demyelination are found in white matter. Headache, confusion, mem psychomotor retardation, myoclonus, seizures, and severe dementia progressing to coma are typical f spanning weeks to months before death. Cortical atrophy on CT, CSF pleocytosis and elevated protei and a diffusely abnormal EEG may be present but are nonspecific. Demonstration of CMV DNA to CS polymerase chain reaction may be diagnostic of CMV encephalitis, ventriculitis, or myelitis/polyradiculo
Less dramatic cognitive and motor disorders occur in many AIDS patients that are less clinically evide socially debilitating and thus are not widely recognized. The areas of cognitive functioning more freque affected are attention, speed of information processing, and learning. These cognitive abnormalities a explained by mood disturbances or drug or alcohol abuse. They are associated with brain atrophy on M immune activation (elevated 2 -microglobulin levels), measurable HIV RNA levels (> 200 copies/mL) in and other neurologic abnormalities. Mild cognitive and motor disorders do not necessarily progress rap
Less dramatic cognitive and motor disorders occur in many AIDS patients that are less clinically evide socially debilitating and thus are not widely recognized. The areas of cognitive functioning more freque affected are attention, speed of information processing, and learning. These cognitive abnormalities a explained by mood disturbances or drug or alcohol abuse. They are associated with brain atrophy on M immune activation (elevated 2 -microglobulin levels), measurable HIV RNA levels (> 200 copies/mL) in and other neurologic abnormalities. Mild cognitive and motor disorders do not necessarily progress rap dementia, but many patients have slowly progressive deterioration. Response to treatment for either C HIV encephalopathy has been documented but is not predictable.
CNS opportunistic infections: Toxoplasmic encephalitis causes headache, lethargy, confusion, seiz and focal signs that evolve over days to weeks. CT or MRI findings include ring-enhancing lesions with predilection for basal ganglia. Serologic tests for IgG antitoxoplasmal antibodies reflecting antecedent latent infection are almost always positive but do not always prove that the lesion is caused by Toxopl organisms. Negative serologic tests greatly reduce the likelihood that a lesion is caused by Toxoplasm The CSF shows a mild to moderate pleocytosis and elevated protein content. Brain biopsy can be dia however, a therapeutic trial of pyrimethamine and sulfadiazine (or clindamycin if the patient is allergic sulfadiazine) is often attempted with close observation for response in 7 to 10 days in seropositive pat With treatment, the prognosis is good and recurrences can be prevented by lifelong prophylaxis with trimethoprim/sulfamethoxazole or clindamycin/pyrimethamine.
Cryptococcal, histoplasmal, and tuberculous (Mycobacterium tuberculosis) meningitides also present w fevers and headache in AIDS and are treatable. Progressive multifocal leukoencephalopathy (see Ch. encephalitis caused by papovaviruses, has not been responsive to therapy and is usually progressive within a few months.
Neoplasms of the brain: Primary B-cell CNS lymphoma (non-Hodgkin's) of the brain produces focal s consistent with its anatomic location. CT usually shows a mass that is sometimes contrast-enhancing cannot reliably be distinguished from focal encephalitis caused by Toxoplasma, TB, Cryptococcus, or opportunistic organisms. In these cases, MRI may be more discriminating, and brain biopsy is necessa definitive diagnosis. Systemic lymphomas in AIDS may involve the CNS, but Kaposi's sarcoma rarely d (See also Ch. 145.)
Hematologic symptoms: Some patients present with symptomatic anemia or immune-mediated thrombocytopenia. HIV-associated thrombocytopenia usually responds to the same interventions (corticosteroids, splenectomy, IV immune globulin) as idiopathic thrombocytopenic purpura and seldom to bleeding. (See also Ch. 145.)
GI symptoms: Abdominal pain, nausea and vomiting, or diarrhea contributes to the weight loss and w that so commonly afflicts advanced AIDS patients. Various opportunistic infections and tumors may in GI tract. Sites include the oropharynx (Candida, Kaposi's sarcoma, lymphoma, herpes simplex, and ap stomatitis), esophagus (herpes simplex, CMV, Candida), stomach (Kaposi's sarcoma and lymphoma), (Salmonella, Clostridium difficile, CMV, herpes simplex virus), and biliary tract (cryptosporidium and CM addition, drug-associated pancreatitis (eg, didanosine) or hepatitis (eg, fluconazole) may complicate th Diarrhea for which no cause can be found may persist for long periods or recur intermittently, even in p without severe immunosuppression or other symptoms.
Dermatologic symptoms: Skin manifestations of HIV infection complicate every stage from the rash genital ulcers of primary infection to widespread Kaposi's sarcoma in AIDS (see Ch. 126). Zoster, whic common throughout the course of infection, is often the first manifestation. Hematogenous lesions of cryptococcosis or bacillary angiomatosis may be important clues to diagnosis of these opportunistic in
Oral symptoms: Oral candidiasis (thrush) is among the earliest and most common manifestations of H infection; it is usually painless, may not be noticed by the patient, and may provide a useful clue in
genital ulcers of primary infection to widespread Kaposi's sarcoma in AIDS (see Ch. 126). Zoster, whic common throughout the course of infection, is often the first manifestation. Hematogenous lesions of cryptococcosis or bacillary angiomatosis may be important clues to diagnosis of these opportunistic in
Oral symptoms: Oral candidiasis (thrush) is among the earliest and most common manifestations of H infection; it is usually painless, may not be noticed by the patient, and may provide a useful clue in undiagnosed patients. Oral hairy leukoplakia, diagnosed by finding asymptomatic enlarged, white, filifo patches on the sides of the tongue, is probably caused by Epstein-Barr virus and is treatable with acyc Ulcers caused by herpes simplex or of unknown etiology (aphthous) may be large, painful, and persist may interfere with nutrition. Periodontal disease may become severe, leading to bleeding, swelling of g and loss of teeth. Both Kaposi's sarcoma and lymphomas may present in the oropharynx, usually as p masses.
Pulmonary symptoms: By far the most important HIV-associated lung infection is TB, which is freque first manifestation of HIV infection where TB is heavily endemic. Atypical presentations (infrequent cav lower-lobe infiltrates, miliary disease, and adenopathy), anergy to tuberculin skin tests, and confusion coexistence with other opportunists may make the diagnosis difficult. The lung is also a common site f opportunistic infections caused by fungi such as Pneumocystis carinii, Cryptococcus neoformans, Hist neoformans, Coccidioides immitis, and Aspergillus sp. Bacterial pneumonias caused by pneumococci, Haemophilus, Pseudomonas, and Rhodococcus are particularly common in IV drug users. Both Kapos sarcoma and B-cell lymphomas may involve mediastinal nodes and the lung.
Symptoms in women: The presentation and course of HIV infection in women resembles that in men with the exception of chronic refractory vaginal candidiasis and increased risk of cervical intraepithelia neoplasia. Some STDs such as pelvic inflammatory disease may be atypical, more aggressive, and re to treatment in HIV-infected women. HIV testing for women with recurrent, aggressive, or unusually re STDs or vaginal candidiasis is recommended.
Cardiovascular complications include marantic (thrombotic) or bacterial endocarditis (especially in I abusers) or a cardiomyopathy with congestive heart failure.
Renal insufficiency or nephrotic syndrome uncommonly complicates AIDS, but may be a source of disability (see also Ch. 224).
Laboratory Diagnosis
The detection of antibodies to HIV is sensitive and specific at most stages of infection, inexpensive, an available. Rapid (10-min) serum tests, home collection systems, and tests for HIV antibody in oral sec and urine are useful in some situations, but they require confirmation by standard serum testing. Detec HIV RNA in blood provides a sensitive and specific diagnosis of HIV infection in patients in the very ea stages of infection when antibodies may not yet be detectable.
Tests for detecting antibody to HIV include ELISA, which can detect antibodies to HIV proteins. ELISA highly sensitive and specific, but some false-positive ELISA tests occur. When reactive, ELISA should repeated on the same sample. If it is positive a second time, a test that is more specific should be perf eg, the Western blot, which is an immunoelectrophoretic procedure for identifying antibodies to speci proteins separated by their molecular weight.
ELISAs that directly measure viral antigens (p24) rather than antiviral antibodies are relatively insensit Tests of antigen levels have been supplanted by more sensitive measurements of plasma RNA.
Several sensitive assays of plasma RNA, such as the reverse-transcription polymerase chain reactio (RT-PCR), which amplifies viral nucleic acids, or the branched DNA (bDNA), which amplifies signal, ar
ELISAs that directly measure viral antigens (p24) rather than antiviral antibodies are relatively insensit Tests of antigen levels have been supplanted by more sensitive measurements of plasma RNA.
Several sensitive assays of plasma RNA, such as the reverse-transcription polymerase chain reactio (RT-PCR), which amplifies viral nucleic acids, or the branched DNA (bDNA), which amplifies signal, ar sensitive and accurate over a wide range of viral concentrations (up to 1,000,000 copies/mL of plasma lower limits of detection are about 400 copies/mL for RT-PCR and 5000 copies/mL for bDNA, and the sensitivity of these tests is being improved. Other methods for nucleic acid amplification, such as nucle sequence-based amplification (NASBA) and transcription-mediated amplification (TMA), are under development to increase the sensitivity of HIV RNA quantitation.
Prognosis
An HIV-infected person's risk of developing AIDS or dying can be estimated by combining CD4+ lymph counts and levels of plasma RNA (see Pathogenesis, above). The CD4+ count provides information on immediate vulnerability to opportunistic infections, and the plasma HIV RNA level predicts future CD4+ Reduction of plasma RNA levels by antiretroviral therapy reduces the risk of complications and death often increases CD4+ lymphocyte counts.
Opportunistic infections have remained the immediate cause of death for nearly all AIDS patients. Adv prophylaxis have decreased the incidence of Pneumocystis, Toxoplasma, Mycobacterium avium comp (MAC), Cryptococcus, and other opportunistic infections, and consequently their contribution to morbid mortality. Better drug treatment of these infections and, to a lesser extent, of Kaposi's sarcoma has im outcomes as well.
The introduction of combination antiretroviral drug therapy has dramatically prolonged the survival for with AIDS over periods of 2 to 3 yr, but the duration of benefit is variable and as yet incompletely defin antiretroviral drugs used in potent combinations and monitored by plasma viral (RNA) levels promise t the survival of patients at all stages of HIV infection. These benefits may be compromised by viral resi as influenced by the patients' prior use and compliance with antiretrovirals and their stage of infection Treatment, below).
Prevention of HIV Transmission
Multiple strategies are being developed to induce protective immunity in persons not infected with HIV Immunogens include attenuated live and whole killed HIV, genetically engineered HIV proteins and p (eg, from the viral envelope), and vaccinia virus genetically modified to express HIV viral proteins. The efforts are hampered by the lack of a measurable marker of protective immunity, such as the neutraliz antibody engendered by polio vaccine, or of a convenient animal model. Nevertheless, vaccines contin developed and tested for safety and immunogenicity.
Sexual contact with an HIV carrier remains the most common cause of transmission. Education to av unsafe sexual practices by reducing the number and frequency of sexual contacts, avoiding high-risk practices (eg, anal intercourse), and using barrier protection such as condoms is the cornerstone of prevention. Consistent use of condoms greatly reduces risk of transmission of HIV. The effect of antire on transmission is uncertain, but will probably reduce the risk. Whether symptomatic or not or treated HIV carriers should be regularly counseled to avoid unsafe sexual practices with uninfected persons.
All pregnant women should be offered a test for antibody to HIV. HIV-infected women should be advi consider deferring pregnancy at least until management of HIV in pregnancy is better studied. The risk
prevention. Consistent use of condoms greatly reduces risk of transmission of HIV. The effect of antire on transmission is uncertain, but will probably reduce the risk. Whether symptomatic or not or treated HIV carriers should be regularly counseled to avoid unsafe sexual practices with uninfected persons.
All pregnant women should be offered a test for antibody to HIV. HIV-infected women should be advi consider deferring pregnancy at least until management of HIV in pregnancy is better studied. The risk transmission in utero, intrapartum, or postpartum transmission to the fetus is estimated to be 30 to 50% zidovudine (ZDV or AZT) alone reduces intrapartum infection by 2/3, and combinations of drugs may b effective. Given the low, but real, risk of transmission even with treatment and the uncertainty of the ef the fetus of drugs needed for their own health, termination of pregnancy may be an alternative for man HIV-infected pregnant women.
Parenteral drug users should be counseled about the risk of sharing needles. Ideally, this effort shou combined with rehabilitation and treatment of drug dependence.
Confidential testing for antibody to HIV should be offered to anyone requesting it, but only in conjunc pretest and posttest counseling. Persons who are at high risk for contracting HIV infection--even those negative HIV antibody test results--should not donate blood or organs for transplantation because of t risk they may have been recently infected and be infectious but antibody-negative.
Isolation of hospitalized patients with HIV infection is unnecessary, except when their complicating infections (eg, suspected or proven TB) are communicable. Surfaces contaminated by blood or other b fluids should be cleaned and disinfected. HIV is readily inactivated by heat and many disinfectants, inc peroxide, alcohols, phenolics, and hypochlorite. The body fluids and tissues of HIV-infected patients s handled with extreme care.
Medical and dental professionals should wear gloves when examining all patients if contact with mu membranes or other wet surfaces may occur. Because needle-stick accidents are common, health car workers must be taught how to avoid them.
Postexposure prophylaxis with immediate antiretroviral therapy after penetrating injuries involving HIV-infected blood (needle sticks) or heavy mucous membrane (eye or mouth) contamination is believ reduce transmission. Combinations of a protease inhibitor with two nucleoside reverse transcriptase in are currently recommended for postexposure prophylaxis of relatively high-risk exposures. Zidovudine AZT) appeared to reduce risk of transmission after needle-stick injuries in one study, which provided th evidence that prophylaxis works. Because of the low risk of infection for most injuries, controlled prosp studies of the effectiveness of prophylaxis are not practical. Cancers or birth defects from the brief exp to these drugs have not been found in the small numbers of otherwise healthy persons who have used this purpose. Because some women in early pregnancy will be offered postexposure prophylaxis befor pregnancy is suspected or confirmed, special caution must be exercised in treating potentially pregnan women. Additional problems arise when the source or HIV status of blood is unknown, but identificatio source and testing of that person for HIV infection should be vigorously pursued.
Prevention of Opportunistic Infections
Primary prophylaxis for P. carinii pneumonia should be recommended to patients with CD4+ lymphoc counts < 200/L. The dosing interval necessary for maximum protection by the preferred drug, trimethoprim-sulfamethoxazole (TMP-SMX), has not been determined. Every-other-day dosing is bette tolerated than daily double-strength dosing, and escalating regimens at the initiation of prophylaxis imp tolerance. Some patients who cannot tolerate TMP-SMX can tolerate dapsone. Because both the sulfonamides and sulfones provoke adverse effects (eg, fever, neutropenia, skin rashes), in a minority patients, aerosolized pentamidine is a useful alternative.
trimethoprim-sulfamethoxazole (TMP-SMX), has not been determined. Every-other-day dosing is bette tolerated than daily double-strength dosing, and escalating regimens at the initiation of prophylaxis imp tolerance. Some patients who cannot tolerate TMP-SMX can tolerate dapsone. Because both the sulfonamides and sulfones provoke adverse effects (eg, fever, neutropenia, skin rashes), in a minority patients, aerosolized pentamidine is a useful alternative.
Primary prophylaxis for mycobacterial, toxoplasmal, and fungal infections has been developed. Ri clarithromycin, and azithromycin can help prevent disseminated MAC infections in AIDS patients with counts < 50 cells/L. Azithromycin may be preferred because it can be given weekly as two 600-mg ta provides protection (70%) similar to daily clarithromycin, and does not interact with other drugs. Preve reactivation of TB is important for patients likely to have inactive infection with Mycobacterium tubercu Daily treatment with isoniazid for 1 yr is recommended.
Risk of reactivation of Toxoplasma gondii, especially in the brain, is indicated by antibodies (IgG) in s that identify latent Toxoplasma infections. Toxoplasmal encephalitis is relatively uncommon in the USA because latent toxoplasmal infection is uncommon in the USA (about 15% of adults) compared with E and most developing countries and because TMP-SMX taken for prevention of pneumocystis pneumo provides excellent protection.
For some deep fungal infections (eg, esophageal candidiasis or cryptococcal meningitis and pneumo primary prophylaxis with oral fluconazole taken daily (100 mg) or weekly (400 mg) has been successfu cost of preventing these diseases is high and may not be indicated since they may be treated in most
Secondary prophylaxis is indicated with fluconazole for patients with recurrent oral, vaginal, or esoph candidiasis or for cryptococcal meningitis or pneumonia; and with itraconazole for histoplasmosis and some forms of aspergillosis (see Ch. 158). Secondary prophylaxis is also indicated to prevent relapses carinii pneumonia, cryptococcal infections, toxoplasmic encephalitis, and herpes simplex (see Chs. 73 161, and 154, respectively).
Treatment
Several new principles of treatment for HIV infection emerged in the mid-1990s. New methods to quick measure the effects of drugs on HIV in the blood, ie, suppression of plasma HIV RNA levels, and a be understanding of the rapid production of HIV, even in the clinically inactive stages of infection, have ch the approach.
Combinations of drugs usually targeting two enzymes (HIV reverse transcriptase and protease) is no standard, and use of single drugs is discouraged. Treatment with two to four drugs can promptly halt v reproduction, preserve immune function, and decrease the likelihood of emergence of drug-resistant v mutants. The length of response to various combinations of drugs varies with their success in complet suppressing viral replication, which usually requires consistent compliance with combinations of three drugs.
Plasma HIV RNA levels provide a means of rapidly and directly measuring effects of antiretroviral dru Therapeutic monitoring of RNA levels assesses the initial (at 4 to 8 wk) and ongoing (every 3 to 4 mo) combination drug regimens. Reduction in plasma RNA has become the accepted method of measurin effects of single or combinations of drugs. Increasing levels may indicate noncompliance with drugs or emergence of genetic variants of HIV resistant to the drugs.
Treatment of patients with measurable plasma RNA levels (> 400 copies/mL) even when they have re high CD4 counts (> 500 cells/L) is now recommended by some experts. Evidence to support this inte and expensive approach to therapy in less advanced (CD4 > 500) patients remains circumstantial. The
effects of single or combinations of drugs. Increasing levels may indicate noncompliance with drugs or emergence of genetic variants of HIV resistant to the drugs.
Treatment of patients with measurable plasma RNA levels (> 400 copies/mL) even when they have re high CD4 counts (> 500 cells/L) is now recommended by some experts. Evidence to support this inte and expensive approach to therapy in less advanced (CD4 > 500) patients remains circumstantial. The rates of viral production and clearance demonstrated for most patients at all stages of HIV infection su this approach.
Antiretroviral drugs: The antiretroviral drugs used to treat HIV infection are listed by their class in Ta 163-3 by generic and abbreviated names. Their status of approval by the FDA in mid 1998 is also sho Three of the four classes of available drugs act by inhibiting HIV reverse transcriptase; protease inhibi interfere with activity of HIV protease (see Pathogenesis, above).
Most experts recommend that patients at any stage of HIV infection with more than 5000 HIV RNA cop of plasma be treated with combination therapy, including two nucleosides (eg, ZDV and lamivudine [3T nucleosides and a protease inhibitor (eg, indinavir), or two nucleosides and a non-nucleoside reverse transcriptase inhibitor (eg, nevaripine). Although some drugs interact with others to influence their rem some cases this is helpful. For example, when two protease inhibitors, saquinavir and ritonavir, are co ritonavir helps to raise the levels of saquinavir by decreasing its removal.
Another useful interaction involves prevention of or compensation for selection of drug-resistant genet mutants of HIV. For example, when given alone, 3TC quickly selects for HIV with a single mutation tha HIV to grow in the presence of the drug. After a few months of ZDV alone, many patients develop a m that reduces the antiviral effect of ZDV. However, if 3TC and ZDV are given together, the combination achieves impressive suppression of HIV, even in patients with ZDV resistance, because the mutation resistance increases the susceptibility of HIV to ZDV.
Combinations can be harmful if they increase or decrease elimination of one of the component drugs, to drug levels that are either too high or too low, or if they have combined toxicity. Information on drug combinations is rapidly accumulating and will inform future choices.
The adverse effects of antiretroviral drugs, which vary by type of drug and dose, remain a central con both patients and physicians. Many adverse effects (eg, headache from ZDV) often become less seve time, but others (eg, stomach pain from didanosine) may indicate serious problems (eg, pancreatitis) t require immediate action. Because some adverse effects (eg, anemia, pancreatitis, hepatitis, glucose intolerance) can be detected by blood tests before they cause symptoms, regular monitoring of hemat and serum chemistries as well as symptoms is crucial. Finally, duration of therapy is uncertain: drugs s be taken only for as long as the antiretroviral benefits outweigh adverse effects and costs. The serious effects of antiretroviral drugs are listed in Table 163-3.
Drug resistance is more likely if patients are given inadequate numbers or doses of drugs or do not ta drugs as instructed. Although drug combinations delay selection of resistant HIV mutants, they usually prevent it unless total suppression of viral replication is achieved. Close attention to patient complianc plasma HIV RNA monitoring help limit the selection of resistant strains.
Some currently untreatable CNS complications of HIV (eg, progressive multifocal leukoencephalopat respond to antiretroviral treatment if the primary immune defect is corrected. Responses to antiretrovir have been documented for HIV-induced cognitive dysfunction. Measurement of levels of HIV RNA in C appears to provide a means of evaluating HIV replication and antiviral treatment effects to the brain, b usefulness of CSF RNA monitoring has not yet been demonstrated.
End-of-life care: Even with combined therapy, AIDS remains a terminal disease. At some time, relief and suffering may become the focus of treatment, and patients may opt for hospice care (see Ch. 294
have been documented for HIV-induced cognitive dysfunction. Measurement of levels of HIV RNA in C appears to provide a means of evaluating HIV replication and antiviral treatment effects to the brain, b usefulness of CSF RNA monitoring has not yet been demonstrated.
End-of-life care: Even with combined therapy, AIDS remains a terminal disease. At some time, relief and suffering may become the focus of treatment, and patients may opt for hospice care (see Ch. 294 Back to top of page
Section 13. Infectious Diseases Chapter 156. Bacteremia And Septic Shock Topics
[General] Bacteremia Septic Shock
[General]
(See also Neonatal Sepsis and Neonatal Meningitis under Neonatal Infections in Ch. 260.)
Bacteremia and septic shock are closely related conditions. Bacteremia denotes bacteria in the blood Septic shock is sepsis with hypoperfusion and hypotension refractory to fluid therapy. Sepsis refers t serious infection, localized or bacteremic, that is accompanied by systemic manifestations of inflamma Sepsis due to bacteremia is often called septicemia; this often imprecisely used term is now being discouraged. The more general term, systemic inflammatory response syndrome, recognizes that severe conditions (eg, infections, pancreatitis, burns, trauma) can trigger an acute inflammatory reacti systemic manifestations of which are associated with release into the bloodstream of a large number o endogenous mediators of inflammation.
Section 13. Infectious Diseases Chapter 164. Sexually Transmitted Diseases Topics
[General] Gonorrhea Sexually Transmitted Chlamydial, Mycoplasmal, And Ureaplasmal Syphilis Trichomoniasis Genital Candidiasis Balanoposthitis Chancroid Lymphogranuloma Venereum Granuloma Inguinale Genital Herpes Genital Warts Sexually Transmitted Enteric Infections
[General]
(See also Ch. 163.)
The incidence of sexually transmitted diseases (STDs), among the most common communicable disea the world, steadily increased from the 1950s to the 1970s but generally stabilized in the 1980s. The in of some diseases (eg, syphilis and gonorrhea) decreased from the mid-1980s to the mid-1990s in the and elsewhere. Nonspecific urethritis, trichomoniasis, chlamydial infections, genital and anorectal herp warts (all discussed in this chapter), scabies, pediculosis pubis, and molluscum contagiosum (see Chs and 115) are probably more prevalent than the five historically defined venereal diseases--syphilis, go chancroid, lymphogranuloma venereum, and granuloma inguinale. However, because the latter diseas more consistently reported, reliable incidence rates for the others are not available.
In 1995, worldwide incidence of gonorrhea was estimated at > 250 million cases (USA, about 400,000 syphilis, 50 million cases (USA, about 70,000, including about 16,000 primary and secondary cases an congenital cases). Chlamydial STDs now approach 1/2 million reported cases annually in the USA, bu estimated 10 to 20% of all cases are reported. Other infections, including salmonellosis, giardiasis, am shigellosis, campylobacteriosis, hepatitis A and B, and cytomegalovirus infection, are transmitted sexu also by other routes. A strong association between cervical cancer (see Ch. 241) and sexually transmi papillomaviruses exists. Since 1978, HIV has spread rapidly among various populations (see Ch. 163)
STD incidence rates remain high in most of the world, despite diagnostic and therapeutic advances th rapidly render patients with many STDs noninfectious and cure most. In many cultures, changing sexu
shigellosis, campylobacteriosis, hepatitis A and B, and cytomegalovirus infection, are transmitted sexu also by other routes. A strong association between cervical cancer (see Ch. 241) and sexually transmi papillomaviruses exists. Since 1978, HIV has spread rapidly among various populations (see Ch. 163)
STD incidence rates remain high in most of the world, despite diagnostic and therapeutic advances th rapidly render patients with many STDs noninfectious and cure most. In many cultures, changing sexu and oral contraceptive use have eliminated traditional sexual restraints, especially for women, and bot physicians and patients have difficulty dealing openly and candidly with sexual issues. Funding to cont is almost uniformly inadequate. Additionally, worldwide dissemination of drug-resistant bacteria (eg, penicillin-resistant gonococci) reflects misuse of antibiotics and spread of resistant clones by mobile populations. The effect of travel is most dramatically illustrated by the rapid spread of the AIDS virus (H from Africa to Europe and the Americas in the late 1970s.
STD control depends on good facilities for diagnosis and treatment; locating and treating patients' sex contacts; following those who received treatment to ensure that they have been cured; educating heal workers and the public; and teaching patients responsible sexual behavior. Despite several decades o effective vaccines for STDs are unavailable outside of clinical trials.

Section 13. Infectious Diseases Chapter 157. Bacterial Diseases Topics
Caused By Gram-Positive Cocci Caused By Gram-Negative, Aerobic Cocci Caused By Gram-Positive Bacilli Caused By Gram-Negative Bacilli Caused By Anaerobic Bacilli Caused By Spirochetes Caused By Mycobacteria
Caused By Gram-Positiv Cocci

STAPHYLOCOCCAL INFECTIONS
Pathogenic staphylococci are ubiquitous; they are carried in the anterior nares of about 30% of healthy and on the skin of about 20%. Hospital patients and personnel have slightly higher rates. Antibiotic-res strains are common in hospitals and in the community.
Newborns and nursing mothers are predisposed to staphylococcal infections, as are patients with influ chronic bronchopulmonary disorders (eg, cystic fibrosis, pulmonary emphysema), leukemia, neoplasm transplants, prostheses or other foreign bodies, burns, chronic skin disorders, surgical incisions, diabe mellitus, and indwelling intravascular plastic catheters. Patients receiving adrenal steroids, irradiation, immunosuppressants, or antitumor chemotherapy are also at increased risk. Predisposed patients ma acquire antibiotic-resistant staphylococci from other colonized areas of their bodies or from hospital pe Transmission via the hands of personnel is the most common means of spread, but airborne spread c occur.
Some staphylococcal disease is toxin-mediated rather than the result of infection per se. Staphylococc poisoning is caused by ingesting a preformed heat-stable staphylococcal enterotoxin (see in Ch. 28). T shock syndrome (below), caused by exotoxin, may occur in association with the use of vaginal tampon a complication of a postoperative infection (often minor appearing). Staphylococcal scalded skin syndr caused by the toxin exfoliatin, is an exfoliative dermatitis of childhood (see in Chs. 112 and 260).
Some staphylococcal disease is toxin-mediated rather than the result of infection per se. Staphylococc poisoning is caused by ingesting a preformed heat-stable staphylococcal enterotoxin (see in Ch. 28). T shock syndrome (below), caused by exotoxin, may occur in association with the use of vaginal tampon a complication of a postoperative infection (often minor appearing). Staphylococcal scalded skin syndr caused by the toxin exfoliatin, is an exfoliative dermatitis of childhood (see in Chs. 112 and 260). The staphylococcal diseases listed below are further discussed elsewhere in The Manual.
Symptoms and Signs
Neonatal infections usually appear within 6 wk after birth. Pustular or bullous skin lesions are most c generally located in the axillary, inguinal, or neck skin folds; but multiple subcutaneous abscesses (esp in breasts), exfoliation, bacteremia, meningitis, or pneumonia also occur. Microscopic examination of p lesions reveals neutrophils and clusters of gram-positive staphylococci, often within the neutrophils. (S Nosocomial Infection in Ch. 260 and Impetigo in Ch. 265.)
Nursing mothers who develop breast abscesses or mastitis 1 to 4 wk postpartum should be conside have antibiotic-resistant staphylococcal infections, probably derived from the nursery via their infants.
Postoperative infections, ranging from stitch abscesses to extensive wound involvement, commonly to staphylococci. Such infections may appear within a few days or several weeks after surgery; they ar to be delayed in onset if the patient received antibiotics at the time of surgery. Furuncles and carbuncles are discussed in Ch. 112.
Staphylococcal pneumonia (see in Ch. 73) should be suspected in patients with influenza or who are receiving corticosteroids or immunosuppressive therapy who develop dyspnea, cyanosis, and persiste recurrent fever and in those hospitalized with chronic bronchopulmonary or other high-risk diseases w develop fever, tachypnea, cough, cyanosis, and leukocytosis. In newborns, staphylococcal pneumonia characterized by abscess formation in the lung, followed by rapid development of pneumatoceles and empyema. Microscopic examination of patients' sputum reveals grapelike clusters of gram-positive coc neutrophils.
Staphylococcal bacteremia may occur with any localized staphylococcal abscess or infection related intravascular catheters or other foreign bodies; in severely burned patients, it is a common cause of de Symptoms and signs are discussed in Ch. 156. Persistent fever is usual and may be associated with s Staphylococcus epidermidis and other coagulase-negative staphylococci are increasingly a cause of nosocomial bacteremia associated with catheters and other foreign bodies. They are important causes morbidity (especially prolongation of hospitalization) and mortality in debilitated patients.
Staphylococcal endocarditis (see under Infective Endocarditis in Ch. 208) develops, particularly in IV users and in patients with prosthetic heart valves. Diagnosis is suspected by the sudden development cardiac murmur, septic emboli, and other classic signs and is confirmed by echocardiogram and blood cultures.
Staphylococcal osteomyelitis (see also Osteomyelitis in Ch. 54) occurs predominantly in children, c chills, fever, and pain over the involved bone. Redness and swelling subsequently appear. Periarticula infection frequently results in effusion, suggesting septic arthritis rather than osteomyelitis. The WBC c usually > 15,000/L, and blood cultures are often positive. X-ray changes may not be apparent for 10 days, and bone rarefaction and periosteal reaction may not be detected for even longer. Abnormalities radionuclide bone scans often are apparent earlier.
Staphylococcal osteomyelitis (see also Osteomyelitis in Ch. 54) occurs predominantly in children, c chills, fever, and pain over the involved bone. Redness and swelling subsequently appear. Periarticula infection frequently results in effusion, suggesting septic arthritis rather than osteomyelitis. The WBC c usually > 15,000/L, and blood cultures are often positive. X-ray changes may not be apparent for 10 days, and bone rarefaction and periosteal reaction may not be detected for even longer. Abnormalities radionuclide bone scans often are apparent earlier.
Staphylococcal enterocolitis, which is now rare, is suggested when hospitalized patients develop fev ileus, abdominal pain and distention, hypotension, or diarrhea--especially if they underwent abdomina recently or received antibiotics. The diagnosis is likely if microscopic examination of the stools reveals of neutrophils and gram-positive cocci. Infection with toxigenic Clostridium difficile, the most common c antibiotic-associated colitis, must be ruled out (see Ch. 29).
Aseptic precautions (eg, thoroughly washing hands between patient examinations and sterilizing share equipment) are important. Infected patients should be isolated from other susceptible patients, and ho personnel with active staphylococcal infections, even of a local nature (eg, boils), should not have con patients or shared equipment until their infections have been cured. An asymptomatic nasal carrier ne be excluded from patient contact unless the strain carried is dangerous and is the suspected source o outbreak.
Management includes abscess drainage, antibiotics (parenteral for seriously ill patients), and general supportive measures. Specimens for culture should be obtained before instituting or altering antibiotic regimens. The choice and dosage of an antibiotic depend on the site of the infection, the severity of th and ultimately the sensitivity of the organism.
Hospital-acquired staphylococci and most community-acquired strains are usually resistant to penicillin ampicillin, and antipseudomonal penicillins. Most strains are susceptible to penicillinase-resistant peni (methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin); cephalosporins (cephalothin, cefazolin, cephale cephradine, cefamandole, cefoxitin, and 3rd-generation cephalosporins); carbapenems (imipenem, meropenem); gentamicin; vancomycin; teicoplanin; lincomycin; and clindamycin.
Although the cephalosporins and vancomycin are effective, the drug of choice is usually one of the penicillinase-resistant penicillins. Many staphylococcal strains are also susceptible to erythromycin, tetracyclines, aminoglycosides, bacitracin, and chloramphenicol. However, chloramphenicol and bacitr seldom indicated because better and safer drugs are available.
Methicillin-resistant Staphylococcus aureus (MRSA) isolates are being encountered with increasing fre in the USA, especially in tertiary care and large city hospitals. These organisms are commonly isolated infected IV drug abusers and patients in ICUs, although they can be isolated from patients with community-acquired infections. MRSA isolates are usually resistant to -lactamase-resistant penicillins, cephalosporins, and carbapenems. Frequently, laboratory reports falsely indicate that these organism susceptible to cephalosporins, but cephalosporins are not reliable for treating MRSA infections. Resist aminoglycosides and macrolides (erythromycin, clarithromycin, azithromycin, lincomycin, and clindamy also common. Although imipenem-cilastatin or the quinolones may be effective against some MRSA in IV vancomycin is the drug of choice. The usual dosage for adults with normal renal function is 500 mg or 1000 mg IV q 12 h infused over at least 1 h. Dosages must be adjusted according to serum levels w renal function is compromised. Duration of therapy is based on the infection site and the patient's resp but is usually 2 to 4 wk. Some patients with severe or complicated infections may require IV treatment 8 wk, followed by oral therapy for a month or more. MRSA isolates with intermediate resistance to van have recently been detected in Japan and the USA.
or 1000 mg IV q 12 h infused over at least 1 h. Dosages must be adjusted according to serum levels w renal function is compromised. Duration of therapy is based on the infection site and the patient's resp but is usually 2 to 4 wk. Some patients with severe or complicated infections may require IV treatment 8 wk, followed by oral therapy for a month or more. MRSA isolates with intermediate resistance to van have recently been detected in Japan and the USA.
The preferred alternative to vancomycin for treating MRSA infection is trimethoprim-sulfamethoxazole (TMP-SMX) given orally or parenterally in a range of 10 mg/kg/day (TMP) and 50 mg/kg/day (SMX) to mg/kg/day (TMP) and 75 mg/kg/day (SMX) in divided doses at 8- or 12-h intervals for 2 to 4 wk (for ad rifampin (600 mg/day) orally or parenterally, or either imipenem-cilastatin (500 mg q 6 h) or meropenem 1 g q 8 h) given parenterally. However, rifampin should not be used alone, as the organism may soon resistance. Rifampin and aminoglycosides are useful adjuncts in treating serious MRSA infections ass with foreign bodies or those involving serous cavities. Cloxacillin, dicloxacillin, TMP-SMX, ciprofloxacin topical mupirocin have been useful in treating MRSA in the carrier state, but the MRSA may become r to all of them.
Vancomycin-resistant enterococcus (VRE) strains, which are increasingly prevalent, can transfer th causing resistance to vancomycin to coagulase-positive S. aureus strains in the laboratory and to coagulase-negative Staphylococcus strains isolated from infected patients. Unfortunately, these staph may already be resistant to other antibiotics used in treatment of these infections. Bacitracin, when av may be tried for treatment of vancomycin-resistant staphylococcal infections. Strict isolation procedure be used for these patients to prevent spread of their organisms.
Toxic Shock Syndrome
A syndrome caused by staphylococcal exotoxin, characterized by high fever, vomiting, diarrhea, confu and skin rash that may rapidly progress to severe and intractable shock.
Toxic shock syndrome occurred predominantly in menstruating women who used tampons. After wide publicity of the role played by tampons and diaphragms as well as the withdrawal of some tampons fro market, the incidence in women dropped precipitously. Less severe cases that lack some manifestatio fairly common. Estimates made from small series suggest about 3 cases/100,000 menstruating wome occur, and cases are still reported in women who do not use tampons and in postoperative and postpa women. About 15% of cases occur postpartum or as postoperative staphylococcal wound infections, w frequently appear insignificant. Cases have also been reported in association with influenza, osteomye cellulitis.
Etiology and Pathogenesis
The exact cause of toxic shock syndrome is unknown, but almost all cases have been associated with exotoxin-producing strains of phage-group 1 Staphylococcus aureus that elaborate the toxic shock syn toxin-1 or related exotoxins. The organisms have been found in mucosal sites (nasopharynx, vagina, t or sequestered (empyema, abscess), and in menstruating women in the vagina. Presumably, women risk for toxic shock syndrome are those with preexisting colonization of the vagina who use tampons. I that mechanical or chemical factors related to tampon use result in enhanced production of the bacter exotoxin, which enters the bloodstream through a mucosal break or via the uterus.
Symptoms, Signs, and Diagnosis
Onset is sudden, with fever (39 to 40.5 C [102 to 105 F], which remains elevated), headache, sore th nonpurulent conjunctivitis, profound lethargy, intermittent confusion without focal neurologic signs, vom
Onset is sudden, with fever (39 to 40.5 C [102 to 105 F], which remains elevated), headache, sore th nonpurulent conjunctivitis, profound lethargy, intermittent confusion without focal neurologic signs, vom profuse watery diarrhea, and a diffuse sunburn-like erythroderma. The syndrome may progress within orthostatic hypotension, syncope, shock, and death. Between the 3rd and 7th days after onset, desqu of the skin begins and leads to epidermal sloughing, particularly of the palms and soles.
Other organ systems are frequently involved, resulting in mild nonhemolytic anemia, moderate leukocy with a predominance of immature granulocytes, and early thrombocytopenia followed by thrombocytos Although clinically important bleeding phenomena are rare, the prothrombin time and partial thrombop time tend to be prolonged. Laboratory evidence of hepatocellular dysfunction (hepatitis) and skeletal m is common during the first week of illness. Cardiopulmonary involvement may occur, manifested by pe and pulmonary edema (with abnormally low central venous pressures, suggesting adult respiratory dis syndrome). Especially in children, profound hypotension and impaired perfusion of the extremities may and renal dysfunction, characterized by diminished urine output and increases in BUN and creatinine l almost always occurs.
Toxic shock syndrome resembles Kawasaki syndrome (mucocutaneous lymph node syndrome--see u Miscellaneous Infections in Ch. 265) but can usually be differentiated on clinical grounds. Kawasaki sy generally occurs in children < 5 yr of age; it does not cause shock, azotemia, or thrombocytopenia; an skin rash is maculopapular. Other disorders to be considered are scarlet fever, Reye's syndrome, the staphylococcal scalded skin syndrome, meningococcemia, Rocky Mountain spotted fever, leptospirosi viral exanthematous diseases. These are ruled out by specific clinical differences, by cultures, and by studies.
Prognosis, Prophylaxis, and Treatment
Mortality ranges between 8 and 15%, but this figure is based only on severe cases. Whether antibiotic the acute course of the illness is unclear. Recurrences are common in women who continue to use tam during the first 4 mo after an episode. Treatment with antibiotics during the acute illness may eradicate staphylococcal foci and protect against recurrences.
Other than eradicating S. aureus, precise recommendations for prevention (primary or secondary) can made with certainty. However, it seems prudent to advise women to avoid tampons throughout the me period and to intermittently use napkins or other hygienic measures.
Patients suspected of having toxic shock syndrome should be hospitalized immediately and treated in tampons, diaphragms, and other foreign bodies should be removed at once. Fluid and electrolyte repla must be given to prevent or treat hypovolemia, hypotension, or shock. Since fluid loss into tissues can widely throughout the body, shock may be profound and resistant, and large quantities of fluid and ele are sometimes required. Obvious infections should be treated; specimens for Gram stain and culture s be taken from mucosal surfaces and blood; treatment with a -lactamase-resistant penicillin or a cepha may be started.
STREPTOCOCCAL INFECTIONS
(See also Rheumatic Fever in Ch. 270.)
When grown on sheep blood agar, -hemolytic streptococci produce zones of clear hemolysis around e
STREPTOCOCCAL INFECTIONS
When grown on sheep blood agar, -hemolytic streptococci produce zones of clear hemolysis around e colony; -hemolytic streptococci (commonly called Streptococcus viridans) are surrounded by green discoloration resulting from incomplete hemolysis; and -hemolytic streptococci are nonhemolytic. Anot classification, based on carbohydrates present in the cell wall, divides streptococci into the Lancefield through H and K through T.
Group A -hemolytic streptococci (S. pyogenes) are the most virulent species for humans, causing pha tonsillitis, wound and skin infections, septicemia, scarlet fever, pneumonia, rheumatic fever, and glomerulonephritis.
Group B -hemolytic streptococci, also known as S. agalactiae, cause serious infections, particularly ne sepsis, postpartum sepsis, endocarditis, and septic arthritis.
Groups C and G -hemolytic streptococci are S. pyogenes-like organisms that are distinguished by the serogrouping and resistance to bacitracin. They are often carried by animals and also colonize the hum pharynx, intestinal tract, vagina, and skin. They can cause severe suppurative infections, including pha pneumonia, cellulitis, pyoderma, erysipelas, impetigo, wound infections, puerperal sepsis, neonatal se endocarditis, septic arthritis, and poststreptococcal glomerulonephritis. Penicillin, vancomycin, the cephalosporins, and erythromycin are useful in therapy, but susceptibility tests can guide therapy, esp very ill, immunocompromised, or debilitated hosts or in those with foreign bodies at the site of the infec Surgery as an adjunct to antimicrobial therapy may be lifesaving.
Group D (usually - or -hemolytic) includes the enterococci E. faecalis, E. durans, and E. faecium (form faecalis, S. durans, S. faecium), and the nonenterococcal group D streptococci, of which S. bovis and equinus are the most common. Most infections of humans caused by group D are caused by E. faeca faecium, or S. bovis. Like the enterococci, S. bovis is commonly found in the GI tract. S. bovis is an im cause of bacterial endocarditis, particularly when an intestinal neoplasm or other significant lesion is p S. bovis is relatively susceptible to antibiotics, whereas enterococci are very resistant unless exposed combination of a cell wall-active drug such as penicillin, ampicillin, or vancomycin plus an aminoglycos as gentamicin or streptomycin. E. faecalis and E. faecium cause endocarditis, UTIs, intra-abdominal in cellulitis, and wound infection as well as concurrent bacteremia.
Viridans streptococci consist of five main species: S. mutans, S. sanguis, S. salivarius, S. mitior, and milleri; the latter is further subdivided into S. constellatus, S. intermedius, and S. anginosus. There is s disagreement about their classification and identification. Although defined as -hemolytic, some are ac -hemolytic, and many of these organisms are nongroupable. Colonization of the oral cavity and its com appears to play an important role in preventing colonization by other more pathogenic organisms, such Pseudomonas and enteric organisms. Most viridans streptococci are susceptible to lysis by serum and produce exotoxins or traditional virulence factors; however, they are important causes of bacterial end because they can adhere to cardiac valves, especially in persons with underlying valvular disease. Me the S. milleri group are variably hemolytic, microaerophilic, or anaerobic, and tend to produce serious infections or localized abscesses in almost any part of the body.
S. iniae, a pathogen in fish, is capable of causing outbreaks of cellulitis and invasive infections in patie skin injuries who handled live or freshly killed aquacultured fish, usually tilapia or trout.
Symptoms and Signs
S. iniae, a pathogen in fish, is capable of causing outbreaks of cellulitis and invasive infections in patie skin injuries who handled live or freshly killed aquacultured fish, usually tilapia or trout.
Symptoms and Signs
Streptococcal infections can be divided into three groups: (1) the carrier state, in which the patient har streptococci without apparent infection; (2) acute infection, often suppurative, caused by streptococcal of tissues; and (3) delayed, nonsuppurative complications, which occur most commonly about 2 wk aft clinically overt streptococcal infection, but the infection may be asymptomatic and the interval may be than 2 wk.
Primary and secondary infections can spread through the affected tissues and along lymphatic channe regional lymph nodes; they can also produce bacteremia. The development of suppuration depends o severity of infection and the susceptibility of tissue.
In acute infection, symptoms and signs depend on the affected tissue, the organism, the state of the h the host's response.
Streptococcal pharyngitis, the most common streptococcal disease, is a primary pharyngeal infectio group A -hemolytic streptococci. About 20% of patients with group A infections present with sore throa a beefy red pharynx, and a purulent tonsillar exudate. The remainder are asymptomatic, have fever or sore throat alone (resembling viral pharyngitis), or have nonspecific symptoms such as headache, ma nausea, vomiting, or tachycardia. Seizures may occur in children. The cervical and submaxillary nodes enlarge and become tender. In children < 4 yr, rhinorrhea is common and sometimes the only symptom Cough, laryngitis, and stuffy nose are uncharacteristic of streptococcal pharyngeal infection, and their presence suggests another cause (usually viral or allergic) or coexisting complications. Definitive diagn rests on the laboratory techniques described below.
Scarlet fever (scarlatina) is uncommon today, presumably because antibiotic therapy prevents the inf from progressing or causing epidemics. Scarlet fever is caused by group A streptococcal (and occasio other) strains that produce an erythrogenic toxin, leading to a diffuse pink-red cutaneous flush that bla pressure. The rash is seen best on the abdomen, on the lateral chest, as dark red lines in skinfolds (P lines), or as circumoral pallor. A strawberry tongue (inflamed papillae protruding through a bright red c also occurs and must be differentiated from that seen in the toxic shock (see above) and Kawasaki (se 265) syndromes. The upper layer of the previously reddened skin often desquamates after fever subsi other symptoms are similar to those in streptococcal pharyngitis, and the course and management of s fever are the same as for other group A infections. Streptococcal pyoderma (impetigo) is discussed under Bacterial Infections in Ch. 265. Impetigo can caused by S. aureus.
Streptococcal toxic shock syndrome, similar to that caused by S. aureus, has recently been attribu group A -hemolytic streptococci strains capable of producing pyrogenic exotoxins. Patients are usually otherwise healthy children or adults with skin and soft tissue infections.
Laboratory Findings
The ESR is usually > 50 mm/h in acute infection, and WBC count is about 12,000 to 20,000/L, with 7 neutrophils, many of which are young forms. The urine commonly shows no specific changes except t attributable to fever (eg, proteinuria).
Laboratory Findings
The ESR is usually > 50 mm/h in acute infection, and WBC count is about 12,000 to 20,000/L, with 7 neutrophils, many of which are young forms. The urine commonly shows no specific changes except t attributable to fever (eg, proteinuria).
The presence of streptococci in specimens taken from the infected site can be established by overnigh incubation on a sheep blood agar plate or, for group A organisms, immediate staining with fluorescent antibodies. The fluorescent method obviates the need for serologic testing to differentiate group A from -hemolytic streptococci, but false-positive reactions with hemolytic staphylococci often occur. Many oth inexpensive tests are available for rapid detection of group A streptococci in throat swabs.
Evidence of infection can be obtained indirectly by demonstrating antistreptococcal antibodies in serum convalescence. Confirmation requires that sequential specimens show recent changes in titer, since a value may be high from a long antecedent infection. Serum specimens need not be taken more often every 2 wk and may be taken every 2 mo. A significant rise (or fall) in titer should span at least 2 seria dilutions. The antistreptolysin O (ASO) titer rises in only 75 to 80% of infections; for completeness in d cases, any one of the other tests (antihyaluronidase, antideoxyribonuclease B, antinicotinamide adeni dinucleotidase, or antistreptokinase) can also be used. Penicillin given within the first 5 days for sympt streptococcal pharyngitis may delay the appearance and decrease the magnitude of the ASO respons Patients with streptococcal pyoderma usually do not have a significant ASO response.
Septicemia, puerperal sepsis, endocarditis, and pneumonias due to streptococci remain serious comp especially if the organism is a multiresistant enterococcus. Although group A streptococci and S. virida strains are almost always susceptible to penicillin, enterococci are relatively resistant and require treat with an aminoglycoside in addition to penicillin, ampicillin, or vancomycin. Enterococci may be resistan high concentrations of vancomycin (VRE), gentamicin, and other aminoglycosides and show no synerg killing with penicillin or vancomycin. There is currently no reliable therapy for such strains, although se new compounds are under study.
The primary pharyngeal group A streptococcal infections, including scarlet fever, ordinarily are self-lim Antibiotics shorten the course in young children, especially those with scarlet fever, but have little effec symptoms in adolescents or adults. They help prevent local suppurative complications such as periton abscess (quinsy), otitis media, sinusitis, and mastoiditis; most importantly, they thwart the nonsuppura complications (eg, rheumatic fever) that may follow untreated infections.
Penicillin is the drug of choice for an established group A streptococcal infection. A single injection of benzathine penicillin G, 600,000 U IM for small children (< 60 lb or 27.3 kg) (50,000 U/kg) or 1.2 millio for adolescents and adults, usually suffices. Oral therapy with penicillin V may be used if the patient ca trusted to maintain the regimen: at least 125 to 250 mg of penicillin V taken tid or qid (for children, 25 t mg/kg/day in divided doses tid or qid). An alternative for patients considered unreliable or unable to ta orally is three injections of procaine penicillin 600,000 U (for children, 50,000 U/kg) IM on the 1st, 4th, days. These injections are usually not as painful as that of benzathine.
When penicillin is contraindicated, erythromycin 250 mg qid or clindamycin 300 mg tid may be given o 10 days. Resistance of group A streptococci to macrolides such as erythromycin, clindamycin, clarithro and azithromycin has been detected; TMP-SMX, most of the fluoroquinolones, and the tetracyclines a unreliable. Clindamycin (20 mg/kg/day in divided doses tid or qid) is preferred in children who have rel chronic tonsillitis, possibly because of its good activity against penicillinase-producing anaerobes co-in the tonsillar crypts and inactivating penicillin G. Sulfadiazine, which is bacteriostatic, should not be use treat an established infection, although it is useful in preventing streptococcal infections.
10 days. Resistance of group A streptococci to macrolides such as erythromycin, clindamycin, clarithro and azithromycin has been detected; TMP-SMX, most of the fluoroquinolones, and the tetracyclines a unreliable. Clindamycin (20 mg/kg/day in divided doses tid or qid) is preferred in children who have rel chronic tonsillitis, possibly because of its good activity against penicillinase-producing anaerobes co-in the tonsillar crypts and inactivating penicillin G. Sulfadiazine, which is bacteriostatic, should not be use treat an established infection, although it is useful in preventing streptococcal infections.
Antistreptococcal therapy can often be withheld for 1 or 2 days, until bacteriologic verification has been obtained, without significantly increasing the risk of complications. However, it is common to begin ora penicillin when infection is suspected and specimens for laboratory tests have been obtained. Treatme be stopped if laboratory tests are negative. Otherwise, the oral drug is continued or replaced by an inje agent.
Other symptoms (eg, sore throat, headache, fever) can be treated with analgesics or antipyretics. Bed isolation are unnecessary. Close contacts who are symptomatic or have a history of poststreptococcal complications should be examined for streptococci.
Enterococci resistant to vancomycin (VRE), gentamicin, and streptomycin have become prevalent in m hospitals. Because of resistance to high levels of aminoglycosides, to cell wall-active -lactams such as penicillin G and ampicillin, and to glycopeptides such as vancomycin and teicoplanin, these enterococ emerged as an important cause of serious and refractory infections, especially in hospitals. Often, no effective treatment is available for serious infections caused by VRE, especially endocarditis. Strict iso techniques should be used. Vancomycin-resistant S. bovis isolates have recently been reported, but fortunately, they remain susceptible to penicillin and aminoglycosides. Most viridans streptococci are h susceptible to penicillin G, although resistance to aminoglycosides and -lactams, often due to the prod altered penicillin-binding proteins, is becoming a concern in many countries. Accordingly, susceptibility are important in choosing therapy.
PNEUMOCOCCAL INFECTIONS
Streptococcus pneumoniae (formerly called Diplococcus pneumoniae) is a gram-positive encapsulated diplococcus, with adjacent surfaces being rounded and the ends pointed to give a lancet shape. It som appears as short chains; in old cultures or purulent exudates, some of the organisms may stain gramThe capsule, visible in smears stained with methylene blue, consists of a complex polysaccharide that determines serologic type and contributes to virulence and pathogenicity. There are > 85 types.
In the Neufeld quellung reaction, the best method for determining type, the capsule swells in the prese type-specific rabbit antiserum. For diagnosis, polyvalent antisera against some groups of specific type available commercially or from the CDC, and sera against all types are available from the Danish Seru Institute in Copenhagen. Typing may also be carried out by specific agglutination or by immunoelectro against specific antisera. A type-specific antipneumococcal antibody may be identified in serum or oth fluids by counterimmunoelectrophoresis.
The most common types of pneumococcus in serious infections have been types 1, 3, 4, 7, 8, and 12 and types 6, 14, 19, and 23 in infants and children, but these patterns are slowly changing, in part bec the wide use of polyvalent vaccine.
Recovery from pneumococcal infection is usually associated with development of circulating type-spec antibodies.
Epidemiology
Recovery from pneumococcal infection is usually associated with development of circulating type-spec antibodies.
Epidemiology
Pneumococci commonly inhabit the human respiratory tract, particularly in winter and early spring, wh may be cultured from up to half of the population. The organisms spread from person to person in dro Isolating patients is not generally required but seems wise if the organism is highly resistant to penicilli epidemics of pneumococcal pneumonia or other infections are rare.
The patients most susceptible to serious and invasive pneumococcal infections are those with lympho Hodgkin's disease, multiple myeloma, splenectomy, other serious debilitating diseases or immunologic deficiencies, and sickle cell disease. Damage to the respiratory epithelium by chronic bronchitis or com respiratory viruses, notably influenza virus, may predispose to pneumococcal invasion. Pneumococca pneumonia is highly prevalent among gold and diamond miners in South Africa and New Guinea.
Diseases Caused by Pneumococcus
Pneumonia is the most frequent serious infection caused by pneumococci. It is usually lobar but often presents as bronchopneumonia or tracheobronchitis without clearly defined parenchymal involvement Pneumococcal Pneumonia in Ch. 73). Empyema complicates < 3% of cases of pneumococcal pneum The exudate may resolve spontaneously or during treatment of the pneumonia; conversely, it may bec thick and fibrinopurulent, is sometimes loculated, and may require surgical drainage (see Treatment, b and under Pneumococcal Pneumonia in Ch. 73, and Pleural Effusion in Ch. 80).
Pneumococci cause about 50% of acute otitis media in infants (after the newborn period) and childre 1/3 of children in most populations have an attack of acute pneumococcal otitis media in the first 2 yr o and recurrent otitis due to pneumococcus is common. Mastoiditis, meningitis, and lateral sinus thromb fairly common complications of otitis media in the preantibiotic era, are now rare (see Acute Otitis Med 84).
Pneumococcus may infect the paranasal sinuses. Infection of the ethmoidal or sphenoidal sinus ma into the meninges, producing bacterial meningitis. Sinusitis may become chronic and polymicrobic (se Sinusitis in Ch. 86).
Pneumococcus is one of the most frequent causes of acute purulent meningitis in all age groups. Pneumococcal meningitis may be secondary to bacteremia from other foci (notably pneumonia); infec the ear, mastoid process, or paranasal sinuses (notably the ethmoidal or sphenoidal sinus); or basilar of the skull involving one of these sites or the cribriform plate. (See Acute Bacterial Meningitis in Ch. 1
Bacteremia may accompany the acute phase of pneumococcal pneumonia, meningitis, endocarditis, infection of paranasal sinus, internal ear, or mastoid. It may even occur in an otherwise normal patient the course of a simple, febrile, viral URI (common cold). Pneumococcal bacteremia may be a primary in susceptible patients (see in Epidemiology, above).
Pneumococcal endocarditis may result from the bacteremia even in patients without previous valvul disease. A new murmur may develop or pneumococcal endocarditis may produce a corrosive valvular with sudden rupture or fenestration leading to rapidly progressive heart failure. Rarely, the illness is fat without having produced changing murmurs, petechiae, or embolic phenomena. Valvular lesions and vegetations may be visualized by echocardiography (see also Infective Endocarditis in Ch. 208).
Pneumococcal endocarditis may result from the bacteremia even in patients without previous valvul disease. A new murmur may develop or pneumococcal endocarditis may produce a corrosive valvular with sudden rupture or fenestration leading to rapidly progressive heart failure. Rarely, the illness is fat without having produced changing murmurs, petechiae, or embolic phenomena. Valvular lesions and vegetations may be visualized by echocardiography (see also Infective Endocarditis in Ch. 208).
Pneumococcal arthritis, an uncommon form of acute purulent (septic) arthritis, is usually a complicat bacteremia from another focus. The clinical picture and therapy are similar to those of septic arthritis c by other gram-positive cocci (see Infectious Arthritis in Ch. 54). Pneumococci can usually be demonst direct smear and by culture of the aspirated purulent synovial fluid.
Pneumococcal peritonitis is rare, occurring most often in young women, presumably as an ascendin infection from the vagina through the fallopian tubes, or in patients with nephrotic syndrome. The symp are similar to those of acute bacterial peritonitis of other causes; the infection responds rapidly to treat with penicillin (see also Acute Peritonitis in Ch. 25).
Prophylaxis
A commercially available polyvalent polysaccharide vaccine is directed against the 23 serotypes that a for > 80% of serious pneumococcal infections. The vaccine elicits production of antibodies against nea types in most children > 2 yr of age and most adults, reducing pneumonia and other bacteremic infect about 80% and mortality by 40%. Immunogenicity and protective effects in children < 2 yr have not be clearly shown, but newer formulations being developed may solve this problem. In the recommended 0.5 mL, it is relatively free of adverse reactions. Protection generally lasts for many years, but in highly susceptible persons, especially children with sickle cell disease, revaccination after 5 yr or more may b desirable.
The vaccine is indicated for persons with chronic cardiac disease, chronic bronchitis and bronchiectas diabetes mellitus, and metabolic disorders; all elderly; and younger debilitated persons in long-term ca facilities. It is not recommended for pregnant women; children < 2 yr; previously splenectomized patien including those with Hodgkin's disease; or anyone hypersensitive to the components of the vaccine. T vaccine prevents severe pneumonia and bacteremia in most patients with sickle cell anemia and in splenectomized patients > 2 yr who received the vaccine before splenectomy. The vaccine may not be effective in preventing pneumococcal meningitis complicating basilar fracture of the skull.
For functional or anatomic asplenic children, continuous oral penicillin V 125 mg bid is recommended.
Treatment
The preferred therapy for most pneumococcal infections has been penicillin G or one of its analogs, un isolate is resistant. Hospitalized adults with highly susceptible organisms are generally given penicillin 10 million U/day or penicillin V 250 to 500 mg (for children, 25 to 50 mg/kg/day in divided doses tid or orally for 5 to 7 days for acute pneumococcal otitis media or sinusitis. Parenteral treatment is preferred arthritis and should be continued for an additional week. Pneumococcal meningitis or endocarditis req to 20 to 40 million U/day (for children, 250,000 to 400,000 U/kg/day in divided doses q 4 to 6 h) of aqu penicillin G, given by intermittent (q 2 h) or continuous IV infusion and maintained for 10 days to 2 wk patient is afebrile and cultures of blood and CSF have become sterile.
Strains highly resistant to penicillin, ampicillin, and other -lactams have become common worldwide. T mechanism of resistance appears to reside in the production of novel penicillin-binding proteins in the cell wall that do not bind penicillin. In many centers, 10 to 15% of strains are moderately (intermediate resistant to penicillin G (MIC 0.1 to 1.0 g/mL), and an additional 10 to 15% are highly resistant to pen
patient is afebrile and cultures of blood and CSF have become sterile.
Strains highly resistant to penicillin, ampicillin, and other -lactams have become common worldwide. T mechanism of resistance appears to reside in the production of novel penicillin-binding proteins in the cell wall that do not bind penicillin. In many centers, 10 to 15% of strains are moderately (intermediate resistant to penicillin G (MIC 0.1 to 1.0 g/mL), and an additional 10 to 15% are highly resistant to pen (> 1.0 g/mL). Intermediately resistant organisms may be treated with ordinary or high doses of penici other beta-lactams, but seriously ill patients with highly penicillin-resistant infections require vancomyc ceftriaxone, or cefotaxime alone or in combination with rifampin; good response has also been reporte very high doses of parenteral penicillin G (20,000 to 40,000 U/day IV for adults). All penicillin-resistant have been susceptible to vancomycin so far, but parenteral vancomycin does not always yield concen in CSF adequate for treatment of meningitis (especially if adrenal corticosteroids are also being used); therefore, ceftriaxone or cefotaxime and/or rifampin are commonly added to the regimen containing vancomycin in patients with meningitis. Reduced susceptibility to ceftriaxone or cefotaxime is becomin common. Some of the newer fluoroquinolones such as ofloxacin and sparfloxacin show promise for tre infections with highly penicillin-resistant pneumococci.
For treatment of pneumococcal pneumonia and of pleural empyema, see Pneumococcal Pneumonia and Pleural Effusion in Ch. 80. For treatment of penicillin-allergic patients with pneumococcal pneumo meningitis, or endocarditis, see Pneumococcal Pneumonia in Ch. 73 and Infective Endocarditis in Ch. Patients with endocarditis should be followed closely for evidence of changing murmurs or sudden or progressive heart failure; the latter requires prompt surgical intervention. Back to top of page
Section 2. Endocrine And Metabolic Disorders Chapter 6. Hypothalamic-Pituitary Relationshi Topics

[General] Hypothalamic Controls Anterior Pituitary Function Posterior Pituitary Function
[General]
The pituitary gland (hypophysis) is no longer considered the "master gland." The hypothalamus is the common pathway that receives input from virtually all other areas of the CNS and directs input to the p
The hypothalamus modulates the activities of the anterior and posterior lobes of the pituitary in two dis ways. Neurohormones synthesized in the hypothalamus reach the anterior pituitary (adenohypophy directly through a specialized portal vascular system and regulate the synthesis and secretion of the s peptide hormones of the anterior pituitary. The pituitary hormones in turn regulate peripheral endocrine (the thyroid, adrenals, and gonads) as well as growth and lactation. No direct neural connection exists the hypothalamus and the anterior pituitary. In contrast, the posterior pituitary (neurohypophysis) c axons originating in neuronal cell bodies located in the hypothalamus. These axons serve as storage s two peptide hormones synthesized in the hypothalamus, which act in the periphery to regulate water b milk ejection, and uterine contraction. An intermediate lobe located between the anterior and posterio is present in some species and during fetal development in humans, but its cells are scattered through anterior and posterior lobes in adult humans, in whom no specific intermediate gland is recognizable.
Virtually all hormones produced by the hypothalamus and the pituitary are secreted in a pulsatile or bu fashion, interspersing brief periods of inactivity and activity. In addition, some of the hormones (eg, adrenocorticotropic hormone [ACTH], growth hormone [GH], and prolactin) have definite circadian or d rhythms with increased secretion during specific hours of the day; other hormones (eg, luteinizing horm [LH] and follicle-stimulating hormone [FSH] during the menstrual cycle) have monthlong rhythms with e of superimposed circadian rhythms.
Section 2. Endocrine And Metabolic Disorders Chapter 13. Disorders Of Carbohydrate Metabo Topics
Diabetes Mellitus Diabetic Ketoacidosis Alcoholic Ketoacidosis Nonketotic Hyperglycemic-Hyperosmolar Coma Hypoglycemia
Diabetes Mellitus
(For gestational diabetes, see Diabetes Mellitus in Ch. 251.)
A syndrome characterized by hyperglycemia resulting from absolute or relative impairment in insulin se and/or insulin action.
Patients with type I diabetes mellitus (DM), also known as insulin-dependent DM (IDDM) or juvenile-on diabetes, may develop diabetic ketoacidosis (DKA). Patients with type II DM, also known as non-insulin-dependent DM (NIDDM), may develop nonketotic hyperglycemic-hyperosmolar coma (NKH Common late microvascular complications include retinopathy, nephropathy, and peripheral and auton neuropathies. Macrovascular complications include atherosclerotic coronary and peripheral arterial dis
Classification and Pathogenesis

General characteristics of the major clinical types of DM are detailed in Table 13-1.
Type I DM: Although it may occur at any age, type I DM most commonly develops in childhood or ado and is the predominant type of DM diagnosed before age 30. This type of diabetes accounts for 10 to all cases of DM and is characterized clinically by hyperglycemia and a propensity to DKA. The pancrea produces little or no insulin.
About 80% of patients with type I DM have specific HLA phenotypes associated with detectable serum cytoplasmic antibodies and islet cell surface antibodies (antibodies to glutamic acid decarboxylase and insulin are found in a similar proportion of cases).
In these patients, type I DM results from a genetically susceptible, immune-mediated, selective destru 90% of their insulin-secreting cells. Their pancreatic islets exhibit insulitis, which is characterized by an
About 80% of patients with type I DM have specific HLA phenotypes associated with detectable serum cytoplasmic antibodies and islet cell surface antibodies (antibodies to glutamic acid decarboxylase and insulin are found in a similar proportion of cases).
In these patients, type I DM results from a genetically susceptible, immune-mediated, selective destru 90% of their insulin-secreting cells. Their pancreatic islets exhibit insulitis, which is characterized by an infiltration of T lymphocytes accompanied by macrophages and B lymphocytes and by the loss of mos cells, without involvement of the glucagon-secreting cells. Cell-mediated immune mechanisms are bel play the major role in the -cell destruction. The antibodies present at diagnosis usually become undete after a few years. They may be primarily a response to -cell destruction, but some are cytotoxic for cel may contribute to their loss. The clinical onset of type I DM may occur in some patients years after the insidious onset of the underlying autoimmune process. Screening for these antibodies is included in nu ongoing preventive studies.
In white populations, a strong association exists between type I DM diagnosed before age 30 and spe HLA-D phenotypes (HLA-DR3, HLA-DR4, and HLA-DR3/HLA-DR4). One or more genes that convey susceptibility to type I DM are believed to be located near or in the HLA-D locus on chromosome 6. Sp HLA-DQ alleles appear to be more intimately related to risks for or protection from type I DM than HLA antigens, and evidence suggests that genetic susceptibility to type I DM is probably polygenic. Only 10 of newly diagnosed children with type I DM have a first-degree relative with type I DM, and the concord rate for type I DM in monozygotic twins is <= 50%. Thus, in addition to the genetic background, enviro factors affect the appearance of type I DM. Such environmental factors may be viruses (congenital ru mumps, and coxsackie B viruses may incite the development of autoimmune -cell destruction) and exp cow's milk rather than maternal milk in infancy (a specific sequence of albumin from cow's milk may cross-react with islet protein). Geography may play a role in exposure, as the incidence of type I DM is particularly high in Finland and Sardinia.
Type II DM: Type II DM is usually the type of diabetes diagnosed in patients > 30 yr, but it also occurs children and adolescents. It is characterized clinically by hyperglycemia and insulin resistance. DKA is Although most patients are treated with diet, exercise, and oral drugs, some patients intermittently or persistently require insulin to control symptomatic hyperglycemia and prevent NKHHC. The concordan for type II DM in monozygotic twins is > 90%. Type II DM is commonly associated with obesity, especi the upper body (visceral/abdominal), and often presents after a period of weight gain. Impaired glucos tolerance associated with aging is closely correlated with the typical weight gain. Type II DM patients w visceral/abdominal obesity may have normal glucose levels after losing weight.
Type II DM is a heterogeneous group of disorders in which hyperglycemia results from both an impaire secretory response to glucose and decreased insulin effectiveness in stimulating glucose uptake by sk muscle and in restraining hepatic glucose production (insulin resistance). However, insulin resistance common, and most patients with insulin resistance will not develop diabetes, because the body compe by adequately increasing insulin secretion. Insulin resistance in the common variety of type II DM is no result of genetic alterations in the insulin receptor or the glucose transporter. However, genetically dete postreceptor intracellular defects likely play a role. The resulting hyperinsulinemia may lead to other co conditions, such as obesity (abdominal), hypertension, hyperlipidemia, and coronary artery disease (th syndrome of insulin resistance).
Genetic factors appear to be the major determinants for the development of type II DM, yet no associa between type II DM and specific HLA phenotypes or islet cell cytoplasmic antibodies has been demon (An exception is a subset of nonobese adults with detectable islet cell cytoplasmic antibodies who carr the HLA phenotypes and who may eventually develop type I DM.)
The pancreatic islets in type II DM retain cells in ratios to cells that are not consistently altered, and no -cell mass appears to be preserved in most patients. Pancreatic islet amyloid, resulting from a deposit amylin, is found in a high percentage of type II DM patients at autopsy, but its relationship to the patho
(An exception is a subset of nonobese adults with detectable islet cell cytoplasmic antibodies who carr the HLA phenotypes and who may eventually develop type I DM.)
The pancreatic islets in type II DM retain cells in ratios to cells that are not consistently altered, and no -cell mass appears to be preserved in most patients. Pancreatic islet amyloid, resulting from a deposit amylin, is found in a high percentage of type II DM patients at autopsy, but its relationship to the patho of type II DM is not well established.
Before diabetes develops, patients generally lose the early insulin secretory response to glucose and m secrete relatively large amounts of proinsulin. In established diabetes, although fasting plasma insulin may be normal or even increased in type II DM patients, glucose-stimulated insulin secretion is clearly decreased. The decreased insulin levels reduce insulin-mediated glucose uptake and fail to restrain he glucose production.
Hyperglycemia may not only be a consequence but also a cause of further impairment in glucose toler the diabetic patient (glucose toxicity) because hyperglycemia decreases insulin sensitivity and increa hepatic glucose production. Once a patient's metabolic control improves, the insulin or hypoglycemic d dose is usually lowered.
Some cases of type II DM occur in young, nonobese adolescents (maturity-onset diabetes of the yo [MODY]) with an autosomal dominant inheritance. Many families with MODY have a mutation in the glucokinase gene. Impairments in insulin secretion and in hepatic glucose regulation have been demo in these patients.
Insulinopathies: Rare cases of DM, with the clinical characteristics of type II DM, result from the hete inheritance of a defective gene, leading to secretion of insulin that does not bind normally to the insulin receptor. These patients have greatly elevated plasma immunoreactive insulin levels associated with n plasma glucose responses to exogenous insulin.
Diabetes attributed to pancreatic disease: Chronic pancreatitis, particularly in alcoholics, is frequen associated with diabetes. Such patients lose both insulin-secreting and glucagon-secreting islets. Ther they may be mildly hyperglycemic and sensitive to low doses of insulin. Given the lack of effective counterregulation (exogenous insulin that is unopposed by glucagon), they frequently suffer from rapid of hypoglycemia. In Asia, Africa, and the Caribbean, DM is commonly observed in young, severely malnourished patients with severe protein deficiency and pancreatic disease; these patients are not DKA-prone but may require insulin.
Diabetes associated with other endocrine diseases: Type II DM can be secondary to Cushing's sy acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism, or somatostatinoma. Most of disorders are associated with peripheral or hepatic insulin resistance. Many patients will become diabe insulin secretion is also decreased. The prevalence of type I DM is increased in patients with certain autoimmune endocrine diseases, eg, Graves' disease, Hashimoto's thyroiditis, and idiopathic Addison disease.
Insulin-resistant diabetes associated with acanthosis nigricans (type A and type B insulin resis syndromes): Two rare syndromes result from marked insulin resistance at the insulin receptor level associated with acanthosis nigricans. Acanthosis nigricans is a velvety hyperpigmentation on the neck and groin and is probably the skin manifestation of severe and chronic hyperinsulinemia. Type A resul genetic alterations in the insulin receptor. Type B results from circulating antibodies to the insulin rece may be associated with other evidence of autoimmune disease.
Lipoatrophic diabetes: This is a rare syndrome in which insulin-resistant DM is associated with an ex symmetric or virtually complete disappearance of subcutaneous adipose tissue. It has been linked to g
and groin and is probably the skin manifestation of severe and chronic hyperinsulinemia. Type A resul genetic alterations in the insulin receptor. Type B results from circulating antibodies to the insulin rece may be associated with other evidence of autoimmune disease.
Lipoatrophic diabetes: This is a rare syndrome in which insulin-resistant DM is associated with an ex symmetric or virtually complete disappearance of subcutaneous adipose tissue. It has been linked to g alterations in the insulin receptor.
Diabetes induced by -cell toxins: Vacor, a rodenticide commonly used in Korea in suicide attempts, cytotoxic for human islets and can cause type I DM in survivors. Streptozocin can induce experimenta diabetes in rats but rarely causes diabetes in humans.
Symptoms and Signs
DM has diverse initial presentations. Type I DM usually presents with symptomatic hyperglycemia or D Type II DM may present with symptomatic hyperglycemia or NKHHC, but is frequently diagnosed in asymptomatic patients during a routine medical examination or when patients present with clinical manifestations of a late complication.
Often following the acute onset of type I DM, there is substantial secretion of insulin. Type I DM patien experience a honeymoon period characterized by a long phase of near-normal glucose levels without treatment.
Symptomatic hyperglycemia: Polyuria followed by polydipsia and weight loss occur when elevated p glucose levels cause marked glucosuria and an osmotic diuresis, resulting in dehydration. Hyperglycem also cause blurred vision, fatigue, and nausea and lead to various fungal and bacterial infections. In ty DM, symptomatic hyperglycemia may persist for days or weeks before medical attention is sought; in w type II DM with symptomatic hyperglycemia is frequently associated with itching due to vaginal candidi
Late complications: Late complications occur after several years of poorly controlled hyperglycemia. levels are increased in all cells except where there is insulin-mediated glucose uptake (mainly muscle) resulting in an increase in glycolysation and in the activity of other metabolic pathways, which may be by complications. Most microvascular complications can be delayed, prevented, or even reversed by t glycemic control, ie, achieving near-normal fasting and postprandial glucose levels, reflected by near-n glycosylated hemoglobin (Hb A 1c ). Macrovascular disease such as atherosclerosis may lead to sympt coronary artery disease, claudication, skin breakdown, and infections. Although hyperglycemia may ac atherosclerosis, many years of hyperinsulinemia preceding the onset of diabetes (with insulin resistanc play a major initiating role. Amputation of a lower limb for severe peripheral vascular disease, intermitt claudication, and gangrene remains common. Background retinopathy (the initial retinal changes see ophthalmoscopic examination or in retinal photographs) does not significantly alter vision, but it can pr to macular edema or proliferative retinopathy with retinal detachment or hemorrhage, which can cause blindness. About 85% of all diabetics eventually develop some degree of retinopathy (see Diabetic Retinopathy in Ch. 99).
Diabetic nephropathy develops in about one third of type I DM patients and in a smaller percentage o DM patients. In patients with type I DM, GFR may be increased initially with hyperglycemia. After abou type I DM, clinically detectable albuminuria (>= 300 mg/L), which is unexplained by other urinary tract may develop. Albuminuria signals a progressive decrease in GFR with a high likelihood of developmen end-stage renal disease within 3 to 20 yr (median, 10 yr). Albuminuria is almost 2.5 times higher in typ patients with diastolic BP > 90 mm Hg than in those with diastolic BP < 70 mm Hg. Thus, both hypergl and hypertension accelerate the progression to end-stage renal disease. Diabetic nephropathy is usua asymptomatic until end-stage renal disease develops, but it can cause the nephrotic syndrome. Album and renal disease may be prevented or delayed with the ACE inhibitor captopril. While aggressive trea
may develop. Albuminuria signals a progressive decrease in GFR with a high likelihood of developmen end-stage renal disease within 3 to 20 yr (median, 10 yr). Albuminuria is almost 2.5 times higher in typ patients with diastolic BP > 90 mm Hg than in those with diastolic BP < 70 mm Hg. Thus, both hypergl and hypertension accelerate the progression to end-stage renal disease. Diabetic nephropathy is usua asymptomatic until end-stage renal disease develops, but it can cause the nephrotic syndrome. Album and renal disease may be prevented or delayed with the ACE inhibitor captopril. While aggressive trea hypertension prevents the deterioration of renal function, ACE inhibitors have shown added benefits o classes of antihypertensives. In fact, ACE inhibitors prevent proteinurea in hypertensive and nonhyper diabetics. Recent evidence suggests that ACE inhibitors also help prevent retinopathy.
Diabetic neuropathy commonly occurs as a distal, symmetric, predominantly sensory polyneuropathy causes sensory deficits, which begin with and are usually most marked by a stocking-glove distribution Diabetic polyneuropathy may cause numbness, tingling, and paresthesias in the extremities and, less debilitating, severe, deep-seated pain and hyperesthesias. Ankle jerks are usually decreased or absen causes of polyneuropathy must be excluded (see Ch. 183). Acute, painful mononeuropathies affectin 3rd, 4th, or 6th cranial nerve as well as other nerves, such as the femoral, may spontaneously improve weeks to months, occur more frequently in older diabetics, and are attributed to nerve infarctions. Auto neuropathy occurs primarily in diabetics with polyneuropathy and can cause postural hypotension, dis sweating, impotence and retrograde ejaculation in men, impaired bladder function, delayed gastric em (sometimes with dumping syndrome), esophageal dysfunction, constipation or diarrhea, and nocturnal diarrhea. A decrease in heart rate response to the Valsalva maneuver or on standing and unchanged rate variation during deep breathing are evidence of autonomic neuropathy in diabetics.
Foot ulcers and joint problems are important causes of morbidity in DM. The major predisposing ca diabetic polyneuropathy--the sensory denervation impairs the perception of trauma from such common as ill-fitting shoes or pebbles. Alterations in proprioception lead to an abnormal pattern of weight beari sometimes to the development of Charcot's joints.
The risk of infection from fungi and bacteria is increased because of decreased cellular immunity cau acute hyperglycemia and circulatory deficits caused by chronic hyperglycemia. Peripheral skin infectio oral and vaginal thrush are most common. A mycotic infection may be the initial process, leading to we interdigital lesions, cracks, fissures, and ulcerations that favor secondary bacterial invasion. Patients w infected foot ulcers frequently feel no pain because of neuropathy and have no systemic symptoms un a neglected course. Deep ulcers and particularly ulcers associated with any detectable cellulitis require immediate hospitalization, since systemic toxicity and permanent disability may develop. Osteomyelitis be ruled out by bone scan. Early surgical debridement is an essential part of management, but amputa sometimes necessary.
Diagnosis
In asymptomatic patients, DM is established when the diagnostic criterion for fasting hyperglycemia recommended by the National Diabetes Data Group (NDDG) is met: a plasma (or serum) glucose leve 140 mg/dL (>= 7.77 mmol/L) after an overnight fast on two occasions in an adult or child. Recently, the American Diabetes Association recommended that fasting plasma glucose levels of > 126 mg/dL ( > 6 mmol/L) be considered diagnostic for DM.
An oral glucose tolerance test (OGTT) may be helpful in diagnosing type II DM in patients whose fas glucose is between 115 and 140 mg/dL (6.38 and 7.77 mmol/L) and in those with a clinical condition th be related to undiagnosed DM (eg, polyneuropathy, retinopathy). However, various conditions other th such as effects of drugs, and normal aging can cause abnormalities in the OGTT.
The NDDG also recommends criteria for the diagnosis of impaired glucose tolerance in patients who meet the OGTT diagnostic criteria for DM. Patients with impaired glucose tolerance may be at increas
glucose is between 115 and 140 mg/dL (6.38 and 7.77 mmol/L) and in those with a clinical condition th be related to undiagnosed DM (eg, polyneuropathy, retinopathy). However, various conditions other th such as effects of drugs, and normal aging can cause abnormalities in the OGTT.
The NDDG also recommends criteria for the diagnosis of impaired glucose tolerance in patients who meet the OGTT diagnostic criteria for DM. Patients with impaired glucose tolerance may be at increas developing fasting or symptomatic hyperglycemia, but in many patients the condition does not progres resolves. The diagnostic criteria of the NDDG are shown in Table 13-2.
Treatment
General considerations: The IDDM Diabetes Control and Complications Trial (DCCT) proved that hyperglycemia is responsible for most of the long-term microvascular complications of diabetes. It demonstrated a linear relationship between the levels of Hb A1c (see below) and the rate at which complications developed. Other studies have suggested that Hb A1c < 8% is a threshold below which complications can be prevented. Thus, therapy for type I DM should try to intensify metabolic control to Hb A1c while avoiding hypoglycemic episodes. However, treatment must be individualized and should modified when circumstances make any risk of hypoglycemia unacceptable (eg, in patients with a sho expectancy and in those with cerebrovascular or cardiac disease) or when the patient's risk of hypogly increased (eg, in patients who are unreliable or who have autonomic neuropathy).
Diet to achieve weight reduction is most important in overweight patients with type II DM. If improveme hyperglycemia is not achieved by diet, trial with an oral drug should be started.
Patient education, together with diet and exercise, is essential to ensure the effectiveness of the pres therapy, to recognize indications for seeking immediate medical attention, and to ensure appropriate fo On each physician visit, the patient should be assessed for symptoms or signs of complications, incl check of feet and pulses and sensation in the feet and legs, and a urine test for albumin. Periodic labo evaluation includes lipid profile, BUN and serum creatinine levels, ECG, and an annual complete ophthalmologic evaluation (see Diabetic Retinopathy in Ch. 99).
Because diabetics are at increased risk of acute renal failure, x-ray studies that require IV injection of dyes should be performed only when absolutely necessary and only when the patient is well hydrated.
Hypercholesterolemia or hypertension increases the risks for specific late complications and requires s attention and appropriate treatment (see Chs. 15 and 199). Although -blockers (eg, propranolol) can b safely in most diabetics, they can mask the -adrenergic symptoms of insulin-induced hypoglycemia an impair the normal counterregulatory response. Thus, ACE inhibitors and calcium antagonists are often drugs of choice.
Plasma glucose monitoring: All patients should learn self-monitoring of glucose, and insulin-treated should be taught to adjust their insulin doses accordingly. Glucose levels can be tested with easy-to-u analyzers using a drop of fingertip blood. A spring-powered lancet is recommended to obtain the finge blood sample. The frequency of testing is determined individually. Insulin-treated diabetic patients idea should test their plasma glucose daily before meals, 1 to 2 h after meals, and at bedtime. However, in two to four measurements may be obtained each day at different times, so that an overall assessment made after a week or so of treatment.
Most physicians periodically determine glycosylated hemoglobin (Hb A1c) to estimate plasma glucos control during the preceding 1 to 3 mo. Hb A1c is the stable product of nonenzymatic glycosylation of t -chain of Hb by plasma glucose and is formed at rates that increase with increasing plasma glucose le most laboratories, the normal Hb A1c level is about 6%; in poorly controlled diabetics, the level ranges
Most physicians periodically determine glycosylated hemoglobin (Hb A1c) to estimate plasma glucos control during the preceding 1 to 3 mo. Hb A1c is the stable product of nonenzymatic glycosylation of t -chain of Hb by plasma glucose and is formed at rates that increase with increasing plasma glucose le most laboratories, the normal Hb A1c level is about 6%; in poorly controlled diabetics, the level ranges to 12%. Hb A1c is not a specific test for diagnosing diabetes; however, elevated Hb A1c often indicates diabetes.
Another test is of the fructosamine level. Fructosamine is formed by a chemical reaction of glucose w plasma protein and reflects glucose control in the previous 1 to 3 weeks. Therefore, this assay may sh change in control before Hb A1c and is often helpful when intensive treatment is applied and in short-te clinical trials.
Patients with type I DM should be instructed to test for urine ketones with commercially available rea strips and be advised to test for urine ketones whenever they develop symptoms of a cold, flu, or othe intercurrent illness; nausea, vomiting, or abdominal pain; or polyuria; or if they find an unexpectedly hi plasma glucose level on self-monitoring. Testing for ketones in all urine samples is recommended for t DM patients who exhibit persistent, rapid, and marked fluctuations in their degree of hyperglycemia.
Insulin: Human insulin is often preferred in initiating insulin treatment because it is less antigenic than animal-derived varieties (see also the discussion of insulin resistance, below). However, detectable ins antibody levels, usually very low, develop in most insulin-treated patients, including those receiving hu insulin preparations.
Insulin is routinely provided in preparations containing 100 U/mL (U-100 insulin) and is injected subcutaneously with disposable insulin syringes. The 1/2-mL syringes are generally preferred by patie routinely inject doses of <= 50 U, because they can be read more easily and facilitate the accurate measurement of smaller doses. A multiple-dose insulin injection device (NovolinPen), commonly refer an insulin pen, is designed to use a cartridge containing several days' dosage. Insulin should be refrig but never frozen; however, most insulin preparations are stable at room temperature for months, which facilitates their use at work and when traveling.
Insulin preparations are classified as short-acting (rapid-acting), intermediate-acting, or long-acting. Th onset of action, time of peak action, and duration of action of the most commonly used preparations a in Table 13-3; these data should be used only as rough guidelines, because there is considerable vari among individuals and with different doses of the same preparation in the same patient. The critical determinant of the onset and duration of action of an insulin preparation is the rate of insulin absorptio the injection site.
Rapid-acting insulins include regular insulin, which is a preparation of zinc insulin crystals in a suspend solution; regular insulin is the only insulin preparation that can be given IV. Lispro, a form of regular ins is genetically engineered with a substitute of one amino acid, provides more rapid absorption of insulin therefore may be administered with food. Semilente insulin is a slightly slower rapid-acting insulin, con zinc insulin microcrystals in an acetate buffer. Intermediate-acting insulin includes neutral protamine H which contains a stoichiometric mixture of regular and protamine zinc insulin, and Lente, which contain Semilente insulin and 70% Ultralente insulin in an acetate buffer. Long-acting protamine zinc insulin co insulin that is negatively charged, combined with an excess of positively charged fish sperm protamine Ultralente contains large zinc insulin crystals in an acetate buffer.
Mixtures of insulin preparations with different onsets and durations of action are frequently given in injection by drawing measured doses of two preparations into the same syringe immediately before us manufacturers recommend that Semilente be mixed only with Lente or Ultralente to maintain the same
insulin that is negatively charged, combined with an excess of positively charged fish sperm protamine Ultralente contains large zinc insulin crystals in an acetate buffer.
Mixtures of insulin preparations with different onsets and durations of action are frequently given in injection by drawing measured doses of two preparations into the same syringe immediately before us manufacturers recommend that Semilente be mixed only with Lente or Ultralente to maintain the same solution. However, individual doses of regular insulin and neutral protamine Hagedorn or Lente insulin commonly drawn up into the same syringe to combine rapid- and intermediate-acting insulin in a single injection. A preparation that contains a mixture of 70% neutral protamine Hagedorn and 30% regular h semisynthetic insulin (Novolin 70/30 or Humulin 70/30) is also available, but its fixed ratio of intermedia rapid-acting insulin may restrict its use. Protamine zinc insulin must always be injected separately, bec contains an excess of protamine.
Initiation of insulin therapy in adults: In DCCT, type I DM patients received an average total dose o 40 U insulin a day. Because type II DM patients are insulin resistant, they require more insulin. Thus, t who are severely hyperglycemic and obese may be started on about 40 U insulin a day. The initial tota dose may be divided so that 1/2 will be administered before breakfast, 1/4 before dinner, and 1/4 at be Because of severe insulin resistance, type II DM patients may need twice that much and often more. A initial dose is selected, adjustments in the amounts, types, and timing are made based on plasma gluc determinations. The dose is adjusted to maintain preprandial plasma glucose between 80 and 150 mg (4.44 and 8.33 mmol/L). Increments in insulin dose are generally restricted to 10% at a time, and the e are assessed over about 3 days before any further increment is made. More rapid adjustments of regu insulin are indicated if hypoglycemia threatens.
Initiation of insulin therapy in children: Children who present at an early stage of type I DM with mo hyperglycemia but without ketonuria or acidosis may be started with a single daily subcutaneous inject 0.3 to 0.5 U/kg of intermediate-acting insulin alone. Children who present with both hyperglycemia and ketonuria but who are not acidotic or dehydrated may be started on 0.5 to 0.7 U/kg of intermediate-act insulin and then supplemented by subcutaneous injections of 0.1 U/kg of regular insulin at 4- to 6-h int Insulin doses are usually adjusted to maintain preprandial plasma glucose levels between 80 and 150 (4.44 and 8.33 mmol/L) or sometimes between 80 and 120 mg/dL (4.44 and 6.66 mmol/L).
Insulin schedules: The goal of insulin therapy is to control hyperglycemic surges after meals and to p baseline levels that support normal glucose metabolism. Regimens must always be individualized, and diabetics will achieve tight control with highly idiosyncratic schedules. However, the approach should in
1. Bedtime intermediate-acting insulin. This helps control nocturnal hepatic glucose production. the day with lower morning glucose levels will improve glucose tolerance throughout the day. Be insulin is associated with less weight gain than is daytime insulin alone. Bedtime insulin is also a reasonable way to initiate insulin therapy in type II DM patients who are not controlled by oral dru alone. 2. Before-breakfast mixed insulin. This often is accomplished with a mixture of about 30% shortand 70% intermediate-acting insulin. Most diabetic patients will need about half the daily insulin d before breakfast. 3. Before-lunch-and-dinner regular insulin. For tight control, supplemental rapid-acting insulin sh taken before meals. The dose should be taken 15 to 30 min before a meal for regular or Semilen with a meal for Lispro.
Multiple subcutaneous insulin injections: These are designed to maintain normal or near-normal p glucose levels throughout the day in patients with type I DM. Such treatment may increase the risks fo frequent and severe episodes of hypoglycemia. Patients should be highly motivated, well educated in informed of the risks and uncertain benefits, competent in self-monitoring of glucose, and under the supervision of a physician experienced in its use. In a typical multiple subcutaneous insulin injection re about 25% of the total daily dose is given as intermediate-acting insulin at bedtime, with additional dos
Multiple subcutaneous insulin injections: These are designed to maintain normal or near-normal p glucose levels throughout the day in patients with type I DM. Such treatment may increase the risks fo frequent and severe episodes of hypoglycemia. Patients should be highly motivated, well educated in informed of the risks and uncertain benefits, competent in self-monitoring of glucose, and under the supervision of a physician experienced in its use. In a typical multiple subcutaneous insulin injection re about 25% of the total daily dose is given as intermediate-acting insulin at bedtime, with additional dos rapid-acting insulin given before each meal (a four-dose regimen). Type I DM patients may require intermediate- or long-acting insulin in the morning to give coverage throughout the day. The patient ad daily dosage on the basis of self-monitoring of glucose before each meal and at bedtime; the plasma g level between 2 and 4 am is assessed at least once/wk.
Continuous subcutaneous insulin infusion: This mode of intensive insulin treatment in patients wit DM involves a small battery-powered infusion pump that provides a continuous subcutaneous infusion rapid-acting insulin through a small needle, usually inserted in the abdominal wall. The pump is progra infuse a selected basal rate of insulin, supplemented by manually triggered or programmed increased before each meal. The patient measures glucose levels several times a day to adjust the dosage. Con obtainable with this method is superior to that obtained with multiple injections. Hypoglycemic episode common with pump therapy, especially during the establishment of metabolic control. However, once metabolic control is established, pumps are not associated with more hypoglycemia than are multiple injections. Experimental pump implants and intraperitoneal deliveries of insulin to the portal system ma superior. However, the indwelling needle increases the risk of infections at needle sites.
Insulin treatment of brittle diabetes: Brittle diabetics are type I DM patients who exhibit frequent, rap swings in glucose levels without apparent cause.
Brittle diabetes is most common in patients with no residual insulin secretory capacity. The metabolic processes through which insulin affects the plasma levels of glucose, albumin-bound free fatty acids, a ketones are normally regulated by shifts in the balance between the effects of insulin and the opposing of glucagon (in the liver) and the adrenergic autonomic nervous system. These counterregulatory mec are independently regulated and normally increased during fasting, exercise, and other conditions that protection against hypoglycemia. Insulin doses must be adequate to deal with a sudden increase in counterregulatory mechanisms and to prevent rapidly developing symptomatic hyperglycemia and hyperketonemia, but this frequently produces transient plasma insulin excess.
Many of these patients improve when switched to a modified multiple subcutaneous insulin regimen th provides most of the daily insulin as rapid-acting insulin in daily adjusted dosages before each meal, w intermediate-acting insulin in the morning, before the evening meal, or at bedtime. The aim is not to m the diurnal plasma glucose level in a near-normal range but to stabilize the fluctuations in a range that prevents symptomatic hyper- and hypoglycemia.
Complications of insulin treatment: Hypoglycemia (see below) may occur because of an error in in dosage, a small or missed meal, or unplanned exercise (patients are usually instructed to reduce their dose or to increase their carbohydrate intake before planned exercise) or without apparent cause. Pat taught to recognize symptoms of hypoglycemia, which usually respond rapidly to the ingestion of suga diabetics should carry candy, lumps of sugar, or glucose tablets. An identification card, bracelet, or ne indicating that the patient is an insulin-treated diabetic aids in recognizing hypoglycemia in emergencie family members should be instructed to administer glucagon with an easy-to-use injection device. Eme medical personnel, after confirming the hypoglycemia with a glucostick, should initiate therapy with a r bolus injection of 25 mL of 50% glucose solution followed by a continuous IV infusion of glucose.
The dawn phenomenon refers to the normal tendency of the plasma glucose to rise in the early morn hours before breakfast, which is frequently exaggerated in patients with type I DM and in some patient type II DM. Fasting glucose levels rise because of an increase in hepatic glucose production, which m secondary to the midnight surge of growth hormone. In some patients with type I DM, nocturnal hypog
bolus injection of 25 mL of 50% glucose solution followed by a continuous IV infusion of glucose.
The dawn phenomenon refers to the normal tendency of the plasma glucose to rise in the early morn hours before breakfast, which is frequently exaggerated in patients with type I DM and in some patient type II DM. Fasting glucose levels rise because of an increase in hepatic glucose production, which m secondary to the midnight surge of growth hormone. In some patients with type I DM, nocturnal hypog may be followed by a marked increase in fasting plasma glucose with an increase in plasma ketones (Somogyi phenomenon). Thus, both the dawn and Somogyi phenomena are characterized by mornin hyperglycemia, but the latter is due to rebound (counterregulation) hyperglycemia. The frequency with the latter phenomenon actually occurs is disputed. When it is suspected, the patient should wake betw and 4 am to monitor blood glucose levels. If intermediate insulin is administered at bedtime, the dawn Somogyi phenomena can often be prevented.
Local allergic reactions at the site of insulin injections are less common with purified porcine and hu insulins. These reactions can produce immediate pain and burning, followed after several hours by loc erythema, pruritus, and induration, the latter sometimes persisting for days. Most reactions spontaneo disappear after weeks of continued insulin injection and require no specific treatment, although antihis are sometimes used.
Generalized insulin allergy (usually to the insulin molecule) is rare but can occur when treatment is discontinued and restarted after a lapse of months or years. Such reactions may occur with any type o including human biosynthetic insulin. Symptoms usually develop shortly after an injection and may inc urticaria, angioedema, pruritus, bronchospasm, and, in some cases, circulatory collapse. Treatment w antihistamines may suffice, but epinephrine and IV glucocorticoids may be required. If continued insuli treatment is required after the condition stabilizes, skin testing with a panel of purified insulin preparati desensitization should be performed by an experienced physician.
Insulin resistance is an increase in insulin requirement to >= 200 U/day and is associated with marke increases in the plasma insulin-binding capacity. Most patients treated with insulin for >= 6 mo develop antibodies to insulin. The relative antigenicity of purified insulin preparations is bovine > porcine > hum genetic factors also affect individual response. Circulating insulin-binding antibodies can modify the pharmacokinetics of free insulin, but treatment usually is not adversely affected. In patients with insulin resistance, switching to purified porcine or human insulin may lower the requirement. Remission may b spontaneous or may be induced in some type II DM patients who can stop insulin treatment for 1 to 3 Prednisone may decrease insulin requirements within 2 wk; treatment is usually initiated with about 30 and is tapered as the requirements decrease.
Local fat atrophy or hypertrophy at injection sites is relatively rare and usually improves by switching human insulin and injecting it directly into the affected area. No specific treatment of local fat hypertrop required, but injection sites should be rotated.
Oral antidiabetic drugs: These drugs are used for type II DM but not for type I DM because they can prevent symptomatic hyperglycemia or DKA in such patients. Oral hypoglycemic drugs are the sulfony Oral antihyperglycemic drugs are the biguanides, the -glucosidase inhibitors, and the insulin sensitizer (thiazolidinediones ["glitazones"]). Characteristics of the oral antidiabetic drugs are shown in Table 13-
Sulfonylureas: The sulfonylureas lower plasma glucose primarily by stimulating insulin secretion. Sec effects on improving peripheral and hepatic insulin sensitivity may be due to the decrease in both gluc toxicity and insulin clearance. Sulfonylureas differ in potency and duration of action (see Table 13-4). A sulfonylureas are metabolized in the liver, but only tolbutamide and tolazamide are inactivated exclusiv the liver. About 30% of chlorpropamide is normally excreted in the urine, and the principal hepatic met of acetohexamide is highly active and excreted in urine; both drugs carry an increased risk of prolonge hypoglycemia in patients with impaired renal function and in the elderly. The 2nd-generation sulfonylur (such as glipizide and glyburide) are about 100 times more potent than the 1st-generation ones, are a
toxicity and insulin clearance. Sulfonylureas differ in potency and duration of action (see Table 13-4). A sulfonylureas are metabolized in the liver, but only tolbutamide and tolazamide are inactivated exclusiv the liver. About 30% of chlorpropamide is normally excreted in the urine, and the principal hepatic met of acetohexamide is highly active and excreted in urine; both drugs carry an increased risk of prolonge hypoglycemia in patients with impaired renal function and in the elderly. The 2nd-generation sulfonylur (such as glipizide and glyburide) are about 100 times more potent than the 1st-generation ones, are a rapidly, and are metabolized mainly in the liver. Clinically, the 2nd-generation sulfonylureas are similar effectiveness.
Allergic reactions and other side effects (eg, cholestatic jaundice) are relatively uncommon. Acetoh may be used in patients who are allergic to other sulfonylureas. Chlorpropamide and acetohexamide s not be used in patients with impaired renal function. In addition, chlorpropamide should not be used in patients, because it can potentiate the action of antidiuretic hormone, often leading to hyponatremia a deterioration in mental status, which in an elderly patient may often not be recognized as a drug-induc effect.
For the initial treatment, many authorities prefer the shorter-acting sulfonylureas, and most do not recommend using a combination of different sulfonylureas. Treatment is started with a low dose, which adjusted after several days until a satisfactory response is obtained or the maximum recommended do reached. About 10 to 20% of patients fail to respond to a trial of treatment (primary failures), and patie fail to respond to one sulfonylurea often fail to respond to others. Of patients who initially respond, 5 to per year experience secondary failures. In such cases, insulin may be added to sulfonylurea treatmen
Hypoglycemia is the most important complication of sulfonylurea treatment. Hypoglycemia can occur i patients treated with any of the sulfonylureas but occurs most frequently with long-acting ones (glyburi chlorpropamide). Sulfonylurea-induced hypoglycemia can be severe and may last or recur for days aft treatment is stopped, even when it occurs in patients treated with tolbutamide, whose usual duration o is 6 to 12 h. A mortality rate of 4.3% in patients hospitalized with sulfonylurea-induced hypoglycemia h reported recently. Therefore, all sulfonylurea-treated patients who develop hypoglycemia should be hospitalized, because even if they respond rapidly to initial treatment for hypoglycemia, they must be c monitored for 2 to 3 days. Most of these patients may not require further treatment with sulfonylureas.
Antihyperglycemic drugs: Metformin (a biguanide) has been used as primary therapy in type II DM for over 30 years in most of the world. It has been recently approved for use in the USA. It acts by dec hepatic glucose production and may improve insulin sensitivity in those who lose weight. It is as effect sulfonylurea as monotherapy (when used alone it rarely causes hypoglycemia) and is synergistic in combination with sulfonylurea therapy. Metformin also promotes weight loss and decreases lipid levels phenformin, metformin rarely causes severe lactic acidosis. GI side effects are common, but often tran and may be prevented if the drug is taken with meals and if the dosage is gradually increased (by 500 up to 2.5 g). Metformin is contraindicated in patients with kidney and liver diseases or alcoholism. It is contraindicated in patients with lactic acidosis and should be withheld during acute hospitalization in m patients.
Acarbose is an -glucosidase inhibitor that competitively inhibits hydrolysis of oligo- and monosaccha This delays carbohydrate digestion in the small intestine and subsequent absorption, resulting in less postprandial elevation of blood glucose levels. Because its mechanism of action differs from that of oth hypoglycemics, it can be used in combination therapy with other oral agents. GI side effects are very c but often transient. The drug must be taken with meals, and the dosage should be gradually increased mg up to 50 to 100 mg with each meal.
Thiazolidinediones are the insulin-sensitizer drugs that improve insulin sensitivity in skeletal muscle a suppress hepatic glucose output. The only such drug available in the USA is troglitazone. It has been approved for use in the treatment of type II DM patients requiring insulin and has moderate effects on decreasing plasma glucose and triglyceride levels. This drug is administered once a day and has pote
mg up to 50 to 100 mg with each meal.
Thiazolidinediones are the insulin-sensitizer drugs that improve insulin sensitivity in skeletal muscle a suppress hepatic glucose output. The only such drug available in the USA is troglitazone. It has been approved for use in the treatment of type II DM patients requiring insulin and has moderate effects on decreasing plasma glucose and triglyceride levels. This drug is administered once a day and has pote idiosyncratic hepatotoxicity. Patients should be instructed to decrease their daily insulin dosage with th initiation of therapy.
Diet management: In insulin-treated diabetics, diet management aims to restrict variations in the tim size, or composition of meals, which could make the prescribed insulin regimen inappropriate and resu hypoglycemia or marked postprandial hyperglycemia. All insulin-treated patients require detailed diet management, including a prescription for their total daily caloric intake; guidelines for proportions of carbohydrate, fat, and protein in their diets; and instruction on distributing calories among individual m snacks. A professional dietitian can tailor the diet plan and education to meet the patient's individual n Flexibility, however, helps maintain patient motivation.
Publications are available from the American Diabetes Association and other sources for diet planning patient education. Exchange lists providing information on the carbohydrate, protein, fat, and caloric co of individual servings are used to translate the dietary prescription into a diet plan, which should conta that the patient likes to eat, provided there is no specific reason to exclude a particular food. Foods wit exchange values (ie, similar calories and contents of carbohydrate, protein, and fat) may have differen on postprandial hyperglycemia in any individual diabetic. However, exchange lists are helpful in reduci variation in the size and composition of the patient's usual breakfasts, lunches, dinners, and snacks.
In obese type II DM patients, the aims of diet management are losing weight and controlling hypergly The diet should meet the patient's minimum daily protein requirement (0.9 g/kg) and be designed to in gradual and sustained weight loss (about 2 lb/wk) until ideal body weight is approached and maintaine dietitian can assist in developing a diet that the patient will follow. Increased physical activity in sedent obese type II DM patients is valuable and may decrease insulin resistance over time. Diabetics with hypertension should be treated with ACE inhibitors, which have been shown to be more protective aga coronary artery disease than Ca channel blockers.
Management of diabetics during hospitalization: Diabetic patients admitted to hospitals commonly coexisting illnesses that aggravate hyperglycemia, such as an infection or coronary artery disease. Be and a regular diet may also aggravate hyperglycemia. Conversely, if the patient is anorectic or vomits, food intake is reduced, continuation of drugs may cause hypoglycemia. The popular insulin coverage w sliding scale for insulin administration should not be the only intervention, because it is reactive rather proactive in correcting hyperglycemia. It may also be inappropriately used when hyperglycemia reflect gluconeogenesis in response to previously uncorrected hypoglycemia.
Hospitalized type II DM patients often do well without any change in drugs. Hypoglycemic drugs may b discontinued during an acute condition associated with decreased food intake or one that has a tende cause hypoglycemia. Insulin may be added if plasma glucose levels remain high.
In type I DM patients, intermediate (NPH or Lente) insulin should be continued at 50 to 70% of the dai divided bid or tid. Supplemental regular insulin can be given on a sliding scale. In patients receiving to partial parenteral nutrition, hyperglycemia may be treated with a continuous IV infusion of insulin or div doses of intermediate-acting insulin. Blood glucose should be measured four times a day before meal
Management of diabetics during surgical procedures: Surgical procedures (including the prior emo stress, the effects of general anesthesia, and the trauma of the procedure) can markedly increase plas glucose in diabetics and induce DKA in type I DM patients. In patients who normally take one or two d injections of insulin, 1/3 to 1/2 of the usual morning dose can be given in the morning before the opera
doses of intermediate-acting insulin. Blood glucose should be measured four times a day before meal
Management of diabetics during surgical procedures: Surgical procedures (including the prior emo stress, the effects of general anesthesia, and the trauma of the procedure) can markedly increase plas glucose in diabetics and induce DKA in type I DM patients. In patients who normally take one or two d injections of insulin, 1/3 to 1/2 of the usual morning dose can be given in the morning before the opera an IV infusion of 5% glucose in either 0.9% sodium chloride solution or water at a rate of 1 L (50 g of g over 6 to 8 h started. After the operation, plasma glucose and the plasma reaction for ketones are che Unless a change in dosage is indicated, the preoperative dose of insulin is repeated when the patient recovered from the anesthesia and the glucose infusion is continued. Plasma glucose and ketones are monitored at 2- to 4-h intervals, and regular insulin is given q 4 to 6 h as needed to maintain the plasm glucose level between 100 and 250 mg/dL (5.55 and 13.88 mmol/L). This is continued until the patient switched to oral feedings and a one- or two-dose insulin schedule.
Some physicians prefer to withhold subcutaneous insulin on the day of the operation and to add 6 to 1 regular insulin to 1 L of 5% glucose in 0.9% sodium chloride solution or water infused initially at 150 m the morning of the operation based on the plasma glucose level. This is continued through recovery, w insulin adjusted based on the plasma glucose levels obtained in the recovery room and at 2- to 4-h int thereafter.
Insulin is not required for diabetics who have maintained a satisfactory plasma glucose level by diet al combination with a sulfonylurea before the operation. Sulfonylureas should be withheld 2 to 4 days be operation, and plasma glucose levels should be measured pre- and postoperatively and q 6 h while pa receive IV fluids. Back to top of page
Section 2. Endocrine And Metabolic Disorders Chapter 7. Pituitary Disorders Topics

[General] Anterior Lobe Disorders Posterior Lobe Disorders
[General]
Pituitary structure and function and relationships between the hypothalamus and the pituitary gland ar discussed in Ch. 6.
Patients with hypothalamic-pituitary disorders present with some combination of (1) symptoms or signs mass lesion (eg, headaches, visual field defects) or (2) hypersecretion or hyposecretion of one or mor pituitary hormones. Other hypothalamic functions also may be affected. Symptoms of hypo- or hyperp secretion are the most common complaints of patients presenting with pituitary or hypothalamic neopla but the symptoms may have other causes. A mass involving the hypothalamus or pituitary also should suspected if the sella turcica is enlarged on skull x-ray or if neurologic symptoms and signs suggest compression of the optic chiasm (especially bilateral hemianopia).
The enlarged sella may represent the empty sella syndrome if no endocrine or visual disorder exists Diagnosis can be confirmed by CT or MRI. Pituitary functions in patients with empty sella syndrome ar frequently normal, but hypopituitarism may be present. The typical patient with this syndrome is female 80%), obese (about 75%), and hypertensive (30%) and may have benign intracranial hypertension (10 spinal fluid rhinorrhea (10%). Headaches and visual field defects may be present. Occasionally, patien small coexisting pituitary tumors that secrete growth hormone, prolactin, or ACTH. No specific therapy needed for an empty sella alone.
Section 2. Endocrine And Metabolic Disorders Chapter 14. The Porphyrias Topics
[General] Most Common Porphyrias Less Common Porphyrias
[General]
The Heme Biosynthetic Pathway
The porphyrias: A group of disorders cause by deficiencies of enzymes of the heme biosynthetic pathw
Abnormally elevated levels of porphyrins or their precursors (eg, -aminolevulinic acid [ALA] and porphobilinogen [PBG]) are produced, accumulate in tissues, and are excreted in urine and stool. Dise manifestations result almost entirely from effects on the nervous system and skin.
Heme, an iron-containing pigment, is the nonprotein functional component of hemoproteins, which are all tissues.
The heme biosynthetic pathway is illustrated in Fig. 14-1. The eight different enzymes that drive the se steps in this pathway are numbered 1 through 8 in Fig. 14-1 and are briefly described below. The first and the last three are found in mitochondria; the intermediate enzymes occur in the cytosol.
1. ALA synthase, the first enzyme of the heme biosynthetic pathway, catalyzes the condensation o and succinyl coenzyme A to form ALA. The enzyme is localized in the inner membrane of mitoch and requires pyridoxal 5-phosphate as a cofactor. Separate genes encode erythroid and nonery ALA synthases. 2. ALA dehydratase, a cytosolic enzyme, converts two molecules of ALA into a monopyrrole, PBG, removal of two molecules of water. Lead inhibits ALA dehydratase activity by displacing zinc (the essential for enzyme activity) from the enzyme. The most potent inhibitor of the enzyme is succinylacetone, a structural analog of ALA, which is found in urine and blood of patients with he tyrosinemia. 3. PBG deaminase catalyzes the condensation of four molecules of PBG to yield a linear tetrapyrro hydroxymethylbilane (HMB). There are two isozymes of PBG deaminase; one is present exclusiv erythroid cells, whereas the other is in nonerythroid cells. The two isoforms of PBG deaminase a encoded by distinct messenger RNAs (mRNAs) that are transcribed from a single gene by altern
3.
4.
5.
6.
7. 8.
succinylacetone, a structural analog of ALA, which is found in urine and blood of patients with he tyrosinemia. PBG deaminase catalyzes the condensation of four molecules of PBG to yield a linear tetrapyrro hydroxymethylbilane (HMB). There are two isozymes of PBG deaminase; one is present exclusiv erythroid cells, whereas the other is in nonerythroid cells. The two isoforms of PBG deaminase a encoded by distinct messenger RNAs (mRNAs) that are transcribed from a single gene by altern transcription and splicing. Uroporphyrinogen III cosynthase catalyzes the formation of uroporphyrinogen III from HMB. This an intramolecular rearrangement that reverses the orientation of ring D (the pyrrole ring on the ri of the HMB molecule shown in Fig. 14-1) followed by closure of the macrocycle to form uroporph III. When this enzyme is deficient, HMB can undergo spontaneous closure of the macrocycle wit reversal of ring D, leading to formation of uroporphyrinogen I. Uroporphyrinogen decarboxylase, a cytosolic enzyme, catalyzes four sequential decarboxylation carboxymethyl side chains in uroporphyrinogen III (an octacarboxyl porphyrin) to yield heptacarb porphyrin, hexacarboxyl porphyrin, pentacarboxyl porphyrin, and, finally, coproporphyrinogen III tetracarboxyl porphyrin). This enzyme can also metabolize uroporphyrinogen I to coproporphyrin Coproporphyrinogen oxidase, a mitochondrial enzyme in mammalian cells, catalyzes the remova carboxyl group and two hydrogens from the proprionic groups of pyrrole rings A and B of coproporphyrinogen III to form vinyl groups at these positions, forming protoporphyrinogen. This is unable to metabolize coproporphyrinogen I. Protoporphyrinogen oxidase mediates the oxidation of protoporphyrinogen IX to protoporphyrin I catalyzing the removal of six hydrogen atoms from the porphyrinogen nucleus. Ferrochelatase catalyzes the insertion of iron into protoporphyrin, which represents the final step heme biosynthetic pathway. The enzyme is not specific for iron and can catalyze the insertion of other metals such as zinc.
The intermediates of the pathway are conserved within cells and therefore are normally excreted only amounts. They differ markedly from each other in molecular size, solubility, and other properties. ALA, and porphyrinogens (hexahydroporphyrins, ie, porphyrins in the chemically reduced state) are colorles nonfluorescent. Protoporphyrin, the final intermediate in the pathway, is the only intermediate that is a oxidized porphyrin. Porphyrins in the oxidized state are reddish and fluoresce when exposed to long-w ultraviolet light. Porphyrinogens that leak into extracellular fluid undergo auto-oxidation and are excrete primarily as porphyrins. However, appreciable amounts of unoxidized coproporphyrinogen may be exc urine. ALA, PBG, uroporphyrin, hepta-, hexa-, and pentacarboxyl porphyrins are water-soluble and are excreted mostly in urine. Coproporphyrin (a tetracarboxyl porphyrin) is excreted in urine and bile. Harderoporphyrin (a tricarboxyl porphyrin) and protoporphyrin (a dicarboxyl porphyrin) are poorly solub water and thus cannot be excreted by the kidneys. If they accumulate in bone marrow or liver they app plasma, are taken up by the liver, and are excreted in bile and feces.
Control of Heme Biosynthesis
Heme is synthesized in largest amounts by the bone marrow, where it is incorporated into hemoglobin is an oxygen transport protein, and by the liver, where most is incorporated into cytochromes, which ar electron transport proteins. The most abundant cytochromes in liver are the cytochrome P-450 enzym metabolize drugs and many other foreign and endogenous chemicals (see Ch. 43).
Heme biosynthesis is controlled differently in liver and bone marrow. Hepatic heme biosynthesis is rate and primarily regulated by the first enzyme, ALA synthase (see Fig. 14-1, enzyme 1). This enzyme's a liver cells is normally very low but increases dramatically by induction of enzyme synthesis when the li produces more heme. Synthesis of the enzyme is also under sensitive feedback control by cellular fre content and decreases when free heme content is high. Certain drugs and hormones induce hepatocy make more ALA synthase, heme, and cytochrome P-450.
In the bone marrow, heme is made in erythroblasts and reticulocytes that still contain mitochondria, wh
liver cells is normally very low but increases dramatically by induction of enzyme synthesis when the li produces more heme. Synthesis of the enzyme is also under sensitive feedback control by cellular fre content and decreases when free heme content is high. Certain drugs and hormones induce hepatocy make more ALA synthase, heme, and cytochrome P-450.
In the bone marrow, heme is made in erythroblasts and reticulocytes that still contain mitochondria, wh circulating erythrocytes lack mitochondria and cannot form heme. Heme biosynthesis in erythroid cells regulated at least in part by the process of cellular uptake of iron. Bone marrow cells express erythroid forms of some pathway enzymes. Erythroid-specific ALA synthase is regulated by an iron-responsive e in the mRNA, and this accounts partly for tissue-specific regulation of heme synthesis for hemoglobin formation.
The genes for all eight enzymes of the heme biosynthetic pathway have been cloned and sequenced chromosomal locations identified (see Table 14-1). Mutations of the erythroid-specific form of ALA syn have been found in some cases of X-linked sideroblastic anemia. Porphyrias and related disorders are associated with deficiencies of the other seven enzymes, and mutations in genes for these enzymes h been characterized in detail. Although each type of hereditary porphyria is associated with deficiency o particular enzyme, unless people with that enzyme deficiency come from the same family, they are like have different mutations in the gene for that enzyme. Thus, these diseases are heterogeneous at the molecular level.
When an enzyme of heme synthesis is deficient, its substrate and other heme precursors may accumu bone marrow or liver. These precursors then appear in excess in the blood, are transported to other tis and are excreted in urine and feces.
Some porphyrias, especially those that increase the early precursors ALA and PBG, damage nerves, l to a variety of symptoms such as abdominal pain and muscle weakness, which can even progress to p Mechanisms for the neurologic disturbances have been postulated, such as effects of excessive heme pathway intermediates, or deficient heme synthesis, in the nervous system. ALA and other products o heme biosynthetic pathway have not been proven to be neurotoxic, and heme deficiency in nervous tis these disorders is also unproven. Therefore, the exact cause remains unclear.
Porphyrias that increase porphyrins such as uroporphyrin, coproporphyrin, and protoporphyrin in tissu plasma cause photosensitivity. When porphyrins are illuminated at wavelengths of about 400 nm in th presence of O2, they generate a charged unstable form of oxygen, called singlet oxygen, which can da tissues. The skin is particularly susceptible because it is the tissue most exposed to light.
Classification
Porphyrias are most accurately classified according to the specific enzyme deficiencies. Other classific are according to major clinical features; these are clinically useful but may overlap. The acute porphy cause neurologic symptoms that are usually intermittent. The cutaneous porphyrias cause photosen the skin. Acute intermittent porphyria, ALA dehydratase-deficient porphyria, hereditary coproporphyria variegate porphyria constitute the acute porphyrias. Porphyria cutanea tarda, hereditary coproporphyri variegate porphyria, erythropoietic protoporphyria, congenital erythropoietic porphyria, and hepatoerythropoietic porphyria constitute the cutaneous porphyrias. In the hepatic and erythropoietic porphyrias, the excess precursors originate primarily from the liver and bone marrow, respectively.
In this chapter, the three most common porphyrias are discussed first, in the order of the deficient enz the heme biosynthetic pathway (see Table 14-2). The less prevalent porphyrias are discussed separat more briefly, also in the order of the deficient enzymes in the heme biosynthetic pathway.
hepatoerythropoietic porphyria constitute the cutaneous porphyrias. In the hepatic and erythropoietic porphyrias, the excess precursors originate primarily from the liver and bone marrow, respectively.
In this chapter, the three most common porphyrias are discussed first, in the order of the deficient enz the heme biosynthetic pathway (see Table 14-2). The less prevalent porphyrias are discussed separat more briefly, also in the order of the deficient enzymes in the heme biosynthetic pathway.
Laboratory Testing
Symptoms of the porphyrias resemble those of many other diseases. Some laboratory tests are sensit specific for diagnosis of porphyrias, and the results are markedly abnormal when these diseases are a However, tests must be properly selected and interpreted to provide specific diagnostic information wh porphyria is suspected. It is best to rely on a few sensitive and specific tests for screening (see Table 1 most situations, screening tests for an acute porphyria can be confined to measuring ALA and PBG in The Watson-Schwartz test is qualitative and is still widely used to detect excess urinary PBG. A much-preferred method for the rapid detection of excess PBG in urine involves using a kit with an anio exchange resin contained in a plastic syringe. The quantitative ion column method of Mauzerall and G should be used to verify positive results from a screening test for PBG and to detect excess ALA. Plas porphyrin can be measured when a cutaneous porphyria is suspected. Erythrocyte enzyme measurem second-line tests that are not performed routinely unless one of these screening tests is abnormal. Measurements of urinary, fecal, and erythrocytic porphyrins are also best regarded as second-line tes lack specificity (ie, they are also abnormal in other conditions) and therefore are not highly suitable for screening (see Table 14-3).
Section 2. Endocrine And Metabolic Disorders Chapter 8. Thyroid Disorders Topics

[General] Euthyroid Goiter Euthyroid Sick Syndrome Hyperthyroidism Hypothyroidism Thyroiditis Thyroid Cancers
[General]
Thyroid disorders include euthyroid goiter, euthyroid sick syndrome, hyperthyroidism, hypothyroidism, thyroiditis, and thyroid cancers. Discussion of the synthesis and physiology of thyroid hormones and o laboratory testing of thyroid function are prerequisites to a thorough understanding of these disorders.
Synthesis and Release of Thyroid Hormon
The general scheme of thyroid hormone biosynthesis is shown in Fig. 8-1. Iodide, which is ingested in and water, is actively concentrated by the thyroid gland, converted to organic iodine by thyroid peroxid incorporated into tyrosine in intrafollicular thyroglobulin within the colloid at the basal cell surface of the follicular cell. The tyrosines are iodinated at one (monoiodotyrosine) or two (diiodotyrosine) sites and t coupled to form the active hormones (diiodotyrosine + diiodotyrosine tetraiodothyronine [thyroxine, T 4 diiodotyrosine + monoiodotyrosine triiodothyronine [T 3]. Another source of T3 within the thyroid gland i result of the outer ring deiodination of T4 by a selenoenzyme: type I 5-deiodinase (5D-I). Thyroglobu glycoprotein containing T 3 and T4 within its matrix, is taken up from the follicle as colloid droplets by th cells.
Lysosomes containing proteases cleave T3 and T4 from thyroglobulin, resulting in release of free T3 an The iodotyrosines (monoiodotyrosine and diiodotyrosine) are also released from thyroglobulin, but onl small amounts reach the bloodstream. Iodine is removed from them by intracellular deiodinases, and t iodine is used by the thyroid gland.
The T 4 and T3 released from the thyroid by proteolysis reach the bloodstream, where they are bound t thyroid hormone-binding serum proteins for transport. The major thyroid hormone-binding protein is
The iodotyrosines (monoiodotyrosine and diiodotyrosine) are also released from thyroglobulin, but onl small amounts reach the bloodstream. Iodine is removed from them by intracellular deiodinases, and t iodine is used by the thyroid gland.
The T 4 and T3 released from the thyroid by proteolysis reach the bloodstream, where they are bound t thyroid hormone-binding serum proteins for transport. The major thyroid hormone-binding protein is thyroxine-binding globulin (TBG), which has high affinity but low capacity for T 4 and T3. TBG normally accounts for about 75% of the bound hormones. Other thyroid hormone-binding proteins--primarily thyroxine-binding prealbumin, also called transthyretin, which has high affinity but low capacity for T4, albumin, which has low affinity but high capacity for T 4 and T3--account for the remainder of the bound thyroid hormones. About 0.03% of the total serum T4 and 0.3% of the total serum T3 are free and in equilibrium with the bound hormones. Only free T4 and T3 are available to the peripheral tissues for th hormone action.
All reactions necessary for the formation of T3 and T4 are influenced and controlled by pituitary thyroid-stimulating hormone (TSH), also called thyrotropin, which stimulates follicular cells in the thyro TSH binds to its thyroid plasma membrane receptor on the external follicular cell surface and activates enzyme adenylate cyclase, thus increasing the formation of adenosine 3:5-cyclic phosphate (cAMP), nucleotide that mediates the intracellular effects of TSH. Pituitary TSH secretion is controlled by a neg feedback mechanism modulated by the circulating level of free T4 and free T 3 and by conversion of T4 the pituitary thyrotropic cells. T3 is the metabolically active iodothyronine. Increased levels of free thyro hormones (T4 and T3) inhibit TSH secretion from the pituitary, whereas decreased levels of T 4 and T3 an increased TSH release from the pituitary. TSH secretion is also influenced by thyrotropin-releasing hormone (TRH), a 3-amino acid peptide synthesized in the hypothalamus. TRH, released into the port system between the hypothalamus and pituitary, binds to a specific TRH receptor on the thyrotropic ce anterior pituitary and causes the subsequent release of TSH. The precise regulation of TRH synthesis release is not clear, although thyroid hormones do play a role.
About 20% of the circulating T3 is produced by the thyroid. The remaining 80% is produced by monodeiodination of the outer ring of T4 (5D-I), mainly in the liver. Monodeiodination of the inner ring (5-deiodinase [5D-III]) also occurs in hepatic and extrahepatic sites to yield 3,3,5-T3 (reverse T3 or rT iodothyronine has minimal metabolic activity but is present in normal human serum and in insignificant amounts in thyroglobulin. About 99% of the circulating rT3 is generated by inner ring deiodination of T 4 peripheral tissues. rT3 levels increase in many instances in which serum T3 levels fall because of decr activity of outer ring 5D-I (eg, chronic liver and renal disease, acute and chronic illness, starvation, an carbohydrate-deficient diets). This increase in rT 3 occurs primarily because of decreased outer ring (5 activity, which markedly decreases the clearance of rT3. These states of chronic illness, therefore, res decreased production of the active hormone, T3 , and in increased serum rT 3 levels due to decreased clearance. The decreased production of T3 might be an adaptive response to illness.
Effects of Thyroid Hormones
Thyroid hormones have two major physiologic effects: (1) They increase protein synthesis in virtually e body tissue. (T3 and T4 enter cells, where T3 , which is derived from the circulation and from conversio to T3 within the cell, binds to discrete nuclear receptors and influences the formation of mRNA.) (2) T3
increases O2 consumption by increasing the activity of the Na+, K+-ATPase (Na pump), primarily in tis responsible for basal O2 consumption (ie, liver, kidney, heart, and skeletal muscle). The increased act
Na+, K+-ATPase is secondary to increased synthesis of this enzyme; therefore, the increased O2 cons
body tissue. (T3 and T4 enter cells, where T3 , which is derived from the circulation and from conversio to T3 within the cell, binds to discrete nuclear receptors and influences the formation of mRNA.) (2) T3
increases O2 consumption by increasing the activity of the Na+, K+-ATPase (Na pump), primarily in tis responsible for basal O2 consumption (ie, liver, kidney, heart, and skeletal muscle). The increased act
Na+, K+-ATPase is secondary to increased synthesis of this enzyme; therefore, the increased O2 cons is also probably related to the nuclear binding of thyroid hormones. However, a direct effect of T 3 on th mitochondrion has not been ruled out. T3 is believed to be the active thyroid hormone, although T4 itse be biologically active.
Laboratory Testing of Thyroid Function
Measurement of serum thyroid-stimulating hormone (TSH): Measuring serum TSH is the best way determine thyroid dysfunction. Normal test results essentially rule out hyperthyroidism or hypothyroidis except in hyperthyroidism secondary to a TSH-secreting pituitary adenoma or pituitary resistance to th hormone and in some patients with central hypothyroidism due to disease in the hypothalamus and/or gland. These conditions are discussed briefly below. The serum TSH level also defines the syndromes subclinical hyperthyroidism (suppressed serum TSH) and subclinical hypothyroidism (elevated serum both associated with normal serum T4, free T4 , T3, and free T3 levels.
New serum TSH assays using immunometric assay methodology are far more sensitive and accurate first-generation assay using radioimmunoassay. This sensitivity allows differentiation between the extr low or undetectable levels found in true hyperthyroidism and the below-normal levels found in certain p eg, patients with euthyroid sick syndrome (see below). Second-generation immunometric assays (IEM IFMAs, and ICMAs) have a functional sensitivity of 0.1 to 0.2 mU/L. Third-generation assays (some IC have a functional sensitivity of 0.01 to 0.02 mU/L. Fourth-generation assays in development have a fu sensitivity of 0.001 to 0.002 mU/L.
Measurement of total serum T4 : Total serum T4 is most commonly measured by immunometric assa isotopic (IRMA) or nonisotopic labels, including an enzyme (immunoenzymometric assay [IEMA]), a flu (immunofluorometric assay [IFMA]), or a chemiluminescent compound (immunochemiluminometric as [ICMA]). Immunometric assays measure total T 4 , both bound and free hormone, although almost all T protein-bound. These assays are simple, inexpensive, and rapid. Total T 4 is a direct measurement of T unaffected by contaminating non-T4 iodine. However, changes in serum-binding protein levels produc corresponding changes in total T 4, even though the physiologically active free T4 is unchanged. Thus, patient may be physiologically normal but have an abnormal total serum T 4 level.
Thyroxine-binding globulin (TBG) is most commonly increased in pregnancy, by estrogen therapy or o contraceptives, and in the acute phase of infectious hepatitis. TBG may also be increased genetically X-linked abnormality.
TBG is decreased primarily by anabolic steroids, including testosterone, and by excess amounts of corticosteroids. TBG may also be decreased genetically. Finally, large doses of drugs such as phenyto aspirin and their derivatives displace T 4 from its binding sites on TBG, thereby falsely lowering the tota T4 level.
Direct measurement of free T4: Since free thyroid hormones are available to peripheral tissues, direc measuring serum free T4 avoids the pitfalls of interpreting total T 4 levels, which are influenced by the l the binding proteins. Thus, serum free T4 levels more accurately diagnose true thyroid function than to
T4 level.
Direct measurement of free T4: Since free thyroid hormones are available to peripheral tissues, direc measuring serum free T4 avoids the pitfalls of interpreting total T 4 levels, which are influenced by the l the binding proteins. Thus, serum free T4 levels more accurately diagnose true thyroid function than to Direct measurement of serum free T4 level is most accurately assessed by equilibrium dialysis, which time-consuming, expensive, technically demanding, and unavailable in most commercial laboratories. method separates bound from free hormone. The gold standard for measuring serum free T4 is overn
equilibrium dialysis of serum containing 125 I-T 4; the percentage of free T 4 is calculated by determining total counts in the dialysate divided by the total 125 I-T 4 added to the serum multiplied by the total T 4 concentration. A simplified version is available in kit form; free T 4 is measured in the dialysate by immunoassay.
Indirect estimation of free T 4: These measurements are readily available, are simpler, and compare extremely well with the methods for measuring direct free T4 mentioned above. Index methods require independent tests, one measuring total serum T4 and the other measuring thyroid hormone-binding ra resin uptake. The free T4 index is then calculated using the total T 4 and the TBG level, the thyroid hormone-binding ratio, or T3 resin uptake. The index is directly proportional to the free T 4 level. Immun methods are standardized against a direct measurement of free T4 by equilibrium dialysis, thus results reported in absolute units (ng/dL or pmol/L). The two most commonly used methods are a two-step an one-step immunoassay method using a T4 analog. These assays are not completely free of the influen binding proteins or substances in serum that may result in false increases or decreases in the free T 4
Measurement of total serum T3 and free T3: Since T3 is tightly bound to TBG (although 10 times les T4) but not to transthyretin, total serum T3 levels measured by the same methods described above for will be influenced by alterations in the serum TBG level and by drugs that affect binding to TBG. Free in the serum are measured by the same direct and indirect methods described above for T4.
Testing with thyrotropin-releasing hormone (TRH): Serum TSH is measured before and after an IV injection of 500 g synthetic TRH. Normally, there is a rapid rise in TSH levels of 5 to 25 U/mL, reach peak in 30 min and returning to normal by 120 min. The rise is exaggerated in primary hypothyroidism TRH test may be useful in distinguishing pituitary from hypothalamic hypothyroidism. Patients with hypothyroidism secondary to a pituitary deficiency have an absent or impaired TSH response to TRH. with a hypothalamic disorder who have deficient TRH reserve and a normal pituitary reserve will usual release normal amounts of TSH in response to TRH, although the release may be delayed and prolon resulting in a shift in the time of release. In hyperthyroidism, TSH release remains suppressed, even in response to injected TRH, because of the inhibitory effects of the elevated free T4 and free T 3 on the p thyrotroph cell. However, with newer TSH assays, the TRH test is rarely needed to diagnose thyroid dysfunction because the basal serum TSH is proportional to the TSH response to TRH.
Measurement of thyroid autoantibodies: Autoantibodies to thyroid peroxidase and, less commonly, thyroglobulin are present in almost all patients with Hashimoto's thyroiditis, and thyroid peroxidase autoantibodies are usually detected in patients with Graves' disease. Both these antibodies are comm measured by enzyme immunoassays; a thyroid peroxidase autoantibody test has replaced the older ta red cell agglutination test for thyroid antimicrosomal (M) autoantibodies. Hyperthyroidism in Graves' di caused by an autoantibody directed against the TSH receptor on the thyroid follicular cell (TRAb). Two methods are used to measure TRAbs. TSH binding-inhibition assays determine the ability of serum Ig inhibit the binding of 125 I-TSH to solubilized TSH receptors. Thyroid-stimulating antibody assay measu
autoantibodies are usually detected in patients with Graves' disease. Both these antibodies are comm measured by enzyme immunoassays; a thyroid peroxidase autoantibody test has replaced the older ta red cell agglutination test for thyroid antimicrosomal (M) autoantibodies. Hyperthyroidism in Graves' di caused by an autoantibody directed against the TSH receptor on the thyroid follicular cell (TRAb). Two methods are used to measure TRAbs. TSH binding-inhibition assays determine the ability of serum Ig inhibit the binding of 125 I-TSH to solubilized TSH receptors. Thyroid-stimulating antibody assay measu ability of these IgGs to stimulate cAMP generation or 125I uptake in different biologic systems, ie, mon cultures of isolated thyroid cells, cultured rat thyroid follicular cells (FRTL-5), or thyroid cells from huma porcine tissue. Finally, antibodies against T4 and T3 may be found in patients with autoimmune thyroid and may affect T4 and T3 measurements but are almost never clinically significant.
Measurement of thyroglobulin: The thyroid is the only source of this iodinated high molecular weigh glycoprotein, which is readily detectable in normal patients and is usually elevated in patients with non toxic goiter. The principle use of serum thyroglobulin is in evaluating patients after near-total or total thyroidectomy with or without 131I ablation for differentiated thyroid cancer. Normal or elevated serum thyroglobulin values indicate the presence of residual normal or malignant thyroid tissue in patients rec TSH suppressive doses of L-thyroxine or after withdrawal of L-thyroxine. The major problem with the c immunometric assay and radioimmunoassay methods in measuring serum thyroglobulin is the presen thyroglobulin antibodies, which usually results in an underestimation of serum thyroglobulin.
Testing for radioactive iodine uptake: This test has disadvantages in cost, time, and patient inconve The isotope of choice is 123 I, which exposes the patient to vanishingly small radiation. It is valuable in differential diagnosis of hyperthyroidism, which is discussed below. The thyroid 123 I uptake varies wide iodine ingestion and will be low in patients exposed to excess iodine. The thyroid 123 I uptake may be h calculating the dose of 131 I in the treatment of hyperthyroidism.
Scanning of the thyroid: Scanning with radioiodine or technetium-99m is not routine. It is useful in de structural abnormalities of the thyroid and in evaluating modular thyroid disease, especially a solitary n determine its functional state, ie, hot vs. cold.
Section 2. Endocrine And Metabolic Disorders Chapter 15. Hyperlipidemia Topics

[General] Type I Hyperlipoproteinemia Type II Hyperlipoproteinemia Type III Hyperlipoproteinemia Type IV Hyperlipoproteinemia Type V Hyperlipoproteinemia Secondary Hypertriglyceridemia Familial Lecithin Cholesterol Acyltransferase Deficiency
[General]
(See also Atherosclerosis in Ch. 201.)
Hyperlipidemia (hyperlipoproteinemia): Elevated lipoprotein levels in the plasma, which may be primar secondary.
The major plasma lipids, including cholesterol (or total cholesterol [TC]) and the triglycerides, do not freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes c lipoproteins. The major lipoprotein classes--chylomicrons, very low density (pre-) lipoproteins (VLDL density (-) lipoproteins (LDL), and high density (-) lipoproteins (HDL)--although closely interrelated, are classified in terms of physicochemical properties (eg, electrophoretic mobility and density after separa the ultracentrifuge). The major lipids transported in the blood are triglycerides; between 70 and 150 g e and leave the plasma daily compared with 1 to 2 g of cholesterol or phospholipid. Chylomicrons, the la lipoproteins, carry exogenous triglyceride from the intestine via the thoracic duct to the venous system capillaries of adipose and muscle tissue, 90% of chylomicron triglyceride is removed by a specific grou lipases. Fatty acids and glycerol, derived from hydrolysis of chylomicrons, enter the adipocytes and mu cells for energy use or storage. The liver then removes the remnant chylomicron particles. VLDL carrie endogenous triglyceride primarily from the liver to the same peripheral sites (adipocytes and muscle ce storage or use. The same lipases that act on chylomicrons quickly degrade endogenous triglyceride in giving rise to intermediate density lipoproteins (IDL) that are shorn of much of their triglyceride and sur apoproteins. Within 2 to 6 h, this IDL is degraded further by removal of more triglyceride, giving rise to which in turn has a plasma half-life of 2 to 3 days. VLDL is, therefore, the main source of plasma LDL.
The fate of LDL is unclear: The liver removes about 70%, and active receptor sites have been found o surfaces of hepatocytes and other cells that specifically bind to apolipoprotein B (apo B, the ligand ass with LDL that binds with LDL receptors) and remove most LDL from the circulation. A small but import
apoproteins. Within 2 to 6 h, this IDL is degraded further by removal of more triglyceride, giving rise to which in turn has a plasma half-life of 2 to 3 days. VLDL is, therefore, the main source of plasma LDL.
The fate of LDL is unclear: The liver removes about 70%, and active receptor sites have been found o surfaces of hepatocytes and other cells that specifically bind to apolipoprotein B (apo B, the ligand ass with LDL that binds with LDL receptors) and remove most LDL from the circulation. A small but import amount of LDL appears to be removed from the circulation by non-LDL receptor pathways, including u scavenger receptors on macrophages that may migrate into arterial walls, where they may become the cells of atherosclerotic plaques.
Hypercholesterolemia can result either from overproduction or defective clearance of VLDL or from inc conversion of VLDL to LDL. Overproduction of VLDL by the liver may be caused by obesity, diabetes m alcohol excess, nephrotic syndrome, or genetic disorders; each condition can result in increased LDL levels and often is associated with hypertriglyceridemia. Defective LDL clearance may be due to gene determined structural defects in apo B (the ligand) that diminish the binding of apo B to otherwise norm receptors. Alternatively, reduced clearance may be due to diminished numbers or abnormal function (l activity) of the LDL receptors, which may result from genetic or dietary causes. Genetically mediated a LDL receptor function usually results from molecular defects in the protein structure of the receptors--t mechanism of the genetic disorders described below.
When dietary cholesterol (as a constituent of chylomicron remnants) reaches the liver, the resulting ele levels of intracellular cholesterol (or a metabolite of cholesterol in the hepatocyte) suppress LDL-recep synthesis; this suppression occurs at the level of transcription of the LDL gene. A reduced number of r results in higher levels of plasma LDL and therefore of TC. Saturated fatty acids also increase plasma TC levels; the mechanism of action is related to a reduced activity of LDL receptors. In the USA, dieta cholesterol and saturated fatty acid intake is high and is thought to account for an average increase of to 40 mg/dL (0.65 to 1.03 mmol/L) of LDL blood levels--enough to increase significantly the risk of coro artery disease (CAD).
Diagnosis
In diagnosing hyperlipoproteinemia, a normal plasma TC level is difficult to define. Prospective studies shown that the incidence of CAD rises continuously with plasma TC and that values previously consid normal in the USA are higher than those found among populations with a low incidence of atheroscler addition, evidence (from well-designed prospective clinical trials) shows that lowering even average Am levels of TC (and LDL) in patients with CAD slows or reverses the progression of CAD.
The optimal plasma TC for a middle-aged adult free of CAD is probably <= 200 mg/dL (<= 5.18 mmol/ Hypercholesterolemia has usually been defined as a value above the 95th percentile for the populati which ranges from 210 mg/dL (5.44 mmol/L) in Americans < 20 yr old to > 280 mg/dL (> 7.25 mmol/L) > 60 yr old. However, these limits are clearly excessive because of the known high risk of cardiovascu disease at these levels.
A consensus of the National Cholesterol Education Program (NCEP) defines TC levels < 200 mg/dL (< mmol/L) as desirable, levels between 200 and 240 mg/dL (5.18 and 6.22 mmol/L) as borderline high, a levels > 240 mg/dL (> 6.22 mmol/L) as high.
For patients without clinical evidence of coronary or other atherosclerotic vascular disease, the NCEP recommends health screening, including measurement of TC and HDL cholesterol, at least once eve Further evaluation is performed for those patients with a high TC, for those with low HDL cholesterol mg/dL [< 0.91 mmol/L]), or for those with borderline TC who have at least two CAD risk factors (age > men or > 55 for women [or postmenopausal state without estrogen replacement], high BP, smoking, d HDL < 35 mg/dL, or a family history of CAD before age 55 in a male first-degree relative or before age
For patients without clinical evidence of coronary or other atherosclerotic vascular disease, the NCEP recommends health screening, including measurement of TC and HDL cholesterol, at least once eve Further evaluation is performed for those patients with a high TC, for those with low HDL cholesterol mg/dL [< 0.91 mmol/L]), or for those with borderline TC who have at least two CAD risk factors (age > men or > 55 for women [or postmenopausal state without estrogen replacement], high BP, smoking, d HDL < 35 mg/dL, or a family history of CAD before age 55 in a male first-degree relative or before age female first-degree relative). This evaluation should include fasting levels of TC, triglyceride, and HDL. then calculated by applying the following formula: LDL cholesterol = TC - HDL cholesterol - triglyceride formula is valid only when triglyceride is < 400 mg/dL [< 4.52 mmol/L]). A high HDL level (> 60 mg/dL [ mmol/L]) is considered a negative risk factor and reduces the number of risk factors by one.
The NCEP recommends that treatment decisions be based on the calculated level of LDL. For patient elevated LDL (>= 160 mg/dL [>= 4.14 mmol/L]) who have fewer than two risk factors in addition to elev LDL and who do not have clinical evidence of atherosclerotic disease, the goal of treatment is an LDL 160 mg/dL. For those who have at least two other risk factors, the goal of treatment is an LDL level < 1 mg/dL (< 3.37 mmol/L). When LDL levels remain > 160 mg/dL despite dietary measures and the patie two or more risk factors (in addition to high LDL), or when LDL levels remain > 190 mg/dL (> 4.92 mm even without added risk factors, the addition of drug treatment should be considered. For those with CAD, peripheral vascular disease, or cerebrovascular disease, the goal of treatment is 100 mg/dL (< 2.59 mmol/L).
All patients with clinical evidence of coronary or other atherosclerotic disease should be evaluated with fasting blood sample for measurement of TC, triglyceride, and HDL. LDL is again calculated, as descr above.
In contrast to plasma TC, it is unclear whether plasma triglycerides are independent risk variables; like they vary with age. A triglyceride level of < 200 mg/dL (< 2.26 mmol/L) is considered normal, 200 to 40 (2.26 to 4.52 mmol/L) is borderline high, and > 400 mg/dL (> 4.52 mmol/L) is high. Hypertriglyceridemi been associated with diabetes, hyperuricemia, and pancreatitis (when levels are > 600 mg/dL [> 6.78 mmol/L]).
As indicated below, even more information can be obtained about CAD risk by considering plasma TC one of several units of lipid transport--the lipoproteins. Sixty to 75% of plasma TC is transported on LD levels of which are directly related to cardiovascular risk. HDL, which normally accounts for 20 to 25% plasma TC, is inversely associated with cardiovascular risk. HDL levels are positively correlated with e moderate alcohol intake, and estrogen replacement therapy and are inversely correlated with smoking obesity, and the use of most progestin-containing contraceptives. Studies show that CAD prevalence a levels of 30 mg/dL (0.78 mmol/L) is more than double that at 60 mg/dL, and high levels of LDL or low l HDL are independently associated with increased CAD risk. One must determine, therefore, whether e TC levels are due to increased LDL or HDL. In countries or in groups (eg, lactovegetarians, Seventh-D Adventists) where TC and LDL cholesterol are low because of nutritional habits (marked reduction in i of total saturated fats and cholesterol), HDL levels are often relatively low and the risk for CAD is low. U.S.-based Framingham Study, however, men and women (eating the typical high-fat American diet) w relatively normal LDL levels (120 to 160 mg/dL [3.11 to 4.14 mmol/L]) with HDL < 30 mg/dL were at in risk for CAD.
Laboratory Methods and Interpretation of Results
A useful clinical appraisal of lipids can usually be made by determining plasma TC, HDL-cholesterol, a triglyceride levels after the patient has fasted for >= 12 h. The specimen should also be observed for a chylomicron layer after it stands overnight in a refrigerator at 4 C (39.2 F). Plasma TC may be determ colorimetric, gas-liquid chromatographic, enzymatic, or other automated "direct" methods. Enzymatic m are usually most accurate and are standard in virtually all clinical laboratories. Plasma triglyceride is
A useful clinical appraisal of lipids can usually be made by determining plasma TC, HDL-cholesterol, a triglyceride levels after the patient has fasted for >= 12 h. The specimen should also be observed for a chylomicron layer after it stands overnight in a refrigerator at 4 C (39.2 F). Plasma TC may be determ colorimetric, gas-liquid chromatographic, enzymatic, or other automated "direct" methods. Enzymatic m are usually most accurate and are standard in virtually all clinical laboratories. Plasma triglyceride is measured as glycerol by either colorimetric, enzymatic, or fluorometric methods after alkaline or enzym hydrolysis to glycerol and formaldehyde. HDL levels are measured enzymatically after precipitation of IDL, and LDL from plasma. (For LDL estimation, see above.) Lipoprotein electrophoresis is useful only dyslipidemia and has generally been supplanted by analysis of the apolipoproteins.
Most elevations of TC and/or triglyceride are modest and are due primarily to dietary excess. More sev hyperlipidemia is due to a heterogeneous group of disorders differing in clinical features, prognosis, an therapeutic response. A high plasma level of any lipoprotein can result in hypercholesterolemia. Simila hypertriglyceridemia may result from increased levels of chylomicrons, VLDL, or both. Thus, defining t precise lipoprotein pattern is important, especially in selecting appropriate diet and drug therapy. Table describes the five types of hyperlipoproteinemia. Since each lipoprotein class has a relatively fixed com with respect to TC and triglyceride and since the two largest particle types (chylomicrons and VLDL) re light and cause plasma turbidity, the specific type of hyperlipoproteinemia can often be determined by observing a standing plasma sample, after 24 h storage at 4 C (39.2 F), followed by a more precise triglyceride assay. A turbid or cloudy plasma must be caused by increased VLDL; if the plasma is clea elevated TC must be caused by elevated LDL or HDL. If a layer of cream has formed, it must be the re increased chylomicrons. Analysis of apolipoproteins or electrophoresis is not usually required.
Determining the lipoprotein pattern does not conclude the diagnostic process. Hyperlipoproteinemia m secondary to other disorders that must be ruled out (eg, hypothyroidism, alcoholism, kidney disease) o be primary (usually familial), in which case screening should be performed to identify other family mem (often asymptomatic) with hyperlipoproteinemia.
In evaluating lipid or lipoprotein measurements, one must be aware of the following: (1) Lipid and lipop levels increase with age. A value acceptable for a middle-aged adult might be alarmingly high in a 10-y child. (2) Because chylomicrons normally appear in the blood 2 to 10 h after a meal, a fasting specime 16 h) should be used. (3) Lipoprotein levels are under dynamic metabolic control and are readily affec diet, illness, drugs, and weight change. Lipid analysis should be performed during a steady state. If res abnormal, at least two more samples should be tested before selecting therapy. (4) When hyperlipoproteinemia is secondary to another disorder, treatment of the latter usually will correct the hyperlipoproteinemia.
Treatment
Treatment of most patients with hyperlipidemia is that described below for primary type II hyperlipopro
Section 2. Endocrine And Metabolic Disorders Chapter 9. Adrenal Disorders Topics

[General] Adrenal Cortical Hypofunction Adrenal Cortical Hyperfunction Pheochromocytoma Nonfunctional Adrenal Masses
[General]
The adrenal cortex produces androgens, glucocorticoids (eg, cortisol), and mineralocorticoids (eg, aldosterone). The physiology of the pituitary-adrenal system is described in Chs. 6 and 7. The distinct syndromes produced by hypofunction or hyperfunction of the adrenal cortex are discussed below.
Section 2. Endocrine And Metabolic Disorders Chapter 16. Hypolipidemia And The Lipidose Topics
Hypolipidemia Lipidoses
Hypolipidemia
(Hypoproteinemia)
Low lipoprotein levels in the plasma seen as rare familial disorders or secondary to hyperthyroidism, malabsorption, and malnutrition.
Low levels of low density (-) lipoproteins (LDL) can be seen in AIDS; hematologic malignancies, such a myelocytic leukemia and chronic myelocytic leukemia; and disorders with splenomegaly, such as Gau disease.
HYPOALPHALIPOPROTEINEMIA
(Low HDL Levels)
In many epidemiologic studies, low levels of high density (-) lipoproteins (HDL) have been associated increased coronary artery disease (CAD) risk. Low HDL levels often are due to genetic factors. Additio HDL levels are reduced by obesity, sedentary lifestyle, cigarette use, diabetes mellitus, uremia and ne syndrome, and several drugs (thiazide diuretics, retinoids, -blockers, androgenic steroids, most proges drugs, and probucol).
Treatment
Although no clinical trials have been designed specifically to test the effects of modifying HDL levels, i seem wise for nearly everyone to pursue nonpharmacologic measures to raise HDL levels. These mea include stopping cigarette smoking, losing weight for the obese, and increasing exercise. Furthermore reasonable to attempt to avoid HDL-lowering drugs in patients who already have low HDL levels.
HDL levels can often be increased substantially by treatment with nicotinic acid and, for hypertriglyceri with fibric acid derivatives. Lesser increases in HDL levels (about 10%) occur when the fibric acid drug used in normotriglyceridemic persons and when 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
include stopping cigarette smoking, losing weight for the obese, and increasing exercise. Furthermore reasonable to attempt to avoid HDL-lowering drugs in patients who already have low HDL levels.
HDL levels can often be increased substantially by treatment with nicotinic acid and, for hypertriglyceri with fibric acid derivatives. Lesser increases in HDL levels (about 10%) occur when the fibric acid drug used in normotriglyceridemic persons and when 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are used in high doses. For patients who warrant treatment to reduce LDL levels, preexisting low HDL level (< 35 mg/dL [< 0.91 mmol/L]) may influence the choice of LDL-reducing drug such patients, nicotinic acid may be the drug of first choice. Isolated low HDL levels, in the absence of risk factors for CAD, often occur in vegetarian populations, in whom LDL levels and CAD rates are low the patient with isolated low HDL levels and without other CAD risk factors should not be given drugs exclusively to raise HDL levels.
HYPOBETALIPOPROTEINEMIA
A rare disorder inherited as a codominant trait and characterized by reduced levels of -lipoprotein (LDL
Hypobetalipoproteinemia is caused by mutations in the gene for apo B. There are usually no clinical manifestations. Plasma lipids are low, with plasma total cholesterol (TC) levels ranging from 70 to 120 (1.81 to 3.11 mmol/L) despite normal food intake; HDL is normal to high; and LDL is 20 to 70 mg/dL (0 1.81 mmol/L), usually < 60 mg/dL (< 1.55 mmol/L). Fat absorption is normal. In the extremely rare homozygous forms, most of the manifestations described for abetalipoproteinemia (see below) are ap Familial hypobetalipoproteinemia and familial hyperalphalipoproteinemia (also transmitted as a domina are associated with a decreased incidence of CAD and other atherosclerotic sequelae and have been to as the "longevity syndromes." No treatment is required.
ABETALIPOPROTEINEMIA
(Acanthocytosis; Bassen-Kornzweig Syndrome)
A rare congenital disorder usually transmitted as a recessive trait and characterized by the complete a of -lipoproteins and by steatorrhea, acanthocytes (RBCs with spiny projections of the membrane), retin pigmentosa, ataxia, and mental retardation.
Abetalipoproteinemia is caused by mutations in the gene for microsomal triglyceride transfer protein. Absorption of fat is markedly impaired. Neither chylomicrons nor very low density (pre-) lipoproteins (V formed. All plasma lipids are significantly reduced, and no postprandial lipemia can be shown. There is specific treatment. Massive parenteral and oral doses of vitamins E and A may delay or retard the neu sequelae. (See also Spinocerebellar Degenerations in Ch. 179.)
TANGIER DISEASE
(Familial -Lipoprotein Deficiency)
A rare familial disorder characterized by recurrent polyneuropathy, lymphadenopathy, orange-yellow to hyperplasia, and hepatosplenomegaly (storage of cholesterol esters in reticuloendothelial cells) assoc with a marked decrease in HDL.
The genetic basis for Tangier disease is unknown. Plasma TC is very low; triglycerides are normal or e The disorder may manifest in adult life with hepatosplenomegaly or recurrent polyneuropathy. There is treatment.
hyperplasia, and hepatosplenomegaly (storage of cholesterol esters in reticuloendothelial cells) assoc with a marked decrease in HDL.
The genetic basis for Tangier disease is unknown. Plasma TC is very low; triglycerides are normal or e The disorder may manifest in adult life with hepatosplenomegaly or recurrent polyneuropathy. There is treatment.
Section 2. Endocrine And Metabolic Disorders Chapter 10. Multiple Endocrine Neoplasia (MEN) Syn Topics
[General] Multiple Endocrine Neoplasia, Type I (MEN-I) Multiple Endocrine Neoplasia, Type IIA (MEN-IIA) Multiple Endocrine Neoplasia, Type IIB (MEN-IIB)
[General]
(Multiple Endocrine Neoplasia (MEN) Syndromes: Multiple Endocrine Adenomatosis; Familial Endocrine Adenoma
A group of genetically distinct familial diseases involving adenomatous hyperplasia and malignant tum formation in several endocrine glands.
Three distinct syndromes have been identified; each is inherited as an autosomal dominant trait with a degree of penetrance, variable expressivity, and significant pleiotropism. The relationship between the abnormality and the pathogenesis of the various tumors is not completely understood. Symptoms and may be noted as early as the first or as late as the ninth decade of life and depend on the type of endo tumors present. Proper management includes the early identification of affected individuals within a kin surgical removal of the tumors where possible, and ongoing biochemical screening of these individuals Although the various syndromes are generally considered to be distinct entities, significant overlap has noted occasionally (see Table 10-1).
Section 2. Endocrine And Metabolic Disorders Chapter 17. Carcinoid Tumors Topics
[General] Carcinoid Syndrome
[General]
Carcinoid tumors arise from neuroendocrine cells, particularly in the GI tract (90%), pancreas, and pul bronchi (see also Chs. 34 and 81). The most common GI sites are the stomach, ileum, and appendix, they may cause pain, luminal bleeding, and obstruction. Although often benign or only locally invasive, carcinoid tumors of the ileum and bronchus are frequently malignant. Carcinoid tumors may be endocrinologically inert or produce a variety of hormones. The most common endocrinologic syndrome carcinoid syndrome, described below.
Section 2. Endocrine And Metabolic Disorders Chapter 11. Polyglandular Deficiency Syndrom Topics
[General]
[General]
(Polyglandular Deficiency Syndromes: Autoimmune Polyglandular Syndromes; Polyendocrine Deficiency Syndrom
Concurrent subnormal function of several endocrine glands.
Endocrine deficiency can be caused by infection, infarction, or tumor resulting in the destruction of all large part of an endocrine gland. However, most often the activity of an endocrine gland is depressed result of an autoimmune reaction that produces inflammation, lymphocytic infiltration, and partial or co destruction of the gland. Autoimmune disease affecting one gland is frequently followed by impairmen glands, resulting in multiple endocrine failure. Two major patterns of failure have been described (see 11-1).
In type I, onset usually occurs in childhood or before age 35. Hypoparathyroidism is most frequently fo (79%), followed by adrenal cortical failure (72%). Gonadal failure occurs after puberty in 60% of wome about 15% of men. Chronic mucocutaneous candidiasis is common. Diabetes mellitus seldom occurs. pattern may be associated with HLA types A3 and A28 or with a locus on chromosome 21. The inherit usually follows an autosomal recessive pattern.
In type II, glandular failure generally occurs in adults, with peak incidence at age 30. It always involves adrenal cortex and frequently the thyroid gland (Schmidt's syndrome) and the pancreatic islets, prod insulin-dependent diabetes mellitus (IDDM). Antibodies against the target glands are frequently presen especially against P-450 cytochrome adrenal cortical enzymes. However, their role in damaging the gl unclear. Some patients have thyroid-stimulating antibodies and initially present with symptoms and sig hyperthyroidism. The glandular destruction is chiefly a result of cell-mediated autoimmunity, either from depressed suppressor T-cell function or some other type of T-cell-mediated injury. In addition, reduced systemic T-cell-mediated immunity is common, manifested by a poor response on skin testing to stand antigens, such as candidin (from Candida), trichophytin (from Trichophyton), and tuberculin. Depresse reactivity is also found in about 30% of first-degree relatives with normal endocrine function. It has bee suggested that the specific HLA types characteristic of type II are associated with susceptibility to certa viruses that induce the destructive reaction.
depressed suppressor T-cell function or some other type of T-cell-mediated injury. In addition, reduced systemic T-cell-mediated immunity is common, manifested by a poor response on skin testing to stand antigens, such as candidin (from Candida), trichophytin (from Trichophyton), and tuberculin. Depresse reactivity is also found in about 30% of first-degree relatives with normal endocrine function. It has bee suggested that the specific HLA types characteristic of type II are associated with susceptibility to certa viruses that induce the destructive reaction.
An additional group, type III, occurs in adults and does not involve the adrenal cortex, but includes at of the following: thyroid deficiency, IDDM, pernicious anemia, vitiligo, and alopecia. Because the distin feature of the type III pattern is the absence of adrenocortical insufficiency, it may merely be a "wasteb of combined disease that is converted to type II if adrenal failure develops.
The clinical appearance of patients with polyglandular deficiency syndromes is the sum of the picture o individual deficiencies. There is no specific sequence for appearance of individual glandular destructio Measuring the levels of circulating antibodies against the endocrine glands or their components does n appear useful, because such antibodies may persist for years without the patient developing endocrine However, detecting the presence of antibodies is helpful in some situations, such as differentiating autoimmune from tuberculous hypoadrenalism and determining the cause of hypothyroidism. Multiple endocrine deficiencies may suggest hypothalamic-pituitary failure. In almost all cases, elevated plasm of pituitary tropic hormones will demonstrate the peripheral nature of the defect; however, rare instanc hypothalamic-pituitary insufficiency also have been reported as part of the type II syndrome.
Treatment
Treatment of the various individual glandular deficiencies is discussed elsewhere in The Manual; howe interaction of multiple deficiencies (eg, adrenal cortical insufficiency combined with diabetes mellitus) m complicate treatment. Patients with hypofunction of one endocrine gland should be observed for deve of additional deficiencies over a period of years. Gonadal failure does not respond to treatment with gonadotropic hormones, and chronic mucocutaneous candidiasis is usually resistant to treatment. If gi early in the course of endocrine failure, immunosuppressive doses of cyclosporin A may benefit some
Section 2. Endocrine And Metabolic Disorders Chapter 18. Amyloidosis Topics

[General]
[General]
Etiology, Pathophysiology, and Classification
Amyloidosis: Accumulation in the tissues of various insoluble fibrillar proteins (amyloid) in amounts suf impair normal function.
The cause of amyloid production and its deposition in tissues is unknown. In the different biochemical amyloidosis, etiologic mechanisms may vary. For example, in secondary amyloidosis (see below), a de the metabolism of the precursor protein (the acute-phase reactant--serum amyloid A) may exist, where hereditary amyloidosis a genetically variant protein appears to be present. In primary amyloidosis, a monoclonal population of marrow cells produces fragments of or whole light chains that may be proce abnormally to form amyloid. Under light microscopy, amyloid is a homogeneous, highly refractile subst with an affinity for Congo red dye both in fixed tissues and in vivo. Under electron microscopy, amyloid consists of 100 A (10 nm) linear nonbranching fibrils; under x-ray diffraction, it has a cross-beta patte
Three major types of amyloid and several less common forms have been defined biochemically. The f which has an N-terminal sequence that is homologous to a portion of the variable region of an immuno light chain, is called AL and occurs in primary amyloidosis and in amyloidosis associated with multiple myeloma. The second type has a unique N-terminal sequence of a nonimmunoglobulin protein called protein and occurs in patients with secondary amyloidosis. The third type, which is associated with fam amyloid polyneuropathy, is usually a transthyretin (prealbumin) molecule that has a single amino acid substitution. Other hereditary amyloids have been found to consist of mutant gelsolin in some families apolipoprotein A-I in several others, and other mutant proteins in hereditary cerebral artery amyloid. In amyloid associated with chronic hemodialysis, 2 -microglobulin has constituted amyloid protein. Amyloi associated with aging in skin and with endocrine organs may represent other biochemical forms of amyloidosis. The amyloid found in the histopathologic lesions of Alzheimer's disease consists of prote Chemical analyses relating to various forms of amyloidosis have led to a more refined classification. A protein (a pentraxin) called AP (or serum AP) is universally associated with all forms of amyloid and fo basis of a diagnostic test.
Three major systemic clinical forms are currently recognized. Amyloidosis is classified as primary or id
amyloidosis. The amyloid found in the histopathologic lesions of Alzheimer's disease consists of prote Chemical analyses relating to various forms of amyloidosis have led to a more refined classification. A protein (a pentraxin) called AP (or serum AP) is universally associated with all forms of amyloid and fo basis of a diagnostic test.
Three major systemic clinical forms are currently recognized. Amyloidosis is classified as primary or id (AL form) when there is no associated disease, and secondary, acquired, or reactive (AA form) when associated with chronic diseases, either infectious (tuberculosis, bronchiectasis, osteomyelitis, leprosy inflammatory (rheumatoid arthritis, granulomatous ileitis). Amyloid is also associated with multiple mye (AL), Hodgkin's disease (AA), other tumors, and familial Mediterranean fever (AA). Amyloidosis may accompany aging. The third major type appears in familial forms unassociated with other disease, ofte distinctive types of neuropathy, nephropathy, and cardiopathy.
In primary (AL) amyloidosis, the heart, lung, skin, tongue, thyroid gland, and intestinal tract may be i Localized amyloid "tumors" may be found in the respiratory tract or other sites. Parenchymal organs (l spleen, kidney) and the vascular system, especially the heart, are involved frequently.
Secondary (AA) amyloidosis shows a predilection for the spleen, liver, kidney, adrenals, and lymph n However, no organ system is spared and vascular involvement may be widespread, though clinically s involvement of the heart is rare. The liver and spleen are often enlarged, firm, and rubbery. The kidney usually enlarged. Sections of the spleen have large, translucent, waxy areas where the normal malpig bodies are replaced by pale amyloid, producing the sago spleen.
Hereditary amyloidosis is characterized by a peripheral sensory and motor neuropathy, often autono neuropathy, and cardiovascular and renal amyloid. Carpal tunnel syndrome and vitreous abnormalities occur.
Amyloid associated with certain malignancies (eg, multiple myeloma) has the same distribution as id (AL) amyloid; with other malignancies (eg, medullary carcinoma of the thyroid gland) it may occur only in association with the tumor or in metastases. Amyloid is frequently found in the pancreas of individua adult-onset diabetes mellitus.
Symptoms and Signs
Symptoms and signs are nonspecific, determined by the organ or system affected, and often are obsc the underlying disease, which may be fatal before amyloidosis is suspected. The nephrotic syndrome most striking early manifestation. In the early stages, only slight proteinuria may be noted; later, the dis symptom complex develops with anasarca, hypoproteinemia, and massive proteinuria.
Hepatic amyloid disease produces hepatomegaly but rarely jaundice. Massive hepatomegaly (liver we kg) has been reported. Liver function test results usually are normal, although abnormal sulfobromoph sodium excretion (seldom performed) or elevated alkaline phosphatase may be observed. Occasional hypertension may occur with esophageal varices and ascites. Skin lesions may be waxy or translucen purpura may result from amyloidosis of small cutaneous vessels.
Cardiac involvement is common and may present as cardiomegaly, intractable heart failure, or any com arrhythmia. Atrial standstill has been found in several kinships.
GI amyloid may cause esophageal motility abnormalities, gastric atony, motility abnormalities of the sm large intestine, malabsorption, bleeding, or pseudo-obstruction. Macroglossia is common in primary an myeloma-related amyloidoses.
arrhythmia. Atrial standstill has been found in several kinships.
GI amyloid may cause esophageal motility abnormalities, gastric atony, motility abnormalities of the sm large intestine, malabsorption, bleeding, or pseudo-obstruction. Macroglossia is common in primary an myeloma-related amyloidoses.
A firm, symmetric, nontender goiter resembling Hashimoto's or Riedel's struma may result from amylo the thyroid gland. Amyloid arthropathy may mimic rheumatoid arthritis in rare cases of multiple myelom Peripheral neuropathy, which is not an uncommon presenting manifestation, is common in some famil amyloidoses and also occurs in some cases of primary or myeloma-associated amyloidosis. Lung invo (mostly in AL amyloidosis) may be characterized by focal pulmonary nodules, tracheobronchial lesions diffuse alveolar deposits. In several hereditary amyloid kinships, amyloid vitreous opacities and bilater scalloped pupillary margins occur.
Diagnosis
Amyloidosis is suspected on the basis of symptoms and signs described above but can be diagnosed biopsy. Subcutaneous abdominal fat pad aspiration and biopsy of rectal mucosa are the best screenin Other useful biopsy sites are gingiva, skin, nerve, kidney, and liver. Tissue sections should be stained Congo red dye and observed with a polarizing microscope for the characteristic green birefringence of Isotopically labeled serum AP has been used in a scintigraphic test to confirm the diagnosis of amyloid
Prognosis
In secondary amyloidosis, prognosis depends on successful treatment of the underlying disease. All fo renal amyloidosis have a poor prognosis, but patients may remain stable and even improve with suppo therapy (eg, eradication of pyelonephritis). Dialysis and kidney transplantation have further improved t prognosis. Amyloidosis associated with multiple myeloma has the poorest prognosis; death within 1 yr common. Localized amyloid tumors may be removed without recurrence. Myocardial amyloidosis is th common cause of death, primarily due to arrhythmias or intractable heart failure. Prognosis in familial amyloidoses varies with each kinship.
Treatment
Treatment is directed first to the underlying cause; such treatment may arrest amyloidosis. Manageme amyloidosis itself is generally symptomatic. Kidney transplantation has been performed in patients with amyloid; long-term survival is comparable to that in other renal diseases, but mortality is higher in the e years. Amyloid will ultimately recur in a donor kidney, but several recipients have done very well and h up to 10 yr. Current treatment of primary amyloidosis includes a program of prednisone/melphalan or prednisone/melphalan/colchicine. Clinical trials in progress are comparing these programs. The progra recently have been augmented with stem cell transplants with considerable success. Digitalis may pre arrhythmias in amyloid heart disease and should be used with care. Heart transplantation has been su in carefully selected patients. Colchicine has been used to prevent the acute attacks of familial Medite fever, and it has been shown that patients so treated develop no new amyloid and established amyloid decreases. It has been shown that in hereditary amyloidosis due to transthyretin mutations, liver transplantation, which removes the site of synthesis of the mutant protein, is very effective.
Ultimately some people with amyloidosis continue to deteriorate and develop terminal complications. Aggressive treatment may no longer be appropriate, and care should focus on relieving pain and suffe Ch. 294).
Section 2. Endocrine And Metabolic Disorders Chapter 12. Water, Electrolyte, Mineral, And Acid Metabolism Topics
[General] Water And Sodium Metabolism Potassium Metabolism Calcium Metabolism Phosphate Metabolism Magnesium Metabolism Acid-Base Metabolism
[General]
Body fluid volume, electrolyte concentration, and acid-base balance are normally maintained within ve narrow limits despite wide variations in dietary intake, metabolic activity, and environmental stresses. Homeostasis of body fluids is preserved primarily by the kidneys and is controlled by various interrelat physiologic mechanisms. This chapter summarizes many aspects of these mechanisms in health, thei response to homeostatic stresses, and the diagnosis and management of several commonly encounte fluid, electrolyte, and acid-base disorders.
Section 14. Neurologic Disorders Chapter 165. Neurologic Approach To The Pati Topics
[General] History Neurologic Examination Neurologic Diagnostic Procedures
[General]
Headache, dizziness, insomnia, back pain, weakness, and fatigue occur often in medical practice, and trivial must be separated from the potentially serious. Some neurologic problems require emergency a before a neurologist can be consulted. Regardless of the problem's magnitude, the following principles help during the neurologic evaluation: the anatomy of the lesion should be defined (to limit diagnostic possibilities); its pathophysiology, determined; and the examiner, prepared to provide immediate lifesa treatment for neurologic emergencies.
Specific problems are discussed in other chapters in this section. Evaluation of the unconscious patien discussed in Ch. 170.

Section 14. Neurologic Disorders Chapter 175. Trauma Of The Head Topics
[General]
[General]
Head injury causes more deaths and disability than any other neurologic condition before age 50 and > 70% of accidents, which are the leading cause of death in men and boys < 35 yr old. Mortality from s injury approaches 50% and is only modestly reduced by treatment.
Damage may result from skull penetration or from rapid brain acceleration or deceleration, which injure at the point of impact, at its opposite pole (contrecoup), or diffusely within the frontal and temporal lobe Nerve tissue, blood vessels, and meninges can be sheared, torn, or ruptured, resulting in neural disrup intracerebral or extracerebral ischemia or hemorrhage, and cerebral edema. Hemorrhage and edema expanding intracranial lesions, causing focal neurologic deficits or increased intracranial swelling and p which can lead to fatal herniation of brain tissue through the tentorium or foramen magnum. Skull frac may lacerate meningeal arteries or large venous sinuses, producing epidural or subdural hematoma. Fractures, especially at the skull base, can also lacerate the meninges, causing CSF to leak through th (rhinorrhea) or ear (otorrhea) or bacteria or air to enter the cranial vault. Infectious organisms may rea meninges via cryptic fractures, especially if they involve the paranasal sinuses.
Concussion is characterized by transient posttraumatic loss of awareness or memory, lasting from se minutes, without causing gross structural lesions in the brain and without leaving serious neurologic re Patients with concussion rarely are deeply unresponsive. Pupillary reactions and other signs of brain s function are intact; extensor plantar responses may be present briefly but neither hemiplegia nor dece postural responses to noxious stimulation appear. Lumbar puncture is generally contraindicated in cas head trauma unless meningitis is suspected and should be performed only after appropriate x-rays or studies.
Postconcussion syndrome commonly follows a mild head injury, more often than a severe one. It inc headache, dizziness, difficulty in concentration, variable amnesia, depression, apathy, and anxiety. Considerable disability can result. The part played by brain damage is unclear. The postconcussion sy is more common in patients with a premorbid neurotic disposition. However, studies suggest that even trauma can cause neuronal damage. Although this situation lends itself to malingering and fraud with t
Postconcussion syndrome commonly follows a mild head injury, more often than a severe one. It inc headache, dizziness, difficulty in concentration, variable amnesia, depression, apathy, and anxiety. Considerable disability can result. The part played by brain damage is unclear. The postconcussion sy is more common in patients with a premorbid neurotic disposition. However, studies suggest that even trauma can cause neuronal damage. Although this situation lends itself to malingering and fraud with t of compensation, many patients have legitimate complaints. The benefits of drug or psychiatric treatm uncertain.
Cerebral contusions and lacerations are more severe injuries. Depending on severity, they are ofte accompanied by severe surface wounds and by basilar skull fractures or depression fractures (see als Temporal Bone Fractures in Ch. 85). Hemiplegia or other focal signs of cortical dysfunction are comm severe injuries may cause severe brain edema, producing decorticate rigidity (arms flexed and adduct and often trunk extended) or decerebrate rigidity (jaws clenched, neck retracted, all limbs extended). C hemiplegia, unilaterally or bilaterally dilated and unreactive pupils, and respiratory irregularity may resu initial trauma or internal brain herniation and require immediate therapy. Increased intracranial pressur producing compression or distortion of the brain stem, sometimes causes BP to rise and pulse and res to slow (Cushing's phenomenon). Brain scans may reveal bloody CSF; lumbar puncture is usually contraindicated.
Nonpenetrating trauma is more likely to affect the cerebral hemispheres and underlying diencephalon, are larger and generally more exposed, than the brain stem. Thus, signs of primary brain stem injury ( irregular breathing, fixation of the pupils to light, loss of oculovestibular reflexes, diffuse motor flaccidit always imply severe injury and poor prognosis.
Thoracic damage often accompanies severe head injuries, producing pulmonary edema (some of whic neurogenic), hypoxia, and unstable circulation. Injury to the cervical spine can damage the spinal cord fatal respiratory paralysis or permanent quadriplegia. Proper immobilization should be maintained unti of the cervical spine has been documented by appropriate imaging studies.
Acute subdural hematomas (blood between the dura mater and arachnoid, usually from bleeding of bridging veins) and intracerebral hematomas are common in severe head injury. Along with severe b edema, they account for most fatalities. All three conditions can cause transtentorial herniation with de coma, widening pulse pressure, pupils in midposition or dilated and fixed, spastic hemiplegia with hyperreflexia, quadrispasticity, decorticate rigidity, or decerebrate rigidity (due to progressive rostral-ca neurologic deterioration). CT or MRI scans can usually identify operable lesions. Surgical excision of la lesions may be lifesaving, but posttraumatic morbidity is often high.
Chronic subdural hematomas may not produce symptoms until several weeks after trauma. Althoug diagnosis (2 to 4 wk after trauma) may be suggested by delayed neurologic deterioration, later diagno be overlooked because of the time lapse between trauma and the onset of symptoms and signs. Subd hematomas are more common in alcoholics and patients > 50 yr, in whom the head injury may have b relatively trivial, even forgotten. Increasing daily headache, fluctuating drowsiness or confusion (which mimic early dementia), and mild-to-moderate hemiparesis are typical. In infants, chronic subdural hem can cause head circumference to enlarge, suggesting hydrocephalus. MRI scans are diagnostic; CT s less consistently so.
Epidural hematomas (blood between the skull and dura mater) are caused by arterial bleeding, most commonly from damage to the middle meningeal artery. Symptoms usually develop within hours of the and consist of increasing headache, deterioration of consciousness, motor dysfunction, and pupillary c A lucid interval of relative neurologic normality often precedes neurologic symptoms. Epidural hematom less common than subdural hematoma but is important because prompt evacuation can prevent rapid shift and compression, which can cause fatal or permanent neurologic deficits. Temporal fracture lines the diagnosis but may not always be seen on skull x-rays. CT or MRI scans or angiograms should be o
commonly from damage to the middle meningeal artery. Symptoms usually develop within hours of the and consist of increasing headache, deterioration of consciousness, motor dysfunction, and pupillary c A lucid interval of relative neurologic normality often precedes neurologic symptoms. Epidural hematom less common than subdural hematoma but is important because prompt evacuation can prevent rapid shift and compression, which can cause fatal or permanent neurologic deficits. Temporal fracture lines the diagnosis but may not always be seen on skull x-rays. CT or MRI scans or angiograms should be o promptly. If scans are unavailable, burr holes should be drilled promptly to aid diagnosis and allow eva of the clot. Posttraumatic epilepsy, with seizures beginning as late as several years after trauma, follows about severe closed head injuries and 40% of penetrating head injuries.
A persistent (chronic) vegetative state (PVS) may follow the most severe form of head injury, which forebrain cognitive functions but spares the brain stem. The PVS can last for many years. In it, the cap self-aware mental activity is absent, but autonomic and motor reflexes and normal sleep-wake cycles a preserved. Few patients recover when PVS lasts for 3 mo after injury, and almost none after 6 mo (se Vegetative State in Ch. 170).
Treatment
At the accident site: Multiple injuries are likely with traffic accidents, less so with gunshot wounds or o localized cranial injury. Once a clear airway is secured and acute bleeding controlled, the victim is mov bloc, with particular care taken to avoid displacing the spine or other bones, so that the spinal cord and vessels are not injured. For care of a victim with possible cord injuries, see Spinal Cord Injury in Ch. 18 Morphine and other depressants are contraindicated during initial management.
In the hospital: Once the airway is secured and IV lines are in place, internal bleeding and other eme complications are evaluated and treated. Hypoxia and hypercarbia can aggravate brain injury and ofte respiratory assistance.
Assessment includes state of consciousness, breathing pattern, pupil size and reaction to light, oculom activity, and motor activity in the limbs. By scoring initial and subsequent responses using the Glasgow Scale (see Table 175-1) and noting neuro-ophthalmologic changes, an examiner can estimate severity and prognosis. Neurologic findings, BP, pulse, and temperature should be recorded at least hourly, be any deterioration demands prompt attention. CT or MRI scans can detect potentially operable intracra hematomas and, if possible, should be obtained in all patients observed to be unconscious for > 2 h a those with focal neurologic abnormalities. If such tests are unavailable, patients should be transported equipped medical facilities. Only when CT or MRI is impossible are cerebral angiograms indicated. Ra scans and EEG are of no diagnostic help immediately after trauma. Frequently, intracranial pressure is continuously monitored in patients with severe head injuries.
Patients with concussion should be closely followed for 24 h. If a CT scan shows no evidence of intrac bleeding or displaced fractures and the patient is neurologically intact, hospitalization is not needed. S x-rays are useless for making this decision.
Skull fractures, if aligned, require no treatment. Depressed fractures are best handled by a neurosurge may require emergency management of lacerated vessels. Antibiotic prophylaxis is not recommended because it encourages drug-resistant strains, but it is often used if CSF is leaking from the patient's no ear.
Patients should be monitored closely and protected against heat loss (hypothermia), hyperthermia, hyponatremia, fluid imbalance, and airway obstruction. Arterial hypoxemia may be minimized by partia oxygenation combined, if necessary, with intermittent positive pressure breathing. Fever is controlled w
because it encourages drug-resistant strains, but it is often used if CSF is leaking from the patient's no ear.
Patients should be monitored closely and protected against heat loss (hypothermia), hyperthermia, hyponatremia, fluid imbalance, and airway obstruction. Arterial hypoxemia may be minimized by partia oxygenation combined, if necessary, with intermittent positive pressure breathing. Fever is controlled w cooling blankets. Lost blood and fluids are replaced promptly. Acute renal failure must be anticipated. recommendations include giving an anticonvulsant for 2 wk; eg, phenytoin may be given as a loading d 50 mg/min IV to a total of 1 g followed by 300 to 400 mg/day po or IV. If no seizures develop within 2 w anticonvulsants should be discontinued because their value in preventing future seizures is not establi Osmotic diuretics (urea, mannitol, glycerol) given IV reduce brain swelling but should be reserved for deteriorating patients or for preoperative use in patients with hematomas. For those with hematomas, 12.5 to 25 g is given IV over 15 to 30 min and repeated q 1 to 4 h. It must be used cautiously in patien heart disease or pulmonary vascular congestion because it induces rapid expansion of vascular volum Because osmotic diuretics increase renal excretion of water relative to sodium, prolonged use may res water depletion and hypernatremia. Fluid and electrolyte balance should be monitored. Corticosteroids contraindicated in head injury.
Restlessness during improvement from coma may require sedation (eg, chlorpromazine 50 mg IM or haloperidol 2 to 5 mg IM). If a patient begins to regain consciousness within 1 wk, the outlook for reaso recovery is good.
During convalescence: After severe head injury, amnesia for the periods immediately before and aft consciousness may occur. Retrograde amnesia is usually brief. The duration of posttraumatic amnesia (measured until the restoration of complete, continuous awareness) provides a good estimate of the e brain damage in closed head injuries. Giddiness, attention difficulties, anxiety, and headache (postcon syndrome--see above) occur for a variable period after concussion but seldom require more than reas
Residual disability should be objectively assessed. Neuropsychologic disturbances, with impaired concentration, attention, and memory, and various mild-to-moderate personality changes are a more c cause of disability in social relations and employment than are specific neurologic impairments. Posttr anosmia, which is relatively common, and acute traumatic blindness, which is rare, seldom resolve. Hemiparesis and aphasia usually abate, except in the elderly or in persons with severe cerebral lacera Most patients with severe head injury (eg, initial Glasgow Coma scores < 8 on admission [see Table 1 benefit from formal rehabilitation during convalescence.
In adults, most recovery after severe head injury occurs within the first 6 mo; smaller adjustments cont perhaps as long as 2 yr. Children have a better immediate recovery from injuries, regardless of severit continue to improve for a longer time.

Section 14. Neurologic Disorders Chapter 166. Neurotransmission Topics
[General]
[General]
A nerve cell (neuron) has two major functions: propagation of an action potential (nerve impulse, signa its axon and transmission of this signal from one neuron to another neuron or to an effector cell to elic response. Effector cells include skeletal and cardiac muscles and exocrine and endocrine cells regula the nervous system. Impulse conduction along an axon is electrical, caused by the exchanges of Na+ ions across the neuronal membrane. In contrast, impulse transmission from one neuron to another ne to a non-neuronal effector cell depends on the action of specific neurotransmitters on specific receptor
A particular neuron generates an identical action potential after each stimulus and conducts it at a fixe velocity along the axon. Velocity depends on axonal diameter and degree of myelination. For myelinat fibers, velocity (m/sec) is approximately 3.7 times the diameter (); eg, for a large (20-) myelinated fib velocity is nearly 75 m/sec. For unmyelinated fibers with diameters of 1 to 4 , velocity is 1 to 4 m/sec.
A neuron simultaneously receives many stimuli--positive and negative--from other neurons and integra them into various patterns of firing. The nerve impulses travel down axons to the next synapse. Once propagation begins, drugs or toxins can modify the amount of neurotransmitter released from the term axon. For example, botulinum toxin blocks release of acetylcholine. Other chemical factors can also in the effect of transmission by modifying a receptor. In myasthenia gravis, antibodies block the nicotinic acetylcholine receptor.
Synapses occur between neuron and neuron and, in the periphery, between neuron and effector (eg, muscle); in the CNS, more complex arrangements exist. Functional contact between two neurons may between axon and cell body, axon and dendrite (the receiving area of a neuron), cell body and cell bod dendrite and dendrite. Neurotransmission can increase or decrease to generate a physiologic function respond to changing physiologic needs. Many neurologic and psychiatric diseases are caused by path overactivity or underactivity of neurotransmission. Many drugs can modify neurotransmission; some (e hallucinogens) cause adverse effects, and some (eg, antipsychotic drugs) correct pathologic condition
Development and maintenance of cells in the nervous system depend on many specific proteins, such nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3.
overactivity or underactivity of neurotransmission. Many drugs can modify neurotransmission; some (e hallucinogens) cause adverse effects, and some (eg, antipsychotic drugs) correct pathologic condition
Development and maintenance of cells in the nervous system depend on many specific proteins, such nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3.
Basic Principles of Neurotransmission
The nerve cell body produces enzymes that are involved in the synthesis of most neurotransmitters. T enzymes act on precursor molecules taken up by the neuron to form the neurotransmitter. The neurotransmitter is stored at the nerve terminal in vesicles (see Fig. 166-1). The amount in one vesicle several thousand molecules) is a quantum. Some neurotransmitter molecules are constantly extruded terminal, but the amount is insufficient to elicit a significant physiologic response. An action potential a the terminal can activate calcium currents and precipitate the simultaneous release of neurotransmitte molecules from many vesicles by fusing the membrane of the vesicles to that of the nerve terminal. An opening forms through which the molecules are expelled into the synaptic cleft by exocytosis.
The quantity of neurotransmitters in the terminals is kept relatively constant and independent of nerve by tight regulation of neurotransmitter formation. Regulation varies among neurons and is achieved by modifying precursor uptake or the activity of enzymes involved in neurotransmitter synthesis or destruc Stimulation or blockade of postsynaptic receptors can decrease or increase presynaptic neurotransmit synthesis.
Neurotransmitters diffuse across the synaptic cleft, bind briefly to receptors, and activate them, causin physiologic responses. Depending on the receptor, the response may be excitatory (ie, initiating a new potential) or inhibitory (ie, inhibiting the development of a new action potential).
The neurotransmitter-receptor interaction must be terminated quickly so that the same receptors can b activated repeatedly. The neurotransmitter is quickly pumped back into the presynaptic nerve terminal active processes (reuptake), is destroyed by enzymes near the receptors, or diffuses into the surround and is destroyed.
Abnormalities of neurotransmitter synthesis, storage, release, or degradation or changes in the numbe affinity of receptors can affect neurotransmission and cause clinical disorders (see Table 166-1).
Major Neurotransmitters
A neurotransmitter is a chemical that is selectively released from a nerve terminal by an action potenti interacts with a specific receptor on an adjacent structure, and, if received in adequate amounts, elicits specific physiologic response. To be a neurotransmitter, a chemical must be present in the nerve term released from the nerve terminal by an action potential, and, when applied experimentally to the recep always produce the identical effect. Many chemicals act as neurotransmitters. There are at least 18 m neurotransmitters; several occur in slightly different forms.
The amino acids glutamate and aspartate are the major excitatory neurotransmitters in the CNS. The in the cortex, cerebellum, and spinal cord.
-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA is derived from glutamic acid, which is decarboxylated by glutamate decarboxylase. After interaction with its receptors is actively pumped back into the nerve terminals and metabolized. Glycine, which resembles GABA in action, occurs principally in the interneurons of the spinal cord. Glycine is probably metabolized from s
in the cortex, cerebellum, and spinal cord.
-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA is derived from glutamic acid, which is decarboxylated by glutamate decarboxylase. After interaction with its receptors is actively pumped back into the nerve terminals and metabolized. Glycine, which resembles GABA in action, occurs principally in the interneurons of the spinal cord. Glycine is probably metabolized from s
Serotonin (5-hydroxytryptamine, or 5-HT) is generated by the raphe nucleus and midline neurons of t and upper brain stem. Tryptophan is hydroxylated by tryptophan hydroxylase to 5-hydroxytryptophan, decarboxylated to serotonin. Serotonin levels are controlled by the uptake of tryptophan and intraneur monoamine oxidase.
Acetylcholine is the major neurotransmitter of the bulbospinal motor neurons, autonomic preganglion postganglionic cholinergic (parasympathetic) fibers, and many neurons in the CNS (eg, basal ganglia, cortex). It is synthesized from choline and mitochondrially derived acetyl coenzyme A by choline acetyltransferase. When released, acetylcholine stimulates specific cholinergic receptors, an interactio terminated by local hydrolysis of acetylcholine to choline and acetate by acetylcholinesterase. Acetylch levels are regulated by choline acetyltransferase and by choline uptake.
Dopamine is the neurotransmitter of some peripheral nerve fibers and many central neurons (eg, in th substantia nigra, midbrain, ventral tegmental area, and hypothalamus). The amino acid tyrosine is take dopaminergic neurons and converted by tyrosine hydroxylase to 3,4-dihydroxyphenylalanine (dopa), w decarboxylated by aromatic-L-amino-acid decarboxylase to dopamine. After release, dopamine interac dopaminergic receptors, and its residue is actively pumped back (reuptake) into the prejunctional neur Tyrosine hydroxylase and monoamine oxidase regulate dopamine levels in nerve terminals.
Norepinephrine is the neurotransmitter of most postganglionic sympathetic fibers and many central n (eg, in the locus caeruleus and hypothalamus). The precursor tyrosine is converted to dopamine, whic hydroxylated by dopamine -hydroxylase to norepinephrine. When released, norepinephrine interacts w adrenergic receptors, a process terminated by its reuptake into the prejunctional neurons with subsequ degradation by monoamine oxidase and by the action of catechol O-methyltransferase (COMT), which located mainly extraneuronally. Tyrosine hydroxylase and monoamine oxidase regulate intraneuronal norepinephrine levels.
-Endorphin and other endorphins are polypeptides that activate many central neurons (eg, in the hypothalamus, amygdala, thalamus, and locus caeruleus). The cell body contains a large polypeptide pro-opiomelanocortin, the precursor of several neuropeptides (eg, -, -, and -endorphins). This polypep transported down the axon and is cleaved into specific fragments; one is -endorphin, which contains 3 acids. After release and interaction with opioid receptors, -endorphin is hydrolyzed by peptidases into inactive peptides and amino acids.
Met-enkephalin and leu-enkephalin are small peptides present in many central neurons (eg, in the g pallidus, thalamus, caudate, and central gray matter). Their precursor, proenkephalin, is formed in the body, then split by specific peptidases into smaller peptides. The resulting fragments include two enke each composed of five amino acids and containing either methionine or leucine terminals. After releas interaction with peptidergic receptors, the enkephalins are hydrolyzed into smaller, inactive peptides a acids, as are dynorphins and substance P.
Dynorphins are a group of seven peptides with similar amino acid sequences. They geographically co with enkephalins. Substance P, a peptide, occurs in central neurons (habenula, substantia nigra, bas ganglia, medulla, and hypothalamus) and in high concentration in the dorsal root ganglia. It is released intense afferent painful stimuli.
Dynorphins are a group of seven peptides with similar amino acid sequences. They geographically co with enkephalins. Substance P, a peptide, occurs in central neurons (habenula, substantia nigra, bas ganglia, medulla, and hypothalamus) and in high concentration in the dorsal root ganglia. It is released intense afferent painful stimuli.
Neurotransmitters whose roles in neurotransmission have been less firmly established include histami vasopressin, vasoactive intestinal peptide, carnosine, bradykinin, cholecystokinin, bombesin, somatos corticotropin releasing factor, neurotensin, and possibly adenosine.
Major Receptors
Neurotransmitter receptors are protein complexes that span the cell membrane. Receptors coupled to second messenger are usually monomeric and consist of three parts: the extracellular part, where glycosylation occurs; the transmembrane part, which forms a pocket where the neurotransmitter is pre to act; and the intracytoplasmic part, where G-protein binding or regulation by phosphorylation of the r occurs. Ion channel receptors are multimeric. In some cases, activation of the receptor results in modi of channel ion permeability. In others, activation of a second messenger results in changes of channe conductance.
Receptors that are continuously stimulated by neurotransmitters or drugs (agonists) become hyposens (down-regulated); those that are not stimulated by their neurotransmitter or are blocked chronically by (antagonists) become hypersensitive (up-regulated). Up- or down-regulation of receptors strongly influ the development of tolerance and physical dependence. Withdrawal is usually a rebound phenomenon altered receptor affinity or density. These concepts are particularly important in organ or tissue transpl which the receptors are deprived of the physiologic neurotransmitter by denervation.
Most neurotransmitters interact primarily with postsynaptic receptors, but some receptors are located o presynaptic neurons, providing fine control of neurotransmitter release.
Cholinergic receptors are classified as nicotinic N 1 (in the adrenal medulla and autonomic ganglia) o skeletal muscle) or muscarinic M1 (in the autonomic nervous system, striatum, cortex, and hippocamp M2 (in the autonomic nervous system, heart, intestinal smooth muscle, hindbrain, and cerebellum).
Adrenergic receptors are classified as 1 (postsynaptic in the sympathetic system), 2 (presynaptic in th sympathetic system and postsynaptic in the brain), 1 (in the heart), or 2 (in other sympathetically innerv structures). Dopaminergic receptors are classified as D1 , D2 , D3 , D4 , and D5 . D3 and D 4 play a role thought control (limit negative symptoms of schizophrenic processes), whereas D2 receptor activation the extrapyramidal system.
GABA receptors are classified as GABA A (activating chloride channels) and GABAB (potentiating cAM formation). The GABAA receptor consists of several distinct polypeptides and is the site of action for s neuroactive drugs, including benzodiazepines, newer anticonvulsants (eg, lamotrigine), barbiturates, picrotoxin, and muscimol.
Serotoninergic (5-HT) receptors (with at least 15 subtypes) are classified as 5-HT1 (with four subtyp 5-HT 2 , and 5-HT3 . 5-HT1A receptors, which occur presynaptically in the raphe nucleus (inhibiting pres uptake of 5-HT) and postsynaptically in the hippocampus, modulate adenylate cyclase. 5-HT2 recepto located in the fourth layer of the cortex, are involved in phosphoinositide hydrolysis (see Table 166-2). receptors occur presynaptically in the nucleus tractus solitarius.
Serotoninergic (5-HT) receptors (with at least 15 subtypes) are classified as 5-HT1 (with four subtyp 5-HT 2 , and 5-HT3 . 5-HT1A receptors, which occur presynaptically in the raphe nucleus (inhibiting pres uptake of 5-HT) and postsynaptically in the hippocampus, modulate adenylate cyclase. 5-HT2 recepto located in the fourth layer of the cortex, are involved in phosphoinositide hydrolysis (see Table 166-2). receptors occur presynaptically in the nucleus tractus solitarius.
Glutamate receptors are classified as ionotrophic NMDA (N-methyl-D-aspartate) receptors, which bin NMDA, glycine, zinc, Mg++, and phencyclidine (PCP, also known as angel dust) and affect the influx o K+, Ca++ , and non-NMDA receptors, which bind quisqualate and kainate. Non-NMDA channels are pe to Na+ and K+ but not to Ca++. These excitatory receptors mediate important toxic effects by increasin calcium, free radicals, and proteinase. In neurons, synthesis of nitric oxide (NO) involving NO synthase increases in response to glutamate.
Endorphin-enkephalin (opioid) receptors are classified as 1 and 2 (affecting sensorimotor integra analgesia), 1 and 2 (affecting motor integration, cognitive function, and analgesia), and 1, 2, and 3 (affe water balance regulation, analgesia, and food intake). Sigma receptors, currently classified as nonopio mostly localized in the hippocampus, bind PCP.
Neurotransmitter Transport
Two types of neurotransmitter transporters are essential for neurotransmission. The uptake carrier, loc presynaptic neurons and plasma cells, pumps neurotransmitters from the extracellular space into the c replenishes the neurotransmitter supply, helps terminate the action of the neurotransmitter, and, in the glutamate, keeps the amount of neurotransmitter below toxic levels. The energy required by these pum provided by ATP. The other type of transporter, located on the membrane of the vesicle, concentrates neurotransmitter into the vesicles for further exocytosis. These transporters are powered by cytoplasm and the voltage gradient across the vesicular membrane. During anoxia or ischemia, the transmembra gradient changes, and glutamate is transported from the vesicles into the cytoplasm, increasing the intracellular concentration of glutamate to potentially lethal levels.
Second messenger systems consist of regulatory G proteins and catalytic proteins (eg, adenylate cy phospholipase C) that link receptors and effectors. A second messenger can be the trigger of a chain or the target of a regulatory pathway (eg, calcium--see Table 166-2).

Section 14. Neurologic Disorders Chapter 176. CNS Infections Topics
[General] Acute Bacterial Meningitis Acute Viral Encephalitis And Aseptic Meningitis Subacute And Chronic Meningitis Brain Abscess Subdural Empyema Helminthic Infections
[General]
(See also Ch. 163 and Cytomegalovirus Infection under Herpesvirus Infections and Central Nervous S Viral Diseases in Ch. 162.)
CNS infections include meningitis (inflammation of the meninges of the brain or spinal cord), cerebritis (cerebral manifestations of CNS bacterial invasion), encephalitis (cerebral manifestations of CNS viral invasion), abscesses, and helminthic infections.

Section 14. Neurologic Disorders Chapter 167. Pain Topics
[General] Acute Postoperative Pain Cancer Pain Neuropathic Pain Psychogenic Pain Syndromes
[General]
(See also Ch. 294 and entries under Pain in the Index.)
Pain: A complex subjective sensation reflecting real or potential tissue damage and the affective respo
Classification
Acute pain, an essential biologic signal of the potential for or the extent of injury, is pain that lasts or is anticipated to last a short time, typically < 1 mo. It is often associated with anxiety and with hyperactivi sympathetic nervous system (eg, tachycardia, increased respiratory rate and BP, diaphoresis, dilated
Chronic pain is usually defined broadly and arbitrarily as pain persisting > 1 mo beyond the resolution acute tissue injury, pain persisting or recurring for > 3 mo, or pain associated with tissue injury that is e to continue or progress. Chronic pain has no adaptive biologic role. Vegetative signs (eg, lassitude, sle disturbance, decreased appetite, loss of taste for food, weight loss, diminished libido, constipation) oft develop gradually, and depression may follow.
Pain may be broadly classified as somatogenic (organic)--explicable in terms of physiologic mechanis psychogenic--occurring without organic pathology sufficient to explain the degree of pain and disabilit thought to be related mostly to psychologic issues (see Psychogenic Pain Syndromes, below). A psyc cause of pain should not be assumed without evidence; if a somatogenic process cannot be identified psychologic process is not clear, the pain should be labeled idiopathic.
Somatogenic pain may be nociceptive or neuropathic. Nociceptive pain is judged to be commensurat ongoing activation of somatic or visceral pain-sensitive nerve fibers. When somatic nerves are affected typically felt as aching or pressure (eg, most cancer pain).
psychologic process is not clear, the pain should be labeled idiopathic.
Somatogenic pain may be nociceptive or neuropathic. Nociceptive pain is judged to be commensurat ongoing activation of somatic or visceral pain-sensitive nerve fibers. When somatic nerves are affected typically felt as aching or pressure (eg, most cancer pain).
Neuropathic pain results from dysfunction in the nervous system; it is believed to be sustained by abe somatosensory processes in the peripheral nervous system, the CNS, or both (see Neuropathic Pain, Pain may involve the efferent function of the sympathetic nervous system (sympathetically maintained identifiable peripheral pathology (eg, nerve compression, neuroma formation) or CNS pathology (eg, s spinal cord injury). Usually, the pain is part of a defined neurologic disorder. Pain believed to involve p processes may be subdivided into peripheral mononeuropathies or polyneuropathies; the most commo painful polyneuropathy is due to diabetes. Pain believed to involve CNS processes, labeled deafferent pain, may be subdivided into a variety of types, such as central pain after stroke or phantom pain after amputation.
Some pain syndromes have a multifactorial pathophysiology; eg, most cancer pain syndromes have a prominent nociceptive component but may also include neuropathic pain due to nerve damage by the its treatment and psychogenic pain related to loss of function and fear of disease progression. Nocicep pain may predominate in pain syndromes related to chronic joint or bone injury (eg, arthritis, sickle cell disease, hemophilia).
Distinguishing between continuous and recurrent acute pain (as in sickle cell disease) is another impo aspect of classification. Treatment plans may differ depending on the temporal description of the pain.
Several pain syndromes are difficult to classify. For example, in most patients, chronic headache (see probably involves a complex interaction of nociceptive disturbances in muscles and in blood vessels w psychologic factors.
Evaluation of Pain
An organic cause should always be sought--even if a prominent psychologic contribution to the pain is likely--because pain is often managed best by removing the underlying cause. Once an organic explan has been ruled out, additional tests are useless. The illusory sense of progress such tests provide for physician and patient may perpetuate maladaptive behavior and impede a return to more normal func
The history should include severity, location, quality, duration, course, timing (including frequency of remissions and degree of fluctuation), exacerbating and relieving factors, and comorbidities associated the pain (with emphasis on psychologic issues, depression, and anxiety). The use, efficacy, and adver effects of drugs and other treatments should be determined. The patient should be asked if litigation is or financial compensation for injury will be sought. A personal or family history of chronic pain can ofte illuminate the current problem. The patient's level of function should be assessed in detail, focusing on relationships (including sexual), social network, and employment or avocations. The interviewer should how the patient's pain affects interactions with others and attempts at normal living. Secondary gain, c and premorbid psychopathology, and the role of family pathology should be assessed.
What pain means to the patient should be determined. Reporting pain is more socially acceptable than reporting anxiety or depression, and appropriate therapy often depends on sorting out these similarly described but divergent perceptions. Similarly, pain and suffering should be distinguished, especially in cancer patient, whose suffering may be due as much to loss of function and fear of impending death a pain. The patient's perception of pain can represent more than the pathology intrinsic to the disease.
Physical examination is essential, often helping to identify underlying causes and to further evaluate th
reporting anxiety or depression, and appropriate therapy often depends on sorting out these similarly described but divergent perceptions. Similarly, pain and suffering should be distinguished, especially in cancer patient, whose suffering may be due as much to loss of function and fear of impending death a pain. The patient's perception of pain can represent more than the pathology intrinsic to the disease.
Physical examination is essential, often helping to identify underlying causes and to further evaluate th degree of functional impairment. Appropriate laboratory tests and x-ray examinations should be perfor
Treatment
Nonopioid analgesics: These drugs, specifically acetaminophen and NSAIDs, are often effective for moderate pain (see Table 167-1 and Rheumatoid Arthritis in Ch. 50). NSAIDs differ in cost, duration o and side effects; results for a given patient are often unpredictable. If initial doses are tolerated but pro inadequate analgesia, a higher dose may be warranted. If additional analgesia occurs but is still inade the ceiling dose has not been reached, so doses can be increased further. However, the dose should increased more than 1-1/2 to 2 times the recommended starting dose to limit the risk of toxicity. Patien should be monitored for occult blood in the stool and changes in CBC, electrolytes, and hepatic and re function. Unlike opioids, NSAIDs do not produce physical dependence or tolerance.
Opioid (narcotic) agonists: "Opioid" is a generic term for natural or synthetic substances that bind to opioid receptors in the CNS, producing an agonist action.
Opioid analgesics are extremely useful in managing severe acute pain, including postoperative pain, a chronic pain, including cancer pain. They are often underused, resulting in needless pain and suffering because the required dosage is often underestimated, their duration of action and risks of side effects overestimated, and physicians and nurses often have unreasonable concerns about the development addiction (see Opioid Dependence in Ch. 195). Although physical dependence occurs in virtually all pa treated for chronic pain with opioids for a long time, addiction is extremely rare in patients without a his substance abuse and should not be considered in the decision to begin or to increase doses in patien severe pain.
Morphine, an opium alkaloid, is the prototype. In a nontolerant patient with acute pain, it provides anal a dose (about 10 mg IM) that does not severely alter consciousness. Morphine affects the initial perce pain and the emotional response to it. Patients with severe pain rarely experience euphoric sensations morphine but may become drowsy and relaxed, partly because of decreased distress.
For acute pain, morphine is usually administered IM or IV; morphine sulfate is the most commonly use water-soluble salt. Traditionally, oral morphine was considered ineffective because it is rapidly transfor principally in the liver, and excreted in the urine. However, with upward titration of the dose, oral morph be very effective. Controlled-release oral morphine is the drug most commonly used to treat severe ca pain. Very low doses of intraspinal morphine (eg, 5 to 10 mg epidurally or 0.5 to 1 mg intrathecally) ca long-lasting (up to 24 h) pain relief postoperatively; with dose adjustment, intraspinal opioids can be us long-term management in selected patients.
Adverse effects of morphine are dose-related (see Table 167-2). Morphine causes contraction of perip smooth muscle, the most important effect of which is decreased propulsive movements in the GI tract, constipation (useful in treating diarrhea). Morphine causes the venules (capacitance vessels) to dilate, hypotension may occur in hypovolemic patients or in persons who suddenly assume an upright positio effect is rare with long-term use. Morphine 6-glucuronide--an active, potent, renally excreted morphine metabolite--may be responsible for the exaggerated response in some patients with renal failure who r multiple doses of morphine. Other opioid agonists include codeine (an opium derivative), fentanyl, hydromorphone, levorphanol,
hypotension may occur in hypovolemic patients or in persons who suddenly assume an upright positio effect is rare with long-term use. Morphine 6-glucuronide--an active, potent, renally excreted morphine metabolite--may be responsible for the exaggerated response in some patients with renal failure who r multiple doses of morphine.
Other opioid agonists include codeine (an opium derivative), fentanyl, hydromorphone, levorphanol, meperidine and methadone (synthetic opioids), oxycodone (a synthetic morphine congener), oxymorp and propoxyphene, which is chemically related to methadone. Usual dosage, potency, duration of effe adverse effects are listed in Table 167-2.
A drug may be preferred because of favorable experience, lower cost (methadone is least expensive), availability, route of administration, or duration of action. Opioids with a short half-life--morphine and hydromorphone--should be used as first-line agents for acute pain but may be replaced with longer-ac drugs if pain persists.
Knowledge of equianalgesic doses of opioids (see Table 167-3) is essential when changing drugs or ro administration. Cross-tolerance between drugs is incomplete, so when one drug is substituted for anot equianalgesic dose should be reduced by 50%. The only exception is methadone, which should be red 75 to 90%.
Because individual responses vary greatly, opioid dosage should be modified according to each patien response. For opioid-naive patients with acute pain, frequent monitoring of pain relief, sedation, respir rate, and BP guides dosage adjustment. Opioid sensitivity is increased in the elderly; they require a sm initial dose and smaller dose increments than younger patients to obtain the same analgesia and are predisposed to side effects. Initially, the drug may be given at the patient's request; most opioids need given at least q 3 h and many q 2 h.
Because steady-state levels are not approached until 4 to 5 half-lives have passed, drugs with a long h (particularly levorphanol and methadone) pose a risk of delayed toxicity as plasma levels rise. Controlled-release opioids typically require several days to approach steady-state plasma levels.
Tolerance (the need for increasing doses to maintain effects) appears to be an uncommon cause of d opioid effectiveness during long-term therapy. The need to increase doses usually reflects worsening underlying disease with progressive pain. Although tolerance to analgesic effects may develop concur is seldom the only reason for increasing doses. Fear of tolerance should not impede the appropriate e aggressive use of an opioid. Development of tolerance to other effects varies from one physiologic sys another; eg, tolerance to the constipating effect develops slowly, but tolerance to respiratory depressio nausea typically develops soon after treatment begins.
Opioids should be used with caution in patients with renal failure, chronic obstructive pulmonary disea (because of respiratory depression), liver disease, or preexisting encephalopathy or dementia. Neonat especially premature infants, are very sensitive to opioids, because they lack adequate metabolic path eliminate them.
The most important guideline to ensure the optimal use of opioids is individualization of the dose throu titration. Dose titration involves incremental increases in dose until a favorable balance between analg side effects is found. If this balance cannot be achieved, the drug is not useful. One efficient technique dose titration uses "rescue doses." This technique treats breakthrough pain while guiding dose escala addition to regular doses around the clock or use of long-acting drugs, an extra dose of a drug with a s half-life is offered q 2 h prn. The rescue dose is empiric, based on the standing dose, and usually 5 to the total daily dose. The standing dose can be increased daily by the total amount of rescue dose use rescue doses continue to be needed or if pain persists. Routes of administration: If possible, opioids should be given orally to prolong the effects and avoid
addition to regular doses around the clock or use of long-acting drugs, an extra dose of a drug with a s half-life is offered q 2 h prn. The rescue dose is empiric, based on the standing dose, and usually 5 to the total daily dose. The standing dose can be increased daily by the total amount of rescue dose use rescue doses continue to be needed or if pain persists.
Routes of administration: If possible, opioids should be given orally to prolong the effects and avoid fluctuations in plasma level. Slow-release morphine or oxycodone tablets (dosing interval of 8 to 12 h) transdermal fentanyl (dosing interval of 2 to 3 days) make infrequent dosing possible. Parenterally, IV preferred to IM for repeated bolus because it provides greater patient comfort. Continuous IV or sc infu should be considered if repeated parenteral doses produce a prominent bolus effect--ie, toxicity at pea early in the dosing interval or later breakthrough pain at trough levels. Patient-controlled analgesia sys which the patient can trigger additional drug delivery) can be added to an infusion to provide suppleme doses.
Epidural and intrathecal administration of opioids requires special expertise. By activating opioid recep spinal level, they may provide analgesia with fewer side effects. However, supraspinal redistribution of with delayed toxicity during acute administration and cost are major concerns.
Opioid side effects: Constipation, a common side effect, should be managed by increasing the fibe of the diet to > 10 g/day (unless bowel obstruction exists) and prescribing a stool softener (eg, docusa sodium 100 mg bid or tid), usually with a stimulant laxative (eg, senna). The stimulant laxative dose is low but can be increased if necessary. Persisting constipation can be managed with an osmotic laxativ magnesium citrate) given q 2 to 3 days or with lactulose given daily (eg, 15 mL bid).
Sedation can be treated specifically with methylphenidate or dextroamphetamine starting with 5 mg p times/day, increased to an effective dose. The maximum dose seldom exceeds 60 mg/day. Nausea can be treated with hydroxyzine 25 to 50 mg po q 6 h, metoclopramide 10 to 20 mg po q 6 h, antiemetic phenothiazine (eg, prochlorperazine 10 mg po or 25 mg rectally q 6 h).
Respiratory depression is rare in patients receiving long-term therapy, because tolerance to this effe develops quickly; if respiratory depression occurs, a contributing pathologic process should be sought. respiratory depression must be treated in a physically dependent patient, dilute solutions of naloxone ( diluted in 10 mL 0.9% sodium chloride) should be given slowly IV, titrated to respiratory rate, not alertn caution to avoid precipitating acute withdrawal (see Opioid antagonists, below).
Agonist-antagonists: These drugs are potent analgesics with somewhat less potential for abuse than agonists; their antagonist activity may induce a withdrawal syndrome in patients already dependent on Pentazocine, a weak antagonist with considerable analgesic activity, is the only agonist-antagonist wit formulation (see Table 167-2). Other drugs in this class include buprenorphine, butorphanol, dezocine nalbuphine.
Opioid antagonists: These opioid-like substances bind to opioid receptors but produce little or no ago activity.
Naloxone, an almost pure opioid antagonist, can reverse the effects of opioids. It acts within minutes w given IV and slightly less rapidly when given IM. However, the duration of antagonism is usually shorte that of opioid-induced respiratory depression, so that repeated doses of naloxone and close monitorin necessary. A common starting dosage in an opioid-naive patient with acute opioid overdosage is 0.4 m to 3 min prn. For patients receiving long-term opioid therapy, it should be used only to reverse respirat depression and must be administered more cautiously to avoid precipitating withdrawal or recurrent pa reasonable starting dose is 0.04 mg (a 0.4-mg ampule diluted in 10 mL saline) IV q 2 to 3 min prn.
that of opioid-induced respiratory depression, so that repeated doses of naloxone and close monitorin necessary. A common starting dosage in an opioid-naive patient with acute opioid overdosage is 0.4 m to 3 min prn. For patients receiving long-term opioid therapy, it should be used only to reverse respirat depression and must be administered more cautiously to avoid precipitating withdrawal or recurrent pa reasonable starting dose is 0.04 mg (a 0.4-mg ampule diluted in 10 mL saline) IV q 2 to 3 min prn. Naltrexone, an orally active opioid antagonist, is given as an adjunct in opioid and alcohol addiction. It long duration of action and is generally well tolerated.
Nondrug analgesic therapies: Nondrug therapies may be used in selected patients with chronic pain include noninvasive approaches (eg, transcutaneous electrical nerve stimulation, diathermy) and vario specialized anesthetic, neurosurgical, and invasive neurostimulatory techniques (see Table 167-4 and Psychogenic Pain Syndromes and Complex Regional Pain Syndrome, below). No controlled studies o techniques have been conducted, but large series suggest their efficacy. The precise role of these tec in easing cancer pain is undefined. The invasive approaches are most useful for localized pain. Specia expertise, which may be available only in certain centers, is required for their safe application. They sh considered only if routine noninvasive measures are ineffective; a notable exception is celiac plexus n block for midabdominal pain, in which the benefits of early treatment appear to outweigh potential risks

Section 14. Neurologic Disorders Chapter 177. CNS Neoplasms Topics
[General] Intracranial Neoplasms Benign Intracranial Hypertension Spinal Cord Neoplasms CNS Paraneoplastic Syndromes Radiation Injury Of The Nervous System
[General]
(See also Chs. 89 and 142.)

Section 14. Neurologic Disorders Chapter 168. Headache Topics
[General] Migraine Cluster Headache Tension Headache
[General]
Headache (cephalalgia) is a common symptom, often associated with disability, but rarely life threaten Headaches may be a primary disorder (migraine, cluster, or tension headache) or a secondary sympto such disorders as acute systemic or intracranial infection, intracranial tumor, head injuries, severe hypertension, cerebral hypoxia, and many diseases of the eyes, nose, throat, teeth, ears, and cervical vertebrae (see Table 168-1). Sometimes no cause is found.
Headaches may result from stimulation of, traction of, or pressure on any of the pain-sensitive structur head: all tissues covering the cranium; the 5th, 9th, and 10th cranial nerves; the upper cervical nerves large intracranial venous sinuses; the large arteries at the base of the brain; the large dural arteries; an dura mater at the skull base. Dilation or contraction of blood vessel walls stimulates nerve endings, ca headache. The cause of most headaches is extracranial rather than intracranial. Stroke, vascular abnormalities, and venous thromboses are uncommon causes of headache.
Diagnosis
The frequency, duration, location, and severity of the headache; the factors that make it better or wors associated symptoms and signs, such as fever, stiff neck, nausea, and vomiting; and special studies h identify the cause of headache.
Secondary headaches may have specific characteristics. An acute whole-cranial, severe headache as with fever, photophobia, and stiff neck indicates an infectious process, such as meningitis, until proved otherwise. Subarachnoid hemorrhage also causes acute headache with symptoms and signs of menin irritation. Space-occupying lesions often cause subacute, progressive headache. New-onset headache adult > 40 yr always requires thorough evaluation. With space-occupying lesions, the following may oc headache on awakening or at night, fluctuation of headache with postural changes, and nausea and v Additional neurologic complaints, such as seizure, confusion, weakness, or sensory changes, may occ and are ominous.
otherwise. Subarachnoid hemorrhage also causes acute headache with symptoms and signs of menin irritation. Space-occupying lesions often cause subacute, progressive headache. New-onset headache adult > 40 yr always requires thorough evaluation. With space-occupying lesions, the following may oc headache on awakening or at night, fluctuation of headache with postural changes, and nausea and v Additional neurologic complaints, such as seizure, confusion, weakness, or sensory changes, may occ and are ominous.
Tension headache tends to be chronic or continuous and commonly originates in the occipital or bifron region, then spreads over the entire head. It is usually described as a pressure sensation or a viselike constriction of the skull. Febrile illnesses, arterial hypertension, and migraine usually cause throbbing p can occur in any part of the head.
Useful tests include CBC, STS, serum chemistry profile, ESR, CSF examination, and, for specific sym ocular tests (acuity, visual fields, refraction, intraocular pressure) or sinus x-rays. If the cause of recen persistent, recurrent, or increasing headache remains in doubt, MRI and/or CT is appropriate, especia abnormal neurologic signs are present.
Treatment
Many headaches are of short duration and require no treatment other than mild analgesics (eg, aspirin acetaminophen) and rest.
Treatment of primary headaches is discussed under the specific disorders, below. Alternative approa such as biofeedback, acupuncture, dietary manipulations, and some less conventional modes, have b advocated for these disorders. None of these treatments has shown clear-cut benefits in rigorous stud However, to the extent that an alternative treatment poses little risk, it may be tried, with the idea that e headache management is multidimensional.
Treatment of secondary headaches depends on treatment of the underlying disorder. For meningitis antibiotic therapy is critical. Subsequently, symptoms can be relieved with analgesics, including acetaminophen, NSAIDs, or opioid narcotics. Certain disorders require more specific treatment; eg, te arteritis is treated with corticosteroids, and headache due to benign intracranial hypertension is treated acetazolamide or diuretics and weight loss. Subdural hematomas or brain tumors may be treated surg (see Chs. 175 and 177, respectively).
Stress management taught by a psychologist often reduces the incidence of headaches. However, mo patients are helped by an understanding physician who accepts the pain as real, sees the patient regu and encourages discussion of emotional difficulties, whether they are the cause or the result of chroni headaches. The physician can reassure the patient that no organic lesion is present and recommend environmental readjustments and the removal of irritants and stresses. For particularly difficult problem team composed of a physician, psychotherapist, and physiotherapist is most effective in managing chr headache (see also Psychogenic Pain Syndromes in Ch. 167).

Section 14. Neurologic Disorders Chapter 178. Neuro-Ophthalmologic And Cranial Disorders Topics
[General] Neuro-Ophthalmologic Disorders Cranial Nerve Disorders
[General]
(See also discussions of 8th nerve disorders under Differentiation of Sensory and Neural Hearing Loss Ch. 82; of olfactory nerve disorders under Anosmia in Ch. 86; of optic nerve disorders in Ch. 101; and cranial nerve examination in Ch. 165.)
Section 14. Neurologic Disorders Chapter 169. Function And Dysfunction Of The Cereb Topics
[General] Aphasia Apraxia Agnosia Amnesias
[General]
Dysfunction or disease of the cerebral hemispheres can be organic (ie, of known structural, chemical, metabolic mechanism) or nonorganic (of unknown cause). The latter includes the major psychoses an behavioral disorders.
Organic cerebral dysfunction may be focal or global in distribution. Most focal disorders are due to stru abnormalities (eg, space-occupying lesions, stroke, trauma, maldevelopment, scars) and usually affec the focal functions of the cortex. In contrast, most global disorders are due to metabolic-chemical diso disseminated structural lesions (eg, diffuse inflammation, vasculopathy, disseminated malignancy). Gl lesions alter multiple dimensions of cerebral sensory and behavioral function and often affect subcortic systems, interfering with arousal levels producing stupor or coma, or with the normal integration of con thought, resulting in delirium or dementia. Some disorders, such as apraxia and amnesia, may result f focal or diffuse brain dysfunction.
The cerebral cortex contains large areas of association cortex and proportionately small primary senso motor areas that specifically express these functions (see Fig. 169-1). Sensory areas directly receive somesthetic, auditory, visual, and olfactory stimuli from peripheral receptors and relay information to m areas. These, in turn, transmit motor signals to striated muscles to regulate voluntary body movement remainder of the cortex consists of the association cortex and limbic system, which together integrate perceptions with instinctual and acquired memories to create learning, thought, expression, and behav
The clinical effects of focal brain lesions depend mainly on the location and amount of damage. Recov hinges on the degree of redundancy, adaptation, plasticity of the remaining cerebrum, and the patient'
In adults, little redundancy exists in the primary cortical receiving areas and pathways for somatic and function and motor control, which are strongly lateralized; direct damage at any age usually causes at some permanent effects. After early childhood, language functions and spatial functions become incre lateralized and nonredundant. Although auditory signals from either ear reach right and left temporal lo
hinges on the degree of redundancy, adaptation, plasticity of the remaining cerebrum, and the patient'
In adults, little redundancy exists in the primary cortical receiving areas and pathways for somatic and function and motor control, which are strongly lateralized; direct damage at any age usually causes at some permanent effects. After early childhood, language functions and spatial functions become incre lateralized and nonredundant. Although auditory signals from either ear reach right and left temporal lo cortices, there is evidence for dominance in the left hemisphere. Many separate areas of the associati cortex have somewhat overlapping functions; this redundancy often allows one part of the brain to com functionally for parts that are damaged (called adaptation). Adaptation is more common in persons < old.
Plasticity is the ability of certain areas of the brain--depending on the kind of stimulation and the pers age--to alter their function. For example, throughout life, the hippocampal processes can convert new and percepts into permanent memory. To a lesser degree, cerebral plasticity contributes to relearning thoughts, movement, and sensory functions after brain injury in adults. However, plasticity is most prom the developing brain; eg, if the dominant left hemisphere language areas are severely damaged before yr, the right hemisphere usually can assume near-normal language capacities.
Frontal lobes: The frontal lobes influence learned motor activity and the planning and organizing of e behavior. The prerolandic-precentral gyrus plus the areas just anterior to it (the premotor and supplem motor areas) on one side of the cerebrum regulate skilled muscular activities on the opposite side of th The premotor and supplementary cortices also control ipsilateral skilled motor behavior, such as hitting ball. Seizures involving the premotor areas characteristically cause adversive movements of the head, trunk, and extremities toward the opposite side; those originating from the precentral gyrus produce cla jacksonian focal motor seizures.
Behavioral changes produced by injury to the more anteriorly located prefrontal area vary according to lesion's location, size, and rate of development. Unilateral lesions < 2 cm in diameter almost never cau symptoms except seizures. Larger lesions, unless they develop rapidly (over weeks or months rather t years) or affect both frontal lobes, may also cause no symptoms. Patients with large basal frontal lesio apathetic, inattentive to stimuli, indifferent to the implications of their acts, and sometimes incontinent. with frontal polar or anterior lateral lesions are likely to disregard the consequences of their behavior a to be distractible, euphoric, facetious, often vulgar, and indifferent to social niceties. Bilateral acute tra the prefrontal areas may produce boisterously talkative, restless, and socially intrusive behavior, often for days or weeks and usually subsiding spontaneously.
Parietal lobes: The postrolandic area of the parietal lobes integrates somesthetic stimuli for recognitio recall of form, texture, and weight. More posterolateral areas provide accurate visual spatial relationsh well as integrate the relative perceptions with other sensations to create awareness of trajectories of m objects. Awareness of the position of body parts is also generated in this area. In the dominant hemisp the inferior parietal area transacts mathematic functions and is closely linked to language recognition a memory. The nondominant parietal lobe integrates the left side of the body with its environment.
Small lesions of the postcentral cortex cause astereognosis (loss of tactile recognition) in the contralat hand and body. Large inferior parietal lesions in the dominant (usually left) hemisphere are commonly associated with severe aphasia; lesser damage can cause apraxia, difficulty in calculating, and somet right-left disorientation and agraphia. Acute injury to the nondominant parietal lobe may remove the pa awareness of the left side of the body and its environment and of the serious nature of his injury (anosognosia). Some patients, particularly elderly ones with large right parietal lesions, even deny the existence of the paralysis that affects the left side of the body. Some of them lapse into states of globa confusion. Others, who have small lesions, become confused when performing learned manual proced this spatial-manual defect is called apraxia. Dressing and other well-learned activities often cannot be performed.
(anosognosia). Some patients, particularly elderly ones with large right parietal lesions, even deny the existence of the paralysis that affects the left side of the body. Some of them lapse into states of globa confusion. Others, who have small lesions, become confused when performing learned manual proced this spatial-manual defect is called apraxia. Dressing and other well-learned activities often cannot be performed.
Temporal lobes: The temporal lobes process visual recognition, auditory perception, memory, and em Patients with acquired unilateral damage to the right temporal lobe commonly lose acuity for nonverba auditory stimuli (eg, music). Left temporal lobe injury interferes severely with the recognition, memory, formation of language. Patients with epileptogenic foci in the medial limbic-emotional parts of the temp lobe commonly have partial complex seizures, characterized by uncontrollable feelings and abnormal autonomic, cognitive, or emotional functions. Occasionally, such patients have personality changes, characterized by humorlessness, philosophic religiosity, and obsessiveness; in men, libido may be dec

Section 14. Neurologic Disorders Chapter 179. Disorders Of Movement Topics
[General] Tremor Dyskinesias Drug-Induced Movement Disorders Parkinson's Disease Progressive Supranuclear Palsy Cerebellar And Spinocerebellar Disorders Idiopathic Orthostatic Hypotension And Shy-Drager Syndrome
[General]
Three major components of the neural motor system are involved in producing voluntary movement: th corticospinal (pyramidal) tracts, which pass through the medullary pyramids to connect the cerebral co lower motor centers of the brain stem and spinal cord; the basal ganglia (caudate nucleus, putamen, g pallidus, and substantia nigra--forming the extrapyramidal system), a group of interrelated structures d the forebrain, whose output is mainly directed rostrally through the thalamus to the cerebral cortex; an cerebellum, the center for motor coordination.
Lesions of the corticospinal tracts result in weakness or total paralysis of predominantly distal volun movement, Babinski's sign, and often spasticity (increased muscle tone and exaggerated deep tendon reflexes). The increase in muscle tone is proportional to the rate and degree of stretch placed on a mu resistance suddenly melts away--producing the clasp-knife phenomenon. Troublesome spasticity resu from such disorders as spinal cord injury or multiple sclerosis can often be reduced by baclofen 30 to 1 mg/day po or diazepam 6 to 20 mg/day po. However, treatment does not improve voluntary power.
Disorders of the basal ganglia (extrapyramidal disorders) do not cause weakness or reflex changes. hallmark is involuntary movement (dyskinesia), causing increased movement (hyperkinesia) or decrea movement (hypokinesia) and changes in muscle tone and posture.
Cerebellar disorders cause abnormalities in the range, rate, and force of movement. Strength is mini affected.

Section 14. Neurologic Disorders Chapter 170. Stupor And Coma Topics
[General]
[General]
Stupor is unresponsiveness from which the patient can be aroused only briefly by vigorous, repeated stimulation. Coma is a state in which the patient is unarousable and unresponsive and any response t repeated stimuli is only primitive avoidance reflexes; in profound coma, all brain stem and myotatic ref may be absent.
The alert state requires intact cognitive functions of the cerebral hemispheres and preservation of arou mechanisms of the reticular activating system (an extensive network of nuclei and interconnecting fibe occupies the gray matter core of the pons, midbrain, and posterior diencephalon). The system receive afferent impulses from many somatic, visceral, auditory, and visual sensory pathways and relays these impulses to intralaminar, paracentral, and thalamic nuclei. These nuclei activate areas widely distribute throughout the cerebral cortex. Feedback neural loops balance normal activity at every level.
Disturbance of these functions impairs arousal, which may be brief or prolonged, mild or profound. Stu coma are extreme forms. Brief losses of arousal--unconsciousness--occur with syncope (see Ch. 200) convulsive seizure, unconsciousness may last somewhat longer; with mild concussion, up to about 1 h unconsciousness for more than a few hours usually results from severe intracranial or metabolic disor Lesser injury can result in apathy, inattention, and hypersomnia (excessively long or deep sleep from w patient can be awakened only by energetic stimulation). Delirium is also a state of impaired arousal an attention; dementia consists of severely impaired cognition, usually without loss of arousal (see Ch. 17
Etiology
Recently gained confusion, severe apathy, stupor, or coma implies dysfunction of the cerebral hemisp the diencephalon, and/or the upper brain stem (see Table 170-1). Focal lesions in supratentorial struc may extensively damage both hemispheres or may produce so much swelling that the hemispheres co the diencephalic activating system and midbrain, causing transtentorial herniation and brain stem dam Primary subtentorial (brain stem or cerebellar) lesions may compress or directly damage the reticular f anywhere between the level of the midpons and (by upward pressure) the diencephalon. Metabolic or infectious diseases may depress hemispheric and brain stem function by a change in blood compositio presence of a direct toxin. Impaired consciousness may also be due to reduced blood flow (as in sync
may extensively damage both hemispheres or may produce so much swelling that the hemispheres co the diencephalic activating system and midbrain, causing transtentorial herniation and brain stem dam Primary subtentorial (brain stem or cerebellar) lesions may compress or directly damage the reticular f anywhere between the level of the midpons and (by upward pressure) the diencephalon. Metabolic or infectious diseases may depress hemispheric and brain stem function by a change in blood compositio presence of a direct toxin. Impaired consciousness may also be due to reduced blood flow (as in sync severe heart failure) or a change in the brain's electrical activity (as in epilepsy). Concussion, anxiolytic and anesthetics impair consciousness without producing detectable structural changes in the brain.
Diagnosis
Often, the cause of unconsciousness is not immediately evident, and diagnosis requires an orderly ap First, a patent airway is secured; BP and pulse are checked and ECG is performed to determine if car output is adequate.
A test for hypoglycemia, which can cause permanent neuronal death, should be performed immediate an IV line is placed, thiamine 100 mg IM is given in either deltoid, and blood glucose, electrolytes, and are measured. Then 50 mL of 50% glucose is given IV. If the patient awakens, hypoglycemia is the ca
A detailed history should be obtained, if possible, while the physical and neurologic examinations are performed. The patient may be wearing an information tag or carrying a diagnostic card in his wallet. Observers or relatives should be questioned about the mode of onset or injury; ingestion of drugs, alco other toxic substances; and infections, convulsions, headache, and previous illnesses (eg, diabetes m nephritis, heart disease, hypertension). Police can help find relatives or associates; containers that ma held food, alcohol, drugs, or poisons should be examined and saved (for chemical analysis and for po legal evidence). Signs of hemorrhage, incontinence, and cranial trauma should be sought. The patient may provide clues: drugs, epilepsy, and cerebral-meningeal infection are common causes in persons cardiovascular disease (especially stroke) and metabolic disorders (eg, diabetes mellitus, hypoglycem hepatic coma, electrolyte disorders, uremia) are more common in those > 40 yr.
Physical examination includes (1) rectal temperature; (2) skin: color, evidence of trauma or hypoderm injections (narcotics, insulin), rashes, petechiae; (3) scalp: contusions, lacerations; (4) eyes: pupil size reaction to light, ocular palsy, corneal reflex, and oculocephalic reflex ("doll's eye" response to head ro performed only if no cervical fractures exist), fundic signs of papilledema or hemorrhage, vascular scle diabetic or uremic retinitis; (5) ENT: escape of CSF or blood, scarred or bitten tongue, breath odor (alc acetone, paraldehyde, or the bitter almond smell of cyanide); (6) respiratory pattern: hyperventilation, Cheyne-Stokes (periodic) breathing; (7) cardiovascular signs: apical rate and rhythm, character of the BP in both arms, signs of cardiac decompensation, sclerosis in peripheral vessels, cyanosis or clubbin fingers and toes; (8) abdomen: spasm, rigidity; and (9) neurologic signs: paresis, stiff neck, reflexes, m twitching, convulsions.
The neurologic examination may disclose whether the disease is supratentorial, subtentorial, or met Breathing may have a periodic pattern (Cheyne-Stokes) in bilateral hemispheric disease or in diencep disorders and an irregular pattern (prolonged or ataxic inspiration) with lower pontine and upper medu lesions. Hyperventilation usually reflects metabolic or pulmonary disease but sometimes reflects uppe or midbrain damage. The pupils are small and reactive to light in hypothalamic disease, pontine diseas narcotic poisoning; they become fixed in midposition when midbrain damage or severe glutethimide overdosage occurs. Pupils are dilated in anoxia or 3rd nerve compression but remain normally reactive metabolic diseases, hemispheric disease, and psychogenic unresponsiveness. Oculovestibular respon cold caloric stimulation show bilateral tonic conjugate deviation toward the ear irrigated with cold water hemispheric depression. Oculovestibular responses are absent or dysconjugate in brain stem impairm show only minimal nystagmus or random movements in psychogenic unresponsiveness. Hemispheric produce hemiplegic motor responses to painful stimuli. Decerebrate rigidity (neck, back, and limbs ext jaws clenched) accompanies diencephalic-midbrain dysfunction; flaccidity accompanies pontomedulla
overdosage occurs. Pupils are dilated in anoxia or 3rd nerve compression but remain normally reactive metabolic diseases, hemispheric disease, and psychogenic unresponsiveness. Oculovestibular respon cold caloric stimulation show bilateral tonic conjugate deviation toward the ear irrigated with cold water hemispheric depression. Oculovestibular responses are absent or dysconjugate in brain stem impairm show only minimal nystagmus or random movements in psychogenic unresponsiveness. Hemispheric produce hemiplegic motor responses to painful stimuli. Decerebrate rigidity (neck, back, and limbs ext jaws clenched) accompanies diencephalic-midbrain dysfunction; flaccidity accompanies pontomedulla stem dysfunction. Symmetric motor abnormalities, often including asterixis or multifocal myoclonus, accompany metabolic diseases, especially anoxia, and diffuse neuronal abnormalities due to drug tox Creutzfeldt-Jakob disease (see Ch. 162). Motor signs and reflexes remain normal in psychogenic unresponsiveness.
Characteristically, when supratentorial lesions cause stupor or coma, neurologic signs and symptoms indicate involvement of one cerebral hemisphere. Then, because the mass enlarges and pressure cha cause brain tissues to shift, signs of progressive rostral-caudal deterioration develop, indicating involve first of the diencephalon and finally of the brain stem. When unconsciousness results from a primary b stem lesion, pupillary and oculomotor signs are abnormal from the start.
Laboratory studies in patients with acute stupor or coma of unknown cause begin with blood glucose measurements. Blood tests should include Hct, respiratory gases, WBC, BUN, sodium, potassium, bicarbonate, chloride, alcohol, and bromide and, if the diagnosis is unclear, spectroscopy for sulfhemo and methemoglobin. Several tubes of clotted blood should be drawn for toxicology studies or measure anticonvulsant levels. Urine should be collected by catheterization and examined for glucose, acetone albumin, and sedative drugs. Gastric lavage is required for diagnosis and treatment in suspected poiso with care to avoid esophageal or gastric perforation if the poison could have been corrosive (see also For patients in deep coma, endotracheal intubation should precede lavage to prevent pulmonary aspir Emergency CT or MRI should be performed when the diagnosis is in doubt. Skull x-rays are usually us undiagnosed cases, lumbar puncture to detect infection should be performed as soon as possible, unl increased intracranial pressure from an expanding lesion is suspected. An EEG taken after a few hour persistent coma may show the electrical signs of nonconvulsive status epilepticus, spikes, sharp wave spike and slow complexes.
The principal diagnostic points for some common causes of unconsciousness are listed in Table 170-2 Specific disorders are discussed further elsewhere in The Manual.
Treatment
Emergency measures: Hemorrhage control, CPR, airway maintenance (by intubation or tracheostom treatment of shock, O2 administration (for hypoxia, which almost always complicates unconsciousness urinary bladder catheterization, fluid or electrolyte replacement, and drugs that reverse narcotic-induce may be necessary. Temperature, pulse, respirations, and BP should be checked frequently. If the diag not immediately evident, an infusion of hypertonic glucose 50 mL IV may be started after blood glucos been measured. Nothing should be given orally. Stimulants and narcotics should be avoided. Parenter feeding and prevention of decubitus ulcers are essential in protracted unconsciousness.
VEGETATIVE STATE
Absence of the capacity for self-aware mental activity due to overwhelming damage or dysfunction of cerebral hemispheres, with sufficient sparing of the diencephalon and brain stem to preserve autonom motor reflexes as well as normal sleep-wake cycles.
The vegetative state appears transiently after several kinds of diffuse brain injuries. A vegetative state
Absence of the capacity for self-aware mental activity due to overwhelming damage or dysfunction of cerebral hemispheres, with sufficient sparing of the diencephalon and brain stem to preserve autonom motor reflexes as well as normal sleep-wake cycles.
The vegetative state appears transiently after several kinds of diffuse brain injuries. A vegetative state lasts > 4 wk is arbitrarily called persistent. Persistent vegetative state is most common after severe he or global anoxia (eg, from cardiac arrest) and has a poor prognosis for recovering consciousness.
When the condition lasts longer than a few months, few patients improve and none recovers fully. Adu persistent vegetative state have about a 50% likelihood of regaining interactive consciousness in the f after a head injury. Permanent functional brain disability usually ensues. After that time, fewer and few become aware of their surroundings in any systematic way. Only 10 to 15% of such patients regain consciousness after cardiac arrest in the hospital and possibly no more than 5% after cardiac arrest ou hospital. About 60% of children in a persistent vegetative state after brain trauma regain consciousnes the following year, but those with anoxic brain injuries do little better than adults. Only a tiny fraction of patients who regain consciousness after 6 mo recover sufficiently to care for themselves independentl
Diagnosis and Treatment
Extreme care must be taken in making the original diagnosis of persistent vegetative state and in reco it repeatedly in the weeks or months that follow.
Treatment is nonspecific and consists of preventing systemic diseases, such as pneumonia, and of pr good nutrition, effective nursing care to prevent pressure ulcers of the back and limbs, and physical th prevent contractures of the extremities. Unconscious persons cannot perceive pain. Those who show of regaining awareness by responding consistently to questions or other specific stimuli must be mana carefully to avoid inflicting any more discomfort than they already experience. Large societal and ethic problems result from maintaining patients in a persistent vegetative state for > 6 mo, especially those w have not left advance directives to guide decisions about terminating treatment.
LOCKED-IN SYNDROME
A condition in which a patient remains awake and sentient but, because of motor paralysis in all parts body, cannot communicate, except sometimes by coded eye movements.
Several diseases can cause this syndrome, which results from bilateral interruption of the corticospina between the midbrain and pons or from extensive peripheral involvement of the lower motor neurons.
BRAIN DEATH
The capacity of ventilators to perpetuate cardiopulmonary functions for a long time despite the failure organs has led to widespread legal and societal acceptance that death of a person is the total cessatio integrated brain function, especially that of the brain stem. For a physician to declare brain death, a str or known metabolic cause of brain damage must be present, and potentially anesthetizing or paralyzin especially self-administered, must be ruled out. Hypothermia below 30 C (86 F) must be corrected. C criteria are given in Table 170-3.

Section 14. Neurologic Disorders Chapter 180. Demyelinating Diseases Topics
[General] Multiple Sclerosis
[General]
(See also Progressive Multifocal Leukoencephalopathy under Slow Virus Infections in Ch. 162.)
Myelin sheaths, which cover many nerve fibers, are composed of lipoprotein layers formed in early life formed by the oligodendroglia in the CNS differs chemically and immunologically from that formed by t Schwann cells peripherally, but both types have the same function: to promote transmission of a neura impulse along an axon.
Many congenital metabolic disorders (eg, phenylketonuria and other aminoacidurias; Tay-Sachs, Niemann-Pick, and Gaucher's diseases; Hurler's syndrome; Krabbe's disease and other leukodystroph affect the developing myelin sheath, mainly in the CNS. Unless the biochemical defect can be correcte compensated for, permanent, often widespread, neurologic deficits result.
Demyelination in later life is a feature of many neurologic disorders; it can result from damage to nerve myelin due to local injury, ischemia, toxic agents, or metabolic disorders. Extensive myelin loss is usua followed by axonal degeneration and often by cell body degeneration, both of which may be irreversibl However, remyelination occurs in many instances, and repair, regeneration, and complete recovery of function can be rapid. Recovery often occurs after the segmental demyelination that characterizes ma peripheral neuropathies; this process may account for the exacerbations and remissions of multiple sc (MS). Central demyelination (ie, of the spinal cord, brain, or optic nerves) is the predominant finding in primary demyelinating diseases, whose etiology is unknown. The most well known is MS (see below). Descriptions of the others follow.
Acute disseminated encephalomyelitis (postinfectious encephalomyelitis--see also Acute Viral Encephalitis and Aseptic Meningitis in Ch. 176) is characterized by perivascular CNS demyelination, w occur spontaneously but usually follows a viral infection or viral vaccination (or, very rarely, bacterial vaccination), suggesting an immunologic cause. Acute inflammatory peripheral neuropathies that follo vaccination or the Guillain-Barr syndrome (see Ch. 183) are similar demyelinating disorders with the presumed immunopathogenesis, but they affect only peripheral structures.
Adrenoleukodystrophy and adrenomyeloneuropathy are rare X-linked recessive metabolic disorde
Encephalitis and Aseptic Meningitis in Ch. 176) is characterized by perivascular CNS demyelination, w occur spontaneously but usually follows a viral infection or viral vaccination (or, very rarely, bacterial vaccination), suggesting an immunologic cause. Acute inflammatory peripheral neuropathies that follo vaccination or the Guillain-Barr syndrome (see Ch. 183) are similar demyelinating disorders with the presumed immunopathogenesis, but they affect only peripheral structures.
Adrenoleukodystrophy and adrenomyeloneuropathy are rare X-linked recessive metabolic disorde characterized by adrenal gland dysfunction and widespread demyelination of the nervous system. Adrenoleukodystrophy occurs in young boys; adrenomyeloneuropathy, in adolescents. Mental deterior spasticity, and blindness may occur. Adrenoleukodystrophy is invariably fatal. Dietary and immunomod treatments are under study.
Leber's hereditary optic atrophy and related mitochondrial disorders are characterized primarily by b loss of central vision, usually affecting young men in their late teens or early twenties. Leber's heredita atrophy can resemble the optic neuritis in MS. Mutations in the maternally inherited mitochondrial DNA been identified. HTLV-associated myelopathy, a slowly progressive spinal cord disease associated with infection by human T-cell lymphotrophic virus, is characterized by spastic weakness of both legs (see Ch. 162).

Section 14. Neurologic Disorders Chapter 171. Delirium And Dementia Topics
[General] Delirium Dementia
[General]
An estimated 4 to 5 million Americans (about 2% of all ages and 15% of those > age 65) have some fo degree of cognitive failure. Cognitive failure (dysfunction or loss of cognitive functions--the processes b knowledge is acquired, retained, and used) is most commonly due to delirium (sometimes called acute confusional state) or dementia. It may also occur in association with disorders of affect, such as depre (see Ch. 189).
Although delirium and dementia have distinct characteristics, distinguishing between them initially can difficult (see Table 171-1). Because no laboratory test can reliably establish a definitive cause of cogn impairment, evaluation is usually based on the history and physical examination. Knowledge of baselin function is essential for determining the extent and rate of change.
Of greatest clinical importance is avoiding the common clinical error of mistaking delirium for dementia older patient. The evaluation of dementia can be slow and prolonged because the cause is rarely imm life-threatening. However, because delirium is usually caused by an acute illness or drug toxicity, patie it may worsen rapidly and are at risk of death unless they are quickly diagnosed and treated.
Section 14. Neurologic Disorders Chapter 181. Craniocervical Junction Abnormal Topics
[General]
[General]
Craniocervical junction abnormalities: Congenital or acquired bony abnormalities of the occipital bone, magnum, or first two cervical vertebrae that decrease the potential space for the lower brain stem and cord and can result in cerebellar, lower cranial nerve, and spinal cord symptoms.
Because the spinal cord is flexible and therefore susceptible to intermittent compression, several types lesions at this level can cause symptoms that vary from patient to patient and that can be intermittent. of the atlas and occipital bone produces symptoms of cervical myelopathy when the anterior-posteri diameter of the foramen magnum behind the odontoid process decreases to < 19 mm. Platybasia is a asymptomatic flattening of the skull base; ie, the angle formed by the intersection of the plane of the c the plane of the anterior fossa is > 135 on lateral skull x-ray. Basilar invagination (protrusion of the o process into the foramen magnum) leads to a short neck and combinations of cerebellar, brain stem, l cranial nerve, and spinal cord signs. The Klippel-Feil malformation (fusion of cervical vertebrae) is us asymptomatic except for a neck deformity with limited range of motion. Atlantoaxial subluxation or dislocation (displacement of the atlas anteriorly in relation to the axis) causes acute or chronic spinal compression.
Etiology
Congenital abnormalities include os odontoideum, atlas assimilation or hypoplasia, and the Chiari malformations (cerebellar tonsils or vermis descend into the cervical spinal canal--see Brain Abnorma Ch. 261). Achondroplasia can cause narrowing of the foramen magnum and neural compression. Dow syndrome, Morquio's syndrome (mucopolysaccharidosis IV), and osteogenesis imperfecta can cause atlantoaxial instability and spinal cord compression.
Acquired abnormalities may be due to trauma or disease. When the occipitoatlantoaxial complex is i mortality at the accident scene is high. Such injuries may be osseous (fractures), ligamentous (luxation complex (subluxation of C-2, transaxial cervicomedullary junction injury, and osteoligamentous disrupt Half are caused by vehicle or bicycle accidents, 25% by falls, and 10% by recreational activities, partic diving accidents. Minor neck injury can precipitate variably progressive symptoms and signs in patients
Acquired abnormalities may be due to trauma or disease. When the occipitoatlantoaxial complex is i mortality at the accident scene is high. Such injuries may be osseous (fractures), ligamentous (luxation complex (subluxation of C-2, transaxial cervicomedullary junction injury, and osteoligamentous disrupt Half are caused by vehicle or bicycle accidents, 25% by falls, and 10% by recreational activities, partic diving accidents. Minor neck injury can precipitate variably progressive symptoms and signs in patients underlying craniocervical junction abnormality. RA and metastatic disease of the cervical spine can ca atlantoaxial dislocation. A slowly growing tumor (eg, meningioma, chordoma) at the craniocervical junc produces symptoms by impinging on the brain stem and the spinal cord. RA and Paget's disease can basilar invagination with spinal cord or brain stem compression. RA is the most common cause of craniocervical instability, which can also result from trauma or erosion by tumor or Paget's disease.
Symptoms and Signs
Presentation varies because bony and soft tissue abnormalities in various combinations can compress cervical spinal cord, brain stem, cranial nerves, cervical nerve roots, or their vascular supply. An abnor head posture is common, and in some patients, the neck is short or webbed. The most common manifestations are neck pain and cord impingement (myelopathy). Compression of motor tracts cause weakness, spasticity, and hyperreflexia in the arms and/or legs. Lower motor neuron involvement caus muscular atrophy and weakness in the arms and hands. Sensory abnormalities (including changes in position sense and vibration sense) often reflect posterior column dysfunction. Patients may describe down the back, and often into the legs, on neck flexion (Lhermitte's sign). Spinothalamic tract involvem with loss of pain and temperature sense) is unusual but can be reflected in stocking-and-glove paresth numbness. Brain stem and cranial nerve deficits include sleep apnea, internuclear ophthalmoplegia (ip eye adduction weakness and horizontal nystagmus in the contralateral abducting eye on lateral gaze), downbeat nystagmus (fast component downward), hoarseness, and dysarthria and dysphagia (due to weakness and incoordination of the tongue, soft palate, pharynx, and larynx). Neck pain spreading to and suboccipital headache radiating to the skull vertex are common. Symptoms worsen with head mo and can be precipitated by coughing or bending forward. Pain is attributed to compression of the C-2 r greater occipital nerve and to local musculoskeletal dysfunction.
Vascular symptoms include syncope, drop attacks, vertigo, intermittent periods of confusion and altere consciousness, episodic weakness, and transient visual disturbance. Vertebrobasilar ischemia may be provoked by moving or by changing head position.
Diagnosis
A craniocervical abnormality should be considered when fixed or progressive neurologic deficits refer t lower brain stem, high cervical spinal cord, or cerebellum.
Plain x-rays (lateral view of the skull showing the cervical spine, anteroposterior view, and oblique view cervical spine) are used to identify factors that influence treatment. These factors include reducibility o abnormality (ability to achieve a normal osseous alignment, thus relieving compression on neural struc bony erosion, the mechanics of compression, and the presence of abnormal ossification centers and epiphysial growth plates with anomalous development. CT after intrathecal administration of contrast d provides anatomic detail of the neural structure abnormality and associated bony distortion. Sagittal M identifies associated neural lesions (hindbrain herniation, syringomyelia, and vascular abnormalities). M correlate bone and soft tissue pathology and define the level and extent of a malformation and associa neural defect (eg, Chiari malformation, syringomyelia). Vertebral angiography or MRI is used selective identify fixed or dynamic vascular compromise.
Treatment
correlate bone and soft tissue pathology and define the level and extent of a malformation and associa neural defect (eg, Chiari malformation, syringomyelia). Vertebral angiography or MRI is used selective identify fixed or dynamic vascular compromise.
Treatment
Certain craniocervical junction abnormalities (eg, acute traumatic atlantoaxial luxations and acute ligam injuries) can be realigned and reduced, relieving compression of neural structures, with head positionin Most patients require skeletal traction with a crown halo ring in gradual increments up to 8 to 9 lb to ac reduction. Traction usually achieves results in 5 to 6 days. If reduction is achieved, immobilization in a vest is maintained for 8 to 12 wk; then x-rays must be taken to confirm stability. If reduction does not r neural compression, surgical decompression, using a ventral or a dorsal approach, is necessary. If ins present after decompression, posterior fixation is required. With other abnormalities (such as RA), exte immobilization alone is unlikely to achieve permanent reduction, and posterior fixation (stabilization) or decompression and stabilization is required.
There are various techniques for fusion in the craniocervical region. In general, all unstable levels mus fused. Instrumentation provides immediate stability until bony fusion develops and provides long-term Radiation therapy and a hard cervical collar often help in metastatic disease. Calcitonin, mithramycin, bisphosphonates may help patients with Paget's disease.

Section 14. Neurologic Disorders Chapter 172. Seizure Disorders Topics
[General]
[General]
(See also Neonatal Seizure Disorders in Ch. 260.)
There are two kinds of seizure disorders: an isolated, nonrecurrent attack, such as may occur during febrile illness or after head trauma, and epilepsy--a recurrent, paroxysmal disorder of cerebral functio characterized by sudden, brief attacks of altered consciousness, motor activity, sensory phenomena, o inappropriate behavior caused by excessive discharge of cerebral neurons.
If given a sufficient stimulus (eg, convulsant drugs, hypoxia, hypoglycemia), even the normal brain can discharge excessively, producing a seizure. In epileptics, seizures are rarely precipitated by exogenou factors, such as sound, light, and touch.
Etiology and Incidence
Seizures result from a focal or generalized disturbance of cortical function, which may be due to variou cerebral or systemic disorders (See Table 172-1). Seizures may also occur as a withdrawal symptom a long-term use of alcohol, hypnotics, or tranquilizers. Hysterical patients occasionally simulate seizures many disorders, single seizures occur. However, seizures may recur at intervals for years or indefinite which case epilepsy is diagnosed.
Epilepsy is classified etiologically as symptomatic or idiopathic. Symptomatic indicates that a probable exists and a specific course of therapy to eliminate that cause may be tried. Idiopathic indicates that n obvious cause can be found. Unexplained genetic factors probably underlie most idiopathic cases.
The risk of developing epilepsy is 1% from birth to age 20 yr and 3% at age 75 yr. Most persons have type of seizure; about 30% have two or more types. About 90% have generalized tonic-clonic seizures in 60%; with other seizures in 30%). Absence seizures occur in about 25% (alone in 4%; with others in Complex partial seizures occur in 18% (alone in 6%; with others in 12%).
Idiopathic epilepsy generally begins between ages 2 and 14. Seizures before age 2 are usually caused
The risk of developing epilepsy is 1% from birth to age 20 yr and 3% at age 75 yr. Most persons have type of seizure; about 30% have two or more types. About 90% have generalized tonic-clonic seizures in 60%; with other seizures in 30%). Absence seizures occur in about 25% (alone in 4%; with others in Complex partial seizures occur in 18% (alone in 6%; with others in 12%).
Idiopathic epilepsy generally begins between ages 2 and 14. Seizures before age 2 are usually caused developmental defects, birth injuries, or a metabolic disease. Those beginning after age 25 may be se to cerebral trauma, tumors, or cerebrovascular disease, but 50% are of unknown etiology.
Symptoms and Signs
Manifestations depend on the type of seizure, which may be classified as partial or generalized. In par seizures, the excess neuronal discharge is contained within one region of the cerebral cortex. In gener seizures, the discharge bilaterally and diffusely involves the entire cortex. Sometimes a focal lesion of of a hemisphere activates the entire cerebrum bilaterally so rapidly that it produces a generalized tonic seizure before a focal sign appears.
Auras are sensory or psychic manifestations that immediately precede complex partial or generalized tonic-clonic seizures and represent seizure onset. A postictal state may follow a seizure (most comm generalized seizure) and is characterized by deep sleep, headache, confusion, and muscle soreness.
Simple partial seizures consist of motor, sensory, or psychomotor phenomena without loss of consci The specific phenomenon reflects the affected area of the brain (see Table 172-2). In jacksonian seiz focal motor symptoms begin in one hand and then "march" up the extremity. Other focal attacks can fi the face area, then spread down the body to involve an arm and sometimes a leg. Some partial motor begin with raising the arm and turning the head toward the moving part. Some proceed to generalized convulsions.
In complex partial seizures, the patient loses contact with the surroundings for 1 to 2 min. At first, the may stare, perform automatic purposeless movements, utter unintelligible sounds without understandi is said, and resist aid. Mental confusion continues another 1 or 2 min after motor components of the a subside. These seizures may develop at any age, and structural pathology (eg, mesial temporal sclero low-grade astrocytomas) should be ruled out. Complex partial seizures most commonly originate in the temporal lobe but may originate in any lobe of the brain.
Complex partial seizures are not characterized by unprovoked aggressive behavior. However, if restra during a complex partial seizure, a patient may lash out at the person restraining him, as may a patien postictal confused state after a generalized seizure. Between seizures, patients with temporal lobe epi have a higher incidence of psychiatric disorders than does the general population; 33% may have psy difficulties, and 10% may have symptoms of schizophreniform or depressive psychoses.
Generalized seizures cause loss of consciousness and motor function from the onset. Such attacks o have a genetic or metabolic cause. They may be primarily generalized (bilateral cerebral cortical involv at onset) or secondarily generalized (local cortical onset with subsequent bilateral spread). Types of generalized seizures include infantile spasms and absence, tonic-clonic, atonic, and myoclonic seizure
Infantile spasms are primarily generalized seizures characterized by sudden flexion of the arms, forw flexion of the trunk, and extension of the legs. Seizures last a few seconds and are repeated many tim day. They occur only in the first 3 yr of life and then are replaced by other types of seizures. Developm abnormalities are usually apparent.
Absence seizures (formerly called petit mal) consist of brief, primarily generalized attacks manifested to 30-sec loss of consciousness and eyelid flutterings at a rate of 3/sec, with or without loss of axial m
flexion of the trunk, and extension of the legs. Seizures last a few seconds and are repeated many tim day. They occur only in the first 3 yr of life and then are replaced by other types of seizures. Developm abnormalities are usually apparent.
Absence seizures (formerly called petit mal) consist of brief, primarily generalized attacks manifested to 30-sec loss of consciousness and eyelid flutterings at a rate of 3/sec, with or without loss of axial m tone. Affected patients do not fall or convulse; they abruptly stop activity and resume it just as abruptly the seizure, with no postictal symptoms or even knowledge that an attack has occurred. Absence seiz genetic and occur predominantly in children. Without treatment, such seizures are likely to occur many day. Seizures often occur when the patient is sitting quietly and can be precipitated by hyperventilation rarely occur during exercise.
Generalized tonic-clonic seizures typically begin with an outcry; they continue with loss of conscious and falling, followed by tonic, then clonic contractions of the muscles of the extremities, trunk, and hea Urinary and fecal incontinence may occur. Seizures usually last 1 to 2 min. Secondarily generalized tonic-clonic seizures begin with a simple partial or complex partial seizure.
Atonic seizures are brief, primarily generalized seizures in children. They are characterized by compl of muscle tone and consciousness. The child falls or pitches to the ground, so that seizures pose the r serious trauma, particularly head injury.
Myoclonic seizures are brief, lightning-like jerks of a limb, several limbs, or the trunk. They may be re leading to a tonic-clonic seizure. There is no loss of consciousness.
Febrile seizures are associated with fever without evidence of intracranial infection. They affect abou children between the ages of 3 mo and 5 yr. Benign febrile seizures are brief, solitary, and generalized tonic-clonic in form; complicated febrile seizures are either focal, last > 15 min, or recur >= 2 times in < Overall, the occurrence of febrile seizures is associated with a 2% incidence of subsequent epilepsy; t incidence of epilepsy and the risk of recurrent febrile seizures are much greater among children with complicated febrile seizures, preexisting neurologic abnormalities, onset before age 1 yr, or a family hi epilepsy.
In status epilepticus, seizures follow one another with no intervening periods of normal neurologic fu Generalized convulsive status epilepticus may be fatal. It may result from too-rapid withdrawal of anticonvulsants. Confusion may be the only manifestation of complex partial or absence status epilept and an EEG may be needed to diagnose seizure activity.
Epilepsia partialis continua is a rare form of focal (usually hand or face) motor seizures that recur at of a few seconds or minutes for days to years at a time. In adults, it is usually due to a structural lesion as a stroke. In children, it is usually due to a focal cerebral cortical inflammatory process (Rasmussen' encephalitis), possibly caused by a chronic viral infection or autoimmune processes.
Diagnosis
Idiopathic epilepsy must be distinguished from symptomatic epilepsy. Focal seizures or focal postictal symptoms imply a focal structural lesion in the brain; generalized seizures are more likely to have a m cause. In newborns, the type of seizure does not help distinguish between structural and metabolic ca
An eyewitness account of a typical seizure, the frequency of seizures, and the longest and shortest int between them should be recorded. A history of prior head trauma, infection, or toxic episodes must be and evaluated. A family history of seizures or neurologic disorders is significant.
Fever and stiff neck accompanying new-onset seizures suggest meningitis, subarachnoid hemorrhage
An eyewitness account of a typical seizure, the frequency of seizures, and the longest and shortest int between them should be recorded. A history of prior head trauma, infection, or toxic episodes must be and evaluated. A family history of seizures or neurologic disorders is significant.
Fever and stiff neck accompanying new-onset seizures suggest meningitis, subarachnoid hemorrhage encephalitis. Lumbar puncture is indicated. Focal cerebral symptoms and signs accompanying seizure suggest brain tumor, cerebrovascular disease, or residual traumatic abnormalities. In an adult, even generalized seizures should stimulate a search for an unsuspected focal lesion.
Appropriate studies include EEG and serum glucose, sodium, magnesium, and calcium. When the EE serum is focally abnormal or when seizures begin in adulthood, MRI is indicated. A lumbar puncture sh performed if infection is suspected.
The EEG between seizures (interictal) in primarily generalized tonic-clonic seizures is characterized by symmetric bursts of sharp and slow, 4- to 7-Hz activity. Focal epileptiform discharges occur in seconda generalized seizures. In absence seizures, spikes and slow waves appear at a rate of 3/sec. Interictal lobe foci (spikes or slow waves) occur with complex partial seizures of temporal lobe origin. Because a taken during a seizure-free interval is normal in 30% of patients, one normal EEG does not exclude ep second EEG performed during sleep in sleep-deprived patients shows epileptiform abnormalities in ha patients whose first EEG was normal. Rarely, repeated EEGs are normal, and epilepsy may have to b diagnosed on clinical grounds.
Prognosis
Drug therapy completely eliminates seizures in 1/3 of patients and greatly reduces the frequency of se another 1/3. About 2/3 of patients with well-controlled seizures can eventually discontinue drugs witho relapse.
Most patients with epilepsy become neurologically normal between seizures, although overuse of anticonvulsants can dull alertness. Progressive mental deterioration is usually related to the neurologic that caused the seizures. Left temporal lobe epilepsy is associated with verbal memory abnormalities; temporal lobe epilepsy sometimes causes visual spatial memory abnormalities. The outlook is best wh brain lesion is demonstrable.
Treatment
General principles: Treatment aims primarily to control seizures. A causative disorder may need to b as well.
A normal life should be encouraged. Exercise is recommended; even such sports as swimming and ho riding can be permitted with proper safeguards. Most state licensing agencies permit automobile drivin seizures have stopped for 1 yr. Social activities should be encouraged. Alcohol intake should be minim Cocaine and several other illicit drugs can trigger seizures.
Family members must be taught a commonsense attitude toward the patient. Overprotection should b replaced with sympathetic support that lessens feelings of inferiority and self-consciousness and other emotional handicaps; prevention of invalidism should be emphasized. Institutional care is rarely advisa should be reserved for severely retarded patients and for patients with seizures so frequent and violen drug therapy that they cannot be cared for elsewhere. During a seizure, injury should be prevented. Protecting the tongue should not be attempted because
replaced with sympathetic support that lessens feelings of inferiority and self-consciousness and other emotional handicaps; prevention of invalidism should be emphasized. Institutional care is rarely advisa should be reserved for severely retarded patients and for patients with seizures so frequent and violen drug therapy that they cannot be cared for elsewhere.
During a seizure, injury should be prevented. Protecting the tongue should not be attempted because may be damaged. Inserting a finger to straighten the tongue is dangerous and unnecessary. Clothing the neck should be loosened, and a pillow placed under the head. The patient should be rolled onto hi prevent aspiration. A responsible fellow worker may be trained to give emergency aid if the patient agr
Causative or precipitating factors should be eliminated. Progressive structural lesions of the brain (eg, abscesses) should be sought and promptly treated. After definitive treatment of structural lesions, con medical treatment (eg, anticonvulsants) is usually necessary. Other physical disorders (eg, systemic in endocrine abnormalities) should be corrected.
Head injuries with skull fractures, intracranial hemorrhages, focal neurologic deficits, or amnesia cause posttraumatic epilepsy in 25 to 75% of cases. Prophylactic treatment with anticonvulsant drugs after th injury reduces the probability of early posttraumatic seizures during the first few weeks after the injury not prevent the development of permanent posttraumatic epilepsy months or years later.
Drug therapy: No single drug controls all types of seizures, and different drugs are required for differe patients. Patients rarely require several drugs. The drug of choice for the particular type of epilepsy is at relatively low dose and increased over about 1 wk to the standard therapeutic dose. After about 1 w dose, blood levels are measured to determine whether the effective therapeutic level has been reache seizures continue, the daily dose is increased by small increments. If toxic blood levels or toxic sympto develop before seizures are controlled, a second anticonvulsant is added, again guarding against toxic Interaction between drugs can interfere with their rate of metabolic degradation. The initial, failed anticonvulsant is then withdrawn gradually. Once seizures are controlled, the drug should be continue interruption until at least 1 yr is seizure-free. At that time, discontinuing the drug should be considered, because about 2/3 of such patients remain seizure-free without drugs. Static encephalopathy and stru brain lesions increase the risk of relapse off medication. Patients whose attacks were initially difficult to those who failed a drug-free trial, and those with important social reasons for avoiding seizures should treated indefinitely.
The most effective anticonvulsants for long-term use and their doses for children and adults are given 172-3. Once the drug response is known, blood levels are less useful to follow than the clinical course patients have toxic symptoms at low levels; others tolerate high levels without symptoms.
For generalized tonic-clonic seizures, phenytoin, carbamazepine, or valproate is the drug of choice adults, phenytoin can be given in divided doses or at bedtime. If seizures continue, the dose can be in cautiously to 500 mg/day with blood level monitoring. At a higher dose, dividing the daily dose may red toxic symptoms.
For partial seizures, treatment begins with carbamazepine, phenytoin, or valproate. If seizures persis high doses of these drugs, gabapentin, lamotrigine, or topiramate may be added.
For absence seizures, ethosuximide orally is preferred. Valproate and clonazepam orally are effectiv tolerance to clonazepam often develops. Acetazolamide is reserved for refractory cases.
Atonic seizures, myoclonic seizures, and infantile spasms are difficult to treat. Valproate is preferr followed, if unsuccessful, by clonazepam. Ethosuximide is sometimes effective, as is acetazolamide (i dosages as for absence seizures). Phenytoin has limited effectiveness. For infantile spasms, corticost for 8 to 10 wk are often effective. The optimal corticosteroid regimen is controversial. ACTH 20 to 60 U
tolerance to clonazepam often develops. Acetazolamide is reserved for refractory cases.
Atonic seizures, myoclonic seizures, and infantile spasms are difficult to treat. Valproate is preferr followed, if unsuccessful, by clonazepam. Ethosuximide is sometimes effective, as is acetazolamide (i dosages as for absence seizures). Phenytoin has limited effectiveness. For infantile spasms, corticost for 8 to 10 wk are often effective. The optimal corticosteroid regimen is controversial. ACTH 20 to 60 U may be used. A ketogenic diet may help but is difficult to maintain. Carbamazepine may make patients primary generalized epilepsy and multiple seizure types worse.
Status epilepticus can be terminated by giving diazepam 10 to 20 mg (for adults) IV or up to 2 doses necessary) of lorazepam 4 mg IV. For children, IV diazepam up to 0.3 mg/kg or lorazepam up to 0.1 m given. For adults, phenytoin 1.5 g IV may be given to prevent recurrence. Fosphenytoin, a water-solub product, is an alternative that in equivalent doses reduces the incidence of hypotension and phlebitis. Anesthetic IV doses of phenobarbital, lorazepam, or pentobarbital may be necessary in refractory case such instances, intubation and O2 therapy are required to prevent hypoxemia.
In acute generalized tonic-clonic seizures due to febrile illnesses, ingestion of alcohol or other toxin acute metabolic disturbance, the causative condition must be treated as well as the seizures. Status epilepticus should be treated at once. If only one seizure has occurred, phenytoin should be given in fu dosage (see Table 172-3) for 7 to 10 days; afterward, a decision concerning long-term therapy must b After a first seizure, 1/3 of patients have recurrent attacks, followed by chronic epilepsy. Anticonvulsan little value in preventing alcohol withdrawal seizures.
Benign febrile convulsions do not require treatment because of the favorable prognosis compared w potential toxic effects of anticonvulsants in a young child. For patients with complicated febrile seizu other risk factors for recurrence (listed above), recurrence rates for febrile seizures can be reduced by continuous prophylactic treatment with phenobarbital 5 to 10 mg/kg/day. However, no evidence sugge such treatment of complicated febrile seizures prevents the development of recurrent nonfebrile seizur (epilepsy). Furthermore, phenobarbital given chronically to children measurably reduces their learning capacity.
Adverse effects: Possible toxic effects of anticonvulsants are listed in Table 172-3. All anticonvulsant cause an allergic scarlatiniform or morbilliform rash.
Patients receiving carbamazepine should have a CBC once a month for the first year of therapy. If the RBC count decreases significantly, the drug should be discontinued immediately. Patients receiving va should have liver function tests every 3 mo for 1 yr; if serum transaminases or ammonia levels increas significantly (to > 2 times the upper limit of normal), the drug should be discontinued. An increase in am up to 1.5 times the upper limit of normal can be tolerated safely.
When an overdose reaction occurs, the amount of drug is reduced until the reaction subsides. When m serious acute poisoning occurs, the patient is given ipecac syrup or, if obtunded, is lavaged. After eme lavage, activated charcoal is administered, followed by a saline cathartic (eg, magnesium citrate). The drug should be discontinued, and a new anticonvulsant started simultaneously.
Fetal antiepileptic drug syndrome (cleft lip, cleft palate, cardiac defects, microcephaly, growth retard developmental delay, abnormal facies, digital hypoplasia) occurs in 4% of the children of epileptic wom take anticonvulsants during pregnancy. Among commonly used drugs, carbamazepine appears to be teratogenic, but only slightly so; valproate may be the most teratogenic. Yet, because uncontrolled gen seizures during pregnancy lead to fetal injury and death, continued treatment with anticonvulsants is g advisable (see Ch. 249).
Surgical therapy: About 10 to 20% of patients have seizures that are refractory to medical treatment.
take anticonvulsants during pregnancy. Among commonly used drugs, carbamazepine appears to be teratogenic, but only slightly so; valproate may be the most teratogenic. Yet, because uncontrolled gen seizures during pregnancy lead to fetal injury and death, continued treatment with anticonvulsants is g advisable (see Ch. 249).
Surgical therapy: About 10 to 20% of patients have seizures that are refractory to medical treatment. patients whose seizures originate from a local area of abnormal brain function improve markedly when epileptic focus is resected. Some are completely cured. Because extensive monitoring and skilled medical-surgical teamwork are required, these patients are best managed in specialized centers.
Vagus nerve stimulation: Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device reduces the number of partial seizures by one third. After the device is program patients can activate it with a magnet when they sense a seizure is imminent. Vagus nerve stimulation as an adjunct to an anticonvulsant. Adverse effects include a deepening of the voice during stimulation and hoarseness. Complications are minimal. Duration of effectiveness is not well established.

Section 14. Neurologic Disorders Chapter 182. Spinal Cord Disorders Topics
[General] Spinal Cord Compression Subdural Or Epidural Abscess And Hematoma Syrinx Vascular Disorders Hereditary Spastic Paraparesis Acute Transverse Myelitis Spinal Cord Injury
[General]
(See also discussion of tabes dorsalis under Syphilis in Ch. 164.)
The spinal cord extends caudally from the medulla at the foramen magnum and terminates at the upp lumbar vertebrae. The white matter at the cord's periphery contains the ascending and descending tra myelinated sensory and motor nerve fibers. The central H-shaped gray matter is composed of cell bod nonmyelinated fibers (see Fig. 182-1). The anterior (ventral) horns of the "H" contain lower motor neur which receive impulses from the motor cortex via the descending corticospinal tracts; the axons of the are the efferent fibers of the spinal nerves. The posterior (dorsal) horns contain sensory fibers that orig cell bodies in the dorsal root ganglia. The gray matter also contains many internuncial neurons that ca motor, sensory, or reflex impulses from dorsal to ventral nerve roots, from one side of the cord to the o and from one level of the cord to another.
Segments of the cord are functional divisions that correspond approximately to the attachments of the of spinal nerve roots. In spinal cord disorders, the integrity of individual segments is assessed clinically examining reflexes and sensory and motor responses in the distribution of the segments (see Spinal C Injury, below, and Table 182-1).

Section 14. Neurologic Disorders Chapter 173. Sleep Disorders Topics
[General] Insomnia Hypersomnia Sleep Apnea Syndromes Parasomnias
[General]
(See also Sleep Problems and Nocturnal Enuresis under Behavioral Problems in Ch. 262.)
Sleep disorders: Disturbances that affect the ability to fall or stay asleep, that involve sleeping too muc that result in abnormal sleep-related behavior.
Although sleep is necessary for survival, its precise homeostatic contribution is unknown. Individual requirements vary widely, ranging from 4 to 10 h every 24 h in healthy persons. Several factors, includ current emotional state and age, influence the duration and satisfaction of sleep.
The two types of sleep, nonrapid eye movement (NREM) and rapid eye movement (REM) sleep, are m by characteristic EEG and other changes, including eye movements. NREM sleep (75 to 80% of total time) normally initiates sleep, is characterized by slow waves (in stages 2 to 4) on an EEG, and ranges depth from stage 1 to 4 (the deepest level), with commensurate difficulty in arousal. Muscle tone, BP, heart and respiratory rates are reduced. REM sleep produces low-voltage fast activity on an EEG. Rat depth of respiration fluctuate, and muscle tone is further reduced. During a normal night's sleep, REM follows each of 4 to 6 cycles of NREM sleep (see Fig. 173-1). Most dreaming occurs during REM sleep night terrors, sleepwalking, and talking occur during stages 3 and 4 NREM sleep.
Section 14. Neurologic Disorders Chapter 183. Disorders Of The Peripheral Nervous Topics
[General] Lower And Upper Motor Neuron Disorders Nerve Root Disorders Plexus Disorders Thoracic Outlet Compression Syndromes Peripheral Neuropathy Disorders Of Neuromuscular Transmission
[General]
The peripheral nervous system consists of cranial and spinal nerves from their points of exit from the C their termination in peripheral structures. The olfactory and optic nerves, which are CNS tracts rather t nerves, are included.
The cranial nerves (except for the olfactory, optic, and part of the spinal accessory) leave the CNS fro brain stem. Their motor nuclei lie deep within the brain stem; their sensory nuclei lie in ganglia just out (see Ch. 178).
Each spinal nerve (in 31 pairs) emerges from a segment of the spinal cord as an anterior (ventral) mo and a posterior (dorsal) sensory root. The efferent motor fibers originate as anterior horn cells in the g matter of the cord; the cell bodies of the afferent sensory fibers lie in dorsal root ganglia. The ventral a dorsal roots combine to form the spinal nerve, which exits via an intervertebral foramen. Because the shorter than the spine, the foramina lie progressively farther from the corresponding cord segment, so the lumbosacral region, the nerve roots from the lower cord segments descend within the spinal colum near-vertical sheaf, forming the cauda equina. The cervical, brachial, and lumbosacral spinal nerves anastomose peripherally into plexuses, then branch into nerve trunks that terminate up to 1 m (3.3 ft) a peripheral structures. The intercostal nerves remain segmental.
The term peripheral nerve is often used to indicate the portion of a spinal nerve distal to the root and Peripheral nerves are bundles of nerve fibers ranging in diameter from 0.3 to 22 m. The larger fibers motor, touch, and proprioceptive impulses; the smaller fibers convey pain, temperature, and autonomi impulses.
Schwann cells form a thin cytoplasmic tube around each fiber and further wrap larger fibers in a mult insulating membrane (myelin sheath), which enhances impulse conduction. Large fibers are fast cond
Peripheral nerves are bundles of nerve fibers ranging in diameter from 0.3 to 22 m. The larger fibers motor, touch, and proprioceptive impulses; the smaller fibers convey pain, temperature, and autonomi impulses.
Schwann cells form a thin cytoplasmic tube around each fiber and further wrap larger fibers in a mult insulating membrane (myelin sheath), which enhances impulse conduction. Large fibers are fast cond and small fibers are slow conductors. Schwann cells are covered by a basement membrane and colla fibers.
Peripheral nerve dysfunction may result from damage to the nerve fibers, cell body, or myelin sheat ischemia or trauma stops the flow of axoplasm down the fiber, the nerve process dies distally (walleria degeneration). When metabolic injury to the cell body alters axoplasmic nutrients, the most distal part nerve process is affected first, and axonal degeneration ascends proximally, producing the distal-to-pr pattern of symptoms characteristic of metabolic neuropathies. Injury to the myelin sheath, directly or in from Schwann cell or neuronal damage, results in demyelination with a consequent slowing of nerve conduction. Each Schwann cell maintains the myelin sheath along one segment of nerve fiber, so that selective Schwann cell damage results in segmental demyelination.
After a crush injury, the fiber regrows within the Schwann cell tube at about 1 mm/day. Regrowth may misdirected, causing aberrant innervation (eg, of fibers in the wrong muscle, of a touch receptor at the site, of a temperature instead of a touch receptor). The myelin sheath can regenerate rapidly, especia segmental demyelination, with complete recovery of function unless axonal destruction has also occur
A motor unit consists of an anterior horn cell, its efferent axon, and all the muscle fibers innervated by axon. Disorders of the motor unit are classified by the segment principally affected (see Table 183-1). neuron disorders, efferent innervation of the anterior horn cell is lost. In some disorders, the upper m neurons from the motor cortex to the brain stem (corticobulbar tracts) or spinal cord (corticospinal trac also involved; in others (bulbar palsies), cranial nerve motor nuclei in the brain stem (bulbar nuclei) are selectively affected.
The neuromuscular junction is affected in myasthenia gravis and the myasthenic syndromes. The m fibers are affected in myopathies (see Ch. 184). Other disorders that can cause myopathy or muscula weakness (eg, polymyositis, dermatomyositis, trichinosis, thyroid and adrenal disorders, hypercalcemi hypophosphatemia) are discussed elsewhere in The Manual.

Section 14. Neurologic Disorders Chapter 174. Cerebrovascular Disease (Stroke; Cerebrovascular Accident) Topics
[General] Ischemic Syndromes Hemorrhagic Syndromes Arteriovenous Malformations
[General]
In Western countries, stroke is the third most common cause of death and the second most common c neurologic disability after Alzheimer's disease. Its incidence has decreased in recent decades, but the decrease appears now to have leveled off, and cerebrovascular disease remains the leading cause of institutional placement for loss of independence among adults.
Most vascular injury to the brain is secondary to atherosclerosis or hypertension. The major types of cerebrovascular disease are cerebral insufficiency due to transient disturbances of blood flow or, rarel hypertensive encephalopathy; infarction due to embolism or thrombosis of intracranial or extracranial a hemorrhage, including hypertensive parenchymal hemorrhage and subarachnoid hemorrhage due to congenital aneurysm; and arteriovenous malformation, which can cause symptoms of a mass lesion, infarction, or hemorrhage.
Symptoms and signs in cerebrovascular disease reflect the damaged area of brain and not necessaril affected artery. For example, occlusion of either the middle cerebral or internal carotid artery can prod similar clinical neurologic abnormality. Nevertheless, cerebrovascular injuries generally conform to fair specific patterns of arterial supply; knowledge of these patterns helps distinguish stroke from other bra lesions that occasionally produce acute symptoms (see Table 174-1).
An accurate history, including onset and duration of symptoms and identification of stroke risk factors, diagnosing cerebrovascular lesions (see Table 174-2). Hemorrhagic stroke has a more catastrophicall onset than ischemic stroke, although both tend to develop abruptly. A brain CT or MRI scan can distin between ischemic and hemorrhagic strokes, thus assisting in urgent treatment decisions.
Various standardized tests are used to assess the severity of stroke. For example, the National Institu Health Stroke Scale assesses consciousness, vision, extraocular movements, facial palsy, limb streng ataxia, sensation, speech, and language using 15 items scored from 0 to 2 or 3. Higher scores reflect increased severity of the deficit; the highest possible total score is 42.
between ischemic and hemorrhagic strokes, thus assisting in urgent treatment decisions.
Various standardized tests are used to assess the severity of stroke. For example, the National Institu Health Stroke Scale assesses consciousness, vision, extraocular movements, facial palsy, limb streng ataxia, sensation, speech, and language using 15 items scored from 0 to 2 or 3. Higher scores reflect increased severity of the deficit; the highest possible total score is 42.
Aggressive treatment is not always warranted, especially when the residual disabilities are profound o comorbidities exist. Supportive care is then the appropriate focus (see Ch. 294).

Section 14. Neurologic Disorders Chapter 184. Muscular Disorders Topics
Muscular Dystrophies Myopathies Channelopathies
Muscular Dystrophies
Duchenne dystrophy is the most common and important form (see below).
A group of inherited, progressive muscle disorders, distinguished clinically by the selective distribution weakness.
Facioscapulohumeral (Landouzy-Dejerine) muscular dystrophy is an autosomal dominant disorde characterized by weakness of the facial muscles and shoulder girdle, usually beginning at age 7 to 20 gene is located on chromosome 4q35 in most families, but the genetic defect has not been identified, pathogenesis is unknown. Difficulty in whistling, eye closure, and elevation of the arms due to weakne scapular stabilizer muscles occurs early. Anterior tibial and peroneal weakness develops in some patie Although footdrop develops, ambulation is rarely lost. Life expectancy is normal.
In limb-girdle muscular dystrophy, weakness develops in a limb girdle and proximal limb distribution Structural (dystrophin-associated glycoproteins) or nonstructural (eg, proteases) proteins can be affec Several chromosomal loci have been identified for autosomal dominant (5q [no known gene product]) recessive (2q, 4q [beta-sarcoglycan], 13q [gamma-sarcoglycan], 15q [calpain, a calcium-activated prot and 17q [alpha-sarcoglycan, or adhalin]) forms.
DUCHENNE DYSTROPHY
An X-linked recessive disorder characterized by progressive proximal muscle weakness with destructio regeneration of muscle fibers and replacement by connective tissue.
Duchenne dystrophy is caused by a mutation at the Xp21 locus, which results in the absence of dystro protein found inside the muscle cell membrane. It affects 1 in 3000 live male births.
regeneration of muscle fibers and replacement by connective tissue.
Duchenne dystrophy is caused by a mutation at the Xp21 locus, which results in the absence of dystro protein found inside the muscle cell membrane. It affects 1 in 3000 live male births.
Symptoms typically start in boys aged 3 to 7 yr; they include waddling gait, toe walking, lordosis, frequ and difficulty in standing up and climbing stairs. The pelvic girdle is affected before the shoulder girdle Progression is steady, and limb flexion contractures and scoliosis develop. Firm pseudohypertrophy (f fibrous replacement of certain enlarged muscle groups, notably the calves) develops. Most patients ar confined to a wheelchair by age 10 or 12 and die of respiratory complications by age 20 yr. Cardiac involvement is usually asymptomatic, although 90% of patients have ECG abnormalities. One third ha nonprogressive intellectual impairment that affects verbal ability more than performance.
Becker muscular dystrophy is a less severe variant, also due to a mutation at the Xp21 locus. Dystr reduced in quantity or in molecular weight. Patients usually remain ambulatory, and most survive into t and 40s.
Diagnosis is based on characteristic clinical findings, age of onset, and family history, supported by ev from electromyography, muscle biopsy, and dystrophin immunostaining. Serum CK is markedly elevat 50 to 100 times normal), beginning in the presymptomatic and early phases of the disease. Nerve con velocities are normal; electromyography reveals rapidly recruited, short, low-amplitude motor unit pote Muscle biopsy shows necrosis and variation in muscle fiber size. Dystrophin analysis of muscle sampl diagnostic test of choice; dystrophin is undetectable in patients with Duchenne dystrophy. Mutation an DNA isolated from peripheral blood leukocytes identifies deletions or duplications in the dystrophin gen about 65% of patients and point mutations in about 25%.
Carrier detection and prenatal diagnosis are possible using conventional studies (pedigree analysis, C determinations, fetal sex determination) combined with recombinant DNA analysis and dystrophin immunostaining of muscle tissue. Referral to major medical centers specialized in these areas is recommended.
No specific treatment exists. However, daily prednisone produces significant, long-term clinical improv But because of side effects, prednisone should be reserved for patients with major functional decline. therapy is not yet available. Moderate exercise should be encouraged as long as possible, and correct surgery considered in slowly progressive forms. Passive exercises may extend the period of ambulatio severely affected patients. Obesity should be avoided; caloric requirements are likely to be less than n Genetic counseling is indicated (see Ch. 247 and Genetic Counseling in Ch. 286).
Section 3. Gastrointestinal Disorders Chapter 19. Diagnostic And Therapeutic Gastroint Procedures Topics
[General]
[General]
(See also discussions of ERCP, percutaneous transhepatic cholangiography, and liver biopsy in Ch. 3 secretin test under Chronic Pancreatitis in Ch. 26.)
Diagnosing and treating patients with GI disorders requires a balanced, individualized, comprehensive approach. The evaluations available through endoscopy, radionuclide scanning, angiography, CT, and permit remarkable precision and accuracy, but at high cost and some risk of morbidity. Also, despite e testing, up to 50% of patients presenting with GI complaints will be diagnosed as having a "functional" (see Chs. 21 and 32) with no anatomic abnormality. A thorough history and physical examination with consideration of both biologic and psychosocial features help minimize unneeded diagnostic studies a develop effective treatment strategies.
The history and physical examination remain the bases of evaluation. Information should be obtaine an interview style that initially encourages the patient to report symptoms through spontaneous associ rather than in response to direct questioning (see also Approach to the Patient in Ch. 21). Facilitating questions (eg, "Can you tell me more about your symptoms?") should precede clarifying questions (eg did the pain begin?" "What makes it better?"). From this information, the clinician develops diagnostic hypotheses to be modified through more specific questions (eg, "Is the pain relieved by an antacid?" " vomit blood?"). Questions that elicit yes or no responses should be used only when specific diagnostic are being considered.
A directed physical examination can refine the differential diagnosis; eg, the finding of an enlarged live patient complaining of dark, tarry stools may expand the previous consideration of gastritis or peptic u disease to include cirrhosis with esophageal varices or GI cancer with liver metastases. Further inquiry alcohol consumption or weight loss or examination of the skin for spider angiomas allows for a more d diagnostic evaluation.
Various procedures are available to further facilitate diagnosis of GI complaints. The selection of proce should be based on findings from the history and physical examination.
X-ray Studies of the Esophagus
diagnostic evaluation.
Various procedures are available to further facilitate diagnosis of GI complaints. The selection of proce should be based on findings from the history and physical examination.
X-ray Studies of the Esophagus Esophagoscopy
In addition to the standard barium meal, video- and cinefluoroscopy aid in detecting anatomic conditio esophageal webs) and in assessing motor disorders (eg, cricopharyngeal spasm, achalasia).
Esophagoscopy can be performed diagnostically to evaluate pain or dysphagia, to identify structural abnormalities or bleeding sites, or to obtain biopsy specimens. Therapeutic procedures include remov foreign bodies, hemostasis by coagulation or variceal banding, debulking of tumors by laser or bipolar electrocoagulation, and dilation of webs or strictures. There is no absolute contraindication, and esophagoscopy can easily be performed on an outpatient basis; it requires local anesthesia of the thro generally, IV sedation. Complications are rare and are usually medication related (eg, respiratory depr bleeding on perforation is less common.
Esophageal Manometry
Esophageal manometry is used to evaluate patients with dysphagia, heartburn, or chest pain. It determ pressure in the upper and lower esophageal sphincters and the effectiveness and coordination of prop movements and detects abnormal contractions. It is used to diagnose achalasia, diffuse spasm, sclero and lower esophageal sphincter hypo- and hypertension and to evaluate esophageal function for certa therapeutic procedures (eg, antireflux surgery, pneumatic dilation for achalasia). It is performed by pas small tube past the throat and into the esophagus. Complications are extremely uncommon but may in trauma to the nasal passages.
Esophageal pH Monitoring Bernstein (Acid Perfusion) Test
Esophageal pH monitoring is performed either during esophageal manometry or as a prolonged study ambulatory patients (see Diagnosis under Gastroesophageal Reflux Disease in Ch. 20).
The Bernstein test is a sensitive means of determining whether acid reflux is the cause of pain, but ma falsely negative in the patient receiving treatment. This test is performed by perfusing the esophagus w alternating solutions of isotonic saline and 0.1 N hydrochloric acid through a nasogastric tube at a rate mL/min.
Nasogastric or Intestinal Intubation
alternating solutions of isotonic saline and 0.1 N hydrochloric acid through a nasogastric tube at a rate mL/min.
Nasogastric or Intestinal Intubation
Nasogastric or intestinal intubation is used to decompress the stomach in treating gastric atony, ileus, obstruction; to remove ingested toxins; to obtain a sample of gastric contents for analysis (volume, aci content, blood); and to supply nutrients through tube feeding. Contraindications include nasopharynge esophageal obstruction, maxillofacial trauma, uncontrollable coagulation abnormalities, and possibly la esophageal varices. Several types of tubes are available. A Levin or Salem sump tube is used for gas decompression or analysis, or rarely for short-term feeding. Hg-weighted balloon tips facilitate passing (eg, Miller-Abbott, Cantor) beyond the stomach for intestinal decompression or feeding. Very flexible, t or tungsten-tipped tubes (eg, Corpak, Dobbhoff, Entriflex) are used mainly for prolonged enteral feedin
For intubation, the patient sits upright or lies in the left lateral decubitus position. With the patient's hea partially flexed, the lubricated tube is inserted through the nares, aimed back and then down to conform the nasopharynx. As the tip reaches the posterior pharyngeal wall, the patient should sip water through straw. (Violent coughing with flow of air through the tube during respiration indicates that the tube is m in the trachea.) Aspiration of gastric juice verifies entry into the stomach. The position of larger tubes m confirmed by instilling 20 to 30 mL of air and listening with the stethoscope under the left subcostal reg rush of air.
Smaller, more flexible intestinal feeding tubes usually require the use of stiffening wires or stylets. The usually require fluoroscopic or endoscopic assistance for passage through the pylorus.
Complications are rare and include nasopharyngeal trauma with or without hemorrhage, pulmonary as traumatic esophageal or gastric hemorrhage or perforation, and (very rarely) intracranial or mediastina penetration.
Gastric Analysis
Gastric analysis is used to evaluate hyperchlorhydria (eg, Zollinger-Ellison syndrome) or hypochlorhyd (eg, pernicious anemia, atrophic gastritis, Mntrier's syndrome); unexplained hypergastrinemia in pat with planned acid-reducing surgery as part of pre- or postoperative assessment; and the possibility of incomplete vagotomy in patients with recurrent peptic ulcer disease after a surgical vagotomy. Contraindications include recent active bleeding or pain caused by active ulcer disease.
A Levin nasogastric tube is passed (for procedure, see Nasogastric or Intestinal Intubation, above). G contents are aspirated and discarded. Four 15-min samples of gastric juice are collected by continuou manual aspiration (basal acid output [BAO]). Next, pentagastrin (6 g/kg) is given sc, and again, four 1 samples are obtained (maximal [or peak] acid output [MAO or PAO]). Samples are titrated with sodium hydroxide to calculate BAO and stimulated MAO secretory rates.
Small-Bowel Biopsy and Duodenal Aspirat
Small-bowel biopsy and duodenal aspiration are used to support, confirm, or exclude inflammatory an structural disorders of the small bowel (eg, celiac sprue, Whipple's disease, Giardia lamblia infection). Uncorrectable coagulation disorders are contraindications.
Small-bowel biopsy and duodenal aspiration are used to support, confirm, or exclude inflammatory an structural disorders of the small bowel (eg, celiac sprue, Whipple's disease, Giardia lamblia infection). Uncorrectable coagulation disorders are contraindications.
A lubricated tube with a Carey capsule at its end is placed in the oropharynx, and the patient swallows entry to the stomach, the tube is manipulated with fluoroscopic guidance through the pylorus to the thi fourth portion of the duodenum. The biopsy specimen is obtained by producing negative pressure with syringe while the aspiration port is open. Mucosa is sucked through the port into the tube or capsule a off by a knife activated by the operator via a wire. Fluid samples for diagnosis of Giardia infection are o by aspirating duodenal contents. Bleeding, entrapment of the tube in the duodenum, bacteremia, and aspiration of fluid or Hg during passage of the tube occur rarely. This technique has been supplanted b endoscopic biopsy, which yields smaller but usually satisfactory tissue samples that are easier to obta
Upper Gastrointestinal Endoscopy
Upper GI endoscopy is used to establish the site of upper GI bleeding; to visually define and biopsy abnormalities seen on upper GI series (gastric ulcers, filling defects, mass lesions); to follow up treate ulcers; and to evaluate dysphagia, dyspepsia, abdominal pain, and gastric outlet obstruction for infecti (Helicobacter pylori, G. lamblia, bacterial overgrowth syndrome). Therapeutic indications include remo foreign bodies or gastric or esophageal polyps, sclerosis or banding of esophageal varices, and coagu hemorrhage. Absolute contraindications include acute shock, acute MI, seizures, acutely perforated ul atlantoaxial subluxation. Relative contraindications include uncooperativeness, coma (unless the patie intubated), coagulopathy (prothrombin time > 3 sec over control, platelet count < 100,000/L, bleeding 10 min), Zenker's diverticulum, myocardial ischemia, and thoracic aortic aneurysm.
The patient should have taken no food for at least 4 h. A topical anesthetic is gargled or sprayed into t pharynx, and usually a narcotic and midazolam are given IV for sedation. The patient is appropriately positioned, and the tip of the endoscope is placed in the hypopharynx. As the patient swallows, the en is gently guided through the cricopharyngeal muscle (upper esophageal sphincter) and advanced unde vision through the stomach into the duodenum. Examination of all structures may be supplemented by photography, cytology, and biopsy sampling. Therapeutic procedures are used as indicated; eg, sclero is performed by passing a needle-tipped cannula through the endoscope and injecting the sclerosing a into the varix.
The overall complication rate is 0.1 to 0.2%; mortality is about 0.03%. Drug-related complications are m common and include phlebitis and respiratory depression. Common procedural complications are asp bleeding from biopsy sites, and perforation. Transient bacteremia often occurs (8%) but is unassociate development of endocarditis. Antibiotic prophylaxis may be indicated in patients with valvular disease. patient with a coagulation disorder is more likely to experience a retropharyngeal hematoma or other b complication. Procedures undertaken concurrently (eg, variceal sclerotherapy, stricture dilations, polyp are associated with higher complication rates.
Anoscopy and Rigid and Flexible Sigmoidoscopy
Sigmoidoscopy is used to evaluate symptoms referable to the rectum or anus (eg, bright rectal bleedin discharge, protrusions, pain), a lesion known to be within reach of the instrument, or the rectum or sigm before anorectal surgery. There are no absolute contraindications. Patients with cardiac arrhythmias o
Sigmoidoscopy
Sigmoidoscopy is used to evaluate symptoms referable to the rectum or anus (eg, bright rectal bleedin discharge, protrusions, pain), a lesion known to be within reach of the instrument, or the rectum or sigm before anorectal surgery. There are no absolute contraindications. Patients with cardiac arrhythmias o myocardial ischemia should have the procedure postponed until the condition improves, or they will ne cardiac monitoring. Patients with valvular heart disease may need antibiotics to prevent endocarditis.
The perianal area and distal rectum can be examined with a 7-cm anoscope, the entire rectum with eit rigid 25-cm or a flexible 60-cm instrument, and the sigmoid with a flexible sigmoidoscope. Flexible sigmoidoscopy is about twice as expensive as rigid sigmoidoscopy but is much more comfortable for t patient and readily permits photography, biopsy, and cytology.
Flexible sigmoidoscopy is performed as described below for colonoscopy, except that IV medication is not needed. Also, preparation is easier: A phosphate enema may be given to empty the rectum. Rigid sigmoidoscopy is usually performed with the patient in the knee-chest position. After rectal examinatio perianal area is examined, and the lubricated instrument is gently inserted 3 to 4 cm past the anal sph The obturator is removed, and the instrument is inserted under direct vision. Considerable skill is requ pass it beyond the rectosigmoid junction (15 cm) without producing patient discomfort. An anoscope is its full length as described above for rigid sigmoidoscopy, usually with the patient in the left lateral pos Complications are exceedingly rare when the procedure is properly performed.
Colonoscopy
Colonoscopy is used diagnostically to screen for colonic polyps or cancer in high-risk individuals (eg, t with a family history of colon cancer); to evaluate an abnormality seen on barium enema; to determine source of occult or active GI bleeding or unexplained (microcytic) anemia; to evaluate patients with col cancer for other lesions during pre- or postoperative assessment; and to determine the extent of inflam bowel disease. Therapeutic indications include removal of polyps, coagulation of bleeding sites, reduc volvulus or intussusception, and decompression of acute or subacute colonic dilatation. Absolute contraindications include acute shock, acute MI, peritonitis, intestinal perforation, and fulminant colitis. contraindications include poor bowel preparation or massive intestinal hemorrhage, poor patient coope diverticulitis, recent abdominal surgery, history of multiple pelvic operations, or a large hernia. Patients cardiac or proximal joint prostheses need antibiotic prophylaxis to prevent endocarditis.
Patient preparation involves taking cathartics and enemas or drinking an intestinal lavage solution (eg, polyethylene glycol electrolyte). The patient is given an IV narcotic and a short-acting benzodiazepine midazolam) for sedation. After rectal examination in the left lateral position, a colonoscope is gently ins through the anal sphincter into the rectum. Under direct visualization, air is infused and the instrument manipulated through the colon to the cecum and terminal ileum. Fluoroscopy is rarely needed. The pa may experience cramplike discomfort that can be relieved by aspiration of air, rotation or retraction of or additional, usually analgesic, medication. Diagnostic evaluation is performed by visualization of stru photography, and obtaining brushings or biopsy specimens of abnormal structures.
Polypectomy is performed using a flexible wire loop attached to a grounded electrocautery unit. The p snared around its neck, and current is applied as the loop is tightened enough to cut through. Bleeding are coagulated with electrocautery using a bipolar probe, with a heat probe, or by injection therapy.
Complications are similar to but slightly more frequent than those for upper endoscopy. Snare cautery polyps is associated with a 1.7% bleeding and 0.3% perforation rate.
snared around its neck, and current is applied as the loop is tightened enough to cut through. Bleeding are coagulated with electrocautery using a bipolar probe, with a heat probe, or by injection therapy.
Complications are similar to but slightly more frequent than those for upper endoscopy. Snare cautery polyps is associated with a 1.7% bleeding and 0.3% perforation rate.
Abdominal Paracentesis
Abdominal paracentesis is used to evaluate the origin of ascitic fluid (eg, caused by portal hypertensio metastasis, TB, pancreatic ascites) and to diagnose a perforated viscus in a patient with a history of b abdominal trauma. It can also be used therapeutically to remove ascites caused by portal hypertensio especially useful in relieving tense ascites causing respiratory difficulties, pain, or acute oliguria. Absol contraindications include uncorrectable and severe disorders of blood coagulation, intestinal obstructio an infected abdominal wall. Poor patient cooperation, surgical scarring over the puncture area, and se portal hypertension with abdominal collateral circulation are relative contraindications.
CBC, platelet count, and coagulation studies are obtained before the procedure. After emptying the bl the patient sits in bed with the head elevated 45 to 90 A point is located at the midline between the u . and the pubic bone and is cleaned with an antiseptic solution and alcohol. Under sterile technique, the anesthetized to the peritoneum with lidocaine 1%. For diagnostic paracentesis, an 18-gauge needle at to a 50-mL syringe is inserted through the peritoneum (generally a "pop" is noted). Fluid is gently aspir sent for cell count, protein or amylase content, cytology, or culture as needed. For therapeutic (large-v paracentesis, a 14-gauge cannula attached to a vacuum aspiration system is used to collect up to 8 L fluid. Postprocedure hypotension caused by fluid redistribution is rare as long as interstitial (leg) edem present.
Hemorrhage is the most common complication. Occasionally, with tense ascites, prolonged leakage o fluid occurs through the needle site.
Diagnostic Peritoneoscopy (Laparoscopy)
Diagnostic peritoneoscopy is used to evaluate intra-abdominal or pelvic pathology (eg, tumor, endome operability of patients with cancer, and patients with acute or chronic abdominal pain; to guide liver bio under direct visualization; and for lymphoma staging. Absolute contraindications include a coagulation bleeding disorder, poor patient cooperation, peritonitis, intestinal obstruction, and infection of the abdo wall. Relative contraindications include severe cardiac or pulmonary disease, large abdominal hernias abdominal operations, and tense ascites.
CBC; coagulation studies; x-rays of the chest, kidneys, ureters, and bladder; and typing and sensitivity for 2 U of whole blood are obtained before the procedure. Laparoscopy is performed with sterile techn well-equipped endoscopy suite or operating room. A narcotic and short-acting benzodiazepine (eg, mi are given IV while the abdomen is sterilized with an antiseptic solution. Lidocaine 1% is injected into th peritoneum at the site of puncture. A 5-mm surgical incision is made, and the Verres pneumoperitoneu needle is inserted. Nitrous oxide is infused into the abdominal cavity. The incision is extended by 10 to and the cannula with trocar is introduced into the peritoneal cavity. The trocar is removed, and the peritoneoscope is inserted through the cannula. The abdominal contents are examined, and aspiration ascitic fluid and biopsy procedures are performed as needed. When the procedure is completed, the n oxide is expelled by the patient with a Valsalva maneuver and the cannula is removed. The incision is An IV line is maintained for 24 h, and the patient is checked at 6 and 24 h for signs of bleeding or infec Complications include bleeding, bacterial peritonitis, and perforation of a viscus.
peritoneoscope is inserted through the cannula. The abdominal contents are examined, and aspiration ascitic fluid and biopsy procedures are performed as needed. When the procedure is completed, the n oxide is expelled by the patient with a Valsalva maneuver and the cannula is removed. The incision is An IV line is maintained for 24 h, and the patient is checked at 6 and 24 h for signs of bleeding or infec Complications include bleeding, bacterial peritonitis, and perforation of a viscus.

Section 3. Gastrointestinal Disorders Chapter 28. Gastroenteritis Topics
[General] Escherichia Coli O157:H7 Infection Staphylococcal Food Poisoning Botulism Clostridium Perfringens Food Poisoning Viral Gastroenteritis Traveler's Diarrhea Chemical Food Poisoning Drug-Related Gastroenteritis
[General]
Gastroenteritis: Inflammation of the lining of the stomach and intestines, predominantly manifested by tract symptoms (anorexia, nausea, vomiting), diarrhea, and abdominal discomfort.
(See also Food Allergy and Intolerance under Disorders with Type I Hypersensitivity Reactions in Ch. Acute Infectious Neonatal Diarrhea under Neonatal Infections in Ch. 260; and Acute Infectious Gastro under Bacterial Infections in Ch. 265.)
The electrolyte and fluid loss associated with gastroenteritis may be little more than an inconvenience otherwise healthy adult but may be of grave significance to a person less able to withstand this loss (e elderly, very young, or debilitated or those with certain concomitant illnesses).
Etiology and Epidemiology
Gastroenteritis may be of nonspecific, uncertain, or unknown etiology or of bacterial, viral, parasitic, or etiology. When a specific cause can be identified, the specific syndrome name can be used, thus avoi less specific term "gastroenteritis."
Campylobacter infection is the most common bacterial cause of diarrheal illness in the USA (see Campylobacter Infections and Noncholera Vibrio Infections in Ch. 157). Person-to-person transmissio especially common with gastroenteritis caused by Shigella, Escherichia coli O157:H7, Giardia, Norwal and rotavirus. Salmonella infection may be acquired through contact with reptiles (eg, iguanas, turtles)
Viral causes of gastroenteritis include Norwalk virus and Norwalk-like viruses, rotaviruses, adenoviruse
Campylobacter infection is the most common bacterial cause of diarrheal illness in the USA (see Campylobacter Infections and Noncholera Vibrio Infections in Ch. 157). Person-to-person transmissio especially common with gastroenteritis caused by Shigella, Escherichia coli O157:H7, Giardia, Norwal and rotavirus. Salmonella infection may be acquired through contact with reptiles (eg, iguanas, turtles)
Viral causes of gastroenteritis include Norwalk virus and Norwalk-like viruses, rotaviruses, adenoviruse astroviruses, and caliciviruses. Epidemics of viral diarrhea in infants, children, and adults are usually s via contaminated water or food or via the fecal-oral route. Norwalk virus infections occur year-round an about 40% of outbreaks of gastroenteritis in children and adults. During winter in temperate climates, rotaviruses are major causes of serious diarrheal illnesses that result in hospitalization of children < 2 Adults, whose infections tend to be milder, probably have some immunity.
Certain intestinal parasites, notably Giardia lamblia (see Giardiasis under Intestinal Protozoa in Ch. 16 adhere to or invade the intestinal mucosa and cause nausea, vomiting, diarrhea, and general malaise. Giardiasis is endemic in many cold climates (eg, Rocky Mountain states, northern USA, Europe). The can become chronic and can cause a malabsorption syndrome (see Ch. 30). It is usually acquired via person-to-person transmission (eg, in day care centers) or from drinking contaminated water (eg, from streams). Another intestinal parasite, Cryptosporidium parvum, causes watery diarrhea that is sometim accompanied by abdominal cramps, nausea, and vomiting. In healthy persons the illness is usually mi self-limited, but in immunocompromised patients the infection may be severe, causing substantial elec and fluid loss. Cryptosporidium is probably most commonly acquired by drinking contaminated water. A Cryptosporidium oocysts are commonly found in municipal water supplies, it is unknown what percenta water supplies contain viable, infectious oocysts.
Intestinal flu or grippe and some types of traveler's diarrhea may be caused by bacterial enterotoxins o infections.
Pathophysiology
Certain bacterial species elaborate enterotoxins, which impair intestinal absorption and can provoke of electrolytes and water. In some instances, a chemically pure toxin has been characterized (eg, the enterotoxin of Vibrio cholerae); pure toxin alone produces the voluminous watery secretion from the sm intestine seen clinically, thereby demonstrating an adequate pathogenic mechanism for diarrhea. Ente are probably the mechanism of other diarrheal syndromes (eg, E. coli enterotoxin may cause some ou of "nursery diarrhea" and traveler's diarrhea).
Some Shigella, Salmonella, and E. coli species penetrate the mucosa of the small intestine or colon a produce microscopic ulceration, bleeding, exudation of protein-rich fluid, and secretion of electrolytes a water. The invasive process and its results may occur whether or not the organism elaborates an ente
Gastroenteritis may follow ingestion of chemical toxins contained in plants (eg, mushrooms, potatoes flora), seafood (fish, clams, mussels), or contaminated food.
Heavy-metal (arsenic, lead, Hg, cadmium) ingestion may cause acute nausea, vomiting, and diarrhea. drugs, including broad-spectrum antibiotics, have major GI side effects. Various mechanisms play a ro including the alteration of normal gut flora.
Symptoms and Signs
The character and severity of symptoms depend on the nature of the causative agent, the duration of action, the patient's resistance, and the extent of GI involvement. Onset is often sudden and sometime dramatic, with anorexia, nausea, vomiting, borborygmi, abdominal cramps, and diarrhea (with or witho
Symptoms and Signs
The character and severity of symptoms depend on the nature of the causative agent, the duration of action, the patient's resistance, and the extent of GI involvement. Onset is often sudden and sometime dramatic, with anorexia, nausea, vomiting, borborygmi, abdominal cramps, and diarrhea (with or witho and mucus). Associated malaise, muscular aches, and prostration may occur.
If vomiting causes excessive fluid loss, metabolic alkalosis with hypochloremia occurs; if diarrhea is m prominent, acidosis is more likely. Excessive vomiting or diarrhea may cause hypokalemia. Hyponatre develop, particularly if hypotonic fluids are used in replacement therapy. Severe dehydration and acidimbalance can produce headache and muscular and nervous irritability. Persistent vomiting and diarrh result in severe dehydration and shock, with vascular collapse and oliguric renal failure.
The abdomen may be distended and tender; in severe cases, muscle guarding may be present. Gas-distended intestinal loops may be visible and palpable. Borborygmi are audible with the stethosco without diarrhea (an important differential feature from paralytic ileus). Signs of extracellular fluid deple (see Disorders of Water and Sodium Metabolism in Ch. 12) may be present (eg, hypotension, tachyca
Diagnosis
A history of ingestion of potentially contaminated food, untreated surface water, or a known GI irritant; travel; and contact with similarly ill persons may be important. Stool examination for fecal WBCs and c are indicated unless symptoms subside within 48 h. Sigmoidoscopy helps diagnose ulcerative colitis a amebic dysentery, although shigellosis and E. coli O157:H7 may produce colonic lesions indistinguish from those of ulcerative colitis. Diagnosis may also require culture of vomitus, food, and blood. Eosino may indicate parasitic infection.
The acute surgical abdomen is usually excluded by a history of frequent stools, a low or normal WBC and lack of muscle spasm and localized tenderness. However, diarrhea may occur at times in acute appendicitis, incomplete small-bowel obstruction, other acute intra-abdominal emergencies, and colon malignancy.
General Principles of Treatment
Supportive treatment is most important. Bed rest with convenient access to a toilet or bedpan is desira When nausea or vomiting is mild or has ended, oral glucose-electrolyte solutions (see Diarrhea in Ch. strained broth, or salted bouillon may prevent dehydration or treat mild dehydration. Even if vomiting, t patient should take frequent but small sips of such fluids because the vomiting may resolve with volum replacement. Children may become dehydrated more quickly and should be given an appropriate rehy solution (several are available commercially). Commonly used liquids, such as carbonated beverages drinks, lack the correct ratio of glucose to Na and thus are not appropriate for children < 5 yr old. If vom protracted or if severe dehydration is prominent, IV replacement of appropriate electrolytes is necessa Cholera in Ch. 157).
If vomiting is severe and a surgical condition has been excluded, an antiemetic (eg, dimenhydrinate 50 q 4 h, chlorpromazine >= 25 to 100 mg/day IM) or prochlorperazine 10 mg po tid (suppository 25 mg b be beneficial. Meperidine 50 mg IM q 3 or 4 h may be given for severe abdominal cramps. Morphine s avoided because it increases intestinal muscle tone and may aggravate vomiting.
When the patient can tolerate fluids without vomiting, bland food (cereal, gelatin, bananas, toast) may added to the diet gradually. If after 12 to 24 h, moderate diarrhea persists without severe systemic sym
q 4 h, chlorpromazine >= 25 to 100 mg/day IM) or prochlorperazine 10 mg po tid (suppository 25 mg b be beneficial. Meperidine 50 mg IM q 3 or 4 h may be given for severe abdominal cramps. Morphine s avoided because it increases intestinal muscle tone and may aggravate vomiting.
When the patient can tolerate fluids without vomiting, bland food (cereal, gelatin, bananas, toast) may added to the diet gradually. If after 12 to 24 h, moderate diarrhea persists without severe systemic sym or blood in the stool, diphenoxylate 2.5 to 5 mg tid or qid in tablet or liquid form, loperamide 2 mg po q bismuth subsalicylate 524 mg (two tablets or 30 mL) po six to eight times/day may be given.
The role of antibiotics is disputed, even for specific infectious diarrheas, but most authorities recomm treating symptomatic shigellosis (see Shigellosis in Ch. 157). Antibiotics appropriate to sensitivity testin should be given when systemic infection is evident. However, antibiotics do not help patients with simp gastroenteritis, nor do they help asymptomatic carriers to "clear" rapidly. In fact, antibiotics may favor a prolong the carrier state of salmonellosis. Indiscriminate use of antibiotics fosters the emergence of drug-resistant organisms and is discouraged.

Section 3. Gastrointestinal Disorders Chapter 20. Esophageal Disorders Topics
[General] Dysphagia Chest Pain Of Esophageal Origin Cricopharyngeal Incoordination Obstructive Disorders Motor Disorders Gastroesophageal Reflux Disease Corrosive Esophagitis And Stricture Esophageal Diverticula Hiatus Hernia Esophageal Laceration And Rupture Infectious Esophageal Disorders
[General]
(See also Gastrointestinal Defects in Ch. 261; for Scleroderma, see Systemic Sclerosis in Ch. 50.)
The human swallowing apparatus consists of the pharynx, the upper esophageal (cricopharyngeal) sp and the body and lower sphincter of the esophagus. The upper 1/3 of the esophagus and structures p to it are composed of skeletal muscle; the distal esophagus and lower esophageal sphincter contain s muscle. This integrated system transports material from the mouth to the stomach and prevents its ref the esophagus.
A history precisely detailing the patient's symptoms has a diagnostic accuracy of about 80%. The only physical findings in esophageal disease are (1) cervical and supraclavicular lymphadenopathy cause metastasis, (2) swellings in the neck from large pharyngeal diverticula, and (3) prolonged swallowing ti time from the act of swallowing to the sound of the bolus of fluid and air entering the stomach, heard b auscultation with the stethoscope over the epigastrium; normally <= 12 sec). Esophageal motor disord associated with prolonged swallowing times. Watching the patient swallow may help to evaluate patien preesophageal dysphagia for aspiration or nasal regurgitation.

Section 3. Gastrointestinal Disorders Chapter 29. Antibiotic-Associated Colitis Topics
[General]
[General]
Etiology and Pathology
Antibiotic-associated colitis: Acute inflammation of the colon caused by Clostridium difficile and associ antibiotic use.
Various antibiotics may alter the balance of normal colonic flora and allow overgrowth of C. difficile, an anaerobic gram-positive bacillus. Colonization occurs by the fecal-oral route through the ingestion of heat-resistant spores, which persist in the environment for long periods and are especially prevalent in care facilities (eg, hospitals, nursing homes). Diarrhea and colitis are caused by toxins produced by pa strains of C. difficile.
Almost any antibiotic can lead to C. difficile infection, but clindamycin, broad-spectrum penicillins (eg, ampicillin, amoxicillin), and the cephalosporins are most often implicated. Other inciting drugs include erythromycin, sulfonamides, tetracyclines, and the quinolones. Antibacterials that inhibit C. difficile in v metronidazole) are rare causes. Diarrhea is most frequent with oral antibiotics, but it can also result fro parenteral administration. Susceptibility increases with age, although young adults and even children m afflicted. Hospitalized patients who are taking antibiotics are at high risk because of nosocomial contam with C. difficile spores.
In mild cases, the colonic mucosa may show only minimal inflammation or edema or can even appear normal. In more severe cases, diffuse friability and ulceration may grossly and microscopically simulat idiopathic ulcerative colitis. In extreme cases, raised, yellowish, exudative plaques are seen lining the mucosa. Histologically, these pseudomembranes consist of fibrin, WBCs, and sloughed, necrotic epith cells. Bacterial invasion of the mucosa, however, is not seen.
Pseudomembranous colitis with positive stool assays for C. difficile toxin may occasionally occur in the absence of antibiotic exposure. In such cases, a specific predisposing condition is often present (eg, r bowel surgery, uremia, intestinal ischemia, chemotherapy, bone marrow transplantation).
cells. Bacterial invasion of the mucosa, however, is not seen.
Pseudomembranous colitis with positive stool assays for C. difficile toxin may occasionally occur in the absence of antibiotic exposure. In such cases, a specific predisposing condition is often present (eg, r bowel surgery, uremia, intestinal ischemia, chemotherapy, bone marrow transplantation).
Symptoms and Signs
Symptoms usually begin during a course of antibiotic therapy, but in 1/3 of patients they may appear 1 days after treatment has ceased. The diagnosis of antibiotic-associated colitis must be considered in a patient who develops diarrhea up to 6 wk after antibiotic exposure. Clinical manifestations may range simple loosening of stool to active colitis with bloody diarrhea, abdominal pain, fever, leukocytosis, and protein-losing enteropathy. In the most severe cases, dehydration, hypotension, toxic megacolon, and perforation may supervene.
Diagnosis
Diagnosis is usually suspected when there is a history of diarrhea after antibiotic use. Endoscopy usua required for diagnosis, but if performed may reveal nonspecific colitis or, in severe cases, pathognomo pseudomembranes. Because most cases involve the distal colon, flexible sigmoidoscopy usually dete disease; however, some cases have distal sparing, with more proximal disease seen only at colonosco
Plain film x-ray of the abdomen may show mucosal edema and an abnormal haustral pattern. Althoug enema examination may further outline the detail of mucosal abnormalities, it is contraindicated in acti severe cases because of the risk of perforation.
Diagnosis is confirmed by detection of C. difficile toxin in stool. Pathogenic C. difficile produces two tox and B, both of which are cytotoxins that can cause disease. The gold standard for detecting cytotoxin is a tissue culture assay, which reflects the action of toxin B. Because the tissue culture assay takes 2 to perform, more rapid enzyme immunoassays are often used, although they have a somewhat lower sensitivity, owing perhaps to the detection of only toxin A by most kits. Optimal results are obtained wh diarrheal stool specimens are tested, fresh or within 24 h of collection and refrigerated at 2 to 8 C (ab 46 F). The frequency of positive toxin assay increases with the severity of the colitis, ranging from 20% most common form of simple postantibiotic diarrhea, without sigmoidoscopically visible inflammation, t in overt pseudomembranous colitis. In contrast, healthy adults show only a 2 to 3% carrier rate of the difficile organism and virtually zero prevalence of C. difficile toxin.
The cause of antibiotic-associated diarrhea in the absence of C. difficile is unclear, but it may include a fatty acid profiles or decreased carbohydrate absorption in association with altered microflora.
Prophylaxis
Antibiotic-associated colitis is best prevented by avoiding indiscriminate use of antibiotics and by keep course of indicated treatment as short as possible. Because clustering of hospital cases has been incr reported, it is essential to institute stool isolation precautions for affected patients, with particular atten routine meticulous hand washing. Patients with prior C. difficile infection should avoid using the same antibiotic, although it has not been proven that repeated use results in a second attack. Attempts to m the homeostasis of fecal flora during antibiotic therapy by using oral lactobacillus preparations have ge been inconclusive. The nonpathogenic yeast Saccharomyces boulardii (250 mg by capsule bid) was fo one study to have a protective effect. Given concurrently with antibiotics, this treatment significantly re the incidence of diarrhea, although isolation of C. difficile was not affected. The precise mechanism of not understood, and this preparation is unavailable in the USA.
antibiotic, although it has not been proven that repeated use results in a second attack. Attempts to m the homeostasis of fecal flora during antibiotic therapy by using oral lactobacillus preparations have ge been inconclusive. The nonpathogenic yeast Saccharomyces boulardii (250 mg by capsule bid) was fo one study to have a protective effect. Given concurrently with antibiotics, this treatment significantly re the incidence of diarrhea, although isolation of C. difficile was not affected. The precise mechanism of not understood, and this preparation is unavailable in the USA.
Treatment
If significant diarrhea occurs during antibiotic treatment, the antibiotic should be stopped immediately, its use is essential. Antiperistaltic drugs (eg, diphenoxylate) should be avoided because they may prot illness by prolonging contact time of the colonic mucosa with the offending drug.
Uncomplicated antibiotic-induced diarrhea, without evidence of frank colitis or toxicity, usually subside spontaneously within 10 to 12 days once the antibiotic is discontinued; no other specific therapy is req mild symptoms persist, the anion exchange resin cholestyramine 4 g po tid for 10 days may be effectiv presumably by binding C. difficile toxin.
For most cases of frank antibiotic-associated colitis, metronidazole 250 mg po qid for 7 to 10 days is th treatment of choice. Metronidazole is much less expensive and usually is as effective as oral vancomy former treatment of choice. Oral vancomycin 125 mg qid is reserved for the most severe or resistant c Although no instances of vancomycin resistance have been reported, clinical relapses may occur in up of patients and may require retreatment. However, asymptomatic persistence of C. difficile toxin in sto for several months after resolution of symptoms, does not require further therapy. Prolonged antibiotic combined with lactobacillus or rectally instilled bacteroides may be required in patients who have multi relapses.
Patients with intractable or fulminant disease may require hospitalization for supportive treatment with electrolytes, and blood transfusion according to the same principles that govern the management of id ulcerative colitis (see Ch. 31). IV metronidazole may be effective in patients who cannot tolerate oral medication; however, IV vancomycin does not result in adequate luminal levels and therefore should n used. The value of systemic corticosteroids is not established. Rarely, subtotal colectomy has been re as a lifesaving measure in fulminant cases.
Section 3. Gastrointestinal Disorders Chapter 21. Functional Upper Gastrointestinal Com Topics
[General] Functional Chest Pain Of Presumed Esophageal Origin Functional Dyspepsia Functional Vomiting Globus Sensation Adult Rumination Halitosis Hiccup
[General]
Functional upper gastrointestinal complaints: Symptoms referred to the upper GI system in which a pa condition is not present, is poorly established, or, if present, does not entirely explain the clinical state.
Functional upper GI complaints are common in the primary care setting, accounting for 30 to 50% of re to gastroenterologists. Referring physicians and GI specialists find functional upper GI complaints diffi understand and treat, and uncertainty may lead to frustration, judgmental attitudes, and the ordering o inappropriate tests in a futile attempt to find a biologic cause.
Histopathologic abnormalities usually are not found; if they are found, they correlate poorly with the sy Evidence may indicate altered physiologic activity (eg, symptomatic diffuse esophageal spasm [see Ch delayed gastric emptying, irritable bowel syndrome [see Ch. 32]), patient preoccupation with normal physiologic function (eg, borborygmus in the hypochondriac), or psychologic illness (conversion disord somatization, depression). In many patients, more than one of these factors is involved. Functional or nonspecific symptoms may also occur along with medical disease (eg, peptic ulcer, esophagitis), but psychologic or cultural factors may more strongly contribute to the symptom presentation, making diag difficult and medical treatment alone insufficient.
Regardless of etiology, experiencing and reporting of symptoms vary, depending on the patient's pers the psychologic meaning of the illness, and sociocultural influences. Symptoms of nausea and vomitin be minimized or reported indirectly or even bizarrely by a severely depressed patient but presented wi dramatic urgency by a histrionic patient. Although distressing, the illness may satisfy certain psycholog for some patients. Secondary benefits from chronic illness help explain why many of these patients ma unexpected side effects to medication and seem resistant to improvement. Finally, cultural influences affect the reporting of symptoms.
be minimized or reported indirectly or even bizarrely by a severely depressed patient but presented wi dramatic urgency by a histrionic patient. Although distressing, the illness may satisfy certain psycholog for some patients. Secondary benefits from chronic illness help explain why many of these patients ma unexpected side effects to medication and seem resistant to improvement. Finally, cultural influences affect the reporting of symptoms.
Approach to the Patient

For patients with inexplicable complaints, a patient-oriented clinical approach with appreciation of the psychosocial aspects of illness should be followed (see also Ch. 185).
The history should be obtained by open-ended, interview-style questions. The physician must identify location and quality of the symptoms, when and where they occur, aggravating and alleviating factors, associated symptoms. The role of psychologic stress factors must be considered. Such data infrequently emerge from direct
A behavioral ("functional") disorder does not preclude medical disease or its future development. Even history contains vague, dramatic, or bizarre symptoms, complaints should not be minimized. Physical or data suggesting disease (eg, blood in the stool, fever, anemia, metabolic disturbance) should promp evaluation.
When in doubt, "don't just do something--stand there." The tendency to order unnecessary studies for insistent patient with inexplicable complaints should be avoided. When a problem is not critical, the ph should wait rather than embark on an uncertain diagnostic or therapeutic plan. In time, new informatio direct evaluation and management.
Diagnostic studies may not entirely explain a patient's clinical condition. Endoscopy can establish the p of a duodenal ulcer, but not the variability in the presence and degree of symptoms.
Removal of the symptom is not always sufficient. Patients who achieve some psychologic adaptation f symptoms may develop other kinds of symptoms when the GI symptoms resolve, or the GI symptoms recur. The adaptations derived from chronic illness may require that the illness be accepted and that tr be oriented toward improving function despite continued symptoms.

Section 3. Gastrointestinal Disorders Chapter 30. Malabsorption Syndromes Topics
[General] Carbohydrate Intolerance Celiac Disease Tropical Sprue Whipple's Disease Intestinal Lymphangiectasia Short Bowel Syndrome Infection And Infestation
[General]
Symptoms and Signs
Malabsorption syndromes: Syndromes resulting from impaired absorption of nutrients from the small b
Many diseases or their consequences can cause malabsorption (see Table 30-1). The mechanism ma direct impairment of absorption or abnormalities of digestion that lead to impaired absorption. Malabso may occur for many nutrients or for specific carbohydrates, fats, or micronutrients.
Symptoms of malabsorption are caused by the effects of osmotically active substances in the GI tract nutritional deficiencies that develop. Some causes of malabsorption have distinct clinical presentations Dermatitis herpetiformis is often associated with a mild degree of celiac-like enteropathy; biliary cirrhos pancreatic cancer cause jaundice; mesenteric ischemia causes abdominal angina; chronic pancreatitis boring central abdominal pain; and Zollinger-Ellison syndrome causes severe, persistent ulcerative dy
Malabsorption causes weight loss, glossitis, carpopedal spasms, absent tendon reflexes, cutaneous b flatulence, and abdominal distention, bloating, or discomfort resulting from increased intestinal bulk an production. Symptoms of lactase deficiency include explosive diarrhea with abdominal bloating and ga milk ingestion. Pancreatic lipase deficiency manifests as greasy stools with undigested dietary fat (triglycerides).
Steatorrhea may occur--pale, soft, bulky, malodorous stools that stick to the side of the toilet bowl or fl are difficult to flush away. Steatorrhea is most likely to occur in celiac disease or tropical sprue. Steato can be present with even relatively normal appearing stools.
(triglycerides).
Steatorrhea may occur--pale, soft, bulky, malodorous stools that stick to the side of the toilet bowl or fl are difficult to flush away. Steatorrhea is most likely to occur in celiac disease or tropical sprue. Steato can be present with even relatively normal appearing stools.
Secondary nutritional deficiencies develop in proportion to the severity of the primary disease and th of the GI tract involved. Many patients with malabsorption are anemic, usually because of deficiencies (microcytic anemia) and folic acid (megaloblastic anemia). Iron deficiency usually occurs in celiac dise after gastrectomy. Folate malabsorption with an adequate diet occurs mainly in celiac disease and trop sprue. B12 deficiency may occur in blind loop syndrome or many years after extensive resection of the ileum or stomach. However, the usual 50-cm resection of the terminal ileum for ileocecal Crohn's disea seldom leads to significant B12 deficiency. Ca deficiency is common, caused partly by vitamin D defici with impaired absorption and partly by Ca binding with unabsorbed fatty acids. Ca deficiency may cau pain and tetany. Infantile rickets is rare, but osteomalacia may occur in severe adult celiac disease. Th (vitamin B1) deficiency (as well as B12 deficiency) may cause paresthesia, and malabsorption of vitam (mainly fat-soluble) can lead to hypoprothrombinemia with bruising and a bleeding tendency. Severe r (vitamin B2) deficiency may cause a sore tongue and angular stomatitis, but vitamin A, vitamin C, and deficiencies seldom cause clinical problems.
Protein malabsorption may lead to hypoproteinemic edema, usually of the lower limbs. Dehydration, K and muscle weakness can follow profuse diarrhea. Secondary endocrine deficiencies may result from malnutrition; for example, primary or secondary amenorrhea is an important presentation of celiac dise young women.
Diagnosis
Symptoms and signs lead to the diagnostic impression of malabsorption. Any combination of weight lo diarrhea, and anemia should raise the suspicion of malabsorption. Laboratory studies confirm the diag
Direct measurement of fecal fat is the most reliable test for establishing malabsorption. Steatorrhea absolute evidence of malabsorption but is not always present. For an adult eating a usual Western die daily fat intake of 50 to 150 g, fecal fat > 6 g/day is abnormal. Accuracy of stool collections is importan feasible and advantageous to measure fecal fat in ambulatory outpatients; a 3- or 4-day collection is u adequate.
Stool inspection and microscopic examination are valuable. The typical stool appearances describ above are unmistakable. The presence of undigested food fragments suggests either extreme hyperm intestinal short circuits (eg, gastrocolic fistula). Greasy stools from a jaundiced patient point to biliary c or pancreatic cancer. Microscopic examination showing fat globules and undigested meat fiber sugges pancreatic insufficiency. Microscopy permits identification of ova or parasites. Sudan III staining of a s smear is a relatively simple and direct, but nonquantitative, screening test for fecal fat.
Absorption tests help define the lesion (for lactose absorption, see Carbohydrate Intolerance, below) D-xylose absorption test is an indirect but relatively specific measure of proximal small-bowel absorptio Abnormal findings are usual in primary jejunal disease but rare in other causes. D-Xylose 5 g po is giv fasting patient, and urine is collected for the next 5 h. This dose is slightly less sensitive than a larger ( dose but does not cause nausea or diarrhea. Provided that urine output is adequate and the GFR is n 1.2 g of D-xylose in the 5-h collection is considered abnormal, and 1.2 to 1.4 g is considered borderlin Although this test is popular in pediatric practice, complete urine collection in young children is difficult some investigators prefer measuring blood levels. However, measuring blood levels is less reliable be normal and abnormal levels overlap considerably unless the D-xylose dose was 0.5 g/kg.
fasting patient, and urine is collected for the next 5 h. This dose is slightly less sensitive than a larger ( dose but does not cause nausea or diarrhea. Provided that urine output is adequate and the GFR is n 1.2 g of D-xylose in the 5-h collection is considered abnormal, and 1.2 to 1.4 g is considered borderlin Although this test is popular in pediatric practice, complete urine collection in young children is difficult some investigators prefer measuring blood levels. However, measuring blood levels is less reliable be normal and abnormal levels overlap considerably unless the D-xylose dose was 0.5 g/kg.
Iron malabsorption can usually be inferred in a patient whose diet is adequate and who has no chron loss or thalassemia but has an iron-deficiency state, indicated by low serum ferritin or iron levels. Dimi iron storage can be seen on bone marrow evaluation.
Folic acid absorption is abnormal if a low serum or RBC folate level is found in a patient eating an ad diet but not consuming excessive alcohol.
Vitamin B12 absorption is abnormal if serum B12 is low. Because stores are extensive, a low level ind chronic condition. The Schilling test helps determine the cause of malabsorption. Reduced urinary exc 5%) of radiolabeled B12 indicates malabsorption. If excretion corrects to normal (> 9%) when intrinsic factor-bound radiolabeled B12 is given, the malabsorption is caused by deficient gastric intrinsic factor (often, true pernicious anemia). When intrinsic factor-bound B12 does not correct excretion, chronic pancreatitis, drugs (eg, aminosalicylic acid), or small-bowel disease (eg, blind loops, jejunal diverticula disease) must be suspected.
Deconjugation of bile salts by intestinal bacteria, which occurs in small-bowel disorders that cause and bacterial overgrowth (eg, blind loops, diverticula, scleroderma), can be tested with carbon 14-labe glycocholic acid breath test. The test is usually unnecessary and expensive and is often unavailable.
X-rays may be nonspecific or diagnostic. An upper GI series with small-bowel follow-through may sho bowel loops with thinned mucosal folds (suggesting celiac disease), thickened mucosal folds (suggest Whipple's disease), and coarse fragmentation of the barium column, but these findings only suggest malabsorption. Diagnostic findings are fistulas, blind loops, or various inter-enteric anastomoses; jejun diverticulosis; and mucosal patterns suggestive of intestinal lymphoma, scleroderma, or Crohn's disea plate x-ray may show pancreatic calcification--a sign of chronic pancreatitis. ERCP may also help iden chronic pancreatic insufficiency, but pancreatic calcification is usually sufficient.
Small-bowel biopsy of the jejunum is a routine procedure that simultaneously allows samples of jejun to be taken for microbiologic testing of the intestinal flora (see Table 30-2). Endoscopic biopsies are a suitable but should be taken beyond the second part of the duodenum. The mucosal sample can be e grossly by hand lens or dissecting microscope and by light or electron microscopy, and tissue homoge can be assayed for enzyme activity. Specific diagnoses include Whipple's disease, lymphosarcoma, in lymphangiectasia, and giardiasis (in which the trophozoite may be seen in close association with the v surface). Jejunal histology (villous atrophy) is also abnormal in celiac disease, tropical sprue, and derm herpetiformis.
Two pancreatic function tests are used; both require duodenal intubation: Pancreatic secretion is ind stimulated by an oral formula diet, and the Lundh test measures lipase levels in the duodenal aspirate Pancreatic secretion is directly stimulated by secretin IV (see Ch. 26). The bentiromide test for pancre function has been introduced, but its accuracy and usefulness must be evaluated. The test is based o cleavage of the synthetic peptide bentiromide by the pancreatic enzyme chymotrypsin. The para-amin acid moiety is absorbed and excreted in the urine. Accuracy depends on normal gastric emptying, norm absorption, and normal renal function; certain drugs (eg, sulfonamides, acetaminophen) can give false
Special tests may help diagnose less common causes of malabsorption, such as serum gastrin levels gastric acid secretion in Zollinger-Ellison syndrome, sweat Cl in cystic fibrosis, lipoprotein electrophore
cleavage of the synthetic peptide bentiromide by the pancreatic enzyme chymotrypsin. The para-amin acid moiety is absorbed and excreted in the urine. Accuracy depends on normal gastric emptying, norm absorption, and normal renal function; certain drugs (eg, sulfonamides, acetaminophen) can give false
Special tests may help diagnose less common causes of malabsorption, such as serum gastrin levels gastric acid secretion in Zollinger-Ellison syndrome, sweat Cl in cystic fibrosis, lipoprotein electrophore abetalipoproteinemia, and plasma cortisol in Addison's disease.

Section 3. Gastrointestinal Disorders Chapter 22. Gastrointestinal Bleeding Topics
[General] Arteriovenous Malformations
[General]
Gastrointestinal bleeding: Vomiting of blood (hematemesis), passage of gross blood through the rectu (hematochezia), passage of black tarry stool (melena), or occult chronic bleeding from the GI tract.
GI bleeding may originate anywhere from the mouth to the anus and may be overt or occult. Hematem emesis with red blood indicates an upper GI source of bleeding (almost always above the ligament of that is often brisk, usually from an arterial source or varix. "Coffee grounds" result from bleeding that h slowed or stopped, with conversion of red Hb to brown hematin by gastric acid. Hematochezia usually indicates lower GI bleeding but may result from vigorous upper GI bleeding with rapid transit of blood t the bowels. Melena typically indicates upper GI bleeding, but a small-bowel or right colon bleeding sou also be the cause. About 100 to 200 mL of blood in the upper GI tract is required to produce melena, w may continue for several days after severe hemorrhage and does not necessarily indicate continued b Black stool that is negative for occult blood may result from ingestion of iron, bismuth, or various foods should not be mistaken for melena. Chronic occult bleeding may occur anywhere in the GI tract and detected by chemical testing of a stool specimen. Common causes of GI bleeding are listed in Table 2
Symptoms and Signs
The manifestations of GI bleeding depend on the source, rate of bleeding, and underlying or coexisten disease; eg, a patient with underlying ischemic heart disease may present with angina or MI after brisk bleeding. Coexistent heart failure, hypertension, pulmonary disease, renal failure, and diabetes mellitu be aggravated by severe GI bleeding, which may present as shock (see Ch. 204). Lesser degrees of b may manifest as orthostatic changes in pulse (a change > 10 beats/min) or BP (a drop of >= 10 mm H Orthostatic changes must be interpreted with caution in patients with underlying heart disease or perip vascular disease or in those taking drugs known to influence peripheral vascular resistance. Patients w chronic blood loss may present with symptoms and signs of anemia (eg, weakness, easy fatigability, p chest pain, dizziness) or of cirrhosis and portal hypertension. GI bleeding may precipitate hepatic encephalopathy (mental status changes secondary to liver failure) or hepatorenal syndrome (kidney fa secondary to liver failure).
vascular disease or in those taking drugs known to influence peripheral vascular resistance. Patients w chronic blood loss may present with symptoms and signs of anemia (eg, weakness, easy fatigability, p chest pain, dizziness) or of cirrhosis and portal hypertension. GI bleeding may precipitate hepatic encephalopathy (mental status changes secondary to liver failure) or hepatorenal syndrome (kidney fa secondary to liver failure).
Diagnosis
Stabilization of the patient with transfusions and other treatment is essential before or during diagnosti evaluation. All patients require a complete history and physical examination; blood studies, including coagulation studies (platelet count, prothrombin time, partial thromboplastin time); and liver function te (bilirubin, alkaline phosphatase, albumin, AST, ALT), with repeated monitoring of Hb and Hct.
A history of epigastric abdominal pain relieved by food or antacids suggests peptic ulcer disease. How many patients with bleeding ulcers have no history of pain. Weight loss and anorexia suggest a GI ma Dysphagia suggests esophageal cancer or stricture. Vomiting and retching before the onset of bleedin suggest a Mallory-Weiss tear of the esophagus, although about 50% of patients with Mallory-Weiss te not have this history. A history of bleeding (eg, purpura, ecchymosis, hematuria) may indicate a bleedi diathesis (eg, hemophilia). Bloody diarrhea, fever, and abdominal pain are consistent with inflammator disease (ulcerative colitis, Crohn's disease) or an infectious colitis (eg, Shigella, Salmonella, Campylob amebiasis). Hematochezia or occult blood in the stool may be the first sign of a colon cancer or polyp, particularly in patients > 45 yr. The most common causes of painless lower GI bleeding in patients > 6 angiodysplasia, diverticulosis, and cancer or an ulcerated polyp. Fresh blood on the surface of formed suggests a distal source for the bleeding (eg, internal hemorrhoids).
A drug history may reveal use of drugs that break the gastric barrier and damage the gastric mucosa aspirin, NSAIDs). The amount and duration of ingestion of these substances are important. Many patie unaware that many OTC cough remedies and analgesics contain aspirin.
Physical examination, after assessment of vital signs, includes inspection of the nasopharynx to exc nose and throat as sources of bleeding. Evidence of trauma, especially to the head, chest, and abdom should be sought. Spider angiomas, hepatosplenomegaly, or ascites is consistent with chronic liver dis Valvular heart disease can be associated with GI bleeding. Arteriovenous malformations, especially of mucous membranes, may be associated with hereditary hemorrhagic telangiectasia (Rendu-Osler-We syndrome), in which multiple angiomas of the GI tract are associated with recurrent episodic bleeding. Cutaneous nail bed and GI telangiectasia may also be associated with scleroderma or mixed connecti disease. A digital rectal examination is necessary to search for masses, fissures, and hemorrhoids. the stool should also be recorded. Chemical testing of a stool specimen for occult blood completes the examination.
Nasogastric aspiration and lavage should be performed in all patients with suspected upper GI bleed Bloody nasogastric aspiration indicates upper GI bleeding, but about 10% of patients with an upper GI bleeding source have a negative nasogastric aspirate. Coffee grounds indicate bleeding that is slow or stopped, but continuous bright red blood indicates active, vigorous bleeding. Nasogastric aspiration als monitor the bleeding status.
Panendoscopy (examination of the esophagus, stomach, and duodenum with a flexible endoscope) o highest yield in diagnosing bleeding and establishing the source. In acute upper GI bleeding, upper GI x-rays have no role because they are less accurate than upper panendoscopy, are unable to detect th bleeding lesion among two or more, and may interfere with subsequent endoscopy or angiography.
If panendoscopy is unavailable, upper GI barium x-rays can be used after the patient is stable for >= h. Upper GI x-rays should also be considered in a patient who has definite evidence of upper GI bleed
highest yield in diagnosing bleeding and establishing the source. In acute upper GI bleeding, upper GI x-rays have no role because they are less accurate than upper panendoscopy, are unable to detect th bleeding lesion among two or more, and may interfere with subsequent endoscopy or angiography.
If panendoscopy is unavailable, upper GI barium x-rays can be used after the patient is stable for >= h. Upper GI x-rays should also be considered in a patient who has definite evidence of upper GI bleed with a negative or inconclusive panendoscopy. Before examination, the patient should be adequately s and the blood volume restored.
In hematochezia, distal lesions (eg, hemorrhoids, inflammatory bowel disease, cancers, polyps) are co seen at flexible sigmoidoscopy, which is usually the first diagnostic test, along with anoscopy with a instrument. If these tests fail to establish a diagnosis and active bleeding continues, further evaluation indicated. Nasogastric aspiration should be performed to exclude an upper GI source. If the aspirate d have bile or is positive for blood or coffee grounds, upper panendoscopy should be performed. If the a has bile or is negative for blood, elective or emergency colonoscopy is indicated, depending on the se the hematochezia. Emergency colonoscopy in experienced hands after adequate bowel preparation oral sulfate purge to clear the bowel of blood, clots, and stool) has a high yield in diagnosing colonic b sites. Angiography and technetium-labeled colloid or RBC scans may be of value, but the magnitude o bleeding required to show the bleeding site limits their usefulness. If the bleeding rate is > 0.5 mL/min stipulate > 1 mL/min), angiography may show extravasation of contrast medium. In patients whose hematochezia stops, elective colonoscopy should be performed.
Diagnosis of occult bleeding often requires judicious use of GI x-rays and endoscopy. The decision to barium x-rays vs. colonoscopy for occult bleeding depends on several factors: local availability, expert patient acceptance. Colonoscopy is generally preferred in lower GI bleeding, but the combination of ai contrast barium enema and sigmoidoscopy is an alternative when colonoscopy is unavailable or the pa refuses it. If the patient is anemic and has occult blood, colonoscopy would be a better diagnostic tool barium enema. If initial study with a barium enema and sigmoidoscopy is negative or reveals only dive colonoscopy should be performed. If the lower GI study is negative and the patient has persistent evid occult bleeding from positive stool tests or symptoms suggestive of upper GI disease, panendoscopy s be performed. If panendoscopy and colonoscopy are negative and occult blood persists in the stool, a GI series with small-bowel follow-through, small-bowel endoscopy (enteroscopy), or technetium-labele or RBC scanning should be considered.
Treatment
Hematemesis, hematochezia, or melena should be considered an emergency until proven otherwise. Admission to an ICU is recommended for all patients with severe GI bleeding. The team approach incl gastroenterologist, a surgeon with expertise in GI surgery, and skilled nurses. A major cause of morbid mortality in patients with active GI bleeding is aspiration of blood with subsequent respiratory comprom particularly in patients who have inadequate gag reflexes or who are obtunded or unconscious. To pre complication in patients with altered mental status, endotracheal intubation should be considered to pr airway.
Assessment and restoration of blood loss: Most GI bleeding stops spontaneously (eg, upper GI ble stops spontaneously in about 80% of patients without portal hypertension). Major blood loss is manifes pulse > 110 beats/min, systolic BP < 100 mm Hg, orthostatic drop in systolic BP of >= 16 mm, oliguria clammy extremities, and often, mental status changes resulting from decreased cerebral perfusion (co disorientation, somnolence, loss of consciousness, coma). The Hct is a valuable index of blood loss bu be inaccurate if the bleeding has occurred over the preceding few hours, because complete restoratio blood volume by hemodilution may take several hours. Transfusions usually maintain the Hct at about there is risk of further hemorrhage, if complicating vascular disease is present, if severe comorbid con critical illness is present, or if the patient is elderly. Most transfusion physicians now recommend only b component therapy. After adequate blood volume is restored, the patient must be observed closely for
disorientation, somnolence, loss of consciousness, coma). The Hct is a valuable index of blood loss bu be inaccurate if the bleeding has occurred over the preceding few hours, because complete restoratio blood volume by hemodilution may take several hours. Transfusions usually maintain the Hct at about there is risk of further hemorrhage, if complicating vascular disease is present, if severe comorbid con critical illness is present, or if the patient is elderly. Most transfusion physicians now recommend only b component therapy. After adequate blood volume is restored, the patient must be observed closely for evidence of further bleeding (eg, increased pulse; decreased BP; vomiting of fresh blood; recurrence o tarry stools).
Continuous gastric aspiration via a nasogastric tube (preferably a Salem pump) may be used in a vom patient and helps monitor continuing or recurrent hemorrhage. Lavage through a large tube (Ewald) m cleanse the stomach of clots, especially before diagnostic endoscopy.
Specific therapy depends on the bleeding site. For treatment of peptic ulcer after bleeding has been co see Ch. 23. Emergency operation is occasionally required to control acute bleeding or rebleeding, alth endoscopic coagulation (with bipolar electrocoagulation, injection sclerosis, heater probes, or laser), a in most hospitals, is usually successful in that it stops the bleeding at least temporarily. It is particularly important to consider early operative control of gastric bleeding in the elderly to minimize mortality rate time of the diagnostic endoscopy, treatment of active ulcer bleeding or of nonbleeding visible vessels i is indicated with endoscopic coagulation. Active variceal bleeding can be treated with vasopressin or octreotide, esophagogastric (Sengstaken-Blakemore) or gastric (Linton) tamponade tubes, endoscopic banding or sclerotherapy, a transjugular intrahepatic portosystemic shunt (TIPS) procedure, or rarely, portal-systemic shunt surgery. No method is clearly superior, although most hospitals use banding or sclerotherapy as the primary treatment of bleeding esophageal varices. For patients who fail banding o sclerotherapy, a TIPS procedure, shunt surgery, or liver transplantation should be considered. Angiogr has a limited but potentially important role in the diagnosis and treatment of upper GI bleeding. Should bleeding lesion be identified, the catheter may be left in place for infusion of vasopressin or embolic th
Most lower GI bleeding does not require specific emergency therapy. For severe, ongoing diverticular surgery or angiography with intra-arterial infusion of vasopressin may be necessary. For severe or rec bleeding from angioma of the colon, endoscopic coagulation with heater probe or bipolar electrocoagu can be used as initial treatment. Angiomas that fail endoscopic management are treated with surgery. Colonoscopic polypectomy or laparotomy can remove other lower GI bleeding lesions (eg, cancers, po Acutely or chronically bleeding internal hemorrhoids can be treated medically in most cases. Failures a treated via anoscopy with rubber band ligation, injection, coagulation, or surgery.

Section 3. Gastrointestinal Disorders Chapter 31. Inflammatory Bowel Diseases Topics
[General] Crohn's Disease Ulcerative Colitis
[General]
Crohn's disease and ulcerative colitis are characterized by chronic inflammation at various sites in the Both cause diarrhea, which may be profuse and bloody. Certain differences in disease patterns justify distinction between Crohn's disease and ulcerative colitis, although groupings and subgroupings are s artificial. Some cases are difficult, if not impossible, to classify.
The term colitis applies only to inflammatory disease of the colon (eg, ulcerative, granulomatous, ische radiation, or infectious colitis). Spastic or mucous colitis is a misnomer often applied to a functional dis that is more properly described as irritable bowel syndrome (see Ch. 32).
Section 3. Gastrointestinal Disorders Chapter 23. Gastritis And Peptic Ulcer Diseas Topics
[General] Gastritis Peptic Ulcer Disease
[General]
Normally, the GI mucosa is protected by several distinct mechanisms: (1) Mucosal production of mucu HCO 3 creates a pH gradient from the gastric lumen (low pH) to the mucosa (neutral pH). The mucus s
a barrier to diffusion of acid and pepsin. (2) Epithelial cells remove excess hydrogen ions (H+) via mem transport systems and have tight junctions, which prevent back diffusion of H+ ions. (3) Mucosal blood removes excess acid that has diffused across the epithelial layer. Several growth factors (eg, epiderm factor, insulin-like growth factor I) and prostaglandins have been linked to mucosal repair and mainten mucosal integrity.

Section 3. Gastrointestinal Disorders Chapter 32. Functional Bowel Disorders Topics
Irritable Bowel Syndrome Gas
Irritable Bowel Syndrom

(Spastic Colon)
A motility disorder involving the entire GI tract, causing recurring upper and lower GI symptoms, includ variable degrees of abdominal pain, constipation and/or diarrhea, and abdominal bloating.
Etiology
The cause of irritable bowel syndrome (IBS) is unknown. No anatomic cause can be found. Emotional diet, drugs, or hormones may precipitate or aggravate heightened GI motility. Some patients have anx disorders, particularly panic disorder; major depressive disorder; and somatization disorder. However, and emotional conflict do not always coincide with symptom onset and recurrence. Some patients with appear to have a learned aberrant illness behavior; ie, they tend to express emotional conflict as a GI complaint, usually abdominal pain. The physician evaluating patients with IBS, particularly those with r symptoms, should investigate for unresolved psychologic issues, including the possibility of sexual or p abuse (see also Approach to the Patient in Ch. 21).
Pathophysiology
In IBS, the circular and longitudinal muscles of the small bowel and sigmoid are particularly susceptibl motor abnormalities. The proximal small bowel appears to be hyperreactive to food or parasympathom drugs. Small- bowel transit is variable in patients with IBS, and changes in bowel transit time often do correlate with symptoms. Intraluminal pressure studies of the sigmoid show that functional constipation occur when haustral segmentation becomes hyperreactive (ie, increased frequency and amplitude of contractions); in contrast, diarrhea is associated with diminished motor function.
Excess mucus production, which often occurs in IBS, is not related to mucosal injury. Its cause is uncl it may be related to cholinergic hyperactivity.
Hypersensitivity to normal amounts of intraluminal distention exists, as does a heightened perception o
contractions); in contrast, diarrhea is associated with diminished motor function.
Excess mucus production, which often occurs in IBS, is not related to mucosal injury. Its cause is uncl it may be related to cholinergic hyperactivity.
Hypersensitivity to normal amounts of intraluminal distention exists, as does a heightened perception o the presence of normal quantity and quality of intestinal gas. The pain of IBS seems to be caused by abnormally strong contraction of the intestinal smooth muscle or by increased sensitivity of the intestin distention. Hypersensitivity to the hormones gastrin and cholecystokinin may also be present. Howeve hormonal fluctuations do not correlate with clinical symptoms. The caloric density of food intake may in the magnitude and frequency of myoelectrical activity and gastric motility. Fat ingestion may cause a d peak of motor activity, which can be exaggerated in IBS. The first few days of menstruation can lead to transiently elevated prostaglandin E 2, resulting in increased pain and diarrhea. This is not caused by e or progesterone but by the release of prostaglandins.
Symptoms and Signs
IBS tends to begin in the second and third decades of life, causing bouts of symptoms that recur at irre periods. Onset in late adult life is rare. Symptoms usually occur in the awake patient and rarely rouse sleeping patient. Symptoms can be triggered by stress or the ingestion of food.
Features of IBS are pain relieved by defecation, an alternating pattern of bowel habits, abdominal dist mucus in the stool, and sensation of incomplete evacuation after defecation. The more symptoms that present, the likelier that the patient has IBS. In general, the character and location of pain, precipitatin and defecatory pattern are distinct for each patient. Variations or deviations from the usual symptoms suggest intercurrent organic disease and should be thoroughly investigated. Patients with IBS may als extraintestinal symptoms (eg, fibromyalgia, headaches, dyspareunia, temporomandibular joint syndrom
Two major clinical types of IBS have been described. In constipation-predominant IBS, constipation common, but bowel habits vary. Most patients have pain over at least one area of the colon, associate periodic constipation alternating with a more normal stool frequency. Stool often contains clear or whit The pain is either colicky, coming in bouts, or a continuous dull ache; it may be relieved by a bowel mo Eating commonly triggers symptoms. Bloating, flatulence, nausea, dyspepsia, and pyrosis can also oc
Diarrhea-predominant IBS is characterized by precipitous diarrhea that occurs immediately on rising during or immediately after eating. Nocturnal diarrhea is unusual. Pain, bloating, and rectal urgency ar common, and incontinence may occur. Painless diarrhea is not typical and should lead the physician t consider other diagnostic possibilities (eg, malabsorption, osmotic diarrhea).
Diagnosis
Diagnosis of IBS is based on characteristic bowel patterns, time and character of pain, and exclusion o disease processes through physical examination and routine diagnostic tests. Standardized criteria ha developed for IBS. The Rome criteria for IBS includes abdominal pain relieved with defecation and a v pattern of altered stool frequency or form, bloating, or mucus. The key to diagnosis is effective history which requires attention to directed, but not controlled, elaboration of the presenting symptoms, history present illness, past medical history, family history, familial interrelationships, and drug and dietary his Equally important are the patient's interpretation of personal problems and overall emotional state. The of patient-physician interaction is key to diagnostic and therapeutic efficacy.
On physical examination, patients with IBS generally appear to be healthy. Palpation of the abdomen reveal tenderness, particularly in the left lower quadrant, at times associated with a palpable, tender si routine digital rectal examination should be performed on all patients, and a pelvic examination on wom
Equally important are the patient's interpretation of personal problems and overall emotional state. The of patient-physician interaction is key to diagnostic and therapeutic efficacy.
On physical examination, patients with IBS generally appear to be healthy. Palpation of the abdomen reveal tenderness, particularly in the left lower quadrant, at times associated with a palpable, tender si routine digital rectal examination should be performed on all patients, and a pelvic examination on wom
Stool examination for occult blood (preferably a 3-day series) should be performed. Routine testing f and parasites or a stool culture is rarely indicated without a supporting travel history or supporting sym (eg, fever, bloody diarrhea, acute onset of severe diarrhea).
Proctosigmoidoscopy with a flexible fiberoptic instrument should be performed. Introduction of the sigmoidoscope and air insufflation frequently trigger bowel spasm and pain. The mucosal and vascula in IBS usually appears normal. In patients with chronic diarrhea, particularly older women, mucosal bio rule out possible microscopic colitis, which has two variants: collagenous colitis, seen on trichrome sta increased submucosal collagen deposition, and lymphocytic colitis, characterized by increased numbe mucosal lymphocytes. The mean age of presentation for these disorders is 60 to 65 yr, with a female predominance. Similar to IBS, presentation involves nonbloody, watery diarrhea. Diagnosis can be ma rectal mucosal biopsy.
Laboratory examination should include a CBC; ESR; 6- and 12-channel biochemical profile (sequen multiple analyses 6 and 12), including serum amylase; urinalysis; and thyroid-stimulating hormone. An abdominal sonogram, barium enema x-ray, and upper GI esophagogastroduodenoscopy or colonosco be selectively used, based on the history, physical examination, patient age, and follow-up evaluations However, these studies should be undertaken only when less invasive and less expensive studies reve objective abnormalities.
Diagnosis of IBS should never preclude suspicion of intercurrent disease. Changes in symptoms may another disease process. For example, a change in the location, type, or intensity of pain; a change in habits; constipation and diarrhea or vice versa; and new symptoms or complaints (eg, nocturnal diarrh be clinically significant. Other symptoms that require investigation include fresh blood in the stool, weig very severe abdominal pain or unusual abdominal distention, steatorrhea or noticeably foul-smelling s fever or chills, persistent vomiting, hematemesis, symptoms that wake the patient from sleep (eg, pain urge to defecate), or a steady progressive worsening of symptoms. Patients > 40 yr are more likely tha younger patients to have an intercurrent organic illness.
Differential Diagnosis
Common illnesses that may be confused with IBS include lactose intolerance, diverticular disease, drug-induced diarrhea, biliary tract disease, laxative abuse, parasitic diseases, bacterial enteritis, eosin gastritis or enteritis, microscopic (collagenous) colitis, and early inflammatory bowel disease. The bimo distribution of patients with inflammatory bowel disease makes it imperative to evaluate both younger patients for these conditions. In patients > 40 yr with a change in bowel habits, particularly those with n previous IBS symptoms, colonic polyps and tumors must be excluded by colonoscopy. In patients > 60 ischemic colitis should be considered.
Pelvic examination in women helps rule out ovarian tumors and cysts or endometriosis, which may mim Hyperthyroidism, carcinoid syndrome, medullary cancer of the thyroid, vipoma, and the Zollinger-Elliso syndrome are possibilities in patients with diarrhea. Patients with constipation and no anatomic lesion be evaluated for hypothyroidism or hyperparathyroidism. If the patient's history and laboratory studies malabsorption, absorption tests should rule out tropical sprue, celiac disease, and Whipple's disease. elimination disorders (eg, pelvic floor dyssynergia) should be considered as a cause of constipation in who report excessive straining on defecation.
Hyperthyroidism, carcinoid syndrome, medullary cancer of the thyroid, vipoma, and the Zollinger-Elliso syndrome are possibilities in patients with diarrhea. Patients with constipation and no anatomic lesion be evaluated for hypothyroidism or hyperparathyroidism. If the patient's history and laboratory studies malabsorption, absorption tests should rule out tropical sprue, celiac disease, and Whipple's disease. elimination disorders (eg, pelvic floor dyssynergia) should be considered as a cause of constipation in who report excessive straining on defecation.
Treatment
Therapy is supportive and palliative. A physician's sympathetic understanding and guidance are of ove importance. The physician must explain the nature of the underlying condition and convincingly demon the patient that no organic disease is present. This requires time for listening and explaining normal bo physiology and the bowel's hypersensitivity to stress, food, or drugs. These explanations form the foun for attempting to reestablish regular bowel routine and individualizing therapy. The prevalence, chronic need for continuing care of IBS should be emphasized. Psychologic stress and anxiety or mood disord should be sought, evaluated, and treated (see Chs. 187 and 189). Regular physical activity helps relie and assists in bowel function, particularly in patients who present with constipation.
In general, a normal diet should be followed. Patients with abdominal distention and increased flatulen benefit from dietary reduction or elimination of beans, cabbage, and other foods containing fermentab carbohydrates. Reduced intake of apple and grape juice, bananas, nuts, and raisins may also lessen t incidence of flatulence. Patients with evidence of lactose intolerance should reduce their intake of milk dairy products. Bowel function may also be disturbed by the ingestion of sorbitol, mannitol, fructose, o combinations of sorbitol and fructose. Sorbitol and mannitol are artificial sweeteners used in dietetic fo as drug vehicles, whereas fructose is a common constituent of fruits, berries, and plants. Patients with postprandial abdominal pain may try a low-fat diet supplemented with increased protein.
Increasing dietary fiber can help many patients with IBS, particularly those with constipation. A bland bulk-producing agent may be used (eg, raw bran, starting with 15 mL [1 tbs] with each meal, suppleme with increased fluid intake). Alternatively, psyllium hydrophilic mucilloid with two glasses of water tends stabilize the water content of the bowel and provide bulk. These agents help retain water in the bowel prevent constipation. They also can reduce colonic transit time and act as a shock absorber to preven of the bowel walls against each other. Fiber added in small amounts may also help reduce IBS-induce diarrhea by absorbing water and solidifying stool. However, excessive use of fiber can lead to bloating diarrhea. Fiber doses must therefore be adjusted to individual patient needs.
Anticholinergic (antispasmodic) drugs (eg, hyoscyamine 0.125 mg 30 to 60 min before meals) may be combination with fiber agents. The use of narcotics, sedative hypnotics, and other drugs that produce dependency is discouraged. In patients with diarrhea, diphenoxylate 2.5 to 5 mg (one to two tablets) o loperamide 2 to 4 mg (one to two capsules) may be given before meals. Chronic use of antidiarrheals discouraged because tolerance to the antidiarrheal effect may occur. Antidepressants (eg, desipramin imipramine, and amitriptyline 50 to 150 mg daily) help many patients with either type of IBS. In addition constipation and diarrhea, abdominal pain and bloating are relieved by antidepressants. These drugs reduce pain by down-regulating the activity of spinal cord and cortical afferent pathways arriving from t intestine. Finally, certain aromatic oils (carminatives) can relax smooth muscle and relieve pain caused cramps in some patients. Peppermint oil is the most commonly used agent in this class.

Section 3. Gastrointestinal Disorders Chapter 24. Bezoars And Foreign Bodies Topics
[General] Bezoars Foreign Bodies
[General]
Many food materials or other objects may collect as solid masses within the GI tract.

Section 3. Gastrointestinal Disorders Chapter 33. Diverticular Disease Topics
[General] Diverticulosis Diverticulitis Diverticular Disease Of The Stomach And Duodenum Diverticular Disease Of The Small Bowel
[General]
(See also Esophageal Diverticula in Ch. 20.)
Diverticular disease: Disease caused by diverticula, acquired sac-like mucosal projections through the muscular layer of the GI tract, which cause symptoms by trapping feces, becoming infected, bleeding, rupturing.
Section 3. Gastrointestinal Disorders Chapter 25. Acute Abdomen And Surgical Gastroen Topics
Abdominal Pain Mechanical Intestinal Obstruction Ileus Ischemic Colitis Appendicitis Acute Peritonitis Chronic Peritonitis
Abdominal Pain
Although abdominal pain is common and often trivial, acute and severe pain nearly always is a sympto intra-abdominal disease. It may be the sole indicator of the need for surgery. Whether the patient has "surgical abdomen" must be swiftly decided. Precious time may be lost in useless testing: Gangrene a perforation of gut can occur as little as 6 h after interruption of the intestinal blood supply from either a strangulating obstruction or an arterial embolus.
Abdominal pain can be acute, in which the question of urgent surgery arises, or it can be chronic, in w case therapy (at least for a protracted time) is medical. Textbook descriptions of abdominal pain have limitations because individuals react to pain differently. Infants and children may be unable to localize discomfort. Obese or elderly patients tend to tolerate pain better than others, but they have difficulty lo the pain. On the other hand, hysterical patients tend to exaggerate symptoms.
Etiology
Common causes of abdominal pain are listed in Table 25-1. Pain is the outstanding symptom in the fo surgical emergencies: twisted ovarian cyst, ectopic pregnancy, intestinal obstruction, appendicitis, gen peritonitis from an unknown cause, perforated peptic ulcer, perforated diverticulitis, a leaking abdomin aneurysm, and mesenteric embolism or thrombosis. Most patients with biliary tract disease, pancreatit kidney stone receive urgent treatment. (See also Mechanical Intestinal Obstruction and Acute Peritoni below, Ch. 26, and Cholecystitis in Ch. 48.)
Abdominal pain in neonates, infants, and children: Abdominal pain in neonates, infants, and childr numerous causes not encountered in adults (see also Recurrent Abdominal Pain in Ch. 268). Causes meconium peritonitis, intestinal obstruction from atresia, stenosis, esophageal webs, volvulus of a gut common mesentery, imperforate anus, and enterocolitis (see Gastrointestinal Defects in Ch. 261 and
below, Ch. 26, and Cholecystitis in Ch. 48.)
Abdominal pain in neonates, infants, and children: Abdominal pain in neonates, infants, and childr numerous causes not encountered in adults (see also Recurrent Abdominal Pain in Ch. 268). Causes meconium peritonitis, intestinal obstruction from atresia, stenosis, esophageal webs, volvulus of a gut common mesentery, imperforate anus, and enterocolitis (see Gastrointestinal Defects in Ch. 261 and Infectious Gastroenteritis under Bacterial Infections in Ch. 265).
Abdominal pain in women (see also Ch. 237): Dysmenorrhea may be trivial or disabling (see Ch. 235 Mittelschmerz is common but not serious unless concomitant bleeding is sufficient to require a laparot
The most troublesome problem in young women is pelvic inflammatory disease (PID), which is treated antibiotics, although tubo-ovarian abscesses require operation. When symptoms are confined to the ri quadrant, it may be difficult to determine whether a patient has PID or appendicitis (see also Pelvic Inflammatory Disease in Ch. 238). When in doubt, exploratory laparotomy and appendectomy are the procedures.
Some ovarian cysts are small and disappear within 3 mo; others are large, may contain teeth or other elements, and may be subject to torsion and gangrene. Endometriosis is a common cause of pain (se 239); it is often controlled by hormones but may require operation. An ectopic pregnancy is life threate without emergency laparotomy. Intrauterine contraceptive devices may migrate into the peritoneal cav produce peritonitis and intestinal obstruction.
Diagnosis
Therapy for severe abdominal pain must proceed simultaneously with diagnosis. The cause is usually established by a history and physical examination, which are of primary importance, and by some labo tests.
History: In many cases, the history is sufficient for proper diagnosis. The history must be detailed, and questions are always important (see Table 25-2).
A past history of previous symptoms may help localize the site of the present problem. Previous symp ulcer disease, gallstone colic, or diverticular disease are especially helpful. A history of gastroesophag reflux, diarrhea, constipation, jaundice, melena, hematuria, hematemesis, weight loss, mucus, or blood stool can help establish a diagnosis.
A drug history should include details concerning prescription and illicit drug use. Some drugs (eg, pota tablets) are highly irritating to the intestine and may lead to perforation and peritonitis. Prednisone or immunosuppressive drugs may increase the chances of perforation of some portion of the GI tract with relatively little pain or leukocytosis. Anticoagulants can increase the chances of bleeding.
A family history of certain diseases (eg, gallstones) may be helpful. If the symptoms include pain, vom and diarrhea and other family members have just recovered from similar attacks, gastroenteritis is a p cause.
Physical examination: The general physical examination must not be neglected. Shock, pallor, swea fainting can accompany abdominal pain and indicates the severity of the pathologic process. BP, pulse of consciousness, and degree of shock must be evaluated in severe cases. However, the focus of exa is the abdomen. Active peristalsis of normal pitch suggests a nonsurgical disease (eg, gastroenteritis). High-pitched peristalsis or borborygmi in rushes suggest intestinal obstruction. Severe pain with a silen abdomen warrants immediate exploration.
fainting can accompany abdominal pain and indicates the severity of the pathologic process. BP, pulse of consciousness, and degree of shock must be evaluated in severe cases. However, the focus of exa is the abdomen. Active peristalsis of normal pitch suggests a nonsurgical disease (eg, gastroenteritis). High-pitched peristalsis or borborygmi in rushes suggest intestinal obstruction. Severe pain with a silen abdomen warrants immediate exploration.
Examination for tenderness, rebound tenderness, degree of distention, and palpable masses is import Operative scars suggest possible adhesions and intestinal obstruction, and abnormal orifices can be t external hernias. Rectal and pelvic examinations are essential. Bleeding in subcutaneous tissues (eg, retroperitoneal bleeding from hemorrhagic pancreatitis) may be indicated by a dissecting bluish discolo frank ecchymoses of the costovertebral angles (Grey Turner's sign) or around the umbilicus (Cullen's s
Diagnostic tests: Diagnostic tests include blood and urine examinations; blood chemistry; x-rays, incl supine and upright views; IV urography; ultrasound; CT; and arteriography. Each has specific indicatio depending on the disease under consideration. However, the most important diagnostic measure in pa with severe abdominal pain often is expeditious exploratory laparotomy.
Some relatively common diseases must be considered in the differential diagnosis of acute abdomina Gastroenteritis is likely if family members or associates have had recent similar complaints. Symptoms colicky pain, nausea, vomiting, and diarrhea, which may be accompanied by mild abdominal tenderne never becomes localized. Gastroenteritis is self-limited. Inflammatory bowel disease can mimic acute appendicitis; diverticulitis can produce similar symptoms (usually in the left lower quadrant). Herpes zo cause severe pain that precedes the typical rash. The pain can be confusing, particularly if the nerves right lower quadrant are involved in a patient whose appendix has not been removed. Pneumonia can diffuse abdominal pain without localized abdominal tenderness. Acute MI may be accompanied by poo localized abdominal pain. Drug addiction or withdrawal may produce severe colicky pains that suggest intestinal obstruction. Anticoagulant use or severe coughing can lead to a hematoma of the abdomina rupture of the deep epigastric artery or vein, events that produce local pain and tenderness. Sickle cel may cause attacks of severe abdominal pain. The most common cause of abdominal pain in spinal co CNS disease is radiculitis, which usually produces chronic rather than acute pain. Psychogenic somat disorders often lead to complaints of attacks of severe abdominal pain for which no organic cause can found (see Ch. 186). Unless the patient has a peptic ulcer, complaints of burning pains are likely to rem unexplained. Typhoid fever may be accompanied by right lower pain; if rose spots are present, this dis must be considered.
Section 3. Gastrointestinal Disorders Chapter 34. Tumors Of The Gastrointestinal Tr Topics

Esophageal Tumors Stomach Cancer Small-Bowel Tumors Large-Bowel Tumors Pancreatic Tumors
Esophageal Tumors
There are many types of benign tumors of the esophagus, but most are of little consequence except fo producing annoying symptoms (see Ch. 20). Leiomyoma, the most common benign esophageal tumor multiple but has an excellent prognosis in most patients.
Most primary esophageal cancers are carcinomas. The most common malignant tumor of the esophag epidermoid carcinoma, followed by adenocarcinoma. Other malignant tumors of the esophagus includ lymphoma, leiomyosarcoma, and metastatic cancer.
ESOPHAGEAL CANCER
(See also Ch. 89.)
Esophageal cancer usually presents with progressive dysphagia for solids over several weeks, associa marked weight loss. Cancer may occur anywhere in the esophagus and may appear as a stricture, ma plaque. The American Cancer Society estimates that in the USA, 8700 men and 2800 women will die esophageal cancer in 1997.
Epidermoid (squamous cell) carcinoma: Epidermoid carcinoma of the esophagus is uncommon in t it accounts for 1.5% of all cancers and 7% of GI cancers. The American Cancer Society estimates tha 1997, there will be 9400 new cases in men and 3100 in women. However, incidence rates are higher i Puerto Rico, Singapore, South Africa, Switzerland, France, and the Caspian littoral area of Iran.
Epidermoid carcinoma is associated with alcohol ingestion, tobacco consumption (in any form), human papillomavirus, lye ingestion (resulting in stricture), sclerotherapy, Plummer-Vinson syndrome, irradiati esophagus, esophageal webs, achalasia, and epidermoid carcinoma of the head and neck. Tylosis (hyperkeratosis palmaris et plantaris) and squamous cell papilloma may be precursor lesions. Epiderm carcinoma is three times more common among blacks than whites. The 5-yr survival for American blac
Puerto Rico, Singapore, South Africa, Switzerland, France, and the Caspian littoral area of Iran.
Epidermoid carcinoma is associated with alcohol ingestion, tobacco consumption (in any form), human papillomavirus, lye ingestion (resulting in stricture), sclerotherapy, Plummer-Vinson syndrome, irradiati esophagus, esophageal webs, achalasia, and epidermoid carcinoma of the head and neck. Tylosis (hyperkeratosis palmaris et plantaris) and squamous cell papilloma may be precursor lesions. Epiderm carcinoma is three times more common among blacks than whites. The 5-yr survival for American blac 4.1 vs. 6.5% for white men.
Adenocarcinoma: The incidence of adenocarcinoma of the distal esophagus is increasing, but the tu uncommon in blacks. Adenocarcinoma of the distal esophagus is difficult to distinguish from adenocar of the gastric cardia invading the distal esophagus.
Nearly all patients with primary adenocarcinoma of the distal esophagus first have Barrett's esophag which results from chronic gastroesophageal reflux disease and reflux esophagitis. In Barrett's esopha columnar, glandular, stomachlike mucosa replaces the stratified squamous epithelium of the distal eso during the healing phase of acute esophagitis. Most adenocarcinomas of the distal esophagus arise in Barrett's esophagus. Tobacco and alcohol are not important in the etiology of this tumor. Adenocarcin the distal esophagus may also have originated in the gastric fundus and spread submucosally around lower third of the esophagus.
Other malignant tumors: Less common malignant tumors of the esophagus include spindle cell carc poorly differentiated variant of epidermoid carcinoma), verrucous carcinoma (a well-differentiated varia epidermoid carcinoma), pseudosarcoma, mucoepidermoid carcinoma, adenosquamous carcinoma, cy (adenoid cystic carcinoma), primary oat cell carcinoma, choriocarcinoma, carcinoid tumor, sarcoma, a primary malignant melanoma.
Cancers of the larynx, pharynx, tonsil, lung, breast, stomach, liver, kidney, prostate, testis, bone, and s metastasize to the esophagus. These malignant tumors usually seed the loose connective tissue strom around the esophagus and grow toward the lumen, whereas primary esophageal cancers begin in the or submucosa and extend both outward and inward.
Symptoms and Signs
Early-stage esophageal cancer may go unnoticed. When the lumen of the esophagus becomes constr < 14 mm, dysphagia (difficulty swallowing, or the sensation that food is sticking on the way down the esophagus) is the most common symptom. The patient first has difficulty swallowing solid food, then s food, and finally liquid food and saliva; this progression over time suggests the presence of a growing malignant process rather than a spasm, benign ring, or peptic stricture. Chest pain usually radiates to
Weight loss, even when the patient maintains a good appetite, is almost universal. Compression of the recurrent laryngeal nerve may lead to vocal cord paralysis and hoarseness. Compression of sympathe nerves may produce Horner's syndrome, and nerve compression elsewhere may also produce spinal p hiccups, or paralysis of the diaphragm. Malignant pleural effusions or pulmonary metastasis may prod dyspnea. Intraluminal tumor involvement may produce odynophagia, vomiting, hematemesis, melena, iron-deficiency anemia, aspiration, cough, lung abscess, and pneumonia. Other symptoms may includ superior vena cava syndrome, malignant ascites, and bone pain.
Because the esophagus is drained along its entire length by a lymphatic plexus, internal jugular, cervic supraclavicular, mediastinal, and celiac lymphadenopathy may occur. The tumor usually metastasizes and liver and possibly to distant sites (eg, bone, heart, brain, adrenal glands, kidneys, peritoneum).
Diagnosis
Because the esophagus is drained along its entire length by a lymphatic plexus, internal jugular, cervic supraclavicular, mediastinal, and celiac lymphadenopathy may occur. The tumor usually metastasizes and liver and possibly to distant sites (eg, bone, heart, brain, adrenal glands, kidneys, peritoneum).
Diagnosis
Although barium x-ray may demonstrate obstructive lesions of the esophagus, endoscopy with biopsy cytology is the preferred diagnostic approach. Although biopsy may be positive in about 70% of patien yield on brush cytology is > 95% positive. Tumors are most often epidermoid carcinoma; of those outs gastroesophageal junction, 30 to 40% are adenocarcinoma.
Barium x-ray may be performed before endoscopy; it demonstrates the location of the tumor, reducin risk of inadvertent esophageal perforation or trauma during insertion of an endoscope. Barium x-ray m indicate the degree of tumor obstruction and whether cough and aspiration are caused by obstruction, of food and saliva into the trachea, or a tracheoesophageal fistula.
Endoscopy provides tissue for diagnostic biopsy and brushings and for additional measurement of tum and determination of location (in relation to the cricopharyngeus and diaphragm). Endoscopy also allo dilation and for placement of a stent to maintain the caliber of the esophageal lumen or to occlude a tracheoesophageal fistula.
CT of the neck, chest, abdomen, and pelvis may help stage the tumor by identifying enlarged lymph n metastasis to distant organs, and malignant fluid collections (pleural effusions, ascites) and may help determine resectability, placement of radiation fields, and prognosis. MRI is more expensive than CT, particular advantage, and is hampered by the lack of a good oral contrast agent.
Endoscopic ultrasound is a newer technique that may provide detailed assessment of the intramura (esophageal wall) extent of tumor and the involvement of adjacent lymph nodes. However, this techniq performed at only a few centers with special equipment and expertise.
Esophageal manometry and radioisotope scintigraphy are not very helpful in the diagnosis of esop cancer.
The overall prognosis for esophageal cancer is poor, with < 5% long-term survival. Overall age-adjuste mortality is 3.4 persons/100,000, which is very similar to the age-adjusted incidence because survival poor. Treatment decisions depend on accurate tumor staging, exact measurement of tumor size, locat the patient's wishes (many choose to forgo treatment).
The treatment option for epidermoid carcinoma is either surgical resection or radiotherapy. Adenocarc the distal esophagus is treated by distal esophagectomy. Radiotherapy is less important because adenocarcinoma is not as radiosensitive as epidermoid carcinoma. Barrett's esophagus responds inconsistently to medical or surgical therapy. Endoscopic surveillance of malignant transformation is of recommended at 3- to 12-month intervals depending on the degree of metaplasia, but its cost-effective controversial.
Surgery offers the patient the most prolonged palliation when feasible. Chemotherapy may prolong su some patients. Other palliative measures include dilation procedures, tube prosthesis (stent), radiothe and laser photocoagulation of the intraluminal mass.
Surgery offers the patient the most prolonged palliation when feasible. Chemotherapy may prolong su some patients. Other palliative measures include dilation procedures, tube prosthesis (stent), radiothe and laser photocoagulation of the intraluminal mass.
Chemotherapy, when used postoperatively, is similar to that used for adenocarcinoma of the mid- or d stomach (see Stomach Cancer, below).
Surgical therapy is associated with a low cure rate and a high mortality rate. Complication, 5-year sur and mortality rates are highly dependent on patient selection. En bloc resection is less likely to be cura those (1) > 75 yr, (2) whose tumor extends beyond the esophageal wall, (3) who have metastasis to ly nodes, (4) who have a cardiac ejection fraction < 40%, and (5) whose forced expiratory volume is < 1. However, palliative surgery is very successful: > 90% of patients will be able to eat a soft or solid diet.
The choice of operation depends on the location and size of the tumor, the experience of the surgeon, intent of surgery. En bloc resection for cure requires removal of the entire tumor, proximal and distal m of normal tissue, all potentially malignant lymph nodes, and a portion of the proximal stomach sufficien contain the distal draining lymphatics. The procedure requires gastric pull-up with esophagogastric anastomosis, small-bowel interposition, or colonic interposition. Pyloroplasty is required to ensure prop gastric drainage because an esophagectomy results in bilateral vagotomy.
Complications of surgery include anastomotic leaks and strictures, bilious gastroesophageal reflux, an dumping syndrome. The burning chest pain of bile reflux after distal esophagectomy can be more ann than the original symptom of dysphagia and may require subsequent Roux-en-Y jejunostomy for bile d An interposed segment of small bowel or colon has a tenuous blood supply, and torsion, ischemia, or gangrene of the interposed bowel may result.
External beam radiotherapy generally is reserved as primary therapy for patients who are poor cand for curative surgery, including those who have advanced disease. Radiotherapy is contraindicated in p with tracheoesophageal fistula because tumor shrinkage will enlarge the fistula. Similarly, patients with vascular encasement by tumor may experience massive hemorrhage when radiotherapy shrinks the tu During the early stages of radiotherapy, edema may worsen esophageal obstruction, dysphagia, and odynophagia. This may require esophageal dilation or placement of a percutaneous endoscopic gastro feeding tube at the beginning of radiotherapy to facilitate enteral nutrition. Other side effects of radioth include nausea, vomiting, anorexia, fatigue, esophagitis, excess esophageal mucus production, xerost stricture, radiation pneumonitis, radiation pericarditis, myocarditis, and myelitis (spinal cord injury).
Chemotherapy is usually used as an adjuvant to surgery or radiotherapy. Several drugs have antineo activity against epidermoid carcinoma when used as single agents, including fluorouracil (5-FU), mitom cisplatin, doxorubicin, vindesine, bleomycin, and methotrexate. Response rates (ie, the percentage of who experience a 50% reduction in all measurable areas of tumor) vary from 10 to 40%, but response generally are incomplete (minor shrinkage of tumor) and temporary. No agent is notably more effective another when response, survival, cost, and toxicity are considered. Cisplatin is most commonly used in combination chemotherapy because it has different adverse effects than the drugs with which it is use usually 5-FU and less commonly bleomycin.
Multimodality therapy (surgery, radiotherapy, and chemotherapy in the same treatment plan) has be to control both local disease and distant metastases. Multimodality therapy is experimental and of unc benefit.
Controlled trials have not established whether radiotherapy or chemotherapy should be given before o surgery and, if so, how much sooner or later. However, preoperative radiotherapy has been used to re tumor bulk, enhance the resectability of epidermoid carcinoma, and destroy microscopic local and reg
to control both local disease and distant metastases. Multimodality therapy is experimental and of unc benefit.
Controlled trials have not established whether radiotherapy or chemotherapy should be given before o surgery and, if so, how much sooner or later. However, preoperative radiotherapy has been used to re tumor bulk, enhance the resectability of epidermoid carcinoma, and destroy microscopic local and reg metastases adjacent to the area of resection. Similarly, preoperative chemotherapy has been used to tumor bulk, enhance the resectability rate of epidermoid carcinoma, and simultaneously control distan metastases. However, there is no evidence that preoperative therapy improves the cure rate.
Preoperative radiotherapy with chemotherapy needs further evaluation. Various combinations of preop radiotherapy with cisplatin, etoposide, and 5-FU have been studied. Although median survival was pro in some instances, postoperative recovery was also prolonged. There is not much evidence that posto radiotherapy combined with chemotherapy and scheduling of modalities prolongs survival compared w surgery alone. However, some data demonstrated that combined modality radiotherapy with 5-FU and may result in prolonged disease-free and overall survival in patients with unresected esophageal canc Benefit occurs in patients with adenomatous or squamous cell cancer and is superior to that achieved radiotherapy alone.
Bougienage (esophageal dilation) is an important adjuvant therapy for maintaining the patency of the esophageal lumen at any time during the course of illness. Newer dilators are passed under direct visi through the endoscope or under fluoroscopic control and are thus safer. The effect of esophageal dila be temporary. Esophageal stents maintain the patency of the esophageal lumen longer and can occlu lumen of a tracheoesophageal fistula.
Endoscopic neodymium:yttrium-aluminum-garnet laser therapy is used to palliate dysphagia by b central channel through the tumor. A distal-to-proximal technique allows the obstruction to be alleviate single treatment session (success rate is about 90%). Laser treatment is palliative, not curative, and c repeated. The complication rate for laser therapy is less than that for stent placement (10 vs. 20%).
Photodynamic therapy is primarily an experimental treatment designed to destroy tumor cells withou damaging surrounding normal tissues. A hematoporphyrin derivative that preferentially localizes in tum is injected IV; when photoactivated by argon dye laser or gold vapor laser, this substance releases cyt oxygen singlets within the tumor.
In extracorporeal bypass, the esophagus proximal to the tumor is connected to a tube that is brough through the skin, passed along the outside of the chest, and run back into the body at the level of the abdomen, where its distal end is inserted into the stomach. With this technique, the esophageal tumor resected. Nutritional support by enteral or parenteral supplementation enhances the tolerability and feasibility treatments.
Because nearly all cases of esophageal cancer are fatal, end-of-life care (see Ch. 294) should always control symptoms, especially pain and inability to swallow secretions. At some point, many patients ne substantial doses of narcotic analgesics to control these symptoms (ie, pain from progressive maligna

Section 3. Gastrointestinal Disorders Chapter 26. Pancreatitis Topics
[General] Acute Pancreatitis Chronic Pancreatitis
[General]
Pancreatitis: Inflammation of the pancreas.
Pancreatitis is classified as either acute or chronic. Acute pancreatitis refers to an acute inflammation resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic changes th persist even after the cause has been removed. The histologic changes in chronic pancreatitis are irre and tend to progress, resulting in serious loss of exocrine and endocrine pancreatic function and deter of pancreatic structure. However, possible discordance between clinical and histologic components ma complicate classification; eg, alcoholic pancreatitis may initially present as acute clinically but may alre chronic histologically.

Section 3. Gastrointestinal Disorders Chapter 35. Anorectal Disorders Topics
[General] Hemorrhoids Anal Fissure Anorectal Abscess Anorectal Fistula Levator Syndrome Proctitis Pilonidal Disease Rectal Prolapse And Procidentia Fecal Incontinence Pruritus Ani Foreign Bodies In The Rectum
[General]
The anal canal is derived from invagination of the ectoderm, and the rectum, from invagination of the entoderm. The resultant anatomic differences are important in evaluating and treating anorectal disord anal canal is lined with anoderm, a continuation of the external skin; the rectal lining consists of red, gl glandular mucosa. The anal canal and adjacent external skin are generously supplied with somatic se nerves and are highly susceptible to painful stimuli; the rectal mucosa has an autonomic nerve supply relatively insensitive to pain.
At the superior boundary of the anal canal is the anorectal junction (pectinate line, mucocutaneous jun dentate line), where there are 8 to 12 anal crypts and 5 to 8 papillae. Anorectal abscesses and fistulas originate in relation to the crypts.
The sphincteric ring encircling the anal canal is composed of the fusion of the internal sphincter, the ce portion of the levators, and the components of the external sphincter. Anteriorly, it is more vulnerable t trauma, which can result in incontinence. The puborectalis forms a muscular sling around the rectum f support and assistance in defecation.
Venous drainage above the anorectal junction is through the portal system; the anal canal is drained t the caval system. The area of the anorectal junction can drain into both the portal and caval systems. Lymphatics from the anal canal pass to the internal iliac nodes, the posterior vaginal wall (in women), inguinal nodes, whereas lymphatic return from the rectum is along the superior hemorrhoidal vascular to the inferior mesenteric and aortic nodes. The venous and lymphatic distributions determine how ma disease and infection spread.
Venous drainage above the anorectal junction is through the portal system; the anal canal is drained t the caval system. The area of the anorectal junction can drain into both the portal and caval systems. Lymphatics from the anal canal pass to the internal iliac nodes, the posterior vaginal wall (in women), inguinal nodes, whereas lymphatic return from the rectum is along the superior hemorrhoidal vascular to the inferior mesenteric and aortic nodes. The venous and lymphatic distributions determine how ma disease and infection spread.
History should include the details of bleeding, pain, protrusion, discharge, swelling, abnormal sensatio bowel movements, nature of the stool, use of cathartics and enemas, and abdominal and urinary symp is important to ask all patients about anal intercourse or other anal insertion trauma.
Examination should be performed gently and with good lighting. It consists of external inspection, per and intrarectal digital palpation, abdominal examination, and rectovaginal bidigital palpation (in women Anoscopy and rigid or flexible sigmoidoscopy to 15 to 60 cm above the anal verge are often included. Inspection, palpation, and anoscopy and sigmoidoscopy are best performed with the patient in the left (Sims') or knee-chest position or inverted on a tilt table. In cases of painful anal lesions, topical (lidoca ointment), regional, or even general anesthesia may be required. If it can be tolerated, a cleansing pho enema may facilitate sigmoidoscopy. Biopsies, smears, and cultures may be taken, and an x-ray exam should be ordered if indicated.

Section 3. Gastrointestinal Disorders Chapter 27. Diarrhea And Constipation Topics
[General] Diarrhea Constipation
[General]
No bodily function is more variable and subject to extraneous influences than defecation. Bowel habits considerably among persons and are affected by age, physiology, diet, and social and cultural influenc Western society, normal stool frequency ranges from 2 to 3/day to 2 to 3/wk. Changes in stool frequen consistency, or volume or blood, mucus, pus, or excess fatty material (eg, oil, grease, film) in the stool indicate disease. Individual preoccupation with bowel habits sometimes causes unwarranted concern.

Section 15. Psychiatric Disorders Chapter 185. Psychiatry In Medicine Topics
[General] Psychiatric Referral Psychosomatic Medicine Munchausen Syndrome
[General]
An organ- and disease-specific approach to diagnosis and therapy often goes awry when the person w organs and disease is ignored. Relating the patient's complaints and disabilities to his personality and circumstances helps determine the nature and causes of the complaints and disabilities.
To assess the patient's personality, a physician has first to listen attentively and show interest in the pa a person. Conducting an interview hastily and indifferently with close-ended queries (following a rigid a of system review) is more likely to prevent the patient from revealing relevant information than help him it. Tracing the history of the presenting illness with open-ended questions that permit the patient to tell in his own words takes no longer but enables him to describe associated social circumstances and rev emotional reactions.
The patient should be asked about his social background, medical and psychiatric history, and adjustm different stages of life. His parents' characteristics and the family atmosphere during his childhood are important because personality features that influence the way a person handles illness and adversity a determined early in life. Information about his behavior during schooling, handling of puberty and adole and of different family and social roles, stability and effectiveness at work, sexual adaptation, pattern o life, and quality and stability of marriage help in appraising his personality. The physician should tactfu about use or abuse of alcohol, drugs, and tobacco; behavior while driving; and any tendencies to antis conduct. The patient's responses to the usual vicissitudes of life--failures, setbacks, losses, previous illnesses--are important.
The personality profile that emerges from these inquiries may include such traits as self-centerednes immaturity, excessive dependency, anxiety, tendencies to deny illness, histrionic behavior, and poor to of frustration or courage, resilience, conscientiousness, modesty, and adaptability. The history may re patterns of repetitive behavior during stress--whether distress is expressed in physical symptoms (eg, headache, abdominal pain), psychologic symptoms (eg, phobic behavior, depression), or social behav withdrawal, rebelliousness). Attitudes should be noted, eg, toward taking drugs in general or specific ty steroids, sedatives) and toward physicians or hospitals. With this information, the physician can better
immaturity, excessive dependency, anxiety, tendencies to deny illness, histrionic behavior, and poor to of frustration or courage, resilience, conscientiousness, modesty, and adaptability. The history may re patterns of repetitive behavior during stress--whether distress is expressed in physical symptoms (eg, headache, abdominal pain), psychologic symptoms (eg, phobic behavior, depression), or social behav withdrawal, rebelliousness). Attitudes should be noted, eg, toward taking drugs in general or specific ty steroids, sedatives) and toward physicians or hospitals. With this information, the physician can better the patient's complaints, anticipate his reactions to the illness, and plan appropriate therapy.
Observation during the interview also provides valuable data. A patient may be depressed and pes or cheerful, facile, and prone to deny illness; he may be friendly and warm or reserved, cold, and susp Nonverbal communication may reveal attitudes and affects denied by the patient's words. For example patient who chokes up or becomes tearful when discussing a parent's death is revealing that it was a significant loss and suggesting that he has unresolved grief. A tear, overt weeping, or other such manifestations of emotion should be recorded as physical signs in the patient's chart. Similarly, if a pa denies being angry, anxious, or depressed while his posture, gestures, and facial expression reveal ot further inquiry may uncover stresses and emotionally depressing circumstances possibly related to the evolution of the present illness. However, such inquiries may lead to erroneous conclusions. Discrimin experienced judgment helps determine whether psychologic conflicts are significant, of limited importa coincidental to the patient's physical disorder.

Section 15. Psychiatric Disorders Chapter 191. Personality Disorders Topics
[General]
[General]
(See also Dissociative Identity Disorder in Ch. 188.)
Personality disorders: Pervasive, inflexible, and stable personality traits that deviate from cultural norm cause distress or functional impairment.
Personality traits are patterns of thinking, perceiving, reacting, and relating that are relatively stable ov and in various situations. Personality disorders occur when these traits are so rigid and maladaptive th impair interpersonal or vocational functioning. Personality traits and their potential maladaptive signific usually evident from early adulthood and persist throughout much of life.
Mental coping mechanisms (defenses) are used unconsciously at times by everyone. But in persons personality disorders, coping mechanisms tend to be immature and maladaptive (see Table 191-1). Repetitious confrontation in prolonged psychotherapy or by peer encounters is usually required to mak persons aware of these mechanisms.
Without environmental frustration, persons with personality disorders may or may not be dissatisfied w themselves. They may seek help because of symptoms (eg, anxiety, depression) or maladaptive beha substance abuse, vengefulness) that results from their personality disorder. Often they do not see a ne therapy, and they are referred by their peers, their families, or a social agency because their maladapt behavior causes difficulties for others. Because these patients usually view their difficulties as discrete outside of themselves, mental health professionals have difficulty getting them to see that the problem based on who they are.
Persons with severe personality disorders are at high risk of hypochondriasis, alcohol or drug abuse, a violent or self-destructive behaviors. They may have inconsistent, detached, overemotional, abusive, o irresponsible styles of parenting, leading to medical and psychiatric problems for their children. Person personality disorder are less likely to comply with a prescribed treatment regimen. Even when they do, symptoms--whether psychotic, depressive, or anxious--are far less responsive to drugs. Persons with personality disorders are often very frustrating to those around them, including physicians--who have t with their unrealistic fears, excessive demands, sense of entitlement, unpaid bills, noncompliance, and
violent or self-destructive behaviors. They may have inconsistent, detached, overemotional, abusive, o irresponsible styles of parenting, leading to medical and psychiatric problems for their children. Person personality disorder are less likely to comply with a prescribed treatment regimen. Even when they do, symptoms--whether psychotic, depressive, or anxious--are far less responsive to drugs. Persons with personality disorders are often very frustrating to those around them, including physicians--who have t with their unrealistic fears, excessive demands, sense of entitlement, unpaid bills, noncompliance, and vilification. Such persons can also cause stress for other patients who are exposed to their dramatic o demanding behaviors.
Diagnosis and Classification
Diagnosis is based on observing repetitive patterns of behavior or perception that cause distress and i social functioning, even when the patient lacks insight about these patterns and despite the fact that th patient often resists change.
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), divides personalit disorders into three clusters: A) odd/eccentric, B) dramatic/erratic, and C) anxious/inhibited.
Cluster A
Paranoid personality: Persons with this personality disorder are generally cold and distant in interper relationships or are controlling and jealous if they become attached. They tend to react with suspicion changes in situations and to find hostile and malevolent motives behind other people's trivial, innocent positive acts. Often these hostile motives represent projections of their own hostilities onto others (see Ch. 193). When they believe they have confirmed their suspicions, they sometimes react in ways that or scare others. They then use the resulting anger of or rejection by others (ie, projective identification justify their original feelings. Paranoid persons tend to take legal action against others, especially when feel a sense of righteous indignation. However, they cannot see their role in a conflict. In their occupat these persons may be highly efficient and conscientious, although they usually need to work in relative isolation.
Paranoid tendencies may develop among persons who feel particularly alienated because of a defect handicap. For example, a person with chronic deafness may mistakenly think he is being talked about laughed at.
Schizoid personality: Persons with this personality disorder are introverted, withdrawn, solitary, emot cold, and distant. They are most often absorbed in their own thoughts and feelings and fear closeness intimacy with others. They are reticent, are given to daydreaming, and prefer theoretic speculation to p action.
Schizotypal personality: Like schizoid persons, persons with this personality disorder are socially iso and emotionally detached, but in addition, they express oddities of thinking, perception, and communic such as magical thinking, clairvoyance, ideas of reference, or paranoid ideation. These oddities sugge schizophrenia but are never severe enough to meet its criteria (see Ch. 193). Nonetheless, persons w personality disorder are believed to have a muted phenotypic expression (spectrum variant) of the gen cause schizophrenia.
Cluster B
Borderline personality: Persons with this personality disorder--predominantly women--are unstable in self-image, mood, behavior, and interpersonal relationships. This personality disorder becomes eviden adult years, but it tends to become milder or to stabilize with age. Such persons believe they were dep
Cluster B
Borderline personality: Persons with this personality disorder--predominantly women--are unstable in self-image, mood, behavior, and interpersonal relationships. This personality disorder becomes eviden adult years, but it tends to become milder or to stabilize with age. Such persons believe they were dep adequate care during their childhood and consequently feel empty, angry, and entitled to nurturance. A result, they are relentless seekers of care. This personality disorder is by far the most common type se psychiatric and all other types of health care services.
When persons with a borderline personality feel cared for, they appear like lonely waifs, who seek help depression, substance abuse, eating disorders, and past mistreatments. However, when they fear the the caring person, their mood shifts dramatically and is frequently expressed as inappropriate and inte anger. The shift in mood is accompanied by extreme changes in their view of the world, themselves, a others--from black to white, from hated to loved, or vice versa (see splitting in Table 191-1). Their view neutral. When they feel abandoned (ie, all alone), they dissociate or become desperately impulsive. A their concept of reality is so poor that they have brief episodes of psychotic thinking, such as paranoid and hallucinations.
Such persons have far more dramatic and intense interpersonal relationships than those with cluster A personality disorders. Their thought processes are disturbed more than those of persons with an antis personality, and aggression is more often turned against the self. They are more angry, more impulsiv more confused about identity than those with a histrionic personality. They tend to evoke intense, initia nurturant responses in caretakers. But after repeated crises, vague unfounded complaints, and failure comply with therapeutic recommendations, caretakers--including the physician--often become very fru with them and view them as help-rejecting complainers. Splitting, acting out, hypochondriasis, and pro are common coping mechanisms (see Table 191-1).
Antisocial personality (previously called psychopathic or sociopathic): Persons with this personalit disorder callously disregard the rights and feelings of others. They exploit others for materialistic gain o personal gratification (unlike narcissistic persons, who exploit others because they think their superiori justifies it). Characteristically, they act out their conflicts in impulsive and irresponsible ways, sometime hostility and serious violence. They tolerate frustration poorly. Often they do not anticipate the negative consequences of their antisocial behaviors and typically do not feel remorse or guilt afterward. Many o have a well-developed capacity for glibly rationalizing their behavior or for blaming it on others. Dishon deceit permeate their relationships. Punishment rarely modifies their behavior or improves their judgm foresight; it usually confirms their harshly unsentimental view of the world.
Antisocial personality disorder is often associated with alcoholism, drug addiction, infidelity, promiscuit in one's occupation, frequent relocation, and imprisonment. In Western culture, more men have this personality disorder than women, and more women have a borderline personality; these two disorders much in common. In the families of patients with both personality patterns, the prevalence of antisocia relatives, substance abuse, divorces, and childhood abuse is high. Often, the patient's parents have a relationship, and the patient was severely emotionally deprived in his formative years. Life expectancy decreased, but among survivors, the disorder tends to diminish or stabilize with age.
Narcissistic personality: Persons with this personality disorder are grandiose; ie, they have an exagg sense of superiority. Their relationships with others are characterized by their need to be admired, and are extremely sensitive to criticism, failure, or defeat. When confronted with a failure to fulfill their high of themselves, they can become enraged or seriously depressed. Because they believe themselves to superior, they often believe others envy them and feel entitled to have their needs attended to without Thus they can justify exploiting others whose needs or beliefs they consider less important. Such characteristics often offend persons they encounter, including their physicians. This personality disord in high achievers but may also occur in persons with few achievements.
are extremely sensitive to criticism, failure, or defeat. When confronted with a failure to fulfill their high of themselves, they can become enraged or seriously depressed. Because they believe themselves to superior, they often believe others envy them and feel entitled to have their needs attended to without Thus they can justify exploiting others whose needs or beliefs they consider less important. Such characteristics often offend persons they encounter, including their physicians. This personality disord in high achievers but may also occur in persons with few achievements.
Histrionic (hysterical) personality: Persons with this personality disorder conspicuously seek attenti conscious of appearance, and are dramatic. Their expression of emotions often seems exaggerated, c and superficial and, like other dramatic behaviors, often evokes sympathetic or erotic attention from ot Thus relationships are often easily established but tend to be superficial and transient. These persons combine sexual provocativeness or sexualization of nonsexual relationships with unexpected sexual in and dissatisfactions. Behind their sexually seductive behaviors and their tendency to exaggerate soma problems (ie, hypochondriasis) often lie more basic wishes for dependency and protection.
Cluster C
Dependent personality: Persons with this disorder surrender responsibility for major areas of their liv others and allow the needs of those they depend on to supersede their own needs. They lack self-con and feel intensely insecure about their ability to take care of themselves. They often protest that they c make decisions and do not know how or what to do. This behavior is due partly to a belief that others a capable and partly to a reluctance to express their views for fear of offending persons they need with t aggressiveness (ie, a form of aggression against self). Dependency occurs in other personality disorde where it may be hidden by obvious behavioral problems; eg, histrionic or borderline behaviors mask un dependency.
Avoidant personality: Persons with this personality disorder are hypersensitive to rejection and fear s relationships or anything new because they may fail or be disappointed. This personality disorder is a spectrum variant of generalized social phobia (see Ch. 187). Because of their strong conscious desire affection and acceptance, persons with an avoidant personality disorder, unlike those with a schizoid personality disorder, are openly distressed by their isolation and inability to relate comfortably to others those with a borderline personality disorder, they respond to rejection with withdrawal, not temper tant Persons with an avoidant personality disorder tend to have an incomplete or a weak response to anxio drugs.
Obsessive-compulsive personality: Persons with this personality disorder are conscientious, orderly reliable, but their inflexibility often makes them unable to adapt to change. Because they are cautious weigh all aspects of a problem, they may have difficulty making decisions. They take responsibilities s but because they hate mistakes and incompleteness, they can become entangled with details and forg purpose of or have trouble completing their tasks. As a result, their responsibilities cause them anxiety they rarely enjoy much satisfaction from their achievements.
Most obsessive-compulsive traits are adaptive, and as long as they are not too marked, persons who h them often achieve much, especially in the sciences and other academic fields in which order, perfecti and perseverance are desirable. However, they can feel uncomfortable with feelings, interpersonal relationships, and situations in which they lack control or must rely on others or in which events are unpredictable.
Other Personality Types
Passive-aggressive, cyclothymic, and depressive types of personality disorders are not classified in th DSM-IV. Yet, they can be useful diagnoses.
Other Personality Types
Passive-aggressive, cyclothymic, and depressive types of personality disorders are not classified in th DSM-IV. Yet, they can be useful diagnoses.
Passive-aggressive (negativistic) personality: Persons with this personality disorder typically appea or passive, but these behaviors are covertly designed to avoid responsibility or to control or punish oth Passive-aggressive behavior is often evident in procrastination, inefficiency, or unrealistic protests of d Frequently, such persons agree to perform tasks they do not want to perform and then subtly undermi completion of the tasks. Such behavior usually serves to deny or conceal hostility or disagreements. Cyclothymic personality (see also Ch. 189)
In persons with this personality disorder, high-spirited buoyancy alternates with gloom and pessimism; mood lasts weeks or longer. Characteristically, the rhythmic mood changes are regular and occur with justifiable external cause. This personality disorder is a spectrum variant of manic-depressive illness (b disorder), but most cyclothymic persons do not develop bipolar disorder. Cyclothymic personality is co a temperament, present in many gifted and creative people.
Depressive (masochistic) personality: Persons with depressive personality disorder are chronically worried, and self-conscious. Their pessimistic outlook impairs their initiative and disheartens persons w spend much time with them. To them, self-satisfaction is undeserved and sinful. They unconsciously b their suffering is a badge of merit needed to earn the love or admiration of others. This personality diso considered a temperament that usually does not result in social dysfunction.
Treatment
Treating a personality disorder takes a long time. Personality traits such as coping mechanisms, belief behavior patterns take many years to develop, and they change slowly. Changes usually occur in a pr sequence, and different treatment modalities are needed to facilitate them. Reducing environmental st quickly relieve symptoms such as anxiety or depression. Behaviors, such as recklessness, social isola of assertiveness, or temper outbursts, can be changed in months. Group therapy and behavior modific sometimes within day care or designed residential settings, are effective. Participation in self-help grou family therapy can also help change socially undesirable behaviors. Behavioral change is most import patients with borderline, antisocial, or avoidant personality disorder.
Interpersonal problems, such as dependency, distrust, arrogance, or manipulativeness, usually take > change. The cornerstone for effecting interpersonal changes is individual psychotherapy that helps the understand the sources of his interpersonal problems in the context of an intimate, cooperative, nonexploitative physician-patient relationship. A therapist must repeatedly point out the undesirable consequences of the patient's thought and behavior patterns and must sometimes set limits on his beh Such therapy is essential for patients with histrionic, dependent, or passive-aggressive personality diso For some patients with personality disorders that involve how attitudes, expectations, and beliefs are m organized (eg, narcissistic or obsessive-compulsive types), psychoanalysis is recommended, usually f years.
General principles: Although treatment differs according to the type of personality disorder, some ge principles apply to all. Family members can act in ways that either reinforce or diminish the patient's problematic behavior or thoughts, so their involvement is helpful and often essential.
Drugs have limited effects. They can be misused or used in suicide attempts. When anxiety and depre result from a personality disorder, drugs are only moderately effective. For persons with personality dis
General principles: Although treatment differs according to the type of personality disorder, some ge principles apply to all. Family members can act in ways that either reinforce or diminish the patient's problematic behavior or thoughts, so their involvement is helpful and often essential.
Drugs have limited effects. They can be misused or used in suicide attempts. When anxiety and depre result from a personality disorder, drugs are only moderately effective. For persons with personality dis anxiety and depression may have positive significance, ie, that the person is experiencing unwanted consequences of his disorder or is undertaking some needed self-examination.
Because personality disorders are particularly difficult to treat, therapists with experience, enthusiasm, understanding of the patient's expected areas of emotional sensitivity and usual ways of coping are im Kindness and direction alone do not change personality disorders.

Section 15. Psychiatric Disorders Chapter 186. Somatoform Disorders Topics
[General] Somatization Disorder Conversion Disorder Hypochondriasis Pain Disorder Body Dysmorphic Disorder
[General]
Somatoform disorders: A group of psychiatric disorders characterized by physical symptoms that sugg are not fully explained by a physical disorder and that cause significant distress or interfere with social occupational, or other functioning.
Somatoform disorder is a relatively new term for what many persons refer to as psychosomatic disorde somatoform disorders, either the physical symptoms or their severity and duration cannot be explained underlying physical condition. The somatoform disorders include somatization disorder, undifferentiate somatoform disorder, conversion disorder, hypochondriasis, pain disorder, body dysmorphic disorder, somatoform disorder not otherwise specified.

Section 15. Psychiatric Disorders Chapter 192. Psychosexual Disorders Topics
[General] Sexual Dysfunctions Gender Identity Disorders Paraphilias
[General]
Psychosexual disorders include sexual dysfunctions, the most common form of psychosexual disorder the practicing physician; gender identity disorders; and paraphilias.
Accepted norms of sexual behavior and attitudes vary greatly within and among different cultures. Masturbation, once widely regarded as a perversion and a cause of mental disorders, is now recogni normal sexual activity throughout life; it is considered a symptom only when it inhibits partner-oriented behavior, is performed in public, or is sufficiently compulsive to cause distress. Its incidence is about 9 males and 80% in females. Although masturbation is harmless, guilt created by the disapproval and pu attitudes of others may cause considerable distress and impair sexual performance.
About 4 to 5% of the population are preferentially homosexual for their entire lives. Since 1973, the A Psychiatric Association has not considered homosexuality a disorder. Like heterosexuality, homosexu results from complex biologic and environmental factors leading to an almost inevitable preference in t selection of a sexual partner. For most, it is not a matter of choice. Nevertheless, many people, includi physicians, regard homosexuality as immoral and sinful, and a physician's intense aversion to homose (homophobia) may interfere with appropriate care of homosexuals.
Frequent sexual activity with many partners, often one-time-only encounters, indicates a diminished for pair-bonding. The fear of AIDS has resulted in a decrease in casual sex. Most cultures discourage extramarital sexuality but accept premarital coitus as normal. In the USA, most people have intercours marriage, as part of the trend toward more sexual freedom in developed countries.
Well-informed physicians can offer sensitive, disciplined advice on sexual matters and should not miss opportunities for helpful intervention, remembering that sexual practices differ by culture and that the s of the sexual drive, individual needs, and the frequency of sexual contact vary greatly.
Etiology
Well-informed physicians can offer sensitive, disciplined advice on sexual matters and should not miss opportunities for helpful intervention, remembering that sexual practices differ by culture and that the s of the sexual drive, individual needs, and the frequency of sexual contact vary greatly.
Etiology
The etiology of psychosexual disorders is complex and varies greatly. Inherited or subtle constitutiona probably play a part. Fetal androgens help prepare the brain for later sexual activity; interference with process may not be damaging in itself, but it may make a person vulnerable to damaging environment influences during childhood psychosexual development.
Parental attitudes toward sexual behavior are important (see also Gender Identity Disorders, below). A forbidding, puritanical rejection of physical sexuality, including touching, by a parent engenders guilt an shame in a child and inhibits his capacity for enjoying sex and developing healthy relationships as an a Relations with parents may be damaged by excessive emotional distance, by punitive behaviors, or by seductiveness and exploitation. Children exposed to hostility, rejection, and cruelty are likely to becom sexually maladjusted. Children need to feel accepted and lovable. (Enabling a person to have confiden he is capable and worthy of being loved for himself is a goal of therapy.)
Problems with parent-child relationships can contribute to sexual dysfunctions, gender identity disorde transsexualism, transvestism), or paraphilias (see below). Love and lust may become dissociated, so t emotional bonds can be formed with persons from the same social class or intellectual circle, but phys sexual relationships can be formed only with those considered inferiors, such as prostitutes, with whom is no affinity or emotional ties. Sexual intercourse with one's spouse is associated with guilt and anxiet sexual release occurs only in relationships or practices in which tender, caring feelings are not arouse
The pattern of erotic arousal is fairly well developed before puberty; therefore, if a gender identity diso paraphilia develops, causes should be sought in the prepubertal years. Three processes are involved: interferes with normal psychosexual development; the standard pattern of arousal is replaced by anoth which allows the person to experience sexual pleasure; and the pattern of sexual arousal often acquire symbolic and conditioning facets (eg, a fetish symbolizes the object of arousal but may have been cho because the fetish was accidently associated with sexual curiosity, desire, and excitement). Whether a transsexual or paraphilic development results from these psychodynamic processes is controversial.

Section 15. Psychiatric Disorders Chapter 187. Anxiety Disorders Topics
[General] Panic Attacks And Panic Disorder Phobic Disorders Obsessive-Compulsive Disorder Posttraumatic Stress Disorder Acute Stress Disorder Generalized Anxiety Disorder Anxiety Due To A Physical Disorder Or A Substance
[General]
All humans experience fear and anxiety. Fear is an emotional, physiologic, and behavioral response to recognized external threat (eg, an intruder, a runaway car). Anxiety is an unpleasant emotional state; i causes are less clear. Anxiety is often accompanied by physiologic changes and behaviors similar to t caused by fear.
Adaptive anxiety helps people prepare, practice, and rehearse so that their functioning is improved an them be appropriately cautious in potentially dangerous situations. Maladaptive anxiety causes distres dysfunction. The Yerkes-Dodson curve (see Fig. 187-1) shows the relationship between emotional aro (anxiety) and performance. As anxiety increases, performance efficiency increases proportionately bu an optimal level, beyond which performance efficiency decreases with further increases in anxiety. Anxiety disorders are more common than any other class of psychiatric disorder. However, they often recognized and consequently not treated.
Etiology
The causes of anxiety disorders are not fully known, but both physiologic and psychologic factors are i Physiologically, all thoughts and feelings may be understood as resulting from electrochemical proces the brain, but this fact tells little about the complex interactions among the > 200 neurotransmitters and neuromodulators of the brain and about normal vs. abnormal arousal and anxiety. Psychologically, an viewed as a response to environmental stressors, such as the rupture of a significant relationship or e to a life-threatening disaster.
A person's anxiety system usually makes appropriate and imperceptible shifts from sleep through arou
the brain, but this fact tells little about the complex interactions among the > 200 neurotransmitters and neuromodulators of the brain and about normal vs. abnormal arousal and anxiety. Psychologically, an viewed as a response to environmental stressors, such as the rupture of a significant relationship or e to a life-threatening disaster.
A person's anxiety system usually makes appropriate and imperceptible shifts from sleep through arou anxiety and fear. Anxiety disorders occur when the anxiety system operates improperly or, sometimes is overwhelmed by events.
Anxiety disorders may be due to a physical disorder or use of a legal or illicit drug (see below). For exa hyperthyroidism or use of corticosteroids or cocaine may produce symptoms and signs identical to tho certain primary anxiety disorders.
Symptoms and Diagnosis
Anxiety can arise suddenly, as in panic, or gradually over many minutes, hours, or even days. Anxiety from a few seconds to years; longer duration is often associated with anxiety disorders. Anxiety ranges intensity from barely noticeable qualms to complete panic, its most extreme form. One person's passio be another's anxiety (eg, some find speaking before a group exhilarating, whereas others dread it), an ability to tolerate anxiety varies from person to person.
Anxiety disorders can be so distressing and disruptive that depression may result. Alternatively, an an disorder and depression may coexist, or depression may develop first, with symptoms and signs of an disorder developing later.
Deciding when anxiety is so severe that it is a disorder depends on several variables, and physicians d making the diagnosis. If anxiety is very distressing, interferes with functioning, and does not stop spontaneously within a few days, an anxiety disorder is present and merits treatment.
Diagnosis of a specific anxiety disorder is based largely on its characteristic symptoms and signs. A fa history of anxiety disorders (except posttraumatic stress disorder) is helpful, because many patients ap have inherited a predisposition to the same anxiety disorders their relatives have as well as a general susceptibility to other anxiety disorders.
Anxiety disorders must be distinguished from anxiety that occurs in many other psychiatric disorders, b they respond to different specific treatments.
Section 15. Psychiatric Disorders Chapter 193. Schizophrenia And Related Disord Topics
[General] Schizophrenia Brief Psychotic Disorder Schizophreniform Disorder Schizoaffective Disorder Delusional Disorder
[General]
In terms of personal and economic costs, schizophrenia has been described as among the worst disea afflicting humankind. Schizophrenia and the related disorders included in this chapter--brief psychotic schizophreniform disorder, schizoaffective disorder, and delusional disorder--are characterized by psy symptoms, which may include delusions, hallucinations, disorganized thinking and speech, and bizarre inappropriate behavior. Typically, these disorders affect patients in late adolescence or early adulthoo are often lifelong. Schizotypal personality disorder may share features with schizophrenia (eg, para ideation, magical thinking, social avoidance, vague and digressed speech), but they are generally not enough to meet the criteria for psychosis.

Section 15. Psychiatric Disorders Chapter 188. Dissociative Disorders Topics
[General] Dissociative Amnesia Dissociative Fugue Dissociative Identity Disorder Depersonalization Disorder
[General]
Dissociative disorders: Failure to integrate one's memories, perceptions, identity, or consciousness no
Everyone occasionally experiences dissociation without its being disruptive. For example, a person ma somewhere and then realize that he does not remember many aspects of the drive because of preocc with personal concerns, a program on the radio, or conversation with a passenger. Perception of pain become dissociated under hypnosis. However, other forms of dissociation disrupt a person's sense of the recollection of life events. When memory is poorly integrated, dissociative amnesia occurs. When is fragmented along with memory, dissociative fugue or dissociative identity disorder occurs. Whe experience and perception of self are disrupted, depersonalization disorder occurs.
Dissociative disorders are usually associated with overwhelming stress, which may be generated by tr life events, accidents, or disasters that are experienced or witnessed or by intolerable inner conflict tha the mind to separate incompatible or unacceptable information and feelings.

Section 15. Psychiatric Disorders Chapter 194. Psychiatric Emergencies Topics
[General]
[General]
Patients with psychiatric symptoms requiring immediate attention frequently present in the emergency department, where triage, assessment, and treatment decisions must often be made without complete information. A clinical psychiatric examination should be supplemented by interviews with relatives or o who accompany the patient. If the patient is already receiving psychiatric care, information should be o from the patient's clinician if possible. The initial information may suggest the need for laboratory or ot diagnostic studies.
The physician must decide whether a patient should be held against his will to ensure the immediate s the patient or others or to allow an emergency assessment to be completed. Some behaviors that are dangerous to self or others may require temporary detention. When the assessment is complete, the p must decide on the least restrictive environment to which the patient can be safely discharged for cont care. Psychiatric emergencies may require a general medical evaluation before a treatment decision c made, hospitalization or other institutional support, psychotherapeutic intervention, or minimal or more comprehensive pharmacologic intervention.
Emergencies Requiring a General Medical Evaluation
Panic attacks must be evaluated to rule out other disorders associated with anxiety, including psycho delusional disorders, phobias, substance abuse or withdrawal, thyrotoxicosis, MI, mitral valve prolapse pheochromocytoma, hyperventilation, and cardiac arrhythmias.
Panic attacks may be treated with propranolol 10 to 30 mg/day po to decrease the peripheral manifest anxiety or clonazepam 0.5 to 2 mg bid (a long-acting benzodiazepine) or alprazolam 0.5 to 1.5 mg bid short-term treatment. Long-term treatment is discussed in Ch. 187.
Mania (see Ch. 189) can be a manifestation of a primary psychiatric disorder (bipolar disorder) or a pr physical disorder affecting the CNS (eg, Cushing's disease, closed head injury, cerebrovascular accide hyperthyroidism). Mania can also be an adverse effect of various drugs, including corticosteroids, cycl other immunosuppressants, amphetamines, baclofen, bromocriptine, captopril, cimetidine, disulfiram, hydralazine, isoniazid, levodopa, methylphenidate, metrizamide, opioids, procarbazine, procyclidine, a
Mania (see Ch. 189) can be a manifestation of a primary psychiatric disorder (bipolar disorder) or a pr physical disorder affecting the CNS (eg, Cushing's disease, closed head injury, cerebrovascular accide hyperthyroidism). Mania can also be an adverse effect of various drugs, including corticosteroids, cycl other immunosuppressants, amphetamines, baclofen, bromocriptine, captopril, cimetidine, disulfiram, hydralazine, isoniazid, levodopa, methylphenidate, metrizamide, opioids, procarbazine, procyclidine, a yohimbine. Patients with bipolar disorder may have a relapse of mania when their depression is treate antidepressants or bright light therapy.
Psychosis occurs in schizophrenia, bipolar disorder, delusional disorders, and major depression. For episode or acute onset of psychosis, the same physical disorders and drugs associated with mania (se above) must be excluded, but extensive diagnostic reevaluation is generally not needed when relapse in a patient known to have a chronic psychotic disorder.
Delirium (see Ch. 171) is caused by a wide variety of toxic and metabolic conditions, and diagnosis re known or presumed identifiable etiology.
Dissociative episodes (see Ch. 188) are noted only after other causes of altered memory (eg, head i cerebrovascular accident, seizure disorder) have been excluded.
Catatonia is diagnosed only after other causes of psychomotor excitement or stupor are excluded, inc drug intoxication causing psychomotor excitement; antipsychotic drugs or antidepressants (eg, selectiv serotonin reuptake inhibitors) causing akathisia; mania; neurologic insult (eg, cerebrovascular acciden severe Parkinson's disease causing psychomotor stupor; neuroleptic malignant syndrome; serotonin syndrome; and benzodiazepine overdose.
Conversion disorders (see Chs. 185 and 186) have a psychologic component and mimic pathophysi disorders, such as blindness or paralysis; however, the anatomic distribution of symptoms usually refle layman's view of structure. Physical disorders must be ruled out before diagnosing conversion disorde
Seizures (see Ch. 172) that are not generalized tonic-clonic seizures can be difficult to differentiate fro psychiatric and physical disorders. Temporal lobe and absence seizures can cause dissociation of consciousness. Assessment of new-onset bizarre or stereotypical behavior should include a neurologi evaluation and EEG.
Assessment of patients with suspected alcohol withdrawal (see Alcoholism in Ch. 195) should includ evaluation of liver function, tests of glucose metabolism to rule out diabetes mellitus, and a neurologic evaluation to rule out possible head injury.
Emergencies Requiring Hospitalization or Other Institutional Support
A patient with a psychiatric disorder who is a danger to himself or to others or who is so disabled that h cannot protect himself requires hospitalization. Persons who are dangerous but do not have a psychia disorder should be referred to law enforcement.
Suicidal behavior (see Ch. 190) requires assessment of suicide risk, including a complete psychiatric evaluation, thorough mental status examination, and a detailed review of circumstances surrounding t suicidal behavior and of available social support. Generally, suicide attempts in which precautions wer against discovery, preparatory acts were required (eg, buying a gun), and violent, lethal, or available m were contemplated or used are considered the most serious. Patients judged to be suicidal should not unwatched.
evaluation, thorough mental status examination, and a detailed review of circumstances surrounding t suicidal behavior and of available social support. Generally, suicide attempts in which precautions wer against discovery, preparatory acts were required (eg, buying a gun), and violent, lethal, or available m were contemplated or used are considered the most serious. Patients judged to be suicidal should not unwatched.
The decision concerning the need for hospital admission is based on the patient's diagnosis; severity o depression, hopelessness, and agitation; availability of social support; and presence of other suicide r factors, including a history of suicide attempts, substance abuse, and recent life stressors. If a patient a psychiatric disorder lacks emotional control, has psychosis, or shows impulsivity with serious threats thoughts, or plans for suicide or homicide, he should be treated in a protective setting and, if required, hospitalized involuntarily. When suicide threats or gestures are judged to be nonlethal, patients may b released after assessment by a psychiatrist.
Homicidal state is not necessarily correlated with a psychiatric disorder. Dangerousness to others is a during a complete psychiatric examination including, if possible, reports of informants.
Thorough evaluation of dangerousness to self and to others should be documented for all patients ass an emergency setting.
Self-neglect may endanger patients with a psychotic disorder, delirium, or severe substance abuse be of impaired ability to obtain food, clothing, and appropriate protection from the elements. Patients who themselves as a result of a psychiatric disorder and those who are psychotic but nonviolent are usually hospitalized when their condition is likely to deteriorate without psychiatric intervention and when appr alternatives are not available.
Psychosocial crises may be the reason that patients with severe, long-standing psychiatric disorders other support system seek help in the emergency department. Such patients often have a reduced ca manage psychosocial stresses of all types. Crises include conflicts with family, landlord, or roommate; problems; and loneliness. Patients may use medically legitimate complaints, such as hallucinations or ideation, to obtain assistance with other psychosocial problems. Emergency assessment should includ effort to understand the psychosocial precipitants of the current visit. Formulating a treatment plan in collaboration with outpatient clinicians and treatment agencies can help reduce the inappropriate use o emergency services.
Emergencies Requiring Minimal Pharmacologic Intervention
Patients who are having a crisis but who do not have a major psychiatric disorder may need minimal o pharmacologic treatment.
Adjustment disorder may require short-term outpatient treatment. Depending on the predominant sy anxiolytic or antidepressant drugs may be used briefly. Antidepressants generally require 2 to 4 wk to symptoms and therefore cannot be used without a coordinated short-term treatment plan. Reestablish normal sleep patterns is often a major treatment goal. Acute grief, an adjustment reaction, may require sedatives or anxiolytics.
Rape or physical assault victims (see Ch. 244) frequently benefit from psychologic assessment and treatment, including an anxiolytic used briefly. Emergency departments should have access to special or assault crisis workers, who can remain with the victim during the medical and legal procedures, pro support, and arrange follow-up care.
Borderline or other personality disorders (see Ch. 191) can produce transient psychotic symptoms impulses, or impulsive aggressive behavior, including self-mutilation and suicide attempts in response
treatment, including an anxiolytic used briefly. Emergency departments should have access to special or assault crisis workers, who can remain with the victim during the medical and legal procedures, pro support, and arrange follow-up care.
Borderline or other personality disorders (see Ch. 191) can produce transient psychotic symptoms impulses, or impulsive aggressive behavior, including self-mutilation and suicide attempts in response psychosocial stressors. Once under observation in the emergency department, a patient with such a d often denies or minimizes the seriousness of his actions and lobbies assertively and coherently for imm release. If possible, the patient's outpatient clinician should be consulted about decisions regarding dis Generally, drugs should not be initiated in the emergency department; they should be prescribed by a psychiatrist who is able to observe the patient over a long period and perform the necessary re-evalua
Emergencies Requiring More Comprehensive Pharmacologic Interventio
Drugs prescribed in an emergency setting should be administered judiciously and target specific symp The etiology of altered mental status should be determined, when possible, before drugs are given be psychoactive drugs suppress psychiatric symptoms secondary to underlying physical disorders. Nonet drugs are often required immediately to control disturbed behavior that poses a danger to the patient o
Assaultive behavior in patients must be controlled so that others are not harmed. Physical restraints be applied only by staff who are adequately trained to protect patient rights and safety. Drugs can be g control dangerous behavior without the psychiatric patient's consent. Drugs commonly used for this pu are listed in Table 194-1.
Acute (agitated) psychosis, with aggressive or violent behavior, is a common emergency. Symptoma treatment must often precede definitive diagnosis. Patients with acute psychosis require hospitalizatio treatment in a crisis group home or other hospital alternative if judged to be a danger to self or others. most common diagnoses of these patients are bipolar I disorder, schizophrenia, brief psychotic disord delirium, dementia, and substance withdrawal or intoxication.
Bipolar I disorder (see Ch. 189) occurs as mania or major depression. An antipsychotic drug is often to control acute manic symptoms. Mood stabilizers, such as lithium, carbamazepine, and valproate, re several weeks to normalize mood and are effective as prophylaxis. When an antidepressant is prescri patients with bipolar disorder, a mood stabilizer should be prescribed concurrently to attempt to preven antidepressant-induced mania.
Schizophrenia (see Ch. 193) can occur with acute exacerbations or relapses. Noncompliance with pr maintenance treatment accounts for about 50% of relapses among patients with schizophrenia. Positi symptoms (hallucinations, loose associations, bizarre behavior, and delusions) are usually prominent. Differential diagnosis includes substance intoxication, seizure disorder (especially temporal lobe epilep CNS neoplasm, and head trauma.
Rapid treatment with high doses of antipsychotics (neuroleptization) used to be advocated for the cont agitated schizophrenic patients. However, this approach has a greater risk of adverse effects with no g efficacy than standard treatment with haloperidol and/or benzodiazepines and therefore is not recomm (see Table 194-1).
Selection of a specific drug and dosage used for emergency treatment of agitated psychosis is based previous response to drugs, severity of psychosis, age, and presence of physical disorders affecting d metabolism. Children, older adults, and patients with hepatic or renal insufficiency typically require low doses. Concurrent administration of anticholinergic drugs (eg, benztropine 0.5 to 2 mg po or IM) may r acute extrapyramidal adverse effects of antipsychotics.
Selection of a specific drug and dosage used for emergency treatment of agitated psychosis is based previous response to drugs, severity of psychosis, age, and presence of physical disorders affecting d metabolism. Children, older adults, and patients with hepatic or renal insufficiency typically require low doses. Concurrent administration of anticholinergic drugs (eg, benztropine 0.5 to 2 mg po or IM) may r acute extrapyramidal adverse effects of antipsychotics.
The relatively benign adverse effect profile of atypical antipsychotics (eg, risperidone, olanzapine, que ziprasidone) favors their use in maintenance treatment, but the unavailability of IM preparations limits in emergency settings.
Brief psychotic disorder (see Ch. 193) is treated similarly to an acute exacerbation of schizophrenia, although lower drug doses are typically required.
Delirium (see Ch. 171) is managed with environmental manipulation to help orient the patient (eg, lea light on at night; frequent orientation to time, place, and person) and with drugs. Drugs should be pres only after the underlying disorder has been diagnosed or the process of determining the diagnosis has initiated. Haloperidol in low doses (0.5 to 2 mg) is frequently the drug of choice. Lorazepam 0.5 to 2 m reduce agitation and is preferable when substance withdrawal is the cause. Anticholinergic drugs (eg, benztropine) should be used with caution in delirious patients, especially the elderly, because antichol toxicity (atropine psychosis) can occur.
Patients with dementia (see Ch. 171) may present in an agitated state secondary to paranoid delusion producing catastrophic reactions (eg, violent resistance to caregivers), or with a complicating physical causing delirium. Agitation may require intervention for the protection of self or others. Because such p are extremely sensitive to adverse effects, drug doses in the lower range should be used (see Table 1 Patients may need to be hospitalized for stabilization if adequate supervision outside the hospital is no available. For aggressive behavior, propranolol, carbamazepine, selective serotonin reuptake inhibitor buspirone can be used.
Substance intoxication and withdrawal (see Ch. 195) may occur with a psychiatric disorder or as a presenting complaint. Phencyclidine (PCP), cocaine, and alcohol are the substances that most commo to violent behavior. PCP users can present with almost any psychiatric symptom. Patients intoxicated should be placed under observation in a secure room away from stimulation; attempting to talk the pat down is not recommended. Physical restraints or sedation may be necessary for violent patients. Lora to 4 mg po or diazepam 10 to 20 mg po is recommended to treat agitation.
Patients who abuse cocaine and also use a monoamine oxidase inhibitor or other psychostimulant are of hypertensive crisis. Haloperidol (see Table 194-1) can be used to manage paranoid psychosis or schizophrenia relapse secondary to cocaine use.
Withdrawal from barbiturates, other sedatives and hypnotics (including benzodiazepines), and alcohol similar clinically. When symptoms are severe, treatment in a hospital is safest and is mandatory if the febrile (> 38.3 C [> 101 F]), cannot hold down fluids to prevent dehydration, or has a severe underlyi physical disorder. Alcohol withdrawal can be life threatening. Seizures can occur. Delirium tremens, a withdrawal syndrome that starts within 7 days of withdrawal (usually within 24 to 72 h), is a medical em and should be treated in an ICU. Treatment is discussed under Alcoholism in Ch. 195.
Overdose of prescribed psychoactive drugs can also cause intoxication. If the patient has taken a dose and is awake, treatment consists of inducing emesis followed by administering activated charcoa Overdose with tricyclic antidepressants or carbamazepine requires cardiac monitoring. Overdose with barbiturates or benzodiazepines and alcohol may cause respiratory arrest. Acetaminophen overdose r monitoring of blood levels, and if the blood level of acetaminophen indicates probable liver damage, acetylcysteine must be given according to protocol (see Acetaminophen Poisoning in Ch. 263).
Overdose of prescribed psychoactive drugs can also cause intoxication. If the patient has taken a dose and is awake, treatment consists of inducing emesis followed by administering activated charcoa Overdose with tricyclic antidepressants or carbamazepine requires cardiac monitoring. Overdose with barbiturates or benzodiazepines and alcohol may cause respiratory arrest. Acetaminophen overdose r monitoring of blood levels, and if the blood level of acetaminophen indicates probable liver damage, acetylcysteine must be given according to protocol (see Acetaminophen Poisoning in Ch. 263).
Antipsychotic drugs, at therapeutic as well as toxic doses, can cause acute extrapyramidal adverse eff including dystonia, oculogyric crisis, torticollis, and akinesia. Akathisia is a common adverse effect of high-potency antipsychotics; when severe, it is accompanied by extreme anxiety or terror. Acute onset oculogyric or orofacial dystonia in an otherwise healthy person may suggest purposeful or inadvertent ingestion of an antipsychotic. For treatment of acute adverse effects of antipsychotics, see Table 194-
Neuroleptic malignant syndrome is a hypermetabolic reaction to dopamine antagonists, primarily antipsychotic drugs, such as phenothiazines and butyrophenones. It usually occurs early in treatment rarely during maintenance treatment. It develops in up to 3% of patients started on antipsychotics. Ris increased in agitated male patients who have received large and rapidly increased doses. No genetic component is apparent. Its pathophysiologic basis is believed to be blockade of central dopamine rece Characteristic signs are muscle rigidity, hyperpyrexia, tachycardia, hypertension, tachypnea, change in status, and autonomic dysfunction. Laboratory abnormalities include respiratory and metabolic acidosi myoglobinuria, elevated CK, and leukocytosis. Mortality approaches 30%.
Treatment includes cessation of antipsychotic drugs, supportive care, and aggressive treatment of myoglobinuria, fever, and acidosis. The dopamine agonist bromocriptine 2.5 to 20 mg tid or dantrolene 10 mg/kg IV q 4 h may be used as a muscle relaxant. Treatment is usually in an ICU. After recovery, reintroduction of the antipsychotic drug retriggers the syndrome in up to 1/3 of patients.
Malignant hyperthermia, induced by inhalation of potent anesthetics or succinylcholine, is clinically s neuroleptic malignant syndrome; however, the pathophysiology and susceptibility appear to be differen most cases (see under Pharmacodynamic Variation in Ch. 301). When patients with neuroleptic malig syndrome require anesthesia, trigger agents for malignant hyperthermia should be avoided, although malignant hyperthermia has not been reported in these patients or their family members.
Legal Considerations
In most states, when a patient expresses the intention to harm a particular person, the evaluating clini required to warn the intended victim and notify a specified law enforcement agency. Specific requirem by state. Typically, state regulations also require reporting suspected abuse of children, the elderly, an spouses.
Criteria and procedures for involuntary hospitalization vary by jurisdiction. Usually a physician or psych and one additional clinician must certify that the patient has a psychiatric disorder, is a danger to hims others, and refuses treatment.

Section 15. Psychiatric Disorders Chapter 189. Mood Disorders Topics
[General] Depression Dysthymic Disorder Bipolar Disorders Cyclothymic Disorder
[General]
(For mood disorders in children, see Ch. 274.)
Mood disorders (affective disorders): A group of heterogeneous, typically recurrent illnesses including (depressive) and bipolar (manic-depressive) disorders that are characterized by pervasive mood distur psychomotor dysfunction, and vegetative symptoms.
Current diagnostic practice emphasizes depression and elation as the core affective components of m disorders. However, anxiety and irritability are equally common, explaining the continued popularity of broader rubric "affective disorder," the previous official designation.
Sadness and joy are part of everyday life and should be differentiated from clinical depression and mo elation. Sadness, or normal depression, is a universal human response to defeat, disappointment, and adverse situations; the response may be adaptive by permitting withdrawal to conserve inner resource Transient depression ("blues") may occur as a reaction to certain holidays or significant anniversaries, the premenstrual phase, and during the first 2 wk postpartum. Such reactions are not abnormal, but pe predisposed to depression may break down during such times.
Grief (normal bereavement), the prototype of reactive depression, occurs in response to significant separations and losses (eg, death, marital separation, romantic disappointment, leaving a familiar environment, forced emigration, or civilian catastrophes). Grief may be manifested by anxiety symptom as insomnia, restlessness, and autonomic nervous system hyperactivity. Like other adversities, separa and losses generally do not cause clinical depression, except in persons predisposed to a mood disor
Elation, usually linked to success and achievement, is sometimes considered a defense against depre a denial of the pain of loss (eg, a rare form of bereavement reaction in which elated hyperactivity may completely replace the expected grief). In predisposed persons, such reactions may lead to mania. Paradoxical depression may follow positive events, possibly because the associated increased
and losses generally do not cause clinical depression, except in persons predisposed to a mood disor
Elation, usually linked to success and achievement, is sometimes considered a defense against depre a denial of the pain of loss (eg, a rare form of bereavement reaction in which elated hyperactivity may completely replace the expected grief). In predisposed persons, such reactions may lead to mania. Paradoxical depression may follow positive events, possibly because the associated increased responsibilities often have to be faced alone.
Depression or mania is diagnosed when sadness or elation is overly intense and continues beyond the expected impact of a life stressor or arises in the absence of a stressor. Symptoms and signs often clu discrete syndromes that typically recur or, less commonly, persist without remission. Clinical depressio mania, unlike normal emotional reactions, cause marked impairment in physical function, social functio work capacity.
Epidemiology
Some type of mood disturbance, which may require clinical attention, affects 20% of women and 12% during their lifetime. These figures largely represent unipolar major depressive disorder and its variant Although the incidence of bipolar disorder in the general population was estimated at < 2%, new estim closer to 4 to 5%. Depression affects twice as many women as men; bipolar disorder affects the sexes but depressive forms predominate in women and manic forms in men. Bipolar disorder usually begins teens, 20s, or 30s; unipolar disorders begin, on average, in the 20s, 30s, or 40s. Persons born in the 2 decades after World War II have higher rates of depression and suicide, often associated with higher substance abuse, than those born earlier. Female sex is the major demographic risk factor for depress social class, culture, and race have not been consistently associated with depression. However, bipola disorder is somewhat more common in upper socioeconomic classes. Cultural factors seem to modify clinical manifestations of mood disorders. For example, physical complaints, worry, tension, and irritab more common manifestations in lower socioeconomic classes; guilty ruminations and self-reproach ar characteristic of depression in Anglo-Saxon cultures; and mania tends to manifest itself more floridly in Mediterranean and African countries and among black Americans. Economic factors, such as unempl and sudden financial reversals, have been linked to increased suicide rates in men.
Mood disorders are the most prevalent psychiatric disorders, accounting for 25% of patients in public m institutions, 65% of psychiatric outpatients, and as many as 10% of all patients seen in nonpsychiatric settings.
Etiology
Primary mood disorders: The interaction of several factors contributes to these disorders. Heredity most important predisposing factor. The precise mode of inheritance is uncertain, but dominant genes (X-linked or autosomal) may be involved in some forms of bipolar disorder. Polygenic inheritance as a genetic substrate for bipolar and recurrent unipolar disorders is a more popular hypothesis. What is in unknown. But the final common pathway of mood disorders is believed to be impaired limbic-dienceph function; recent brain imaging studies further implicate subcortical extrapyramidal structures and their prefrontal connections. Cholinergic, catecholaminergic (noradrenergic or dopaminergic), and serotone (5-HT) neurotransmission appears to be dysregulated. Heredity may also increase the likelihood of de by exposing children to the negative effects of their parent's mood disorders (eg, disruption of affective
Childhood loss of a parent does not increase a person's risk of developing a mood disorder. Howeve such a person develops a mood disorder, depression tends to develop at a younger age and follow a chronically intermittent course, leading to marked personality disturbance and suicide attempts.
Childhood loss of a parent does not increase a person's risk of developing a mood disorder. Howeve such a person develops a mood disorder, depression tends to develop at a younger age and follow a chronically intermittent course, leading to marked personality disturbance and suicide attempts.
Stressors that provoke affective episodes can be psychologic or biologic. Traumatic life events, espe separations, commonly precede depressive and manic episodes; however, such events may represen prodromal manifestations of a mood disorder rather than its cause (eg, affectively ill persons often alie their loved ones). The switch from depression to mania is often heralded by reduced sleep for 1 to 3 d can be experimentally induced by sleep deprivation, particularly of rapid eye movement (REM) sleep. switch commonly follows therapy with antidepressants. Stimulant use, sedative-hypnotic withdrawal, transmeridian travel, and seasonal changes in light may also induce mania.
Although persons with any personality type can develop clinical depression, it is more common in pers temperaments inclined to dysthymia and cyclothymia. Unipolar depression is more likely to develop in persons who are introverted and have anxious tendencies. Such persons often lack the requisite socia adjust to significant life pressures and have difficulty recovering from a depressive episode. Persons w bipolar disorders tend to be extroverted and achievement-oriented; they often use activity to combat depression.
Female sex as a risk factor for depression is customarily explained by women's presumed more affilia nature, dependency traits, and helplessness in controlling their destiny in male-oriented societies. How biologic vulnerabilities are also relevant. Having two X chromosomes is important in bipolar disorders i dominant X-linkage is involved. Compared with men, women have higher levels of monoamine oxidas enzyme that degrades neurotransmitters considered important for mood). Thyroid function is more com dysregulated in women. Women may use oral contraceptives containing progesterone, believed to be depressant, and undergo premenstrual and postpartum endocrine changes. Depressed women are m to exhibit the introverted, brooding/inhibited personality style typical of unipolar disorders, whereas dep men are significantly more likely to exhibit the extroverted, action-oriented personality style typical of b disorders.
Secondary mood disorders: Often, a mood disorder develops in association with a nonaffective diso a physiologic or psychologic mechanism or both (see Table 189-1). Some disorders, such as myxedem depression, result from physiochemical factors and are considered symptomatic depressions. Others, the depression that accompanies debilitating cardiopulmonary disorders, are usually explained as dep reactions to the underlying disorder. Often, both mechanisms are operative (eg, in patients with AIDS have cerebral dysfunction and profound sadness). Bipolar disorder rarely complicates another psychia disorder; if alcohol or substance use precedes a bipolar disorder, it is most likely an attempt to self-tre prodromal manifestations of the disorder.
The foregoing findings concerning nonaffective disorders and drugs that produce depression suggest pathogenesis for all mood disorders forms a continuum and that the distinction between primary and secondary mood disorders is arbitrary. All patients who meet the criteria for a mood disorder must be t regardless of whether other disorders are present and no matter how understandable the depression s light of the underlying disorder.
Risk of Suicide
Suicide, the most serious complication in patients with mood disorders, is the cause of death in 15 to 2 untreated patients with mood disorders; unrecognized or inadequately treated depression contributes 70% of all completed suicides. Suicide, which is most common in young and elderly men who do not h good social support, tends to occur within 4 to 5 yr of the first clinical episode. The immediate recovery from depression (when psychomotor activity is returning to normal, but the mood is still dark), mixed b
Suicide, the most serious complication in patients with mood disorders, is the cause of death in 15 to 2 untreated patients with mood disorders; unrecognized or inadequately treated depression contributes 70% of all completed suicides. Suicide, which is most common in young and elderly men who do not h good social support, tends to occur within 4 to 5 yr of the first clinical episode. The immediate recovery from depression (when psychomotor activity is returning to normal, but the mood is still dark), mixed b states, the premenstrual state, and personally significant anniversaries are major risk periods (see also 190). Concurrent alcohol and substance abuse also increases the risk of suicide. Serotonin dysfunctio appears to be one of the biochemical factors in suicide, and prophylaxis with lithium (which stabilizes t serotonin system) is effective in suicide prevention.
Of drugs prescribed for mood disorders, an overdose with a heterocyclic antidepressant or lithium (se Table 307-3) is most likely to be life threatening; alcohol is often a complicating factor. Heterocyclic antidepressant overdose causes a hyperactive coma with atropinism; cause of death is usually cardiac arrhythmia or status epilepticus. Because of protein-binding, forced diuresis and hemodialysis are use treatment focuses on stabilizing cardiac and cerebral function. For lithium overdose, forced diuresis wi sodium chloride or mannitol, alkalinization of urine, and hemodialysis may be lifesaving. Monoamine o inhibitors, less commonly prescribed now, rarely result in overdose. Newer antidepressants (eg, select serotonin reuptake inhibitors, venlafaxine, nefazodone, mirtazapine, bupropion) appear to be usually n in suicidal overdose--one of their major advantages.
Diagnosis
Diagnosis is based on the symptomatic picture (see Table 189-2), course, family history, and, sometim unequivocal response to somatic interventions. Secondary medical or neurologic causes should be ex especially after age 40.
There are no pathognomonic laboratory findings in mood disorders. Tests for limbic-diencephalic dysfu such as the thyrotropin-releasing hormone (TRH) stimulation test, the dexamethasone suppression tes and sleep EEG for rapid eye movement (REM) latency, are sometimes used in academic settings. The consensus on the diagnostic sensitivities and specificities of these tests, and the tests are not useful fo screening. A negative test result does not exclude a depressive disorder; a positive result is more sign clinically.
Diagnosis of depression may be difficult when anxiety symptoms are the prominent presentation (see 189-3). Excessive worrying, panic attacks, and obsessions are common in primary depressive disorde disappear when the depressive episode remits. Conversely, in primary anxiety disorders, these sympto usually fluctuate irregularly and remission of depressive symptoms typically does not eliminate them. Prominent anxiety symptoms first appearing after age 40 most likely represent a primary mood disorde
Mixed anxiety-depression (anxious depression) refers to conditions in which mild symptoms comm anxiety and mood disorders are present. They usually pursue a chronically intermittent course. Becaus greater gravity of depressive disorders and the risk of suicide, patients with mixed anxiety-depression be treated for depression. Obsessions, panic, and social phobias with hypersomnic depression sugge II disorder.
In the elderly, depressive pseudodementia is associated with psychomotor retardation, decreased concentration, and memory impairment and therefore may be confused with early dementia, which oft begins with affective changes (see Dementia in Ch. 171). In general, when the diagnosis is uncertain, treatment of depressive disorder should be tried, because of its better prognosis. Several features (se 189-4) can help in differential diagnosis.
The terms masked depression and affective equivalents are often used to explain prominent physic
concentration, and memory impairment and therefore may be confused with early dementia, which oft begins with affective changes (see Dementia in Ch. 171). In general, when the diagnosis is uncertain, treatment of depressive disorder should be tried, because of its better prognosis. Several features (se 189-4) can help in differential diagnosis.
The terms masked depression and affective equivalents are often used to explain prominent physic symptoms (eg, headache, fatigue, insomnia) or behavioral disturbance when mood change is minimal absent. Affective equivalents include antisocial acting out (especially in children and adolescents), imp risk taking, gambling, chronic pain, hypochondriasis, anxiety states, and so-called psychosomatic diso Without core affective symptoms, the diagnosis of a mood disorder is not appropriate unless affective episodes have occurred in the past, the condition recurs periodically, and the family history includes m disorders. Because diagnosis may be difficult, therapeutic trials with antidepressants and/or mood stab are often conducted.
Differentiating chronically intermittent mood disorders, such as cyclothymia and dysthymia, from subs use disorders is difficult. Unipolar depression is a less common cause of alcoholism and drug abuse once thought (see Ch. 195). Depressed and manic patients may use alcohol or drugs in an attempt to sleep disturbances, and manic patients may seek drugs (eg, cocaine) to enhance excitement, usually catastrophic effects on their illness. Toxic effects of drugs, drug withdrawal, or social complications ma accompany substance use disorders, causing transient or intermittent depression. Episodic substance especially of alcohol (dipsomania), or onset after age 30 suggests diagnosis of a primary mood disord secondary substance abuse. When the diagnosis is in doubt, a therapeutic trial with antidepressant or mood-stabilizing drugs can often be defended clinically.
Differentiating between affective psychosis and schizophrenia or schizoaffective disorder (see Ch. may be difficult because many schizophrenic features (eg, mood-incongruent delusions or hallucinatio occur in mood disorders. The correct diagnosis is important because lithium may cause neurotoxicity i schizophrenia, and neuroleptics may cause tardive dyskinesia in mood disorders. Diagnosis must be b the overall clinical picture, family history, course, and associated features (see Table 189-5). Alcoholic hallucinosis, sedative-hypnotic withdrawal, psychedelic-induced psychosis, and other systemic or brain disorders may also produce psychotic symptoms. Diagnosis of a schizoaffective disorder should not b until such complicating factors are excluded. When the diagnosis is in doubt, a therapeutic trial with an antidepressant, a mood stabilizer, or electroconvulsive therapy is indicated, because of the better prog mood disorders.
Differentiating mood disorders from severe personality disorders (eg, borderline personality) is also especially when the mood disorder has a chronic or intermittent course--eg, dysthymia, cyclothymia, o II disorder. Past course with affective manifestations, especially when biphasic, and a family history of disorders support a diagnosis of mood disorder. Some laboratory findings (especially REM latency and stimulation) in patients with borderline personality disorder and in those with mood disorder are similar similarity can be interpreted to mean that the two disorders are related or that these tests are not helpf differential diagnosis. Some experts believe that at least some forms of borderline personality disorder represent a mood disorder variant, but this theory is controversial. For young patients pursuing a temp impulsive course that could culminate in serious suicide attempts, a trial with thymoleptic and mood-st drugs conducted by experts in a controlled setting--a hospital or mood clinic--is recommended.
Section 15. Psychiatric Disorders Chapter 195. Drug Use And Dependence (Substance Use Disorders; Drug Addiction; Drug Abu Habituation) Topics
[General] Alcoholism Opioid Dependence Anxiolytic And Hypnotic Drug Dependence Cannabis (Marijuana) Dependence Cocaine Dependence Amphetamine Dependence Hallucinogen Dependence Phencyclidine Use Volatile Solvent Dependence Volatile Nitrites
[General]
A single definition for drug dependence is neither desirable nor possible. Some illicit drug use, althoug considered abuse because it is illegal, does not involve dependence of any kind. Drug dependence of specific type (eg, cocaine dependence) emphasizes that different drugs have different effects, includin and risk of dependence.
Two concepts contribute to the definition of drug dependence: tolerance, which describes the need to progressively increase the dose to produce the effect originally achieved with smaller doses, and phys dependence, a state of physiologic adaptation to a drug, manifested by a withdrawal (abstinence) syn In a withdrawal syndrome, untoward physiologic changes occur when the drug is discontinued or when effect is counteracted by a specific antagonist that displaces the agonist from its binding site on cell re Physical dependence does not accompany all forms of drug dependence.
Psychologic dependence is accompanied by feelings of satisfaction and a desire to repeat the drug experience or to avoid the discontent of not having it. This anticipation of effect is a powerful factor in t chronic use of psychoactive drugs and, with some drugs, may be the only obvious factor associated w intense craving and apparent compulsive use. Drugs that cause chiefly psychologic dependence inclu cocaine, marijuana, amphetamine, and hallucinogens, such as lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and peyote.
Drugs that produce strong physical dependence (eg, heroin, alcohol) are prone to abuse, and depend
chronic use of psychoactive drugs and, with some drugs, may be the only obvious factor associated w intense craving and apparent compulsive use. Drugs that cause chiefly psychologic dependence inclu cocaine, marijuana, amphetamine, and hallucinogens, such as lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and peyote.
Drugs that produce strong physical dependence (eg, heroin, alcohol) are prone to abuse, and depend difficult to treat. If a drug does not cause physical dependence, discontinuing the drug does not cause stereotypical withdrawal syndrome. However, most psychoactive drugs cause tolerance, and in some reactions after discontinuation resemble a withdrawal syndrome (eg, depression and lethargy after wit of cocaine or amphetamine; characteristic changes in the EEG after withdrawal of amphetamine). Com used psychoactive drugs vary in their potential for different types of dependence (see Table 195-1).
Drugs that produce dependence act on the CNS and have one or more of the following effects: reduce anxiety and tension; elation, euphoria, or other mood changes pleasurable to the user; feelings of incr mental and physical ability; altered sensory perception; and changes in behavior.
Addiction, a concept without a consistent, universally accepted definition, is used here to refer to a life characterized by compulsive use and overwhelming involvement with a drug; it may occur without phy dependence. Addiction implies the risk of harm and the need to stop drug use, whether the addict und and agrees or not.
Drug abuse is definable only in terms of societal disapproval. It may involve experimental and recreat of drugs, which is usually illegal with risk of arrest; unsanctioned use of psychoactive drugs to relieve p or symptoms; or use of drugs first for the previous two reasons but later because of dependence and t to continue at least partially to prevent the discomfort of withdrawal. Abuse of prescription and illegal d occurs in all socioeconomic groups, including among persons with advanced education and profession status. However, the most devastating use of psychoactive drugs still occurs in the context of poverty.
Recreational drug use has increasingly become a part of Western culture, although in general, it is n sanctioned by society and is usually illegal. Some users are apparently not harmed; they tend to use d episodically in relatively small doses, precluding clinical toxicity and development of tolerance and phy dependence. Many recreational drugs (eg, crude opium, alcoholic beverages, marijuana products, cof other caffeine-containing beverages, hallucinogenic mushrooms, coca leaf) are "natural," ie, close to p origin; they contain a mixture of relatively low concentrations of psychoactive compounds and are not psychoactive chemicals. Recreational drugs are most often taken orally or inhaled. Taking active poten compounds by injection is usually hard to control. Recreational use is often accompanied by ritualizati a set of observed rules, and is seldom practiced alone. Most drugs used this way are psychostimulant hallucinogens designed to obtain a "high" or altered consciousness rather than to relieve psychologic d depressant drugs are difficult to use in this controlled way.
In the USA, the Comprehensive Drug Abuse Prevention and Control Act of 1970 and subsequent mod require the pharmaceutical industry to maintain physical security and strict record keeping for certain t drugs. Controlled substances are divided into five schedules (or classes) on the basis of their potentia abuse, accepted medical use, and accepted safety under medical supervision. Substances in Schedu a high potential for abuse, no accredited medical use, and a lack of accepted safety. From Schedules substances decrease in potential for abuse. The schedule a substance is placed in determines how it controlled. Prescriptions for drugs in all schedules must bear the physician's federal Drug Enforcemen Administration (DEA) license number, but some drugs in Schedule V do not require a prescription. Sta schedules may vary from federal schedules.
Etiology of Drug Dependence
Drug dependence develops in a manner both complex and unclear. The process is influenced by the properties of the psychoactive drugs; the user's predisposing physical characteristics (probably includi
schedules may vary from federal schedules.
Etiology of Drug Dependence
Drug dependence develops in a manner both complex and unclear. The process is influenced by the properties of the psychoactive drugs; the user's predisposing physical characteristics (probably includi genetic predisposition), personality, and socioeconomic class; and the cultural and social setting. The psychology of the individual and drug availability determine the choice of psychoactive drug and the pa and frequency of use.
In particular, progression from experimentation to occasional use and then to tolerance and physical dependence is poorly understood. Factors leading to increased use and dependence or addiction may peer or group pressure, emotional distress that is symptomatically relieved by specific drug effects, sa social alienation, and environmental stress (particularly if accompanied by feelings of impotence to eff change or to accomplish goals). Physicians may inadvertently contribute to harmful use of psychoactiv by overzealously prescribing them to patients with stressful problems and falling victim to ruse by man patients. Many social factors and the mass media may contribute to the expectation that drugs can sa relieve distress or gratify needs. Stated simply, the outcome of drug use depends on interaction betwe drug, the user, and the setting.
There are no proven differences between the biochemical, drug dispositional, or physiologic responsiv persons who become addicted or dependent and those of persons who do not, although such differen been vigorously sought. However, sober relatives of alcoholics have a diminished physical response to
A neural substrate for reinforcement (the tendency to seek more drugs and other stimuli) has been ide animal models. In animal studies, self-administration of such drugs as opioids, cocaine, amphetamine nicotine, and benzodiazepines is associated with enhanced dopaminergic transmission in specific mid and cortical circuits. This finding suggests the existence of a brain reward pathway involving dopamine mammalian brain. However, evidence that psychedelic drugs and cannabinoids activate this system is insufficient, and not everyone who experiences these "rewards" becomes dependent or addicted.
An addictive personality has been described variously by behavioral scientists, but there is little scienti evidence that characteristic predisposing personality traits exist. Some describe addicts as escapists, who cannot face reality and who run away. Others describe addicts as schizoid persons who are fearfu withdrawn, and depressed, with a history of frequent suicide attempts and numerous self-inflicted injur Addicts have also been described as basically dependent and grasping in their relationships, frequent exhibiting overt, unconscious rage and immature sexuality. However, before persons develop drug dependence, they do not exhibit the deviant pleasure-oriented, irresponsible behavior usually attribute addicts. Sometimes addicts justify drug use because of a crisis, job pressure, or a family catastrophe t produces temporary anxiety or depression. Clinicians, patients, and the culture see drug abuse in the a dysfunctional life or life episode yet place blame exclusively on the drug or drug use. Most addicts ab alcohol along with other drugs, and they may have repeated hospital admissions for overdose, advers reactions, or withdrawal problems.

Section 15. Psychiatric Disorders Chapter 190. Suicidal Behavior Topics
[General]
[General]
(See also Chs. 189 and 274.)
Suicidal behavior includes suicide gestures, attempted suicide, and completed suicide. Suicide plans a actions that appear unlikely to succeed are often termed suicide gestures; they are predominantly communicative. However, they should not be dismissed lightly; they are pleas for help and require tho evaluation and treatment aimed at relieving misery and preventing repeated attempts, especially since persons who attempt suicide try again within 1 yr and 10% finally succeed. Attempted suicide is a su that is not fatal, possibly because the self-destructive intention was slight, vague, or ambiguous or the taken had a low lethal potential. Most persons who attempt suicide are ambivalent about their wish to the attempt may be a plea for help and may fail because of a strong wish to live. Completed suicide death. The distinction between completed and attempted suicides is not absolute, because attempted also include acts by persons whose determination to die is thwarted only because they are discovered and resuscitated effectively and because a suicide attempt may be unintentionally fatal by miscalculat
Self-destructive behavior may be direct (usually including suicidal thoughts, attempted suicides, and co suicides) or indirect (characterized by taking a life-threatening risk without intending to die, generally repeatedly and often unconsciously, with consequences that are ultimately likely to be self-destructive Examples of the indirect type are excessive drinking and drug use, heavy smoking, overeating, neglec one's health, self-mutilation, polysurgical addiction, hunger strikes, criminal behavior, and reckless driv
Incidence
Statistics on suicidal behavior are based mainly on death certificates and inquest reports, and they underestimate the true incidence. Even so, suicide is one of the top 10 causes of death among adults communities. In Europe, the urban rate is higher than the rural; in the USA, they are about the same. I USA, about 75 persons commit suicide every day. Suicide accounts for 10% of deaths among those a to 34 yr and for 30% of deaths among university students. It is the second leading cause of death amo adolescents (see Ch. 274). The steady rise in adolescent suicides during the last decade is due mainly increase in male suicides, which has more than doubled. More than 70% of persons who complete su > 40 yr old, and the incidence rises sharply among those > 60 yr old, particularly men. About 65% of th
communities. In Europe, the urban rate is higher than the rural; in the USA, they are about the same. I USA, about 75 persons commit suicide every day. Suicide accounts for 10% of deaths among those a to 34 yr and for 30% of deaths among university students. It is the second leading cause of death amo adolescents (see Ch. 274). The steady rise in adolescent suicides during the last decade is due mainly increase in male suicides, which has more than doubled. More than 70% of persons who complete su > 40 yr old, and the incidence rises sharply among those > 60 yr old, particularly men. About 65% of th attempt suicide are < 40 yr old.
Of about 200,000 suicide attempts in the USA each year, 10% are completed. Attempted suicides acc about 20% of emergency medical admissions and for 10% of all medical admissions. Women attempt 2 to 3 times more often than men, but men are generally more apt to die in their attempts. Several stu have found a higher incidence of suicide among family members of patients who have attempted suici
Married persons of either sex, particularly in a secure relationship, have a significantly lower suicide ra single persons. Attempted and completed suicide rates are higher among those who live alone becaus separation, divorce, or spouse's death. The incidence of attempted suicide is disproportionately high a single adolescent girls and is also high among single men in their 30s.
Suicide among black women has increased 80% in the last 20 yr, so that the overall rate for blacks no that for whites, especially in urban areas. Among American Indians, the rate has also risen recently; in tribes, it is 5 times the national average.
Suicides occur in prisons, particularly by young men who have not committed violent crimes, usually d first week of imprisonment. Hanging is the usual method.
Group suicides, whether of many persons or only two (such as lovers or spouses), represent an extrem of personal identification with others. Suicides in large groups tend to occur in highly emotional setting overcome the strong drive for self-preservation.
Professional persons, including lawyers, dentists, military personnel, and physicians, seem to have higher-than-average suicide rates. The rate among physicians is high largely because of women phys whose annual rate of suicide is 4 times that of a matched general population. For physicians < 40 yr o suicide is the leading cause of death. Overdosage with drugs is a more common method among men women physicians than among the general population, possibly because physicians have easy access drugs and know what constitutes a fatal dose. By medical specialty, the rate is highest among psychia
Suicide is less common among practicing members of most religious groups (particularly Roman Cath who are generally supported by their beliefs and are provided with close social bonds protecting again self-destruction. The rates reported in Catholic countries are low only partly because coroners tend to verdicts of suicide; the rates appear to be actually lower, as they are for Jews. However, religious affili and strong religious beliefs do not necessarily prevent individual impetuous, unpremeditated suicidal a during times of frustration, anger, and despair, especially when accompanied by delusions of guilt and unworthiness.
Suicide notes are left by about one in six persons who complete suicide. The notes often refer to pers relationships and events that will follow the person's death. Notes left by elderly people often express for those left behind, whereas those of younger people may express anger or vindictiveness. The cont indicate the mental disorder that led to the suicidal act. In attempted suicides, a note is less common; indicates premeditation and a high risk of repeated attempts and completed suicide.
Etiology
Psychologic mechanisms leading to suicidal behavior resemble those frequently implicated in other fo
indicates premeditation and a high risk of repeated attempts and completed suicide.
Etiology
Psychologic mechanisms leading to suicidal behavior resemble those frequently implicated in other fo self-destructive behavior, such as alcoholism, reckless driving, self-mutilation, and violent antisocial ac Suicide is often the final act in a course of such behavior. Traumatic childhood experiences, particular distresses of a broken home or parental deprivation, are significantly more common among persons w tendency to self-destructive behavior, perhaps because such persons are more likely to have difficultie establishing secure, meaningful relationships. Attempted suicide is more likely among battered wives a victims of child abuse, reflecting a cycle of deprivation and violence within the family.
Suicidal acts usually result from multiple and complex motivations. The principal causative factors incl mental disorders (primarily depression), social factors (disappointment and loss), personality abnorma (impulsivity and aggression), and physical disorders (see also Table 190-1). Often, one factor (commo disruption of an important relationship) is the last straw.
Depression is involved in over half of all attempted suicides. Depression may be precipitated by socia such as marital discord, broken and unhappy love affairs, disputes with parents (among the young), an bereavements (particularly among the elderly). Depression associated with a physical disorder may lea suicide attempt, but physical disability, particularly if chronic or painful, is more commonly associated w completed suicide. A physical disorder, especially if serious, chronic, and painful, plays an important ro about 20% of suicides among the elderly.
Alcohol predisposes to suicidal acts by intensifying a depressive mood swing and by reducing self-co About 30% of persons who attempt suicide have consumed alcohol before the attempt, and about half were intoxicated at the time. Because alcoholism, particularly binge drinking, often causes deep feelin remorse during dry periods, alcoholics are suicide-prone even when sober. In one study, 10% of alcoh committed suicide. Treatment programs for alcoholics that include measures aimed at preventing suic would probably reduce the suicide rate.
Some patients with schizophrenia commit suicide. In chronic schizophrenia, suicide may result from t episodes of depression to which these patients are prone. The suicide method is usually bizarre and o violent. Attempted suicide is uncommon, although it may be the first gross sign of psychiatric disturban occurring early in schizophrenia, possibly when the patient becomes aware of the disorganization of h thought and volitional processes.
Persons with personality disorders are prone to attempted suicide--especially emotionally immature who have a borderline or an antisocial personality disorder, tolerate frustration poorly, and react to stre impetuously with violence and aggression. Some have a history of excessive alcohol consumption, dru abuse, or criminal behavior. An inability to form mature, lasting relationships may lead to reduced soci opportunity, loneliness, and depression, perhaps accounting for the large number of attempted suicide separated or divorced persons. In such persons, the precipitants are the stresses that inevitably result dissolution of relationships, even troubled ones, and the burdens of establishing new associations and lifestyles.
The element of Russian roulette is important in some suicide attempts. The person decides to let fate determine the outcome. Some unstable persons find excitement in this aspect of perilous activities tha with death, such as reckless driving and dangerous sports.
Aggression toward others is often evident in suicidal behavior--particularly in homicide followed by su in the high incidence of suicide among prisoners serving terms for violent crimes. When the distressing is considered, suicide appears to be directed at other, significant persons.
determine the outcome. Some unstable persons find excitement in this aspect of perilous activities tha with death, such as reckless driving and dangerous sports.
Aggression toward others is often evident in suicidal behavior--particularly in homicide followed by su in the high incidence of suicide among prisoners serving terms for violent crimes. When the distressing is considered, suicide appears to be directed at other, significant persons.
Organic brain disease--as in delirium (eg, due to drugs, infection, or heart failure) or dementia (see C 171)--may be accompanied by emotional lability. Serious violent acts of self-injury may occur during a transient depressive mood swing. Because consciousness is usually impaired at such times, the patie have only a vague recollection of the event. Patients with epilepsy, especially temporal lobe epilepsy, frequently have brief but profound episodes of depression. Having drugs prescribed for their condition them at a greater-than-normal risk of suicidal behavior.
Methods
The choice of methods is determined by cultural factors and availability and may reflect the seriousnes intent, since some (eg, jumping from heights) make survival virtually impossible, whereas others (eg, d ingestion) make rescue possible. However, using a method that proves not to be fatal does not necess imply that the intent was less serious. A bizarre method suggests an underlying psychosis.
Drug ingestion is the most common method used in suicide attempts. Use of barbiturates has decreas 5% of cases), but use of other psychoactive drugs is increasing. Use of salicylates has decreased from of cases to about 10%, but use of acetaminophen is increasing. The public perceives acetaminophen safe analgesic, but an overdose can be very dangerous (see Acetaminophen Poisoning in Ch. 263 an 307-3).
Two or more methods or a combination of drugs is used in about 20% of attempted suicides, increasin risk of death, particularly when drugs with serious interactions are combined. When multiple drugs are ingested, blood levels of all possible drugs should be obtained.
Violent methods, such as shooting and hanging, are uncommon among attempted suicides. For comp suicides, firearms are the most common method used by men (74%) and by women (31%). Rates of s with firearms vary with the availability of guns and with handgun regulations.
Prevention
Any suicidal act or threat must be taken seriously. Although some attempted or completed suicides are surprise and shock, even to close relatives and associates, clear warnings are given in most cases, ge to relatives, friends, medical personnel, or trained volunteers in emergency suicide prevention centers a 24-h service to persons in distress. Volunteers attempt to identify the potentially suicidal person, ma conversation, evaluate the risk, and offer help with immediate problems; they usually ask others (famil physician, police) for urgent assistance in a crisis and try to guide the suicidal person to appropriate fa for follow-up assistance. Although this approach to helping potentially suicidal persons is logical, no ha indicate that it reduces suicide incidence.
On average, physicians will encounter six or more potentially suicidal persons in their practice each ye than half of persons who commit suicide have consulted their physician within the previous few month least 20% have been under psychiatric care during the preceding year. Because depression is often in in suicide, recognition and treatment of depression (see Ch. 189) are the most important contributions physician can make to suicide prevention.
On average, physicians will encounter six or more potentially suicidal persons in their practice each ye than half of persons who commit suicide have consulted their physician within the previous few month least 20% have been under psychiatric care during the preceding year. Because depression is often in in suicide, recognition and treatment of depression (see Ch. 189) are the most important contributions physician can make to suicide prevention.
Each depressed patient should be questioned carefully about any thoughts of suicide. The fear that su inquiry, even in a tactful and sympathetic form, may implant the idea of self-destruction in the patient i baseless. Inquiry helps the physician obtain a clearer picture of the depth of the depression, encourag constructive discussion, and conveys the physician's awareness of the patient's deep despair and hopelessness. Rating scales for depression (eg, Beck Depression Inventory) may help determine whe suicide is a serious risk.
The risk of suicide is increased early in the treatment of depression, when retardation and indecisivene ameliorated but a depressed mood is still present or only partially lifted. Early results of treatment may therefore, enable the patient to set about self-destruction more effectively. Psychoactive drugs must b prescribed carefully and in controlled amounts. Insomnia may be a symptom of depression; if it is, trea with hypnotics without treating the underlying depression is not only ineffective but also dangerous.
In persons threatening imminent suicide (eg, a patient who calls and declares that he is going to take a dose of a drug or a person who threatens to jump from a height), the desire to die is ambivalent and o transient. The physician or another person to whom the person appeals for help must support the des live. The person threatening suicide is in an immediate crisis, and he should be offered hope of its res Emergency psychologic aid includes establishing a relationship and open communication with the pers reminding him of his identity (ie, using his name repeatedly); helping him sort out the problem that has the crisis; offering constructive help with the problem; encouraging him to take positive action; and rem him that his family and friends care for him and want to help.
If a person calls to say he has already committed a suicidal act (eg, taken a drug or turned on the gas) the process of doing so, his address should be obtained, if possible. Another person should immediate contact the police to trace the call and attempt a rescue while the suicidal person is kept talking on the telephone until the police arrive.
For patients who have attempted suicide, appropriate psychiatric and social aftercare is the best mean reducing repeated suicide attempts and completed suicide. A psychiatric assessment should be perfor (see below).
Management of Attempted Suicide
Many persons who attempt suicide are admitted to a hospital emergency department in a comatose st Ch. 170). After an overdose of a potentially lethal drug has been confirmed, the drug should be remov the patient, attempting to prevent absorption and expedite excretion; symptomatic treatment to keep th patient alive should be started; and any known antidote should be given if the specific drug can be ide (see Ch. 307). Every person with a life-threatening self-injury should be hospitalized to treat the physic and to obtain psychiatric assessment. Most patients are well enough to be discharged as soon as the injury is treated; all should be offered follow-up care.
Psychiatric assessment should be performed as soon as possible for all patients who attempt suicid the attempt, the patient may deny any problems, because the severe depression that led to the suicida may be followed by a short-lived mood elevation, a cathartic effect probably accounting for the rarity o repeated suicide attempts immediately after the initial one. Nevertheless, the risk of later, completed s high unless the patient's problems are resolved. The patient needs a secure, strong source of help, wh begins when the physician provides sympathetic attention and expresses concern, commitment, and understanding of the patient's troubled feelings.
the attempt, the patient may deny any problems, because the severe depression that led to the suicida may be followed by a short-lived mood elevation, a cathartic effect probably accounting for the rarity o repeated suicide attempts immediately after the initial one. Nevertheless, the risk of later, completed s high unless the patient's problems are resolved. The patient needs a secure, strong source of help, wh begins when the physician provides sympathetic attention and expresses concern, commitment, and understanding of the patient's troubled feelings.
The psychiatric assessment identifies some of the problems that contributed to the attempt and helps physician plan appropriate treatment. It consists of establishing rapport; understanding the suicide atte background, the events preceding it, and the circumstances in which it occurred; appreciating the curr difficulties and problems; thoroughly understanding personal and family relationships, which are often to the suicide attempt; fully assessing the patient's mental state, with particular emphasis on recognizi depression or other mental disorders and alcohol or drug abuse, which require specific treatment in ad crisis intervention; interviewing the spouse, close relatives, or friends; and contacting the family physic
The initial assessment should be made by a psychiatrist, although nonmedical personnel trained in the management of suicidal behavior can deal with suicidal patients satisfactorily.
Duration of hospital stay and the kind of treatment required vary. Patients with a psychotic disorder, or brain disease, or epilepsy and some with severe depression and an unresolved crisis should be admit psychiatric unit until they resolve underlying problems or can cope with them. If the patient's family phy not in charge, he should be kept fully informed and given specific suggestions for follow-up care.
Effect of Suicide
Any suicidal act has a marked emotional effect on all involved. The physician, family, and friends may guilt, shame, and remorse at not having prevented a completed suicide as well as anger toward the de or others. However, they must realize that they are not omniscient or omnipotent and that the complet suicide was ultimately not preventable. The physician can provide valuable assistance to the deceased and friends in dealing with their feelings of guilt and sorrow. The effect of attempted suicide is similar. However, family members and friends have the opportunity resolve their feelings by responding appropriately to the person's cry for help.
Assisted Suicide
This term describes the assistance given by physicians or other professionals to a person who wishes his life. Assisted suicide is very controversial because it reverses the physician's usual approach to pa Sophisticated, competent, compassionate care can often relieve pain and distress, helping patients in terminal stages of illness achieve good control of their symptoms and retain their dignity (see Ch. 294) However, sometimes adequate relief is not possible, or certain patients may still request earlier death exercise autonomy and to end their lives on their own terms.

Section 15. Psychiatric Disorders Chapter 196. Eating Disorders Topics
Anorexia Nervosa Bulimia Nervosa Binge Eating Disorder
Anorexia Nervosa
A disorder characterized by a disturbed sense of body image, a morbid fear of obesity, a refusal to ma minimally normal body weight, and, in women, amenorrhea.
The etiology is unknown, but social factors appear to be important. Emphasis on the desirability of bei pervades Western society, and obesity is considered unattractive, unhealthy, and undesirable. About 8 90% of prepubertal children are aware of these attitudes, and > 50% of prepubertal girls diet or take o measures to control their weight. However, since only a small percentage develop anorexia nervosa, o factors must be important. Some persons are probably predisposed because of undefined psychologic genetic, or metabolic vulnerability. Anorexia nervosa is rare in areas with a genuine food shortage.
About 95% of persons with this disorder are female. Onset usually occurs during adolescence, occasio earlier, and less commonly in adulthood. Many patients belong to middle or upper socioeconomic clas Mortality rates of 10 to 20% have been reported. However, because most mild cases are probably undiagnosed, true prevalence and mortality rates are unknown.
Symptoms and Signs
Anorexia nervosa may be mild and transient or severe and long-standing. Many persons who develop disorder are meticulous, compulsive, and intelligent, with very high standards for achievement and suc The first indications of the impending disorder are concern about body weight (even among patients w lean, which most are) and restriction of food intake. Preoccupation and anxiety about weight increase, emaciation develops. Denial of the disorder is a prominent feature. Patients do not complain about an weight loss, usually resist treatment, and are brought to the physician's attention by their families, by intercurrent illness, or by complaints about other symptoms (eg, bloating, abdominal distress, constipa
Anorexia is a misnomer, because appetite remains unless the patient becomes cachectic. Patients are preoccupied with food: They study diets and calories; hoard, conceal, and waste food; collect recipes; prepare elaborate meals for others. Patients are often manipulative, lying about food intake and conce
weight loss, usually resist treatment, and are brought to the physician's attention by their families, by intercurrent illness, or by complaints about other symptoms (eg, bloating, abdominal distress, constipa
Anorexia is a misnomer, because appetite remains unless the patient becomes cachectic. Patients are preoccupied with food: They study diets and calories; hoard, conceal, and waste food; collect recipes; prepare elaborate meals for others. Patients are often manipulative, lying about food intake and conce behavior, such as induced vomiting. Binge eating followed by induced vomiting and the use of laxative diuretics (binge-purge behavior--see Bulimia Nervosa, below) occurs in 50% of anorectics. The other 5 simply restrict the amount of food they eat. Most also exercise excessively to control weight.
Patients usually lose interest in sex. Other common findings include bradycardia, low BP, hypothermia hair or slight hirsutism, and edema. Even patients who appear cachectic tend to remain very active (in pursuing vigorous exercise programs), are free of symptoms of nutritional deficiencies, and have no un susceptibility to infections. Depression is common.
Endocrine changes include prepubertal or early pubertal patterns of luteinizing hormone secretion, low of thyroxine and triiodothyronine, and increased cortisol secretion. In a severely malnourished patient, every major organ system may malfunction, but cardiac and fluid and electrolyte disorders are the mos dangerous. Cardiac muscle mass, chamber size, and output decrease. Dehydration and metabolic alk may occur, and serum potassium may be low; all are aggravated by induced vomiting and use of laxat diuretics. Sudden death, most likely due to ventricular tachyarrhythmias, may occur. Some patients ha prolonged QT intervals (even when corrected for heart rate), which, with the risks imposed by electroly disturbances, may predispose to tachyarrhythmias.
Diagnosis
Anorexia nervosa is usually apparent from the constellation of symptoms and signs described above, particularly the loss of >= 15% of body weight in a young person who fears obesity, becomes amenorr denies illness, and otherwise appears well. The key to diagnosis is eliciting the central fear of obesity, not diminished by weight loss. In females, amenorrhea is required for the diagnosis. In severe cases, m depression or symptoms suggesting another disorder, such as schizophrenia, may require differentiati Rarely, a severe physical disorder, such as regional enteritis or a CNS tumor, is misdiagnosed as ano nervosa.
Treatment
Treatment has two phases: short-term intervention to restore body weight and save life and long-term to improve psychologic functioning and prevent relapse.
When weight loss has been severe or rapid or when weight has fallen below an arbitrary level (eg, 75% ideal), prompt restoration of weight becomes crucial, and hospitalization is imperative. If any doubt exi patient should be hospitalized. Removing the patient from her home sometimes reverses a downhill co although more active psychiatric treatment is often required. Tube or parenteral nutrition is rarely nece
Once the patient's nutritional, fluid, and electrolyte status has been stabilized, long-term treatment beg complicated by the patient's abhorrence of weight gain, denial of illness, and manipulative behavior. T physician should attempt to provide a calm, concerned, stable relationship while encouraging a reason caloric intake. Combined management by the family physician and a psychiatrist often helps, and cons with or referral to a specialist in eating disorders is wise. Individual psychotherapy--behavioral, cognitiv psychodynamic--is helpful, as is family therapy for younger patients. Fluoxetine is useful for preventing after weight has been restored.

Section 4. Hepatic And Biliary Disorders Chapter 36. Anatomy And Physiology Topics
[General]
[General]
The liver is the largest and most metabolically complex organ. It consists of many microscopic function traditionally called lobules, bounded by portal triads and central veins. According to Rappaport, howev functional division of the liver is physiologic: Each portal triad is perceived as the center, not the periph functional microvascular unit or acinus. Each acinus is divided into three zones based on distance from feeding vessels; the traditional centrizonal region of the lobule is in reality the periphery (zone 3) of two more acini.
For clinical purposes, the liver can be considered in terms of blood supply, hepatocytes, biliary passag sinusoidal lining cells, and extracellular matrix. Blood supply to the liver is from both the portal vein a hepatic artery; the former provides about 75% of the total 1500-mL/min flow. Small branches of each v the terminal portal venule and terminal hepatic arteriole, enter each acinus at the portal triad (zone 1). pooled blood then flows through sinusoids between plates of hepatocytes. Nutrients are exchanged ac spaces of Disse, which separate hepatocytes from the porous sinusoidal lining. Sinusoidal flow from a acini merges at terminal hepatic venules (central veins, zone 3). These tiny vessels coalesce and even form the hepatic vein, which carries all efferent blood into the inferior vena cava. A rich supply of lymp vessels also drains the liver. Interference with the hepatic blood supply is common in cirrhosis and oth chronic diseases and is usually manifested by portal hypertension (see Ch. 38).
Hepatocytes (parenchymal cells) make up the bulk of the liver. These polygonal cells lie next to the blood-filled sinusoids and are arranged in sheets or plates that radiate from each portal triad toward ad central veins. Hepatocytes are responsible for the liver's central role in metabolism. Their important fun include formation and excretion of bile; regulation of carbohydrate homeostasis; lipid synthesis and se of plasma lipoproteins; control of cholesterol metabolism; formation of urea, serum albumin, clotting fa enzymes, and numerous other proteins; and metabolism or detoxification of drugs and other foreign substances. Hepatocytes in differing regions of the acinus demonstrate metabolic heterogeneity in car these complex processes (eg, gluconeogenesis is primarily a function of zone 1 cells, whereas glycoly mainly occurs in zone 3 cells). In most liver diseases, hepatocellular dysfunction occurs to some degre produces various clinical and laboratory abnormalities.
Biliary passages begin as tiny bile canaliculi formed by adjacent hepatocytes. These microvilli-lined s progressively coalesce into ductules, interlobular bile ducts, and larger hepatic ducts. Outside the port
these complex processes (eg, gluconeogenesis is primarily a function of zone 1 cells, whereas glycoly mainly occurs in zone 3 cells). In most liver diseases, hepatocellular dysfunction occurs to some degre produces various clinical and laboratory abnormalities.
Biliary passages begin as tiny bile canaliculi formed by adjacent hepatocytes. These microvilli-lined s progressively coalesce into ductules, interlobular bile ducts, and larger hepatic ducts. Outside the port hepatis, the main hepatic duct joins the cystic duct from the gallbladder to form the common bile duct, drains into the duodenum. Interference with the flow of bile anywhere along this route produces the characteristic clinical and biochemical picture of cholestasis (see Ch. 38).
Sinusoidal lining cells comprise at least four types of cells: endothelial, Kupffer, perisinusoidal fat-sto and pit cells. (1) Endothelial cells differ from vascular endothelium elsewhere because they lack a bas membrane and contain numerous pores (fenestrae), thereby permitting the exchange of nutrients and macromolecules with nearby hepatocytes across the spaces of Disse. Endothelial cells also endocytos various molecules and particles, synthesize proteins that influence the extracellular matrix, and play a lipoprotein metabolism. (2) Spindle-shaped Kupffer cells line the sinusoids and form an important part reticuloendothelial system; they derive from bone marrow precursors and serve as tissue macrophage functions include phagocytosis of foreign particles, removal of endotoxin and other noxious substance modulation of the immune response. Because of its Kupffer cells and rich blood supply, the liver is ofte secondarily involved in infections and other systemic disorders. (3) Perisinusoidal fat-storing cells (Ito store vitamin A, synthesize various matrix proteins, and can transform into fibroblasts in response to h injury. They are probably the major source of hepatic fibrosis. (4) The uncommon pit cells are believed tissue lymphocytes with natural killer cell functions. Their role in hepatic disorders is unknown.
The extracellular matrix of the liver includes the organ's reticulin framework, consisting of several mo forms of collagen, laminin, fibronectin, and other extracellular glycoproteins. Matrix interactions and fu are not fully understood.
Specific diseases tend to affect these components in predictable patterns, often with characteristic clin biochemical consequences (eg, acute viral hepatitis is primarily manifested by hepatocellular injury, pr biliary cirrhosis by impairment of biliary secretion, and cryptogenic cirrhosis by fibrogenesis and resulta interference with vascular flow). Some disorders (eg, severe alcoholic liver disease) affect all hepatic structures, resulting in multiple functional derangements.
Symptoms of liver disease most often reflect hepatocellular necrosis or impaired bile secretion. These are usually reversible, and the liver has a remarkable capacity for regeneration in response to hepatoc injury. The mechanisms of hepatocellular necrosis are extremely complex; recent attention has focuse apoptosis, a form of programmed cell death regulated by the cell's genetic material and matrix-signalin pathways. Even extensive patchy necrosis can resolve completely (eg, in acute viral hepatitis). Incomp regeneration and fibrosis, however, may result from confluent injury that bridges entire acini or from le pronounced but ongoing chronic damage. Fibrosis itself causes no symptoms; clinical manifestations a usually caused by resultant portal hypertension.

Section 4. Hepatic And Biliary Disorders Chapter 43. Drugs And The Liver Topics
[General] Drug Metabolism Effects Of Liver Disease On Drug Metabolism Liver Damage Caused By Drugs
[General]
Interaction between drugs and the liver can be categorized as: (1) hepatic drug metabolism, (2) effects disease on drug metabolism, and (3) liver damage caused by drugs.
Section 4. Hepatic And Biliary Disorders Chapter 37. Screening And Diagnostic Evaluat Topics
[General]
[General]
Laboratory Tests
The liver is a complex organ with interdependent metabolic, excretory, and defense functions. No sing simple test assesses overall liver function; sensitivity and specificity are limited. Use of several screen improves the detection of hepatobiliary abnormalities, helps differentiate the basis for clinically suspec disease, and determines the severity of liver disease. Many tests are available, but relatively few impro patient care.
Among automatic analyses, the most useful are serum bilirubin, alkaline phosphatase, and aminotrans (transaminase). Cholesterol and LDH are less valuable. The prothrombin time indicates the severity of hepatocellular disease. Only a few biochemical and serologic tests are diagnostic by themselves (eg, h B surface antigen [HBsAg] for hepatitis B virus, serum copper and ceruloplasmin for suspected Wilson disease, serum 1-antitrypsin for 1-antitrypsin deficiency).
Bilirubin: Hyperbilirubinemia results from increased bilirubin production, decreased liver uptake or conjugation, or decreased biliary excretion (see Jaundice in Ch. 38). Increased bilirubin production (eg hemolysis) or decreased liver uptake or conjugation (eg, Gilbert's disease) causes unconjugated (or fr bilirubin in serum to increase. Decreased bile formation and excretion (cholestasis) elevates conjugate bilirubin in serum, and the latter appears in urine.
The van den Bergh reaction measures serum bilirubin via fractionation. A direct reaction measures co bilirubin. The addition of methanol causes a complete reaction, which measures total bilirubin (conjuga unconjugated); the difference measures unconjugated bilirubin (an indirect reaction).
Serum bilirubin may not be a particularly sensitive index of liver dysfunction or disease prognosis, but established test. Total bilirubin is normally < 1.2 mg/dL (20 mol/L). The only value of fractionating bili its components is to detect unconjugated hyperbilirubinemia (present when the unconjugated fraction of total bilirubin). Fractionation is usually required in cases of an isolated bilirubin elevation (ie, other conventional liver tests are normal) or neonatal jaundice. Sophisticated techniques to separate the var conjugates of bilirubin have no clinical value.
Serum bilirubin may not be a particularly sensitive index of liver dysfunction or disease prognosis, but established test. Total bilirubin is normally < 1.2 mg/dL (20 mol/L). The only value of fractionating bili its components is to detect unconjugated hyperbilirubinemia (present when the unconjugated fraction of total bilirubin). Fractionation is usually required in cases of an isolated bilirubin elevation (ie, other conventional liver tests are normal) or neonatal jaundice. Sophisticated techniques to separate the var conjugates of bilirubin have no clinical value.
Urine bilirubin is normally absent. Its presence, readily detected at the bedside with a commercial urine strip, indicates hepatobiliary disease. Unconjugated hyperbilirubin is tightly bound to albumin, not filter the glomerulus, and absent from urine even with raised serum levels of unconjugated bilirubin. A posit for urine bilirubin confirms that any raised plasma levels are from conjugated hyperbilirubinemia. There need to fractionate the total plasma bilirubin. An early feature of hepatobiliary disease can be bilirubinu which develops in acute viral hepatitis even before clinical jaundice appears. It may be absent, howeve other circumstances despite increased serum bilirubin. False-negatives occur with prolonged storage o urine specimen, which may oxidize bilirubin, or in the presence of ascorbic acid (from vitamin C ingest nitrate in the urine (from urosepsis).
Urobilinogen is normally present in trace amounts in the urine (10 mg/L [17 mol/L]) and can be asses commercial test strips. This intestinal metabolite of bilirubin becomes elevated from hemolysis (excess pigment formation) or from mildly impaired liver uptake and excretion (ie, when the enterohepatic circu this pigment exceeds the liver's capacity to clear and excrete it). Failure of bilirubin excretion into the s intestine reduces urobilinogen formation so that the urine may test falsely low or absent. Thus, althoug sensitive for mild liver disease, urobilinogen is too nonspecific and too difficult to interpret.
Alkaline phosphatases: These isoenzymes can hydrolyze organic phosphatase ester bonds in an alk medium, generating an organic radical and inorganic phosphate. Their biologic function is unknown.
Alkaline phosphatase in serum normally comes from the liver and bone and, during pregnancy, from th placenta. It is present in some tumors (eg, bronchogenic carcinoma). Bone growth causes an age-dep rise in normal values, particularly in children < 2 yr and adolescents. Thereafter, alkaline phosphatase declines, reaching normal adult levels after a growth spurt during adolescence. It is slightly increased i people. During pregnancy, serum levels rise two- to fourfold by the 9th mo and return to normal by 21 postpartum.
Alkaline phosphatase increases markedly in diseases that impair bile formation (cholestasis) and to a extent in hepatocellular disease. Values in cholestasis, whether from intrahepatic causes (primary bilia cirrhosis, drug-induced liver disease, liver transplantation rejection) or graft-vs.-host disease or from extrahepatic causes (bile duct obstruction from stricture, stone, or tumor), rise similarly, up to fourfold. elevation is not discriminatory. In hepatocellular disease (eg, various forms of hepatitis, cirrhosis, infiltr disorders), alkaline phosphatase levels tend to be somewhat lower, although overlap exists.
Isolated elevations (ie, other liver tests are normal) occur in granulomatous hepatitis or focal liver disea abscess, neoplastic infiltration, partial bile duct obstruction). In some nonhepatic malignancies without metastasis, the mechanism is obscure. For example, bronchogenic carcinoma may produce its own al phosphatase; hypernephroma in 15% of cases induces nonspecific hepatitis as the presumed origin o enzyme elevation. For Hodgkin's lymphoma, the cause of the isolated alkaline phosphatase elevation unknown. Generally, an isolated alkaline phosphatase elevation in an otherwise asymptomatic elderly not worth investigating. Most cases originate from the bone (eg, in Paget's disease).
5-Nucleotidase: Measurement of 5-nucleotidase is simpler than available techniques that assess el alkaline phosphatase to distinguish bone from liver origin. 5-Nucleotidase differs biochemically from a phosphatase and is more restricted to the plasma membranes of the liver cell. Values are low in childh rise gradually during adolescence, and plateau after age 50 yr. 5-Nucleotidase is normally elevated in women during the last trimester of pregnancy. This serum enzyme increases in hepatobiliary but not in
5-Nucleotidase: Measurement of 5-nucleotidase is simpler than available techniques that assess el alkaline phosphatase to distinguish bone from liver origin. 5-Nucleotidase differs biochemically from a phosphatase and is more restricted to the plasma membranes of the liver cell. Values are low in childh rise gradually during adolescence, and plateau after age 50 yr. 5-Nucleotidase is normally elevated in women during the last trimester of pregnancy. This serum enzyme increases in hepatobiliary but not in diseases. It is useful in assessing the anicteric patient. Because of its specificity for liver disease, 5-nucleotidase offers some advantage over alkaline phosphatase, but neither can differentiate obstru from hepatocellular disease. They may or may not rise and fall in parallel.
-Glutamyl transpeptidase (GGT): Also known as -glutamyltransferase, GGT (present in the liver, pan and kidney) transfers the -glutamyl group from one peptide to another or to an L-amino acid. GGT leve elevated in diseases of the liver, biliary tract, and pancreas when the common duct is obstructed. GGT parallel those of alkaline phosphatase and 5-nucleotidase in cholestatic conditions. The extreme sens GGT (greater than that of alkaline phosphatase) limits its usefulness, but it helps detect hepatobiliary d as the cause of an isolated rise in alkaline phosphatase. GGT is normal in pregnancy and bone diseas Because it is not physiologically elevated in pregnancy or childhood, GGT may distinguish hepatobiliar disease in such cases. Drug use and alcohol ingestion, which induce microsomal enzymes, also eleva As a marker for alcoholic liver disease, GGT is poor when used alone but more secure when combine transaminases.
Transaminases: Aspartate transaminase (AST) and alanine aminotransferase (ALT) are sensitive ind of liver injury. AST is present in the heart, skeletal muscle, brain, and kidney as well as in the liver. AS thus rise in MI, heart failure, muscle injury, CNS disease, and other nonhepatic disorders. AST is relat nonspecific, but high levels indicate liver cell injury. ALT is reliable for routine screening for liver diseas Values > 500 IU/L suggest acute viral or toxic hepatitis and occur with marked heart failure (ischemic h and occasionally with common duct stones. The magnitude of the elevation has no prognostic value a not correlate with the degree of liver damage. Serial testing provides good monitoring: A fall to normal indicates recovery unless associated with the end stages of massive hepatic necrosis.
ALT is found primarily in liver cells and thus has greater specificity for liver disease but offers little othe advantage. In most liver diseases, the AST increase is less than that of ALT (AST/ALT ratio < 1), but i alcohol-related liver injury, the ratio frequently is > 2. The basis for this is the greater need of pyridoxal 5-phosphate (vitamin B6) as a cofactor for ALT; this cofactor is deficient in the alcoholic, limiting the ri ALT. Although the practicality of the ratio is limited, an AST/ALT ratio > 3 with an inordinate increase in (more than twice the alkaline phosphatase) is highly suggestive of alcohol-related liver injury (eg, alcoh hepatitis). Lactic dehydrogenase: LDH, commonly included in routine analysis, is insensitive as an indicator of hepatocellular injury but is better as a marker for hemolysis, MI, or pulmonary embolism. LDH can be high with malignancies involving the liver.
Serum proteins: The liver synthesizes most serum proteins: - and -globulins, albumin, and clotting fac not -globulin, which is produced by B lymphocytes). Hepatocytes also make specific proteins: 1 -antitry (absent in 1-antitrypsin deficiency), ceruloplasmin (reduced in Wilson's disease), and transferrin and fe (saturated with iron and greatly increased, respectively, in hemochromatosis). These serum proteins a others increase nonspecifically in response to tissue injury (eg, inflammation) with the release of cytok Such acute phase reactions may produce a spuriously normal or elevated value.
Serum albumin, the main determinant of plasma oncotic pressure, transports numerous substances ( unconjugated bilirubin). Its serum concentration is determined by the relative rates of its synthesis and degradation or loss, by its distribution between the intra- and extravascular beds, and by the plasma v adults, the liver normally synthesizes 10 to 15 g (0.2 mmol) of albumin daily, which represents about 3
Such acute phase reactions may produce a spuriously normal or elevated value.
Serum albumin, the main determinant of plasma oncotic pressure, transports numerous substances ( unconjugated bilirubin). Its serum concentration is determined by the relative rates of its synthesis and degradation or loss, by its distribution between the intra- and extravascular beds, and by the plasma v adults, the liver normally synthesizes 10 to 15 g (0.2 mmol) of albumin daily, which represents about 3 total body pool. Its biologic half-life is about 20 days; thus, serum levels do not reflect hepatocellular fu acute liver disease. Serum albumin (and its synthesis) is decreased in chronic liver disease (eg, cirrho ascites), largely because of the increased volume of distribution. Alcoholism, chronic inflammation, an malnutrition depress albumin synthesis. Hypoalbuminemia can result from excess albumin loss from th kidney (nephrotic syndrome), gut (protein-losing gastroenteropathies), and skin (burns).
Serum immunoglobulins rise in most cases of chronic liver disease when the reticuloendothelial sys defective or bypassed by portal venous shunts. The inability to clear portal venous blood of transient bacteremias from normal colonic flora results in chronic antigenic stimulation of extrahepatic lymphoid and hypergammaglobulinemia. Serum globulin levels rise slightly in acute hepatitis and more markedly chronic active hepatitis, particularly of the autoimmune variety. The pattern of immunoglobulin increas little: IgM is quite elevated in primary biliary cirrhosis, IgA in alcoholic liver disease, and IgG in chronic hepatitis.
Antibodies: Specific proteins may be diagnostic. Viral antigens and antibodies are associated with sp causes of hepatitis (see Acute Viral Hepatitis in Ch. 42 and Infectious Mononucleosis under Viral Infec Ch. 265).
Antimitochondrial antibodies are directed against antigens on the inner mitochondrial membrane of se tissues. The M2 antigen is most closely associated with primary biliary cirrhosis. Antimitochondrial anti are positive, usually in high titers, in > 95% of patients with primary biliary cirrhosis. These heterogene antibodies are also present in 30% of cases of autoimmune chronic active hepatitis and in some cases hepatitis and collagen vascular disease. They are absent in mechanical biliary obstruction and primary sclerosing cholangitis; hence, they have important diagnostic value, particularly when liver histopatholo equivocal.
Other antibodies occur in autoimmune chronic active hepatitis: Smooth muscle antibodies directed aga actin are found in 70%, and antinuclear antibodies providing a homogenous (diffuse) fluorescence are in high titers. Some patients with chronic active hepatitis exhibit a different autoantibody, anti-liver-kidney-microsome (LKM-1) antibody. However, none of these antibodies is diagnostic by itse none reveals the pathogenesis of the disease process.
-Fetoprotein (AFP): Synthesized by the fetal liver, AFP is normally elevated in the mother and newbo yr of age, infants achieve adult values (normally < 20 ng/mL). Marked elevations develop in primary hepatocellular carcinoma; the level correlates with tumor size. AFP is a useful screening test because other conditions (embryonic teratocarcinomas, hepatoblastomas, infrequent hepatic metastases from tract, some cholangiocarcinomas) cause levels > 400 ng/mL. In fulminant hepatitis, AFP can be > 100 lesser elevations (100 to 400 ng/mL) occur in acute and chronic hepatitis. These values may represen regeneration.
Prothrombin time (PT): PT involves the interactions of factors I (fibrinogen), II (prothrombin), V, VII, a which are synthesized by the liver (see also discussion under Hemostasis in Ch. 131). PT may be exp in time (sec) or as a ratio of measured PT vs. control PT, termed the INR. Vitamin K is necessary for prothrombin conversion. The precursors of factors VII, IX, X, and possibly V require it for activation thr carboxylation step, which is essential for them to function as clotting factors. Vitamin K deficiencies res inadequate intake or malabsorption. Because it is fat-soluble, vitamin K requires bile salts for intestina absorption and would therefore be deficient in cholestasis. Malabsorption of vitamin K as a cause of a prolonged PT can be differentiated by repeating the PT 24 to 48 h after administration of vitamin K 10
in time (sec) or as a ratio of measured PT vs. control PT, termed the INR. Vitamin K is necessary for prothrombin conversion. The precursors of factors VII, IX, X, and possibly V require it for activation thr carboxylation step, which is essential for them to function as clotting factors. Vitamin K deficiencies res inadequate intake or malabsorption. Because it is fat-soluble, vitamin K requires bile salts for intestina absorption and would therefore be deficient in cholestasis. Malabsorption of vitamin K as a cause of a prolonged PT can be differentiated by repeating the PT 24 to 48 h after administration of vitamin K 10 Little or no improvement occurs with parenchymal liver disease.
PT is relatively insensitive for detecting mild hepatocellular dysfunction. Because the biologic half-lives involved clotting factors are short (hours to a few days), the PT has a high prognostic value in acute liv In acute viral or toxic hepatitis, PT > 5 sec above control is an early indicator of fulminant hepatic failur
Tests for hepatic transport and metabolism: Several tests can determine the ability of the liver to tr organic material and metabolize drugs. Bilirubin measurements are common; other tests, although ofte sensitive, are complex, costly, and nonspecific.
Bile acids are specific to the liver, being synthesized only in the liver, constituting the driving force for formation and exhibiting a 70 to 90% first-pass hepatic extraction. Serum bile acid concentrations norm extremely low (about 5 mol/L). Elevations are specific and very sensitive for hepatobiliary disease, bu do not assist in differential diagnosis nor indicate prognosis. Values are normal in isolated hyperbilirub (eg, Gilbert's syndrome). Sophisticated analysis of individual serum bile acids may aid clinical research acid therapy for gallstone disease and primary biliary cirrhosis.
Imaging Studies
Radionuclide scanning, ultrasound (US), CT, and MRI have replaced traditional imaging techniques (e cholecystogram, IV cholangiogram). Invasive radiography (eg, ERCP) allows for sophisticated instrum and treatment procedures.
Plain x-ray of the abdomen: The usefulness of x-rays is limited to identifying calcifications in the liver gallbladder, opaque gallstones, and air in the biliary tract. Hepatic or splenic enlargement and ascites detected.
Oral cholecystogram: This procedure is simple, reliable, and relatively safe for visualizing the gallbla 25% of patients experience diarrhea. Rarely, a patient has a hypersensitivity reaction to the iodine in t contrast agent. An abnormal study includes failure to visualize the gallbladder after a second dose of c agent, provided the obvious has been excluded: vomiting, gastric outlet obstruction, malabsorption, Dubin-Johnson syndrome, and significant hepatocellular disease. Sensitivity for diagnosing gallbladde disease (eg, cholelithiasis) is about 95%, but specificity is much lower. Conversely, gallstones and tum readily identified and differentiated. Besides defining gallbladder anatomy, oral cholecystography also assesses the patency of the cystic duct and, to a lesser extent, the concentrating function of the gallbl Radiologic gallbladder filling is an important criterion when assessing patients for gallstone dissolution with bile salts and for biliary lithotripsy. This technique is also more useful than US for determining sto number and type (lucency implies that the stones are composed of cholesterol). However, US and bilia cholescintigraphy have largely replaced this former gold standard because of their greater ease of use lower false-negative rates. Cholescintigraphy is also better at assessing gallbladder filling and emptyin
Ultrasound: Findings obtained by US are morphologic and independent of function. US is the most im investigative tool in screening for biliary tract abnormalities and mass lesions in the liver. US is better a detecting focal lesions (> 1 cm in diameter) than diffuse disease (eg, fatty liver, cirrhosis). In general, c echo-free; solid lesions (eg, tumors, abscesses) tend to be echogenic. The ability to localize focal lesio permits US-guided aspiration and biopsy.
Ultrasound: Findings obtained by US are morphologic and independent of function. US is the most im investigative tool in screening for biliary tract abnormalities and mass lesions in the liver. US is better a detecting focal lesions (> 1 cm in diameter) than diffuse disease (eg, fatty liver, cirrhosis). In general, c echo-free; solid lesions (eg, tumors, abscesses) tend to be echogenic. The ability to localize focal lesio permits US-guided aspiration and biopsy.
US is the least expensive, safest, and most sensitive technique for visualizing the biliary system, espe gallbladder. Accuracy in detecting gallbladder or gallstone disease is close to 100%, although an elem operator skill is needed. Gallstones cast intense echoes with distal shadowing and may move with gra can be accurately defined, but the number of stones may be difficult to determine because of overlap many are present. Criteria for acute cholecystitis include a thickened gallbladder wall, pericholecystic f impacted stone in the gallbladder neck, and gallbladder tenderness on palpation (Murphy's sign). Poly gallbladder are a frequent incidental finding. Carcinoma presents as a nonspecific solid mass.
US is the procedure of choice for evaluating cholestasis and differentiating extrahepatic from intrahepa causes of jaundice. Bile ducts stand out as echo-free tubular structures. The diameter of the common normally < 6 mm, increases slightly with age, and can reach 10 mm after cholecystectomy. Dilated duc virtually pathognomonic for extrahepatic obstruction, but normal bile ducts do not exclude obstruction it may be recent or intermittent. US does not readily detect common duct stones, but they may be infe the common duct is dilated and stones are identified in the gallbladder. Visualization of the pancreas, and blood vessels is an added bonus. Finding enlargement or a mass in the head of the pancreas ma the cause of cholestasis or upper abdominal pain.
Doppler US measures the frequency change of a backscattered US wave reflected from moving RBC can show the patency of hepatic vessels, particularly the portal vein, and the direction of blood flow. D US can reveal hepatic artery thrombosis after liver transplantation. It also can detect unusual vascular structures (eg, cavernous transformation of the portal vein).
Radionuclide scanning: This procedure involves hepatic extraction of an injected radiopharmaceutic the blood, most commonly technetium 99m (99m Tc).
Liver-spleen scanning uses 99mTc-sulfur colloid, which is rapidly extracted from the blood by reticuloendothelial cells. Normally, radioactivity is uniformly distributed. In a space-occupying lesion > (eg, cyst, abscess, metastasis, hepatic tumor), the replaced liver cells produce a cold spot. Generalize disease (eg, cirrhosis, hepatitis) causes a heterogenous decrease in liver uptake and increased uptak spleen and bone marrow. In hepatic vein obstruction, there is decreased visualization of the liver exce caudate lobe because of its special drainage into the inferior vena cava. US or CT has largely supplan radionuclide scanning for space-occupying lesions and diffuse parenchymal disease.
Cholescintigraphy: For scanning the hepatobiliary excretory system, cholescintigraphy uses 99m Tc-iminodiacetic acid derivatives. These radiopharmaceuticals are organic anions, which the liver a clears from plasma into bile much like bilirubin. A minimum 2-h fast is necessary. A normal scan show uniform liver uptake; prompt excretion into the bile ducts; and a visible gallbladder and duodenum by 1 acute cholecystitis (with cystic duct obstruction), the gallbladder is not visible by 1 h. Acute acalculous cholecystitis can similarly be detected. Chronic cholecystitis is more problematic: It can be reasonably diagnosed if gallbladder visualization is delayed beyond 1 h, sometimes until 24 h, or if the gallbladder visualized, but confounded by false-negatives and false-positives. Several factors may contribute to nonvisualization of the gallbladder (eg, significant cholestasis with markedly elevated bilirubin, a nonfa state, fasting > 24 h, certain drugs).
Cholescintigraphy also assesses hepatobiliary integrity (bile leaks may be especially important after su trauma) and anatomy (from congenital choledochal cysts to choledochoenteric anastomoses). After cholecystectomy, this biliary scan can quantitate biliary drainage and assist in defining sphincter of Od
nonvisualization of the gallbladder (eg, significant cholestasis with markedly elevated bilirubin, a nonfa state, fasting > 24 h, certain drugs).
Cholescintigraphy also assesses hepatobiliary integrity (bile leaks may be especially important after su trauma) and anatomy (from congenital choledochal cysts to choledochoenteric anastomoses). After cholecystectomy, this biliary scan can quantitate biliary drainage and assist in defining sphincter of Od dysfunction. In neonatal jaundice, hepatobiliary imaging helps distinguish hepatitis from biliary atresia.
Computed tomography: CT is sensitive to variations in density of differing hepatic lesions. The additi IV contrast agent helps differentiate more subtle differences between soft tissues and define the vascu system and the biliary tract. CT shows liver structures more consistently than US; neither obesity nor i gas obscures them. CT is especially useful for visualizing space-occupying lesions (eg, metastases) in and masses in the pancreas. CT can detect fatty liver and the increased hepatic density associated wi overload. CT is expensive and necessitates radiation exposure; both factors lessen its routine use com with US.
Magnetic resonance imaging: MRI is an exciting, although expensive, technology that may prove advantageous for identification of tumors and hepatic blood flow. Blood vessels are easily identified wi contrast agents. Although still evolving, MRI is comparable to CT for detecting mass lesions and can v perihepatic vessels and the biliary system. Magnetic resonance cholangiography is becoming an incre useful screening tool before proceeding to more invasive techniques.
Operative cholangiography: This procedure entails direct injection of a contrast agent into the cystic common bile duct at laparotomy. Excellent visualization results. This diagnostic approach is indicated stones when jaundice occurs or when a common duct stone is suspected. Technical difficulties have li use at laparoscopic cholecystectomy. Direct visualization of the common duct can also be obtained by choledochoscopy. IV cholangiography for identifying the common duct has been virtually abandoned because of poor diagnostic yield, the risk of a hypersensitivity reaction, and the advent of ERCP.
Endoscopic retrograde cholangiopancreatography: ERCP combines (1) endoscopy (for upper GI endoscopy, see Ch. 19) for identifying and cannulating the ampulla of Vater in the second portion of th duodenum and (2) radiology after injection of a contrast agent into the biliary and pancreatic ducts. Th technique places a side-viewing endoscope in the descending duodenum, identifies and cannulates th of Vater, and then injects a contrast agent to visualize the pancreatic duct and the biliary duct systems Besides obtaining excellent images of the biliary tract and pancreas, ERCP allows some visualization upper GI tract and the periampullary area. Biopsies and interventional procedures may be performed ( sphincterotomy, biliary stone extraction, placement of a biliary stent in a stricture). ERCP is an outpatie procedure that, in experienced hands, has relatively low risk (mainly pancreatitis in 3% after sphinctero has revolutionized the diagnosis and management of pancreaticobiliary disease. ERCP is especially v in assessing the biliary tract in cases of persistent jaundice and in seeking a lesion amenable to interv (eg, stone, stricture, sphincter of Oddi dysfunction). In jaundice and cholestasis, US to assess duct siz precede ERCP.
Percutaneous transhepatic cholangiography (PTC): This procedure involves puncture of the liver w 22-gauge needle under fluoroscopic or US control to enter the peripheral intrahepatic bile duct system the common hepatic duct. PTC has a high diagnostic yield but only for the biliary system. Some therap techniques (eg, decompression of the biliary system, insertion of an endoprosthesis) are possible. ER generally is preferred, particularly if ducts are not dilated (eg, sclerosing cholangitis). PTC is used afte ERCP or when altered anatomy (gastroenterostomy) precludes accessing the ampulla. It may complem ERCP in hilar lesions at the porta hepatis. PTC is generally safe but has a higher complication rate (eg sepsis, bleeding, bile leaks) than ERCP. Local expertise often dictates the choice between PTC and E
Liver Biopsy
ERCP or when altered anatomy (gastroenterostomy) precludes accessing the ampulla. It may complem ERCP in hilar lesions at the porta hepatis. PTC is generally safe but has a higher complication rate (eg sepsis, bleeding, bile leaks) than ERCP. Local expertise often dictates the choice between PTC and E
Liver Biopsy
Percutaneous liver biopsy provides valuable diagnostic information with relatively small risk and little discomfort. Performed with the patient under local anesthesia, this bedside procedure entails aspiratio the Menghini needle or the disposable and therefore always sharp Jamshidi needle) or cutting (using t disposable Trucut--a variation of the Vim-Silverman needle). The needle is inserted through an anesth intercostal space anterior to the midaxillary line, just below the point of maximal dullness on expiration patient lies still and maintains expiration. The liver is rapidly entered with either suction applied (Jamsh cutting sheath advanced (Trucut). The result is a procedure that takes 1 to 2 sec and yields a liver spe mm in diameter and 2 cm long. Occasionally, a second pass is necessary; if a second or third attempt unsuccessful, then needle biopsy should be guided by ultrasound (US) or CT. US-guided biopsies usin biopsy gun, whose spring mechanism fires a modified Trucut needle, are less painful and provide a hig US guidance is particularly useful for sampling focal lesions or avoiding vascular lesions (eg, hemangi
At biopsy, the liver's texture can be ascertained on needle insertion: a hard, gritty feel suggests cirrhos biopsy is examined routinely for histopathology. Cytology, frozen section, and culture may be useful in cases. In suspected Wilson's disease, copper content should be measured. Gross inspection provides information: fragmentation suggests cirrhosis; a fatty liver is pale yellow and floats in formaldehyde; ca is whitish.
Liver biopsy is sufficiently safe to perform as an outpatient procedure. After biopsy, the patient is moni 3 to 4 h, during which complications (eg, intra-abdominal hemorrhage, bile peritonitis, lacerated liver) a likely. Because delayed bleeding can occur as long as 15 days later, discharged patients should rema 1 h of the hospital. Mild right upper quadrant discomfort, sometimes radiating from the diaphragm to th shoulder tip, is common and responds to mild analgesics. Mortality is low at 0.01%; major complication reportedly about 2%.
Indications for percutaneous liver biopsy are listed in Table 37-1. Fine-needle biopsy under US guidan detects metastatic carcinoma in at least 66% of cases and may establish the diagnosis despite negativ scanning techniques; cytologic examination of the biopsy fluid yields positive findings in an additional 1 cases. Results are less valuable in lymphoma and correlate poorly with the clinical impression of hepa involvement. Biopsy is especially valuable in detecting TB or other granulomatous infiltrations and can graft problems (ischemic injury, rejection, biliary tract disease, viral hepatitis) after liver transplantation
Limitations of the procedure include (1) the need for a skilled histopathologist (many pathologists have experience with needle specimens); (2) sampling error (nonrepresentative tissue seldom occurs in hep and other diffuse conditions but can be a problem in cirrhosis and space-occupying lesions); (3) inabili differentiate hepatitis etiologically (eg, viral vs. drug-induced); and (4) occasional errors or uncertainty of cholestasis.
Relative contraindications include a clinical bleeding tendency or a coagulation disorder (prothrombin t sec over control values [INR > 1.2] despite giving vitamin K, bleeding time > 10 min), severe thromboc (50,000/L), severe anemia, peritonitis, marked ascites, high-grade biliary obstruction, and subphrenic pleural infection or effusion.
Transvenous liver biopsy is performed by threading a modified Trucut needle through a catheter ins the right internal jugular vein and through the right atrium into the inferior vena cava and hepatic vein. needle is advanced through the hepatic vein into the liver. Hepatic vein and wedge pressures can also obtained. Although the specimen obtained is relatively small and the operator must be skilled in angiog this technique can be used even when the patient has a significant coagulation disorder. It is surprisin
Transvenous liver biopsy is performed by threading a modified Trucut needle through a catheter ins the right internal jugular vein and through the right atrium into the inferior vena cava and hepatic vein. needle is advanced through the hepatic vein into the liver. Hepatic vein and wedge pressures can also obtained. Although the specimen obtained is relatively small and the operator must be skilled in angiog this technique can be used even when the patient has a significant coagulation disorder. It is surprisin tolerated and requires minimal sedation, if any, except in the case of an uncooperative patient. The yie liver tissue is > 95% in experienced hands. The complication rate is very low: 0.2% bleed from punctur liver capsule. One center reported no mortality in > 1000 transvenous biopsies.

Section 4. Hepatic And Biliary Disorders Chapter 44. Postoperative Liver Disorders Topics
[General]
[General]
Mild liver dysfunction sometimes occurs after major surgery and reflects poorly understood effects of anesthetic and operative stress. Patients with well-compensated liver disease (eg, inactive cirrhosis) u tolerate surgery well. However, patients with underlying liver disease may develop more severe dysfun postoperatively; eg, in a patient with viral or alcoholic hepatitis, laparotomy may precipitate acute liver
Postoperative jaundice in patients without previous liver disease can take several forms. The most freq multifactorial mixed hyperbilirubinemia caused by a complex interaction between enhanced bilirubi and diminished hepatic clearance. This most often occurs after major surgery or trauma requiring mult transfusions. Hemolysis, sepsis, resorption of hematomas, and blood transfusions can contribute to in pigment production; simultaneously, hypoxemia, circulatory failure, and other poorly understood factor hepatic function. The result is variable, but severe jaundice with nondescript aminotransferase and alk phosphatase elevations often occurs. Frank liver failure is rare, and the syndrome typically resolves sl completely.
Transient hypotension during anesthesia or from perioperative shock can cause acute zone 3 (centrilo liver necrosis, manifested by a rapid and dramatic increase in aminotransferase levels (often > 1000 U Jaundice is usually mild. This so-called ischemic hepatitis reflects hypoxic injury, not inflammatory ne and characteristically resolves within a few days unless complicating factors are present.
True postoperative hepatitis is usually caused by viral transmission during blood transfusion, especi hepatitis C virus, and must be differentiated from the above abnormalities. The latter are usually maxim within a few days of operation, whereas hepatitis C develops beyond 2 wk. Until recently, postoperativ hepatitis was more common than generally realized, because most cases are subclinical or anicteric. R screening of donor blood for hepatitis C has dramatically decreased this risk. Anesthetics containing h or related agents may also produce postoperative hepatitis and should be suspected if hepatitis develo within 10 days of surgery, especially if preceded by unexplained fever (see Ch. 43).
Cholestatic reactions are most often caused by biliary obstruction from intra-abdominal complication drugs given postoperatively. Obscure intrahepatic cholestasis occasionally develops in patients who h undergone major surgery, especially abdominal or cardiovascular procedures (benign postoperative
or related agents may also produce postoperative hepatitis and should be suspected if hepatitis develo within 10 days of surgery, especially if preceded by unexplained fever (see Ch. 43).
Cholestatic reactions are most often caused by biliary obstruction from intra-abdominal complication drugs given postoperatively. Obscure intrahepatic cholestasis occasionally develops in patients who h undergone major surgery, especially abdominal or cardiovascular procedures (benign postoperative intrahepatic cholestasis). The pathogenesis is unknown, but the disorder usually slowly resolves spontaneously; ultrasound helps to differentiate it from mechanical obstruction. Occasionally, acute ac cholecystitis or pancreatitis is responsible for postoperative cholestatic jaundice.
Patients receiving prolonged total parenteral nutrition (TPN) perioperatively may develop a progressive cholestatic syndrome that usually has a component of hepatocellular inflammation (TPN cholestasis). syndrome rarely occurs with < 3 wk of TPN, but the risk increases with the duration of therapy; infants particularly susceptible. Despite intense study, the pathogenesis is still uncertain. Liver biopsy usually nonspecific mixed cholestatic-inflammatory picture, sometimes with progressive fibrosis. The syndrom regresses with discontinuation of TPN, but it can otherwise lead to liver failure or irreversible scarring.
Section 4. Hepatic And Biliary Disorders Chapter 38. Clinical Features Of Liver Diseas Topics
[General] Jaundice Hepatomegaly Portal Hypertension Ascites Portal-Systemic Encephalopathy Other Symptoms And Signs Of Liver Disease
[General]
Liver disease has numerous clinical manifestations, some of which are seen in either acute or chronic disorders whereas others occur only in chronic disease.

Section 4. Hepatic And Biliary Disorders Chapter 45. Hepatic Granulomas Topics
[General]
[General]
Hepatic granulomas: A multifactorial infiltrative liver disorder with or without inflammation and fibrosis.
Although often termed granulomatous hepatitis, hepatic granulomas do not represent a true hepatiti Hepatic granulomas are found in about 3 to 10% of liver biopsies. The granulomas may be insignifican incidentally, but more often reflect clinically relevant disease--usually a systemic disorder rather than p liver disease.
Etiology
There are many causes of liver granulomas. Infectious disorders are the most important: bacterial (eg, other mycobacterial infections, brucellosis, tularemia, actinomycosis, cat-scratch fever); fungal (eg, histoplasmosis, cryptococcosis, blastomycosis); parasitic (eg, schistosomiasis, the most important infe cause of granulomas worldwide; toxoplasmosis; visceral larva migrans); viral, which is less common (e infectious mononucleosis, cytomegalovirus); rickettsial (eg, Q fever); and numerous other infections (e syphilis).
Sarcoidosis is the most important noninfectious cause; liver involvement occurs in about 2/3 of patient sarcoidosis and occasionally is the dominant clinical manifestation. Various drugs can be responsible quinidine, sulfonamides, allopurinol, phenylbutazone). Hepatic granulomas can also occur in polymyal rheumatica and other collagen vascular diseases; in Hodgkin's disease, sometimes without other morp evidence of the lymphoma; and in many other systemic conditions.
Granulomas are less common in primary liver disease. Of these, primary biliary cirrhosis is the only im cause; periportal granulomas are typical in this disorder, especially in the early stages, usually coupled other characteristic histologic features. Small granulomas occasionally occur in other liver diseases, m associated with fat droplets (lipogranulomas), but are of no clinical significance.
In many cases, no cause can be established. A few patients have recurrent fever, myalgias, fatigue, a systemic symptoms, often occurring intermittently for years. Whether this idiopathic granulomatous hepatitis represents a specific syndrome or a variant of sarcoidosis is debated.
cause; periportal granulomas are typical in this disorder, especially in the early stages, usually coupled other characteristic histologic features. Small granulomas occasionally occur in other liver diseases, m associated with fat droplets (lipogranulomas), but are of no clinical significance.
In many cases, no cause can be established. A few patients have recurrent fever, myalgias, fatigue, a systemic symptoms, often occurring intermittently for years. Whether this idiopathic granulomatous hepatitis represents a specific syndrome or a variant of sarcoidosis is debated.
Pathophysiology
Granuloma formation is incompletely understood. The lesions are regarded as the host's attempt to pr against poorly soluble exogenous or endogenous irritants. Immunologic mechanisms convert cells of t mononuclear phagocytic system into the typical collection of epithelioid cells that constitute a granulom multinucleated giant cells are believed to derive from fusion of macrophages.
In the liver, granulomas often incite little or no hepatocellular reaction and merely serve as the morpho clue to some underlying systemic process; liver disease is not apparent clinically, and liver function is preserved. However, when granulomas are part of a broader inflammatory reaction involving the liver ( reactions, infectious mononucleosis), clinical and biochemical evidence of hepatocellular dysfunction i present. Sometimes an aggressive inflammatory response around the granulomas ensues, resulting in progressive hepatic fibrosis and portal hypertension. This is typical of schistosomiasis and occasionall in extensive sarcoidal infiltration.
Symptoms and Signs
Clinical features reflect the underlying cause. Granulomas themselves are typically subclinical; even e infiltration usually produces only minor hepatomegaly and little or no jaundice. Fever, malaise, and oth systemic symptoms are the usual presenting manifestations of infection; prolonged FUO is especially in TB and fungal infections. History is critical in establishing a drug etiology. Various systemic features indicate sarcoidosis, collagen vascular disease, lymphoma, and other causes. Signs of primary liver di are usually lacking, and hepatosplenomegaly is typically absent or mild except in schistosomiasis.
Diagnosis
In most cases, liver function tests are only mildly deranged, usually with a disproportionate elevation o phosphatase. Bilirubin levels are typically normal or only mildly elevated, unless hepatocellular injury c Enzyme values may simulate those of viral hepatitis if extensive hepatocellular necrosis is present (eg infectious mononucleosis or a drug reaction). A predominant cholestatic reaction suggests primary bili cirrhosis, especially if long-standing. Other laboratory abnormalities depend on the specific cause.
Liver biopsy is essential for diagnosis and should be considered whenever a systemic granulomatous is suspected, even in the absence of apparent liver involvement. Biopsy demonstrates granulomas an provide histologic evidence of the specific etiology (eg, schistosomal ova, caseation of TB, fungal orga primary biliary cirrhosis). However, the morphologic pattern is often nonspecific, and diagnosis must b pursued with appropriate studies (eg, cultures, skin tests, laboratory tests, x-rays, other tissue specime infectious etiology is especially important to establish in patients with FUO; this task often proves chall A portion of the fresh biopsy specimen should be sent for culture; special stains for acid-fast bacilli, fun other organisms can sometimes prove the cause, although negative results do not exclude infection.
Hepatic granulomas caused by drugs or infection regress completely after appropriate therapy. Sarcoi
A portion of the fresh biopsy specimen should be sent for culture; special stains for acid-fast bacilli, fun other organisms can sometimes prove the cause, although negative results do not exclude infection.
Hepatic granulomas caused by drugs or infection regress completely after appropriate therapy. Sarcoi granulomas may disappear spontaneously or persist for years, usually without clinically important liver but progressive fibrosis and portal hypertension occasionally develop (sarcoidal cirrhosis). In schistoso progressive portal scarring is the rule (pipestem fibrosis); liver function usually remains well preserved increasing portal hypertension leads to marked splenomegaly and risk of variceal hemorrhage.
Treatment depends on the cause. When the cause is unknown, it is generally best to follow up the pat rather than to blindly treat with antibiotics or other therapies. Antituberculous therapy may be justified i patient with prolonged fever, a compatible clinical picture, and a downhill systemic course. Patients wit progressive hepatic sarcoidosis may benefit from corticosteroids, although it is unclear whether these prevent hepatic fibrosis; corticosteroids are not indicated for most patients with sarcoidosis and should given only if TB and other infectious disorders can be excluded confidently. Corticosteroids usually sup recurrent fever in patients with idiopathic granulomatous hepatitis.

Section 4. Hepatic And Biliary Disorders Chapter 39. Fatty Liver Topics
[General]
[General]
Fatty liver (hepatic steatosis): Excessive accumulation of lipid in hepatocytes, the most common respo the liver to injury.
The liver occupies a central position in lipid metabolism. A small, rapidly used pool of free fatty acids ( absorbed from the diet or released into the blood from chylomicrons or fat cells, accommodates almos the energy requirements of a fasting animal. FFAs are taken up by the liver to join the hepatic pool of F portion of which the liver synthesizes. Some FFAs are oxidized to CO2 in the liver for energy, but mos rapidly incorporated into complex lipids (eg, triglycerides, phospholipids, glycolipids, cholesterol esters of these complex lipids enter a slowly used pool that comprises the structural lipids of liver cells and th storage site. Most triglycerides enter an active pool where they combine with specific apoproteins to fo lipoproteins (eg, very low density lipoproteins [VLDLs]), which are secreted into plasma. The liver is als responsible for lipid degradation (eg, low density lipoproteins, chylomicron remnants).
Fatty liver occurs when lipid accumulation exceeds the normal 5% of liver weight. In the macrovesicu large fat droplets balloon the liver cell, displacing the nucleus to the periphery of the cell, like an adipo Triglyceride accumulates most commonly because it has the highest turnover rate of all hepatic fatty a esters. Liver uptake of FFA from adipose tissue and the diet is unrestrained, whereas FFA disposition oxidation, esterification, and VLDL secretion is limited.
In microvesicular fatty liver, small fat droplets accumulate, cells appear foamy, and nuclei are central Triglycerides collect in subcellular organelles (eg, endoplasmic reticulum), reflecting widespread metab disturbance. Mitochondrial injury limits FFA oxidation, while apoprotein synthesis necessary for VLDL is depressed, leading to triglyceride accumulation.
In phospholipidosis, phospholipids accumulate in association with certain drug use (eg, amiodarone) cells are large and foamy.
Etiology
In phospholipidosis, phospholipids accumulate in association with certain drug use (eg, amiodarone) cells are large and foamy.
Etiology
Diffuse fatty change of the liver, often zonal in distribution, is associated with many clinical situations Alcoholism, obesity, and diabetes are the most common causes of macrovesicular fatty liver in develo countries. Other causes include malnutrition (especially the protein-deficient diet of children with kwas inborn metabolic disorders (of glycogen, galactose, tyrosine, or homocysteine), drugs (eg, corticostero systemic illnesses with fever. Microvesicular fatty liver occurs in acute fatty liver of pregnancy, Reye's syndrome, certain drug toxicities (valproic acid, tetracycline, salicylate), or inborn metabolic defects (of urea cycle enzymes or involving mitochondria in FFA oxidation).
Focal fatty change is much less common and less well recognized. These nodules of fatty liver cells a subcapsular. They are usually an incidental finding on ultrasound or CT, presenting as multiple space-occupying lesions of the liver. Such focal fat may appear in patients apparently at risk of develo change (eg, obese or alcoholic patients).
Pathogenesis
Triglycerides accumulate in the liver because of increased input through synthesis from FFA or decrea export as VLDL from the hepatocytes. Increased triglyceride synthesis may result from increased deliv availability of FFA (from the diet or mobilized from adipose tissue), from acetylcoenzyme A, or from de oxidation of FFA in the liver. Reduced elimination of triglyceride involves depressed packaging with apolipoprotein, phospholipid, and cholesterol, resulting in decreased VLDL secretion.
The several possible mechanisms involved in the pathogenesis of the fatty liver may operate alone or In obesity, delivery of dietary fat or mobilization from adipose tissue is increased. Decreased oxidation may contribute to the fatty liver induced by carbon tetrachloride, yellow phosphorus, hypoxia, or certain deficiencies (niacin, riboflavin, pantothenic acid). Blocked production and secretion of lipoproteins is o main cause of triglyceride accumulation in the liver. Impaired apolipoprotein synthesis is the most impo pathogenetic factor in several types of toxic fatty liver and in the fatty liver produced by protein-calorie malnutrition. Toxic inhibition of protein synthesis can lead to a fatty liver through inhibition of mRNA sy or translation.
In microvesicular fatty liver, small droplets of triglyceride plus FFA, cholesterol, and phospholipid collec subcellular organelles. The basic defect is unknown, even though pathologic and clinical features from causes are somewhat similar. The biochemical basis may be a disturbance in the mitochondrial-oxida pathway, depressing FFA oxidation and impairing apolipoprotein synthesis for VLDL assembly.
Fatty liver may result from the accumulation of other neutral lipids. Fat and cholesterol (seen as rhomb birefringent crystals under polarizing microscopy) are present in Wolman's disease and cholesterol es storage disease. The fat vacuolization is small to medium. In Niemann-Pick disease, the phospholipid sphingomyelin accumulates in hepatocytes and Kupffer cells. Cells appear foamy.
Pathology
When lipid deposition is marked, the liver tends to be grossly enlarged, smooth, and pale. Microscopic general architecture can be normal. Triglyceride accumulations appear as large droplets that coalesce displace the cell nucleus to the periphery. In the typical example, alcoholic fatty liver, hepatocytes are with fat vacuoles that displace the nuclei to the periphery of the cell, appearing like a large fat cell (see discussion of fatty liver under Pathology in Ch. 40). In microvesicular fatty liver, small droplets collect i
When lipid deposition is marked, the liver tends to be grossly enlarged, smooth, and pale. Microscopic general architecture can be normal. Triglyceride accumulations appear as large droplets that coalesce displace the cell nucleus to the periphery. In the typical example, alcoholic fatty liver, hepatocytes are with fat vacuoles that displace the nuclei to the periphery of the cell, appearing like a large fat cell (see discussion of fatty liver under Pathology in Ch. 40). In microvesicular fatty liver, small droplets collect i endoplasmic reticulum and in secondary lysosomes that do not fuse. Hepatocytes exhibit a foamy cyto and a central nucleus.
With hepatotoxins primarily affecting protein synthesis or with protein malnutrition, the lipid tends to co zone 1 (periportal). Microvesicular fat tends to collect in zone 3 (central).
Macrovesicular fatty liver most often is discovered on physical examination as nontender, smooth, d hepatomegaly in an alcoholic, obese, or diabetic patient. It can present with right upper quadrant pain, tenderness, and jaundice, or it may be the only physical abnormality found after a sudden, unexpected presumably metabolic death.
There is a poor association between fatty liver and abnormal findings on the commonly used biochem for liver disease. A mild increase may occur in alkaline phosphatase or transaminase. Ultrasound and especially CT may reveal excess fat. Fatty liver is diagnosed with certainty only by liver biopsy. Becaus accumulation of fat in the liver may indicate the action of a hepatotoxin or the presence of an unrecogn disease or metabolic abnormality, the diagnosis calls for further evaluation of the patient.
Nonalcoholic fatty liver disease (nonalcoholic steatohepatitis) is an increasingly recognized accumu fat in the liver of females who tend to be obese or diabetic. It also occurs after jejunal bypass surgery, malnutrition, and in association with certain drugs (eg, glucocorticoids, synthetic estrogens, amiodaron tamoxifen). Hepatomegaly may be present. Histologic diagnosis is based on macrovesicular fatty chan lobular inflammation, sometimes accompanied by fibrosis and Mallory hyaline bodies. The condition is detected on liver biopsy performed for other reasons, usually in asymptomatic patients who present w to threefold increase in plasma aminotransferase. For diagnosis, negligible alcohol intake must be evid
Microvesicular fatty liver has a pronounced presentation, with fatigue, nausea, and vomiting soon fo by jaundice, hypoglycemia, coma, and a disseminated intravascular coagulopathy.
Potentially reversible, macrovesicular fatty liver usually is not in itself harmful. It is reversible even in po fatal instances (eg, in fatty liver of pregnancy, early delivery may be lifesaving). Alcoholic fatty liver ma accompanied by inflammation and necrosis (alcoholic hepatitis) and permanent damage in the form of cirrhosis. Microvesicular fatty liver presents acutely but is reversible if the patient survives.
No specific therapy is available except to eliminate the cause or treat the underlying disorder. Even ob and diabetes mellitus with fatty liver are thought not to progress to cirrhosis. Although hepatotoxins su alcohol and carbon tetrachloride (which also produce necrosis) can eventually result in cirrhosis, there evidence that a fatty liver per se leads to cirrhosis. Some other event must occur.
Nonalcoholic fatty liver disease generally has a good prognosis, without histologic or clinical progressio Some livers may show increased fibrosis and progression to cirrhosis. Management includes weight lo obese patients, although this is of unproven benefit. Anecdotal reports indicate a benefit from ursodeo acid therapy.
evidence that a fatty liver per se leads to cirrhosis. Some other event must occur.
Nonalcoholic fatty liver disease generally has a good prognosis, without histologic or clinical progressio Some livers may show increased fibrosis and progression to cirrhosis. Management includes weight lo obese patients, although this is of unproven benefit. Anecdotal reports indicate a benefit from ursodeo acid therapy.

Section 4. Hepatic And Biliary Disorders Chapter 46. Vascular Lesions Topics
[General] Lesions Of The Hepatic Artery Lesions Of The Hepatic Veins Lesions Of The Portal Vein Lesions Of The Sinusoids Disorders Associated With Systemic Disease
[General]
Vascular lesions: Thrombotic, occlusive, and inflammatory lesions of arteries and veins within and adjo the liver.

Section 4. Hepatic And Biliary Disorders Chapter 40. Alcoholic Liver Disease Topics
[General]
[General]
Pathogenesis
Alcoholic liver disease: A spectrum of clinical syndromes and pathologic changes in the liver caused b (ethanol).
The major factors are the quantity of alcohol consumed, the patient's nutritional status, and genetic an metabolic traits. A linear correlation generally exists between the dose and duration of alcohol abuse a development of liver disease, although not all who overuse alcohol develop significant liver damage. T alcohol equivalent to 10 g is 30 mL of 40-proof whiskey, 100 mL of 12% wine, or 250 mL of 5% beer. A as 20 g of alcohol in women or 60 g in men can produce liver injury when consumed daily for years. Fo example, ingestion of 150 to 200 g of alcohol for 10 to 12 days produces fatty liver even in otherwise h men. For alcoholic hepatitis, patients consume 80 g of alcohol daily for almost a decade, whereas the threshold to develop cirrhosis is 160 g daily over 8 to 10 yr. Duration is important.
By providing empty calories, decreasing the appetite, and causing malabsorption through its toxic effe the gut and pancreas, alcohol promotes malnutrition. Malnutrition alone does not cause cirrhosis, but a one or more nutritional factors may hasten the effects of alcohol.
Alcohol is a hepatotoxin whose metabolism creates profound liver cell derangements. Apparent variati susceptibility (only 10 to 15% of alcoholics develop cirrhosis) and the greater susceptibility of females when adjusting for smaller body size) to alcohol-induced liver disease suggest that other factors are al significant. One may be that females have decreased alcohol dehydrogenase in their gastric mucosa, lessening metabolism. Family clustering of alcoholic liver disease occurs frequently. Thus, genetic fact also be involved in alcohol metabolism: some people may be deficient in oxidizing alcohol. Certain HL histocompatibility types have also been associated with alcohol-induced liver disease. Immunologic sta does not appear to help determine susceptibility to alcohol, but immunologic mechanisms (particularly mediators) may be important in the inflammatory response and in liver injury.
Metabolism of Alcohol
histocompatibility types have also been associated with alcohol-induced liver disease. Immunologic sta does not appear to help determine susceptibility to alcohol, but immunologic mechanisms (particularly mediators) may be important in the inflammatory response and in liver injury.
Metabolism of Alcohol
Alcohol is readily absorbed from the GI tract, and > 90% is metabolized by the liver through oxidative mechanisms involving mainly alcohol dehydrogenase and certain microsomal enzymes (microsomal e oxidizing system). Alcohol cannot be stored and must be metabolized. Alcohol dehydrogenase produc acetaldehyde, the major catabolite, which is further oxidized to acetate. Acetaldehyde may be toxic to and other organs. The conversion of alcohol to acetaldehyde and of the latter to either acetate or acet coenzyme A involves the generation of reduced nicotinamide adenine dinucleotide (NADH), which shu mitochondria, increasing the NADH/nicotinamide adenine dinucleotide ratio and thus the redox state o liver. Thus, alcohol metabolism promotes a reduced intracellular state that interferes with carbohydrate and other aspects of intermediary metabolism. The oxidation of alcohol is coupled with the reduction o pyruvate to lactate, which promotes hyperuricemia, hypoglycemia, and acidosis. Alcohol oxidation also coupled with the reduction of oxaloacetic acid to malate. This may explain the reduced activity of the c cycle, reduced gluconeogenesis, and increased fatty acid synthesis associated with alcohol metabolis
-Glycerophosphate increases after alcohol consumption; the glycerol produced promotes increased tri synthesis and leads to hyperlipidemia. Although O2 consumption is normal after alcohol ingestion, the metabolic shift from O2 consumption during the breakdown of fatty acids to the oxidation of alcohol to This shift may explain the reduced lipid oxidation and increased ketone formation recorded after alcoh ingestion. Alcohol metabolism may also induce a local hypermetabolic state in the liver, promoting hyp damage in zone 3 (the area around the terminal hepatic venules). The net effect is a reduced redox st inhibited protein synthesis, and increased lipid peroxidation.
Whether alcoholics metabolize alcohol differently from nonalcoholics is unknown. Clearly, chronic inge alcohol leads to hepatic adaptation with hypertrophy of the smooth endoplasmic reticulum and increas activity of the hepatic drug-metabolizing enzymes. Alcohol induces the microsomal ethanol oxidizing s which is responsible in part for alcohol metabolism. Alcohol also induces microsomal P-450, which is i in drug metabolism. Thus, the alcohol abuser acquires an increased tolerance to alcohol and drugs (e sedatives, tranquilizers, antibiotics), and neurologic adaptation develops. The result is a complex inter between drugs, other chemicals, and alcohol.
Pathology
The spectrum of hepatic pathology associated with prolonged alcohol consumption ranges from the si accumulation of neutral fat in hepatocytes to cirrhosis and hepatocellular carcinoma. The widely accep liver-alcoholic hepatitis-cirrhosis spectrum is a concept of convenience. The findings usually overlap, a patients present with features of the entire spectrum. The key lesion may be fibrosis around the termin hepatic venules and perhaps also the perisinusoidal space. From the perspective of pathology, it is be diagnose alcoholic liver disease and describe the specific findings in each patient.
Fatty liver or steatosis (see also Ch. 39) appears to be the initial change and is the most common res alcohol ingestion. The liver is large; the cut surface, yellow. The increased liver fat is derived from the from free fatty acids mobilized from adipose tissue, and from lipid synthesized in the liver and inadequ degraded or excreted. Fat droplets of varying size are found in most hepatocytes except in regeneratin The droplets tend to coalesce, forming large (macrovesicular) globules that frequently occupy the entir cytoplasm. Fat accumulates in zones 3 (centrizonal) and 2 (midzonal). Fatty cysts probably represent stages of the fatty change. These cysts are usually located periportally and form through fusion of the content of several hepatocytes. Other features include hydropic change in early stages of alcoholic live and giant spherical mitochondria. The former--swollen, balloonlike hepatocytes--result from impaired r
from free fatty acids mobilized from adipose tissue, and from lipid synthesized in the liver and inadequ degraded or excreted. Fat droplets of varying size are found in most hepatocytes except in regeneratin The droplets tend to coalesce, forming large (macrovesicular) globules that frequently occupy the entir cytoplasm. Fat accumulates in zones 3 (centrizonal) and 2 (midzonal). Fatty cysts probably represent stages of the fatty change. These cysts are usually located periportally and form through fusion of the content of several hepatocytes. Other features include hydropic change in early stages of alcoholic live and giant spherical mitochondria. The former--swollen, balloonlike hepatocytes--result from impaired r protein and lipoproteins. These cells degenerate and disintegrate.
Alcoholic hepatitis includes the macrovesicular fatty change plus a diffuse inflammatory response to and necrosis (often focal); established cirrhosis may also be present.
Mallory (alcoholic hyaline) bodies are fibrillar proteins of intracytoplasmic inclusions within swollen hepatocytes; these cells contain little or no fat. With hematoxylin and eosin stain, Mallory bodies appe irregular aggregates of purplish red material. Although characteristic of alcoholic hepatitis, Mallory bod also found in some cases of Wilson's disease, Indian childhood cirrhosis, cirrhosis following small-bow bypass surgery, primary biliary cirrhosis (or other causes of prolonged cholestasis), diabetes mellitus, obesity, and hepatocellular carcinoma. A polymorphonuclear reaction develops locally in response to t Mallory-containing and necrotic liver cells. In zone 3 of the liver acinus, connective tissue is laid down sinusoids and around hepatocytes. Collagen fibers also creep into the space of Disse, developing into continuous membrane under the sinusoidal endothelium. Venous lesions also develop, such as promi sclerosis around the terminal hepatic venules, termed sclerosing hyaline necrosis or central hyaline sc This lesion can lead to portal hypertension before cirrhosis becomes established and may be the earli manifestation of cirrhosis. Venous scarring alone (as it occurs in veno-occlusive disease) can lead to t development of portal hypertension without overt cirrhosis.
Alcoholic hepatitis, with its diffuse inflammatory cell infiltrate and necrosis, is often viewed as the interm step between fatty liver and cirrhosis. Cell necrosis and centrizonal (zone 3) hypoxia can stimulate col formation. Fibrosis, however, occurs from the transformation of fat-storing Ito cells into fibroblasts. Thu fibrosis can proceed to cirrhosis without an intervening stage of alcoholic hepatitis. About 20% of heav drinkers develop cirrhosis, in which the liver is finely nodular, with its architecture disorganized by fibro and nodules. Although the inflammatory cell infiltrate and fatty liver are characteristic, occasionally the histology may resemble chronic active hepatitis. If drinking stops and the liver undergoes a constructiv regenerative response, the clinical picture can be that of a mixed cirrhosis (see Ch. 41).
Increased liver iron occurs in alcoholics with normal, fatty, or cirrhotic livers, but the incidence is < 10% deposited in parenchymal and Kupffer cells. There is no relationship with the amount of iron in the alco beverage consumed or with the length of drinking history. Body iron stores are not significantly increas
Alcoholic cirrhosis represents end-stage disease, developing in 10 to 20% of those who are chronica heavy drinkers. Micronodular cirrhosis is evident, although this may be a lingering feature of fatty liver alcoholic hepatitis. Some regeneration occurs from the surviving liver cells. The cirrhosis may slowly p to a nonspecific macronodular pattern. The liver shrinks and becomes small.
Variations in drinking patterns, individual susceptibility to hepatotoxic effects of alcohol, and the many tissue damage promote a highly variable clinical picture. For a long time, no manifestations may be re to the liver. Symptoms generally can be related to the quantity of alcohol ingested and the overall dura alcohol abuse. As a guideline, symptoms usually become apparent in patients during their 30s, and se problems tend to appear in patients in their 40s.
Patients with a fatty liver are usually asymptomatic. In 33%, the liver is enlarged, smooth, and occasio tender. Routine biochemical studies are often within normal limits; -glutamyl transpeptidase (GGT) is o
to the liver. Symptoms generally can be related to the quantity of alcohol ingested and the overall dura alcohol abuse. As a guideline, symptoms usually become apparent in patients during their 30s, and se problems tend to appear in patients in their 40s.
Patients with a fatty liver are usually asymptomatic. In 33%, the liver is enlarged, smooth, and occasio tender. Routine biochemical studies are often within normal limits; -glutamyl transpeptidase (GGT) is o elevated. Vascular spiders and features of hyperestrogenism and hypoandrogenism from the alcoholis se may be evident.
Alcoholic hepatitis can be suspected clinically, but the diagnosis depends on examination of a biopsy s The histologic lesion can be found throughout the clinical spectrum of alcoholic liver disease. Patients alcoholic hepatitis may present with fatigue, fever, jaundice, right upper quadrant pain, a hepatic bruit, hepatomegaly, and leukocytosis, but so may patients with sepsis, cholecystitis, or mechanical extrahe biliary obstruction.
Cirrhosis may also be relatively asymptomatic, have features of alcoholic hepatitis, or be dominated by complications: portal hypertension with splenomegaly, ascites, hepatorenal syndrome, hepatic encephalopathy, or even hepatocellular carcinoma.
Laboratory Findings
Although sometimes suggestive, routine blood and biochemical tests are nonspecific and do not perm definitive diagnosis. In alcoholic liver disease, various abnormalities of RBC morphology can exist, inc target cells, macrocytes, spur cells, and stomatocytes. An elevated MCV is usual and can be a useful of alcohol abuse because it gradually returns to normal after cessation of drinking. Thrombocytopenia common, either from the direct toxic effects of alcohol on the bone marrow or secondary to hypersplen
In alcoholic hepatitis, transaminase levels are moderately raised (about 250 U/L). Conjugated bilirubin actually deepens in the hospital. The activity of serum ALT is depressed (caused by a depletion of pyr 5-phosphate) relative to that of serum AST (AST:ALT ratio > 2). The activity of the serum GGT may h detect alcohol consumption. The value of GGT lies not in its specificity but in its being markedly elevat patients with excessive alcohol intake or alcoholic liver disease. MCV, GGT, and alkaline phosphatase best combination of routine tests to identify chronic alcohol abuse. Liver scans and ultrasound are som helpful. Liver biopsy (see Ch. 37) is the only basis for a secure diagnosis, particularly in alcoholic hepa Even in alcoholics, other forms of liver disease occur.
With abstinence, nonfibrotic liver damage may be reversed, and the survival of patients with alcoholic fibrosis, and cirrhosis improves. The significance of alcoholic hepatitis appears to be determined by th of associated fibrosis and liver cell necrosis. The reversibility of sclerosing hyaline necrosis is unknown
In theory, treatment of alcoholic liver disease is simple and straightforward; in practice, it is difficult: the must stop drinking alcohol. After severe bouts of illness, major adverse social consequences (eg, job l family unit breakdown), and a review of the facts by a physician with whom a rapport has been establis many patients stop drinking. It helps to point out to the patient that much of the damage caused by alc liver disease is reversible. Otherwise, management focuses on nonspecific supportive care. Acute alco withdrawal requires supportive care, fluid and electrolyte balance, and sedatives (eg, benzodiazepines carefully titrated to the severity of the withdrawal symptoms. Excessive sedation in patients with marke disease can precipitate hepatic encephalopathy. (See also Alcoholism in Ch. 195.)
Nutritional and general support is time-honored. The value of corticosteroids in alcoholic hepatitis is m
liver disease is reversible. Otherwise, management focuses on nonspecific supportive care. Acute alco withdrawal requires supportive care, fluid and electrolyte balance, and sedatives (eg, benzodiazepines carefully titrated to the severity of the withdrawal symptoms. Excessive sedation in patients with marke disease can precipitate hepatic encephalopathy. (See also Alcoholism in Ch. 195.)
Nutritional and general support is time-honored. The value of corticosteroids in alcoholic hepatitis is m perhaps showing greatest promise in more severe disease, especially with hepatic encephalopathy. Antifibrinogenic agents (eg, colchicine, penicillamine) have not proven effective, whereas propylthioura treat the possible hypermetabolic state of the alcoholic liver provides some benefit but has never gaine acceptance. Trauma, infection, GI bleeding, nutritional deficiencies, fluid retention, and hepatic encephalopathy require specific attention, as discussed elsewhere in The Manual.

Section 4. Hepatic And Biliary Disorders Chapter 47. Liver Tumors Topics
Benign Liver Tumors Liver Metastases Primary Liver Cancer Hematologic Malignancies And The Liver
Benign Liver Tumors
Benign liver tumors are relatively common but usually subclinical. Most are detected incidentally by ult (US) or other scanning techniques. Others are discovered because of hepatomegaly, right upper quad discomfort, or intraperitoneal hemorrhage. Liver function tests are usually normal or only slightly eleva diagnosis is sometimes established only at laparotomy, although scanning and arteriography often pro preoperative clues.
Hepatocellular adenoma is the most important benign tumor of the liver. Occurring primarily in wome childbearing age, it has increased in prevalence because of widespread use of oral contraceptives, wh a role in pathogenesis (see also Chs. 43 and 246). Most adenomas are asymptomatic. Rarely, adenom present as an acute surgical problem caused by abrupt rupture and bleeding into the peritoneal cavity Although adenomas generally are not precancerous, a few cases of malignant transformation have be described. Adenomas related to contraceptive use often regress if the drug is stopped.
Focal nodular hyperplasia is a localized tumorlike disorder that histologically may resemble macrono cirrhosis. Oral contraceptives have been implicated in enhancing the size of this hamartoma but are no causative. Other rare non-neoplastic nodular lesions of the liver also exist.
Asymptomatic small hemangiomas are estimated to occur in 1 to 5% of adults. They often have a characteristic appearance on US, CT, or MRI and should be left alone. Large hemangiomas are occas apparent in infants because of associated consumption coagulopathy or hemodynamic disturbances. duct adenomas and various rare mesenchymal tumors also occur.
HEPATIC CYSTS
Hepatic cysts are not neoplasms but are conveniently discussed here. Isolated cysts are commonly d incidentally on abdominal US or CT and have no clinical significance. The rare congenital polycystic
HEPATIC CYSTS
Hepatic cysts are not neoplasms but are conveniently discussed here. Isolated cysts are commonly d incidentally on abdominal US or CT and have no clinical significance. The rare congenital polycystic produces progressive lumpy hepatomegaly (sometimes massive) in adults. Nevertheless, hepatocellul function is remarkably well preserved, and portal hypertension does not develop. In contrast, related congenital hepatic fibrosis is characterized by cystic proliferation of microscopic bile ducts, hepatic f and progressive portal hypertension; the condition is often misdiagnosed as cryptogenic cirrhosis. Both variants are commonly associated with polycystic disease of the kidneys and other organs (see Cystic Nephropathies in Ch. 230). Other hepatic cysts include hydatid cysts (see Hydatid Disease in Ch. 161 rare Caroli's disease, characterized by segmental cystic dilation of intrahepatic bile ducts (often comp by stone formation and cholangitis); and true cystic tumors (rare).

Section 4. Hepatic And Biliary Disorders Chapter 41. Chronic Liver Disease Topics
Fibrosis Cirrhosis Primary Biliary Cirrhosis 1-Antitrypsin Deficiency
Fibrosis
Etiology
An accumulation in the liver of connective tissue resulting from an imbalance between production and degradation of the extracellular matrix and accentuated by the collapse and condensation of preexistin
Fibrosis is a common response to hepatocellular necrosis or injury, which may be induced by a wide v agents, eg, any process disturbing hepatic homeostasis (especially inflammation, toxic injury, or altere hepatic blood flow) and infections of the liver (viral, bacterial, fungal, and parasitic). Numerous storage disorders resulting from inborn errors of metabolism are often associated with fibrosis, including lipid abnormalities (Gaucher's disease); glycogen storage diseases (especially types III, IV, VI, IX, and X); 1 -antitrypsin deficiency; storage of exogenous substances, as seen in iron-overload syndromes (hemochromatosis) and copper storage diseases (Wilson's disease); accumulation of toxic metabolite tyrosinemia, fructosemia, and galactosemia); and peroxisomal disorders (Zellweger syndrome). Nume chemicals and drugs cause fibrosis, especially alcohol, methotrexate, isoniazid, oxyphenisatin, methyl chlorpromazine, tolbutamide, and amiodarone. Disturbances of hepatic circulation (eg, chronic heart fa Budd-Chiari syndrome, veno-occlusive disease, portal vein thrombosis) and chronic obstruction to bile lead to fibrosis. Lastly, congenital hepatic fibrosis is an autosomal recessive malformation.
Pathogenesis
The normal liver is made up of hepatocytes and sinusoids distributed within an extracellular matrix com of collagen (predominantly types I, III, and IV) and noncollagen proteins, including glycoproteins (eg, fibronectin, laminin) and several proteoglycans (eg, heparan sulfate, chondroitin sulfate, dermatan sulf hyaluronate). Fibroblasts, normally found only in the portal tracts, can produce collagen, large glycopro and proteoglycans.
The normal liver is made up of hepatocytes and sinusoids distributed within an extracellular matrix com of collagen (predominantly types I, III, and IV) and noncollagen proteins, including glycoproteins (eg, fibronectin, laminin) and several proteoglycans (eg, heparan sulfate, chondroitin sulfate, dermatan sulf hyaluronate). Fibroblasts, normally found only in the portal tracts, can produce collagen, large glycopro and proteoglycans.
Other liver cells (particularly hepatocytes and fat-storing [Ito], Kupffer, and endothelial cells) also can p extracellular matrix components. Fat-storing cells, located beneath the sinusoidal endothelium in the s Disse, are precursors of fibroblasts, capable of proliferating and producing an excess of extracellular m The development of fibrosis from active deposition of collagen is a consequence of liver cell injury, par necrosis, and inflammatory cells. The precise factors released from these cells is not known, but one o cytokines or products of lipid peroxidation are likely. Kupffer cells and activated macrophages produce inflammatory cytokines. New fibroblasts form around necrotic liver cells; increased collagen synthesis scarring. Fibrosis may derive from active fibrogenesis and from impaired degradation of normal or alte collagen. Fat-storing cells, Kupffer cells, and endothelial cells are important in the clearance of type I c several proteoglycans, and denatured collagens. Changes in these cells' activities may modify the exte fibrosis. For the histopathologist, fibrous tissue may become more apparent from passive collapse and condensation of preexisting fibers.
Thus, increased synthesis or reduced degradation of collagen results in active deposition of excessive connective tissue, which affects hepatic function: (1) Pericellular fibrosis impairs cellular nutrition and r hepatocellular atrophy. (2) Within the space of Disse, fibrous tissue accumulates around the sinusoids obstructs the free passage of substances from the blood to the hepatocytes. (3) Fibrosis around hepa venules and the portal tracts disturbs hepatic blood flow. Venous resistance across the liver increases portal vein branches to sinusoids and finally to hepatic veins. All three routes can be involved.
The fibrous bands that link portal tracts with central veins also promote anastomotic channels: Arterial bypassing the normal hepatocytes, is shunted to efferent hepatic veins, which further impairs hepatic f and can accentuate hepatocellular necrosis. The extent to which these processes are present determi magnitude of hepatic dysfunction: eg, in congenital hepatic fibrosis, large fibrous bands involve predom the portal regions but usually spare the hepatic parenchyma. Congenital hepatic fibrosis thus presents portal hypertension with preserved hepatocellular function.
Although fibrosis is common to several chronic liver diseases, the clinical feature that predominantly re hepatic fibrosis is portal hypertension (see Ch. 38).
Histologic diagnosis depends on examination of a liver biopsy. Special stains (eg, aniline blue, trichrom stains) may highlight the fibrous tissue. Because fibrosis is a sign of hepatic injury, its management is directed at the underlying cause.

Section 4. Hepatic And Biliary Disorders Chapter 48. Extrahepatic Biliary Disorders Topics
[General] Cholelithiasis Cholecystitis Choledocholithiasis Primary Sclerosing Cholangitis Bile Duct Tumors Other Causes Of Extrahepatic Obstruction Cholesterolosis Of The Gallbladder Diverticulosis Of The Gallbladder
[General]
Physiology of Bile Acid Metabolism
Bile is formed in the liver as an isosmotic solution of bile acids, electrolytes, bilirubin, cholesterol, and phospholipids. Bile flow is generated by the active transport of bile salts and electrolytes and the accompanying obligate passive movement of water.
The liver synthesizes water-soluble bile acids from water-insoluble cholesterol, but precise mechanism not completely understood. Cholic and chenodeoxycholic acids form in the liver in a ratio of about 2:1 constitute 80% of bile acids. After virtually complete conjugation in the hepatocyte with both glycine an taurine, bile acids are excreted in bile, which flows from the intrahepatic collecting system into the prox common hepatic duct. About 50% of bile secreted in the fasting state passes into the gallbladder via th duct; the rest flows directly into the distal or common bile duct. Up to 90% of water in gallbladder bile i absorbed as an electrolyte solution, principally via gallbladder mucosal intracellular pathways. Bile rem the gallbladder is thus a concentrated solution consisting primarily of bile acids and sodium.
During fasting, bile acids are concentrated in the gallbladder, and little bile acid-dependent bile flows fr liver. Food entering the duodenum initiates an exquisite hormonal and neural sequence. Cholecystokin perhaps other GI hormone peptides (eg, gastrin-releasing peptide) are released from duodenal mucos cholecystokinin stimulates the gallbladder to contract and the biliary sphincter to relax. Bile flows into t duodenum to mix with food contents and to perform its several functions: (1) Bile salts solubilize dietar cholesterol, fats, and fat-soluble vitamins to facilitate their absorption in the form of mixed micelles. (2) acids induce water secretion by the colon as they enter that organ, thus promoting catharsis. (3) Bilirub excreted in bile as degradation products of heme compounds from worn-out RBCs. (4) Drugs, ions, an
liver. Food entering the duodenum initiates an exquisite hormonal and neural sequence. Cholecystokin perhaps other GI hormone peptides (eg, gastrin-releasing peptide) are released from duodenal mucos cholecystokinin stimulates the gallbladder to contract and the biliary sphincter to relax. Bile flows into t duodenum to mix with food contents and to perform its several functions: (1) Bile salts solubilize dietar cholesterol, fats, and fat-soluble vitamins to facilitate their absorption in the form of mixed micelles. (2) acids induce water secretion by the colon as they enter that organ, thus promoting catharsis. (3) Bilirub excreted in bile as degradation products of heme compounds from worn-out RBCs. (4) Drugs, ions, an endogenously produced compounds are excreted in bile and subsequently eliminated from the body. ( Various proteins important in GI function are secreted in bile.
Food entering the duodenum stimulates gallbladder contraction, releasing much of the body pool (tota g) of bile acids into the small intestine. Bile acids are poorly absorbed by passive diffusion in the proxim intestine; most of the pool reaches the terminal ileum, where 90% is absorbed into the portal venous circulation by active transport. Bile salts are efficiently extracted by the liver, promptly modified, and se back into bile.
Bile acids undergo enterohepatic circulation 10 to 12 times per day. During each pass, a small amoun primary bile acids reaches the colon, where anaerobic bacteria containing 7-hydroxylase form seconda acids. Cholic acid is thus converted to deoxycholic acid, which is largely reabsorbed and conjugated. Chenodeoxycholic acid conjugates are converted in the colon to their secondary bile acid form, lithoch This insoluble secondary bile acid is partially reabsorbed; the rest is lost in the feces.
Anatomy of the Biliary Tract
Other than absorptive functions of the normal gallbladder and bile storage mediation by the sphincters extrahepatic ductal system is a passive conduit. There are no functional smooth muscle fibers in the b duct walls. Ductal secretions stimulated by secretin contain a high concentration of bicarbonate and co variably to total bile volume.
The ampulla of Vater consists of the terminal intramural segments of the biliary and pancreatic ducts a the two or three sphincter segments and surrounding soft tissue. The sphincter of Oddi surrounds both or their common channel, and each duct has its separate (inconstant) sphincter. The sphincters have "tone" of up to 10 mm Hg and phasic spike activity that is independent of duodenal smooth muscle ac These muscles respond to extremely small amounts of hormones, GI peptides, anticholinergics, and o drugs. Much is being learned about these important and finely tuned structures located at the nutrition important confluence of bile, pancreatic juice, and food. Normal sphincter function results in timely rele bile and pancreatic enzymes during food passage; during fasting, however, gallbladder filling is facilita two systems normally remain independent (ie, bile does not flow retrograde into the pancreatic duct).

Section 4. Hepatic And Biliary Disorders Chapter 42. Hepatitis Topics
[General] Acute Viral Hepatitis Chronic Hepatitis
[General]
Hepatitis: An inflammation of the liver characterized by diffuse or patchy necrosis affecting all acini.
The major causes of hepatitis are specific hepatitis viruses, alcohol (see Ch. 40), and drugs (see Ch. 4 common causes include other viruses (eg, infectious mononucleosis, yellow fever, cytomegalovirus) a leptospirosis. Parasitic infections (eg, schistosomiasis, malaria, amebiasis) affect the liver but do not c true hepatitis. Pyogenic infections and abscesses are also generally considered to be separate proble Involvement of the liver with TB and other granulomatous infiltrations is sometimes called granulomato hepatitis (see Ch. 45), but the clinical, biochemical, and histologic features differ from those of diffuse hepatitis.
Various systemic infections and other illnesses may produce small focal areas of hepatic necrosis and inflammation. This nonspecific reactive hepatitis causes minor liver function abnormalities but is usua asymptomatic.
Noninfectious liver inflammation and some hepatic infections are described under their specific topic h and are summarized in Table 42-1.
Section 16. Cardiovascular Disorders Chapter 197. Approach To The Cardiac Patie Topics
[General] History Physical Examination
[General]
Cardiovascular disease can usually be diagnosed by a thorough history and physical examination. Sel confirmatory and quantitative noninvasive and invasive tests are usually performed (see Ch. 198).
Section 16. Cardiovascular Disorders Chapter 206. Cardiac And Respiratory Arrest A Cardiopulmonary Resuscitation Topics
Cardiac Arrest Respiratory Arrest Cardiopulmonary Resuscitation
Cardiac Arrest
Absent or inadequate ventricular contraction that immediately results in systemic circulatory failure.
Cardiac arrest is a medical emergency that overrides all others except exsanguinating external hemor airway obstruction, which should be controlled simultaneously. Unless rapidly corrected, cardiac arrest rapidly fatal. For treatment, see Cardiopulmonary Resuscitation, below.
Etiology and Pathophysiology
Cardiac arrest primarily results from cardiac causes, including electrical dysfunction in 80% of patients mechanical failure in 20%. Additional causes include circulatory shock or abnormalities in ventilation le significant respiratory acidosis (cardiopulmonary arrest). Although either the heart or lungs may fail firs events usually are closely related.
Electrical dysfunction is the most common mechanism of sudden cardiac death, with ventricular fibr representing the major rhythm in prehospital cardiac arrest (70% of patients).
In ventricular fibrillation (VF), loss of coordinated global ventricular myocardial contraction leads to immediate loss of effective cardiac output, resulting in circulatory arrest. Although acute MI is often the underlying precipitant of VF in cardiac arrest, about 50% of victims have no evidence of MI on follow-u and enzyme studies. VF can also result from worsening of chronic ventricular arrhythmias (primary VF low-voltage electric shock (110 to 220 volts for 2 to 3 sec), electrolyte imbalances (especially K and Ca hemolysis from freshwater near drowning, profound hypothermia (< 28 C [< 82.4 F]), and excessive sympathetic stimulation of ventricular myocardium sensitized by hypoxemia and vasoactive drugs (eg, dopamine, theophylline, epinephrine). Sustained ventricular tachycardia (VT) is a relatively uncommon cause of cardiac arrest but has the prognosis in terms of resuscitation and survival. Underlying diseases include coronary artery disease,
hemolysis from freshwater near drowning, profound hypothermia (< 28 C [< 82.4 F]), and excessive sympathetic stimulation of ventricular myocardium sensitized by hypoxemia and vasoactive drugs (eg, dopamine, theophylline, epinephrine).
Sustained ventricular tachycardia (VT) is a relatively uncommon cause of cardiac arrest but has the prognosis in terms of resuscitation and survival. Underlying diseases include coronary artery disease, cardiomyopathy, hypokalemia, and digitalis toxicity. Torsade de pointes (see Ch. 205) is a unique form with a prolonged QT interval that occurs in patients receiving class I and III antiarrhythmic drugs, antidepressants, or phenothiazines or in patients with hypokalemia or hypomagnesemia.
Asystole is the absence of electrical activity on ECG, with absent perfusion, BP, and pulse. Causes in severe generalized myocardial ischemia, ventricular rupture, and hyperpolarization of cardiac cell mem in severe hyperkalemia (serum K+ > 7 mEq/L) or hypermagnesemia.
Electromechanical dissociation refers to organized electrical depolarization without mechanical con The primary mechanisms are cardiac rupture, acute tamponade, global ischemia, acute MI, obstructin intracardiac tumor or thrombus, and chronic heart failure.
Circulatory shock has many causes, including decreased effective circulating blood volume (eg, hypo due to massive hemorrhage, massive 3rd-space fluid losses [severe burns, pancreatitis]); loss of perip vasomotor tone, reducing venous return (eg, sepsis, anaphylaxis, profound hypothermia, CNS damag or anesthetic overdose); or obstructed ventricular filling or ventricular output (eg, cardiac tamponade, m pulmonary embolus, tension pneumothorax). However, diastolic arterial hypotension is the common denominator leading to impaired coronary artery blood flow, myocardial electrical instability, and cardia
Symptoms and Signs
Major clinical findings in cardiac arrest include loss of consciousness; rapid, shallow breathing leading to apnea; profound arterial hypotension with nonpalpable pulses over major vessels; and absent heart Within several minutes, tissue hypoxemia results, leading to vital organ injury.
Section 16. Cardiovascular Disorders Chapter 198. Diagnostic Cardiovascular Proced Topics
[General] Noninvasive Procedures Invasive Procedures
[General]
Diagnosis of cardiovascular disorders involves a wide array of procedures. Auscultation is described in 197, and ECG is discussed under specific cardiovascular disorders. Other noninvasive and invasive procedures are discussed below.

Section 16. Cardiovascular Disorders Chapter 207. Valvular Heart Disease Topics
[General] Mitral Valve Disease Aortic Valve Disease Tricuspid Valve Disease
[General]
(For discussion of pulmonic valve disease and other congenital cardiac abnormalities, see Congenital Disease in Ch. 261.)

Section 16. Cardiovascular Disorders Chapter 199. Arterial Hypertension Topics
[General] Renovascular Hypertension Hypertensive Encephalopathy
[General]
Arterial hypertension: Elevation of systolic and/or diastolic BP, either primary or secondary. (For a discussion of hypertension in pregnancy, see Ch. 250.)
Prevalence
It is estimated that there are nearly 50 million hypertensives in the USA (systolic BP >= 140 mm Hg an diastolic >= 90 mm Hg, or taking antihypertensive medication). For unknown reasons, the prevalence hypertension seems to be decreasing in the USA (see Table 199-1). Hypertension occurs more often i adults (32%) than in white (23%) or Mexican American (23%) adults, and morbidity and mortality are g blacks. Diastolic BP increases with age until age 55 or 60.
Prevalence of isolated systolic hypertension (ISH-- >= 140 mm Hg systolic, < 90 mm Hg diastolic) incr with age until at least age 80. If persons with ISH and diastolic hypertension are considered, > 50% of and white men and > 60% of women over age 65 have hypertension. ISH is more prevalent among wo than men in both races. Prevalence data, derived mainly from large screening programs such as the N Health and Nutrition Examination Survey, rely on one or more BP determinations made during one vis these percentages are higher than they would be if BP had been measured over time (regression towa mean). Between 85 and 90% of cases are primary (essential); in 5 or 10%, hypertension is secondary bilateral renal parenchymal disease, and only 1 or 2% of cases are due to a potentially curable conditi
Primary hypertension: Primary (essential) hypertension is of unknown etiology; its diverse hemodyna pathophysiologic derangements are unlikely to result from a single cause. Heredity is a predisposing fa the exact mechanism is unclear. Environmental factors (eg, dietary Na, obesity, stress) seem to act on genetically susceptible persons. Isolated, perfused kidneys from Dahl salt-sensitive rats (which are ge
Primary hypertension: Primary (essential) hypertension is of unknown etiology; its diverse hemodyna pathophysiologic derangements are unlikely to result from a single cause. Heredity is a predisposing fa the exact mechanism is unclear. Environmental factors (eg, dietary Na, obesity, stress) seem to act on genetically susceptible persons. Isolated, perfused kidneys from Dahl salt-sensitive rats (which are ge prone to hypertension when fed a high-salt diet) do not excrete water or Na as rapidly as those from D salt-resistant rats, even before hypertension develops.
The pathogenic mechanisms must lead to increased total peripheral vascular resistance (TPR) by indu vasoconstriction, to increased cardiac output (CO), or to both because BP equals CO (flow) times resi Although expansion of intravascular and extravascular fluid volume is widely claimed to be important, expansion can only raise BP by increasing CO (by increasing venous return to the heart), by increasin (by causing vasoconstriction), or by both; it frequently does neither.
Abnormal Na transport across the cell wall due to a defect in or inhibition of the Na-K pump (Na+,K+or due to increased permeability to Na + has been described in some cases of hypertension. The net re increased intracellular Na, which makes the cell more sensitive to sympathetic stimulation. Because C Na, it is postulated that the accumulation of intracellular Ca (and not Na per se) is responsible for the increased sensitivity. Na+,K+-ATPase may also be responsible for pumping norepinephrine back into t sympathetic neurons to inactivate this neurotransmitter. Thus, inhibition of this mechanism could conc enhance the effect of norepinephrine. Defects in Na transport have been described in normotensive ch hypertensive parents.
Stimulation of the sympathetic nervous system raises BP, usually more in hypertensive or prehype patients than in normotensive patients. Whether this hyperresponsiveness resides in the sympathetic system itself or in the myocardium and vascular smooth muscle that it innervates is unknown, but it ca be detected before sustained hypertension develops. A high resting pulse rate, which can be a manife of increased sympathetic nervous activity, is a well-known predictor of subsequent hypertension. Som hypertensive patients have a higher-than-normal circulating plasma catecholamine level at rest, espec early in clinical development.
Drugs that depress sympathetic nervous activity frequently reduce BP in patients with primary hyperte However, this observation cannot be considered evidence for implicating the sympathetic nervous sys the causative factor in primary hypertension. In hypertensive patients, the baroreflexes tend to sustain than counteract hypertension, a phenomenon known as "resetting the barostats," which may be a resu than a cause of hypertension. Some hypertensive patients have defective storage of norepinephrine, t permitting more to circulate.
In the renin-angiotensin-aldosterone system, the juxtaglomerular apparatus helps regulate volume pressure. Renin, a proteolytic enzyme formed in the granules of the juxtaglomerular apparatus cells, c conversion of the protein angiotensinogen to angiotensin I, a decapeptide. This inactive product is clea a converting enzyme, mainly in the lung but also in the kidney and brain, to an octapeptide, angiotensi which is a potent vasoconstrictor that also stimulates release of aldosterone. Also found in the circulat des-ASP heptapeptide (angiotensin III) is as active as angiotensin II in stimulating aldosterone release much less pressor activity.
Renin secretion is controlled by at least four mechanisms that are not mutually exclusive: A renal vasc receptor responds to changes in tension in the afferent arteriolar wall; a macula densa receptor detect changes in the delivery rate or concentration of NaCl in the distal tubule; circulating angiotensin has a feedback effect on renin secretion; and the sympathetic nervous system stimulates renin secretion via renal nerve mediated by receptors.
Plasma renin activity (PRA) is usually normal in patients with primary hypertension but is suppressed i
receptor responds to changes in tension in the afferent arteriolar wall; a macula densa receptor detect changes in the delivery rate or concentration of NaCl in the distal tubule; circulating angiotensin has a feedback effect on renin secretion; and the sympathetic nervous system stimulates renin secretion via renal nerve mediated by receptors.
Plasma renin activity (PRA) is usually normal in patients with primary hypertension but is suppressed i 25% and elevated in about 15%. Hypertension is more likely to be accompanied by low renin levels in and the elderly. The accelerated (malignant) phase of hypertension is usually accompanied by elevate (see Malignant Hypertensive Arteriolar Nephrosclerosis in Ch. 228). Although angiotensin is generally acknowledged to be responsible for renovascular hypertension (see below), at least in the early phase no consensus regarding the role of the renin-angiotensin-aldosterone system in patients with primary hypertension, even in those with high PRA.
The mosaic theory states that multiple factors sustain elevated BP even though an aberration of only initially responsible; eg, the interaction between the sympathetic nervous system and the renin-angiotensin-aldosterone system. Sympathetic innervation of the juxtaglomerular apparatus in the releases renin; angiotensin stimulates autonomic centers in the brain to increase sympathetic discharg Angiotensin also stimulates production of aldosterone, which leads to Na retention; excessive intracell enhances the reactivity of vascular smooth muscle to sympathetic stimulation.
Hypertension leads to more hypertension. Other mechanisms become involved when hypertension du identifiable cause (eg, catecholamine release from a pheochromocytoma, renin and angiotensin from artery stenosis, aldosterone from an adrenal cortical adenoma) has existed for some time. Smooth mu hypertrophy and hyperplasia in the arterioles resulting from prolonged hypertension reduce the caliber lumen, thus increasing TPR. In addition, trivial shortening of hypertrophied smooth muscle in the thick wall of an arteriole will reduce the radius of an already narrowed lumen to a much greater extent than muscle and lumen were normal. This may be why the longer hypertension has existed, the less likely s for secondary causes will restore BP to normal.
Deficiency of a vasodilator substance rather than excess of a vasoconstrictor (eg, angiotensin, norepinephrine) may cause hypertension. The kallikrein system, which produces the potent vasodilato bradykinin, is beginning to be studied. Extracts of renal medulla contain vasodilators, including a neutr and a prostaglandin; absence of these vasodilators due to renal parenchymal disease or bilateral neph would permit BP to rise. Modest hypertension sensitive to Na and water balance is characteristic in an persons (renoprival hypertension).
Endothelial cells produce potent vasodilators (nitric oxide, prostacyclin) and the most potent vasocons endothelin. Therefore, dysfunction of the endothelium could have a profound effect on BP. The endoth role in hypertension is being investigated. Evidence that hypertensive persons have decreased activity oxide is preliminary.
Secondary hypertension: Secondary hypertension is associated with renal parenchymal disease (eg glomerulonephritis or pyelonephritis, polycystic renal disease, collagen disease of the kidney, obstruct uropathy) or pheochromocytoma, Cushing's syndrome, primary aldosteronism, hyperthyroidism, myxe coarctation of the aorta, or renovascular disease (see Renovascular Hypertension, below). It may also associated with the use of excessive alcohol, oral contraceptives, sympathomimetics, corticosteroids, or licorice.
Hypertension associated with chronic renal parenchymal disease results from combination of a renin-dependent mechanism and a volume-dependent mechanism. In most cases, increased renin ac cannot be demonstrated in peripheral blood, and meticulous attention to fluid balance usually controls
Diagnosis and treatment of secondary causes of hypertension are dealt with elsewhere in The Manual remainder of this discussion focuses almost entirely on primary hypertension.
Hypertension associated with chronic renal parenchymal disease results from combination of a renin-dependent mechanism and a volume-dependent mechanism. In most cases, increased renin ac cannot be demonstrated in peripheral blood, and meticulous attention to fluid balance usually controls
Diagnosis and treatment of secondary causes of hypertension are dealt with elsewhere in The Manual remainder of this discussion focuses almost entirely on primary hypertension.
Pathology
No early pathologic changes occur in primary hypertension. Ultimately, generalized arteriolar sclerosis develops; it is particularly apparent in the kidney (nephrosclerosis) and is characterized by medial hyp and hyalinization. Nephrosclerosis is the hallmark of primary hypertension. Left ventricular hypertrophy eventually, dilation develop gradually. Coronary, cerebral, aortic, renal, and peripheral atherosclerosis more common and more severe in hypertensives because hypertension accelerates atherogenesis. Hypertension is a more important risk factor for stroke than for atherosclerotic heart disease. Tiny Charcot-Bouchard aneurysms, frequently found in perforating arteries (especially in the basal ganglia) hypertensives, may be the source of intracerebral hemorrhage.
Hemodynamics
Not all patients with primary hypertension have normal CO and increased TPR. CO is increased, and T inappropriately normal for the level of CO in the early labile phase of primary hypertension. TPR increa CO later returns to normal, probably because of autoregulation. Patients with high, fixed diastolic pres often have decreased CO. The role of the large veins in the pathophysiology of primary hypertension h largely been ignored, but venoconstriction early in the disease may contribute to the increased CO.
Plasma volume tends to decrease as BP increases, although some patients have expanded plasma v Hemodynamic, plasma volume, and PRA variations are evidence that primary hypertension is more th single entity or that different mechanisms are involved in different stages of the disorder.
Renal blood flow gradually decreases as the diastolic BP increases and arteriolar sclerosis begins. GF remains normal until late in the disease, and, as a result, the filtration fraction is increased. Coronary, and muscle blood flow are maintained unless concomitant severe atherosclerosis is present in these v beds.
In the absence of heart failure, CO is normal or increased, and peripheral resistance is usually high in hypertension due to pheochromocytoma, primary aldosteronism, renal artery disease, and renal paren disease. Plasma volume tends to be high in hypertension due to primary aldosteronism or renal paren disease and may be subnormal in pheochromocytoma.
Systolic hypertension (with normal diastolic pressure) is not a discrete entity. It often results from inc CO or stroke volume (eg, labile phase of primary hypertension, thyrotoxicosis, arteriovenous fistula, ao regurgitation); in elderly persons with normal or low CO, it usually reflects inelasticity of the aorta and i branches (arteriosclerotic hypertension).
Symptoms and Signs
Primary hypertension is asymptomatic until complications develop in target organs (eg, left ventricular atherosclerotic heart disease, cerebrovascular insufficiency with or without stroke, renal failure). Howe symptoms of hypertensive encephalopathy due to severe hypertension and cerebral edema are discus below. Dizziness, flushed facies, headache, fatigue, epistaxis, and nervousness are not caused by
Primary hypertension is asymptomatic until complications develop in target organs (eg, left ventricular atherosclerotic heart disease, cerebrovascular insufficiency with or without stroke, renal failure). Howe symptoms of hypertensive encephalopathy due to severe hypertension and cerebral edema are discus below. Dizziness, flushed facies, headache, fatigue, epistaxis, and nervousness are not caused by uncomplicated hypertension.
A fourth heart sound and broad, notched P-wave abnormalities on the ECG are among the earliest sig hypertensive heart disease. Echocardiographic evidence of left ventricular hypertrophy may appear lat Chest x-ray is often normal until the late dilated phase of hypertensive heart disease. Aortic dissection leaking aneurysm of the aorta may be the first sign of hypertension or may complicate untreated hype Polyuria, nocturia, diminished renal concentrating ability, proteinuria, microhematuria, cylindruria, and retention are late manifestations of arteriolar nephrosclerosis.
Retinal changes may include retinal hemorrhages, exudates, papilledema, and vascular accidents. On basis of retinal changes, Keith, Wagener, and Barker classified hypertension into groups that have imp prognostic implications: group 1--constriction of retinal arterioles only; group 2--constriction and sclero retinal arterioles; group 3--hemorrhages and exudates in addition to vascular changes; group 4 (malign hypertension)--papilledema.
Diagnosis
Diagnosis of primary hypertension depends on repeatedly demonstrating higher-than-normal systolic a diastolic BP and excluding secondary causes.
At least two BP determinations should be taken on each of 3 days before a patient is diagnosed as hypertensive (see Table 199-2). More BP determinations are desirable for patients in the low hyperten range and especially for patients with markedly labile BP. Normal BP is much lower for infants and chi (see Screening in Ch. 256). Sporadic higher levels in patients who have been resting for > 5 min sugg unusual lability of BP that may precede sustained hypertension. For example, office or white coat hype refers to BP that is consistently elevated in the physician's office but normal when measured at home ambulatory BP monitoring.
The basic or minimal evaluation recommended for patients with hypertension includes history and phy examination, CBC, urinalysis, serum analysis (creatinine; K; Na; glucose; total, high density, and low d lipoprotein cholesterol), and ECG. The more severe the hypertension and the younger the patient, the extensive the evaluation should be. Ambulatory BP monitoring, renal scintigraphy, chest x-ray, screen for pheochromocytoma, and renin-sodium profiling are not routinely necessary. Peripheral plasma ren has not been helpful in diagnosis or drug selection, but it may be an independent risk factor for corona disease (but not for stroke or total cardiovascular mortality).
Pheochromocytoma (see also Ch. 9) secretes catecholamines, which, besides elevating BP, usually symptoms (various combinations of headache, palpitations, tachycardia, excessive perspiration, tremo pallor) that should alert the physician to this possibility. Catecholamines (eg, epinephrine, norepinephr eventually metabolized in the body to a common product, 3-methoxy-4-hydroxymandelic acid, often ca vanillylmandelic acid (VMA). Diagnosis depends on demonstrating increased urinary or plasma concen of catecholamine or increased urinary concentrations of metanephrines and VMA.
Hypokalemia not due to diuretics should suggest primary aldosteronism. Proteinuria, cylindruria, or microhematuria with or without nitrogen retention early in the course of hypertension is strong evidenc underlying primary renal disease. Absent or markedly reduced and delayed femoral arterial pulses in hypertensive patient aged < 30 yr are presumptive evidence of coarctation of the aorta. Cushing's sy collagen disease, toxemia of pregnancy, acute porphyria, hyperthyroidism, myxedema, acromegaly, so
Hypokalemia not due to diuretics should suggest primary aldosteronism. Proteinuria, cylindruria, or microhematuria with or without nitrogen retention early in the course of hypertension is strong evidenc underlying primary renal disease. Absent or markedly reduced and delayed femoral arterial pulses in hypertensive patient aged < 30 yr are presumptive evidence of coarctation of the aorta. Cushing's sy collagen disease, toxemia of pregnancy, acute porphyria, hyperthyroidism, myxedema, acromegaly, so CNS disorders, and primary aldosteronism must be excluded; these disorders are discussed elsewher Manual.
Prognosis
An untreated hypertensive patient is at great risk of disabling or fatal left ventricular failure, MI, cerebra hemorrhage or infarction, or renal failure at an early age. Hypertension is the most important risk facto predisposing to stroke. It is one of three risk factors (along with cigarette smoking and hypercholestero predisposing to coronary atherosclerosis. The higher the BP and the more severe the changes in the r the worse the prognosis. Fewer than 5% of patients with group 4 or malignant hypertension characteri papilledema and < 10% of patients with group 3 changes in the fundus survive 1 yr without treatment. medical control of hypertension will prevent or forestall most complications and will prolong life in patie ISH or diastolic hypertension. Coronary artery disease is the most common cause of death among trea hypertensive patients. Systolic BP is a more important predictor of fatal and nonfatal cardiovascular ev than diastolic BP. In a follow-up of men screened for the Multiple Risk Factor Intervention Trial, overal mortality was related to systolic BP, regardless of diastolic BP.
Treatment
Primary hypertension has no cure, but treatment can modify its course. It is estimated that only 24% o hypertensive patients in the USA have their BP controlled to < 140/90 mm Hg, and 30% are unaware t have hypertension.
Lifestyle modifications: Extra rest, prolonged vacations, moderate weight reduction, and dietary Na restriction are not as effective as antihypertensive drug therapy. Patients with uncomplicated hyperten need not restrict their activities as long as their BP is controlled. Dietary restrictions can help control di mellitus, obesity, and blood lipid abnormalities. In stage 1 hypertension, weight reduction to ideal level modest dietary Na restriction to < 2 g/day, and alcohol consumption to < 1 oz/day may make drug ther unnecessary. Prudent exercise should be encouraged. Smoking should be unambiguously discourage
Antihypertensive drug therapy: Most authorities would agree that patients with systolic BP averaging 159 mm Hg and/or diastolic BP of 90 to 94 mm Hg should receive antihypertensive drugs if lifestyle modifications do not normalize BP. The benefit of drug therapy for patients with stage 1 hypertension unequivocal. There are no data on the efficacy of antihypertensive therapy for borderline hypertension target organ damage or other risk factors are present, or when the systolic BP is >= 160 mm Hg and/o diastolic BP is >= 100 mm Hg, drug therapy should not be deferred to await the uncertain results of life modifications. Heart failure, symptomatic coronary atherosclerosis, cerebrovascular disease, and rena require urgent and judicious antihypertensive therapy.
The Systolic Hypertension in the Elderly Trial showed marked benefit from antihypertensive treatment patients >= 60 yr with systolic BP >= 160 and diastolic BP < 90 mm Hg, chlorthalidone (plus atenolol, i necessary) reduced the incidence of stroke (by 36%) and other major cardiovascular events. Benefit w found in both young elderly and old elderly. The goal was to lower systolic BP to < 160 mm Hg and by 20 mm Hg for patients whose pretreatment systolic BP was 160 to 179 mm Hg.
Except in patients > 65 yr, the goal of therapy should be to reduce BP to < 135/80 mm Hg or as near t
patients >= 60 yr with systolic BP >= 160 and diastolic BP < 90 mm Hg, chlorthalidone (plus atenolol, i necessary) reduced the incidence of stroke (by 36%) and other major cardiovascular events. Benefit w found in both young elderly and old elderly. The goal was to lower systolic BP to < 160 mm Hg and by 20 mm Hg for patients whose pretreatment systolic BP was 160 to 179 mm Hg.
Except in patients > 65 yr, the goal of therapy should be to reduce BP to < 135/80 mm Hg or as near t level as tolerable. Retrospective studies indicate that coronary mortality may increase if diastolic BP is to < 85 mm Hg, especially for patients with clinical evidence of preexisting atherosclerotic heart diseas so-called J curve). However, other observations have failed to confirm this, and most reports have faile show a J curve for systolic BP, even when a J curve in diastolic BP was observed. Usually, it is advant to have the patient measure BP at home, provided that the patient or a family member is thoroughly in and closely monitored and the sphygmomanometer is carefully calibrated at regular intervals.
Drug therapy should be initiated with a diuretic or a -blocker, unless these drugs are contraindicated o class of drugs is indicated. If these drugs are ineffective, alternative classes suitable for initial therapy Ca blockers, ACE inhibitors, angiotensin II receptor blockers, 1 -adrenergic blockers, and --blockers (se 199-3). However, none of these except nitrendipine, a dihydropyridine Ca blocker, has been shown to cardiovascular morbidity and mortality in prospective, randomized trials, whereas diuretics or -blockers initial therapy have shown beneficial effects on cardiovascular and cerebrovascular morbidity and mor Nitrendipine significantly reduced fatal and nonfatal strokes but not coronary events in elderly patients isolated systolic hypertension.
Selection of the initial drug should be guided by age and race of the patient and by coexisting disease conditions that may represent a contraindication for certain drugs (eg, asthma and -blockers) or a spec indication for certain drugs (eg, angina pectoris and -blockers or Ca blockers). In the Veterans Adminis Trial of single drug therapy for hypertension in men, black patients responded best to a Ca blocker (dil Hydrochlorothiazide was more effective in white or black men aged > 60 yr than in younger patients. T -blocker atenolol was more effective in white patients than in blacks, regardless of age. Race and age guidelines to which there are many exceptions.
If the initial drug is ineffective or causes intolerable adverse effects, another can be substituted (seque monotherapy). Alternatively, if the original drug is only partially effective but well tolerated, the dose ma increased or a second drug can be added, which should be of a different class (stepped care). The central-acting sympathetic inhibiting drugs are not recommended for initial therapy because of their hig adverse effect profile. However, they are effective and can be used in small doses in combination regi direct vasodilator (hydralazine or minoxidil) may be used with a diuretic to prevent fluid retention and w -blocker to prevent reflex tachycardia.
Preferably, treatment is started with only one drug unless hypertension is severe. However, combinatio diuretic with a -blocker or an ACE inhibitor are available in single tablets in subtherapeutic doses of ea compound that together have an antihypertensive effect with minimal adverse effects. Two of these combinations are available in the USA for initial therapy of stage 1 or 2 hypertension (see Table 199-4 or four drugs in combination may be necessary for severe or resistant hypertension.
All thiazide derivatives and their congeners are equally effective in equivalent doses (see Table 199Metolazone, indapamide, and the loop diuretics furosemide, bumetanide, ethacrynic acid, and torsemi no more effective than the thiazides but are preferred in patients with chronic renal failure. The antihypertensive action of diuretics seems to be due to a modest reduction in plasma volume and a de in vascular reactivity, possibly mediated by shifts in Na from intracellular to extracellular loci.
K supplementation or the use of a K-sparing diuretic is recommended with kaliuretic diuretics for patie are also taking digitalis, have known heart disease, have an abnormal ECG, have ectopy or arrhythmia develop ectopy or arrhythmias while taking the diuretic. The K-sparing distal tubular diuretics (spironol triamterene, amiloride) do not cause hypokalemia, hyperuricemia, or hyperglycemia, but they are not a
in vascular reactivity, possibly mediated by shifts in Na from intracellular to extracellular loci.
K supplementation or the use of a K-sparing diuretic is recommended with kaliuretic diuretics for patie are also taking digitalis, have known heart disease, have an abnormal ECG, have ectopy or arrhythmia develop ectopy or arrhythmias while taking the diuretic. The K-sparing distal tubular diuretics (spironol triamterene, amiloride) do not cause hypokalemia, hyperuricemia, or hyperglycemia, but they are not a effective as the thiazides in controlling hypertension. Instead of K supplementation, spironolactone 25 mg/day, triamterene 50 to 150 mg/day, or amiloride 5 to 10 mg/day can be added to thiazide therapy t prevent hypokalemia.
A disadvantage of diuretics is sexual dysfunction, which occurs more commonly than with some of the drugs proposed for initial therapy. Metabolic adverse effects of diuretics (hypokalemia, hypomagnesem hyperuricemia, hyperglycemia, hypercalcemia, hyperlipidemia) are dose-related and, if properly manag not usually prevent diuretic use. Spironolactone can cause breast tenderness, making amiloride or tria preferable when a K-sparing drug is chosen for males.
Diuretics uncommonly precipitate clinical type II diabetes or aggravate preexisting type II diabetes in susceptible patients. Most diabetics can tolerate a low-dose thiazide diuretic with little or no effect on t control of their diabetes, although it may aggravate hyperinsulinemia. Exercise and weight loss will am but not eliminate these adverse effects.
Thiazide and related diuretics can increase serum cholesterol (mostly in the low-density lipoprotein fra and triglyceride concentration, although most long-term studies failed to show an adverse effect at > 1 Furthermore, increased concentration seems to occur only in susceptible patients, is apparent within 4 treatment, and can be ameliorated by a low-fat diet. Elevated concentration of serum cholesterol or triglycerides is not an a priori contraindication to the use of diuretics in the management of hypertensio because the lipidemic effect is more likely to occur in patients with normal concentrations than in patie hyperlipidemia.
A hereditary predisposition probably explains the few cases in which diuretic-induced hyperuricemia h clinical gout. The Hypertension Detection and Follow-Up Program recorded only 15 cases of gout in 5 among 3693 participants at risk. Diuretic-induced hyperuricemia in the absence of gout is not an indica antiuricemic therapy, nor does it contraindicate continued diuretic use. Diuretics are less expensive tha alternatives for initial therapy.
All -blockers (see Table 199-6) are equivalent in terms of antihypertensive efficacy. If the patient also diabetes mellitus, chronic occlusive peripheral arterial disease, or COPD, it is preferable to use a cardioselective -blocker (acebutolol, atenolol, betaxolol, bisoprolol, metoprolol). However, cardioselect only relative and diminishes as the dose of the -blocker increases. Even cardioselective -blockers are contraindicated in the presence of severe asthma or COPD with a prominent bronchospastic compone of a cardioselective -blocker in the absence of one of these indications offers no advantage over nons -blockers.
-Blockers with intrinsic sympathomimetic activity (ISA--eg, acebutolol, carteolol, penbutolol, pindolol) d have an adverse effect on serum lipids; they are also less likely to produce severe bradycardia than ar non-ISA -blockers. However, asymptomatic sinus bradycardia, even with rates in the 40s, usually is no harmful.
-Blockers without ISA and without -blocking properties have a cardioprotective effect for patients who h an MI; these drugs are thus indicated for such hypertensive patients.
Disadvantages of -blockers include a high incidence of CNS adverse effects (sleep disturbances, fatig lethargy) and contraindications (greater than first-degree heart block, asthma, sick sinus syndrome, he failure). Similar to diuretics, -blockers can cause sexual dysfunction in men and metabolic adverse effe
-Blockers without ISA and without -blocking properties have a cardioprotective effect for patients who h an MI; these drugs are thus indicated for such hypertensive patients.
Disadvantages of -blockers include a high incidence of CNS adverse effects (sleep disturbances, fatig lethargy) and contraindications (greater than first-degree heart block, asthma, sick sinus syndrome, he failure). Similar to diuretics, -blockers can cause sexual dysfunction in men and metabolic adverse effe including impaired glucose tolerance, depressed high density lipoprotein cholesterol, and increased se total cholesterol and triglyceride concentrations.
Similar to ISA -blockers, the --blocker labetalol does not reduce resting pulse rate as much as the non -blockers and does not seem to have an adverse effect on serum lipids.
Ca blockers (see Table 199-7) are potent peripheral vasodilators and reduce BP by decreasing TPR. diphenylalkylamine derivative verapamil and the benzothiazepine derivative diltiazem slow the heart ra decrease atrioventricular conduction, and have a negative inotropic effect on myocardial contractility, s -blockers. Consequently, they should not be prescribed for patients with greater than first-degree hear left ventricular failure. In general, -blockers and verapamil or diltiazem should not be prescribed in the regimen for patients with left ventricular dysfunction.
The dihydropyridine derivatives (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine) lesser negative inotropic effect than the nondihydropyridines but can sometimes cause reflexive tachy These drugs are more potent peripheral vasodilators than are the nondihydropyridines and should the more effective. However, in long-term antihypertensive therapy, they do not seem to be more potent th nondihydropyridine Ca blockers.
Short-acting nifedipine has been associated in nonrandomized case-control and cohort studies with in rates of MI compared with other classes of drugs and therefore should not be used to treat hypertensi which it is not indicated). Short-acting diltiazem also is not indicated for treating hypertension. Long-ac blockers are preferred. A Ca blocker is preferred to a -blocker for hypertensive patients with angina pectoris who also have bronchospastic disease or Raynaud's disease.
Ca blockers do not have metabolic adverse effects, but they can be more expensive than ACE inhibito
ACE inhibitors (see Table 199-8) are vasodilators that reduce BP by interfering with the generation o angiotensin II from angiotensin I and by inhibiting the degradation of bradykinin, thereby decreasing pe vascular resistance without inciting reflex tachycardia. They reduce BP in many hypertensive patients, regardless of plasma renin activity.
One of the advantages of ACE inhibitors in the management of hypertension is the low adverse effect A dry irritating cough is the most frequent adverse effect. ACE inhibitors do not adversely affect serum plasma glucose, or uric acid. They tend to increase serum K, especially in patients with chronic renal f in patients taking K-sparing diuretics, K supplements, or NSAIDs. These drugs are least likely to cause dysfunction in males. Angioedema is a rare adverse effect of ACE inhibitors and can be life-threatenin involves the oropharyngeal area.
ACE inhibitors reduce proteinuria for patients with diabetic nephropathy and may retard glomeruloscle selectively dilating the efferent (postglomerular) arteriole, thus reducing glomerular capillary pressure w compromising blood flow. They retard the loss of renal function in patients with nephropathy due to typ diabetes. If ACE inhibitors are prescribed for patients with chronic renal disease, especially when azot present, serum creatinine and K levels should be monitored frequently. ACE inhibitors can cause acut failure in patients who have severe bilateral renal artery stenosis or severe stenosis in the artery to a s kidney, presumably because under these conditions GFR is maintained by angiotensin II-mediated co
selectively dilating the efferent (postglomerular) arteriole, thus reducing glomerular capillary pressure w compromising blood flow. They retard the loss of renal function in patients with nephropathy due to typ diabetes. If ACE inhibitors are prescribed for patients with chronic renal disease, especially when azot present, serum creatinine and K levels should be monitored frequently. ACE inhibitors can cause acut failure in patients who have severe bilateral renal artery stenosis or severe stenosis in the artery to a s kidney, presumably because under these conditions GFR is maintained by angiotensin II-mediated co of the efferent arteriole, which is abolished by ACE inhibition. For the same reason, they can cause ac failure in hypovolemic patients and in patients with severe heart failure. Nevertheless, ACE inhibitors r mortality and re-hospitalization rates for patients with left ventricular dysfunction and ejection fractions
Diuretics consistently enhance the antihypertensive activity of ACE inhibitors as much as, if not more t they do for any other class of antihypertensive drugs. A disadvantage of treatment with ACE inhibitors is expense.
Angiotensin II receptor blockers (see Table 199-8) block angiotensin II receptors and therefore inter the renin-angiotensin system, perhaps more completely than do the ACE inhibitors. They do not block degradation of bradykinin, which perhaps explains why they do not cause a dry irritating cough. To the that bradykinin may contribute to the hypotensive effect of ACE inhibitors, the angiotensin II receptor b may less effectively reduce BP. However, to the extent that tissue ACE is not blocked by ACE inhibitor angiotensin II receptor blockers may more effectively reduce BP. Studies have shown that they are eq effective as antihypertensive drugs. Angiotensin II receptor blockers seem to be remarkably free of ad effects and have been implicated in fewer cases of angioedema than have the ACE inhibitors, but this effect is very rare with either class of drugs. Presumably, angiotensin II receptor blockers have the sam beneficial effects as ACE inhibitors in patients with left ventricular failure and in type I diabetics with nephropathy, but definitive controlled trials have not been reported. Precautions for the use of ACE inh patients with renovascular hypertension, hypovolemia, and severe heart failure also apply to the angio receptor blockers.
Adrenergic inhibitors (see Table 199-9) include 2 agonists, which have a central action and are more than other drugs to produce drowsiness, lethargy, and sometimes depression. Methyldopa, clonidine, guanabenz, and guanfacine reduce sympathetic nervous activity by stimulating the presynaptic 2-adre receptors in the brain stem. Clonidine is available for transdermal administration in 2.5-, 5-, or 7.5-mg impregnated patches applied once weekly, delivering respectively 0.1, 0.2, or 0.3 mg/day. This unique form seems to be as effective as the oral route with fewer adverse effects. However, about 20% of pat develop cutaneous reactions at the site of application, requiring discontinuation of the drug in this form
Prazosin, terazosin, and doxazosin are peripheral postsynaptic 1-adrenergic blockers that act on ve arterioles. They all relieve symptoms of benign prostatic hyperplasia and are the only group of antihyp drugs that have a modest effect on reducing serum cholesterol, especially the low density lipoprotein f
Guanethidine and guanadrel block sympathetic transmission at the neuroeffector junction and, similar reserpine, deplete tissue stores of norepinephrine. Guanethidine, in particular, is potent but difficult to so it has largely been discontinued with the advent of newer drugs. Guanadrel is a shorter-acting drug guanethidine and produces fewer adverse effects. Reserpine depletes the brain of norepinephrine and serotonin and also depletes the peripheral sympathetic nerve terminals of norepinephrine. Except for 1 receptor blockers, these adrenergic blockers are not recommended for routine initial therapy because may cause subtle fluid retention, leading to pseudotolerance, and they also have higher adverse effec than the drugs recommended for step 1. However, 2-agonists and reserpine are excellent step-2 drugs especially when used with a diuretic.
The mechanism of direct vasodilators (independent of the autonomic nervous system) is different fro of Ca blockers and ACE inhibitors (see Table 199-11): Minoxidil is more potent than hydralazine but is
may cause subtle fluid retention, leading to pseudotolerance, and they also have higher adverse effec than the drugs recommended for step 1. However, 2-agonists and reserpine are excellent step-2 drugs especially when used with a diuretic.
The mechanism of direct vasodilators (independent of the autonomic nervous system) is different fro of Ca blockers and ACE inhibitors (see Table 199-11): Minoxidil is more potent than hydralazine but is associated with more adverse effects, including Na and water retention and hirsutism, which is poorly by women; it should be reserved for severe, resistant hypertension. Hydralazine has long been used a remains) a step-3 drug because its antihypertensive effect is additive to that of other vasodilating drug lupus syndrome is rarely observed if the dosage is < 300 mg/day.
Vasodilating prostaglandins and compounds that enhance endothelial production of nitric oxide, dep endothelial release of endothelin, or block endothelin receptors may offer new possibilities in treating hypertension.
Drug treatment of hypertensive emergencies: Hypertensive crises may be classified as true emerg requiring immediate reduction of BP (eg, hypertensive encephalopathy, acute left ventricular failure wi pulmonary edema, eclampsia, acute aortic dissection, severe hypertension accompanying unstable an acute MI), usually with parenteral drugs (see Table 199-10), or hypertensive urgencies in which the ph is more concerned than the patient. Hypertensive urgencies are frequently overtreated.
Prompt BP reduction with parenteral drugs is indicated for patients with hypertensive encephalopa acute left ventricular failure, or other true emergencies. IV diazoxide, sodium nitroprusside, nitroglycer nicardipine, or labetalol is usually used for this purpose. Because diazoxide is a nondiuretic thiazide de that can cause fluid retention, furosemide 40 or 80 mg IV is usually given with it. Diazoxide is administ rapid IV injections of 50 to 100 mg (1 to 1.5 mg/kg, <= 100 mg/dose) given q 5 to 10 min until the BP r the optimal level. Adverse effects include nausea, vomiting, hyperglycemia, hyperuricemia, tachycardi only occasionally, hypotension (generally without shock).
Sodium nitroprusside 0.25 to 10 g/kg/min (for <= 10 min at the highest dose to minimize the risk of cy toxicity) given by continuous IV infusion in 5% D/W can promptly reduce BP in a hypertensive crisis, b evanescent effect and potency require almost continuous monitoring of BP in an ICU. Unlike diazoxide produces venodilation and arteriolar dilation and therefore reduces preload and afterload, making it es useful for managing hypertensive patients with heart failure. Adverse effects include nausea, vomiting agitation, muscular twitching, and cutis anserina (goose flesh) if BP is reduced too rapidly. Acute psyc from thiocyanate intoxication can result from prolonged therapy, especially in patients with renal failure drug should be discontinued if the serum thiocyanate concentration is > 12 mg/dL (206 mol/dL).
Nitroglycerin, similar to sodium nitroprusside, relaxes the resistance vessels and the large capacitance Compared with sodium nitroprusside, it has a greater effect on veins than on arterioles. IV infusions of nitroglycerin have been used to manage hypertension during and after coronary bypass, heart failure, MI, unstable angina pectoris, and acute pulmonary edema. Hemodynamic studies indicate that IV nitro is preferable to sodium nitroprusside in managing hypertension associated with severe coronary disea because it increases coronary flow, whereas sodium nitroprusside tends to decrease coronary flow to areas, possibly because of a "steal" mechanism. The most frequent adverse reaction is headache, wh occurs in about 2% of patients; tachycardia, nausea, vomiting, apprehension, restlessness, muscular t and palpitations have also been observed.
Labetalol 20 to 40 mg IV q 10 min or as an infusion is as effective as nitroprusside, diazoxide, or nitrog in managing hypertensive crises. Serious hypotensive episodes have not been observed when labetal given by this method, and adverse effects have been minimal. Because of its -blocking activity, labeta should probably not be used for hypertensive emergencies in patients with acute left ventricular failure asthmatic patients.
Labetalol 20 to 40 mg IV q 10 min or as an infusion is as effective as nitroprusside, diazoxide, or nitrog in managing hypertensive crises. Serious hypotensive episodes have not been observed when labetal given by this method, and adverse effects have been minimal. Because of its -blocking activity, labeta should probably not be used for hypertensive emergencies in patients with acute left ventricular failure asthmatic patients.
Although short-acting nifedipine given orally usually reduces BP rapidly, it has been associated with ac cardiovascular and cerebrovascular events (sometimes fatal) and is not recommended for treating hypertensive emergencies or urgencies. It is not indicated for managing hypertension. Back to top of page

Section 16. Cardiovascular Disorders Chapter 208. Endocarditis Topics
Infective Endocarditis Noninfective Endocarditis
Infective Endocarditis
Microbial infections of the endocardium, characterized by fever, heart murmurs, petechiae, anemia, em phenomena, and endocardial vegetations that may result in valvular incompetence or obstruction, myo abscess, or mycotic aneurysm.
The overall incidence has not changed significantly in the past 3 decades. Men are affected about twic often as women. However, the median age of onset has increased from about 35 yr before antibiotics available to > 50 yr. Also, there is a higher incidence of right-sided endocarditis associated with IV dru and diagnostic and therapeutic procedures requiring vascular lines. Cardiac surgery and other invasive procedures have led to an increase in nosocomial endocarditis (10 to 15% in recent series).
Classification and Etiology
Subacute bacterial endocarditis (SBE) is usually caused by streptococcal species (especially viridan streptococci, microaerophilic and anaerobic streptococci, nonenterococcal group D streptococci, and enterococci) and less commonly by Staphylococcus aureus, S. epidermidis, and fastidious Haemophil SBE often develops on abnormal valves after asymptomatic bacteremias from infected gums or the G tract. Acute bacterial endocarditis (ABE) is usually caused by S. aureus, group A hemolytic streptococci, pneumococci, or gonococci and by less virulent microorganisms. It can develop on normal valves.
Prosthetic valvular endocarditis (PVE) develops in 2 to 3% of patients within 1 yr after valve replace and in 0.5%/yr thereafter; it is more common with aortic than mitral valve prostheses and least commo porcine valves (heterografts). Early-onset infections (< 2 mo postsurgery) are caused mainly by antimicrobial-resistant contamination at surgery (eg, S. epidermidis, diphtheroids, coliform bacilli, Cand Aspergillus sp). Late-onset infections are caused mainly by contamination with low-virulence organism
Prosthetic valvular endocarditis (PVE) develops in 2 to 3% of patients within 1 yr after valve replace and in 0.5%/yr thereafter; it is more common with aortic than mitral valve prostheses and least commo porcine valves (heterografts). Early-onset infections (< 2 mo postsurgery) are caused mainly by antimicrobial-resistant contamination at surgery (eg, S. epidermidis, diphtheroids, coliform bacilli, Cand Aspergillus sp). Late-onset infections are caused mainly by contamination with low-virulence organism surgery or by transient asymptomatic bacteremias, most often Streptococcus sp, S. epidermidis, dipht and the fastidious gram-negative bacilli--Haemophilus sp, Actinobacillus actinomycetemcomitans, and Cardiobacterium hominis. S. epidermidis can be an early or late pathogen.
Right-sided endocarditis involving the tricuspid valve and less often the pulmonary valve and artery result from IV use of illicit drugs or from central vascular lines, which facilitate entry of microorganisms may damage the endocardium. Organisms may originate from the skin (eg, S. aureus, Candida sp, co bacilli).
Pathology
The intravascular nidus for microorganisms within the heart and blood vessels is thought to be a sterile fibrin-platelet vegetation formed when tissue factor is released by damaged endothelial cells. Microorg that colonize vegetations are covered by a layer of fibrin and platelets, preventing access by neutrophi immunoglobulin, and complement, thus permitting the pathogens to resist host defenses.
Infective endocarditis occurs most often on the left side, involving the mitral, aortic, tricuspid, and pulm valves (in descending order of frequency). Congenital defects and rheumatic valvular disease are majo predisposing factors along with bicuspid or calcific aortic valves, mitral valve prolapse, hypertrophic su stenosis, and prosthetic valves. Mural thrombi, arteriovenous fistulas, ventricular-septal defects, and p ductus arteriosus sites may also become infected. Infections treated with antimicrobial drugs heal by endothelialization of vegetations.
Death usually follows heart failure, which develops from exacerbation of underlying heart disease or a valve dysfunction; embolization of vegetations to vital organs, producing infarction; a ruptured mycotic aneurysm; septic shock in ABE; renal failure; or complications of cardiac surgery.
Symptoms and Signs
SBE has an insidious onset and may mimic other systemic illnesses with low-grade fever (< 39 C [< 1 F]), night sweats, fatigability, malaise, weight loss, and valvular insufficiency. Chills and arthralgias ma Emboli may produce stroke, MI, flank pain and hematuria, abdominal pain, or acute arterial insufficien extremity. Physical examination may be normal or show chronic illness with pallor; fever; a change in a preexisting murmur or a new regurgitant cardiac valvular murmur; tachycardia; petechiae over the upp conjunctiva, mucous membranes, and distal extremities; painful erythematous subcutaneous nodules the tips of the digits (Osler nodes); splinter hemorrhages under the nails; or hemorrhagic retinal lesion (particularly Roth's spots--round or oval lesions with small white centers). With prolonged infection, splenomegaly or clubbing of the fingers and toes may also be present.
Hematuria and proteinuria may result from embolic infarction of the kidney or diffuse glomerulonephrit immune complex deposition. Manifestations of CNS involvement (in about 35% of patients) may range transient ischemic attacks and toxic encephalopathy to brain abscess and subarachnoid hemorrhage f rupture of a mycotic aneurysm.
In ABE, symptoms and signs are similar to those of SBE, but the course is more rapid. ABE is marked variable presence of high fever, toxic appearance, rapid valvular destruction, valve ring abscesses, se
immune complex deposition. Manifestations of CNS involvement (in about 35% of patients) may range transient ischemic attacks and toxic encephalopathy to brain abscess and subarachnoid hemorrhage f rupture of a mycotic aneurysm.
In ABE, symptoms and signs are similar to those of SBE, but the course is more rapid. ABE is marked variable presence of high fever, toxic appearance, rapid valvular destruction, valve ring abscesses, se emboli, an obvious source of infection, and septic shock. Purulent meningitis may occur.
PVE often results in valve ring abscesses; obstructing vegetations; myocardial abscesses; mycotic an manifested by valve obstruction, dehiscence, and cardiac conduction disturbances; and the usual sym SBE or ABE.
Right-sided endocarditis is characterized by septic phlebitis, fever, pleurisy, hemoptysis, septic pulm infarction, and tricuspid regurgitation.
Diagnosis
Because symptoms and signs are nonspecific, are highly variable, and may present insidiously, diagno requires a high index of suspicion; risk is greatest in patients with a history of cardiac valvular disease, invasive medical procedures, or dental work and in drug addicts. Fever and heart murmurs are the mo constant finding; although <= 15% of patients may not have fever or a murmur initially, almost all deve Patients with bacteremia from organisms known to be frequent causes of infective endocarditis should examined carefully and repeatedly for new valvular murmurs and signs of embolic phenomena. Any pa with suspected septicemia, especially with fever and a murmur, must have blood drawn for cultures as possible.
Because of continuous bacteremia in intravascular infections, three to five blood cultures (20 to 30 mL within 24 h may be needed to isolate the etiologic agent. Identification of the organism and its antimicr susceptibility is vital to guide bactericidal treatment. Blood cultures may require 3 to 4 wk incubation fo organisms; other organisms (ie, Aspergillus sp) may not produce positive cultures, and others require serodiagnosis (Coxiella burnetii, Chlamydia psittaci, Barcella sp, Rochalimaea) or special culture medi (Legionella pneumophila).
Other than positive blood cultures, there are no specific laboratory findings. Negative blood cultures m indicate suppression due to prior antimicrobial therapy, infection with organisms that do not grow in rou laboratory culture media, or another diagnosis (eg, noninfective endocarditis [see below], atrial myxom embolic phenomena, or a vasculitis).
Transthoracic two-dimensional echocardiography detects vegetations in 50% of patients with endocard may eliminate the need for more invasive procedures. Transesophageal echocardiography detects ve in > 90% of patients, including those with negative blood cultures, and can detect myocardial abscesse established infections, a normocytic-normochromic anemia, elevated ESR, neutrophilia, increased immunoglobulins, circulating immune complexes, and rheumatoid factor are often present.
Prognosis
Untreated, infective endocarditis is always fatal. When treatment is given, mortality depends on the pa age and condition, duration of infection before treatment, severity of underlying diseases, site of infect susceptibility of the microorganism to antibiotics, and complications. Right-sided endocarditis often res antimicrobial therapy and has a better prognosis than left-sided endocarditis. The expected mortality o viridans streptococcal endocarditis without major complications is < 10%, but mortality is virtually 100% Aspergillus endocarditis after prosthetic valve surgery. Cardiac surgery that corrects acute valvular
Untreated, infective endocarditis is always fatal. When treatment is given, mortality depends on the pa age and condition, duration of infection before treatment, severity of underlying diseases, site of infect susceptibility of the microorganism to antibiotics, and complications. Right-sided endocarditis often res antimicrobial therapy and has a better prognosis than left-sided endocarditis. The expected mortality o viridans streptococcal endocarditis without major complications is < 10%, but mortality is virtually 100% Aspergillus endocarditis after prosthetic valve surgery. Cardiac surgery that corrects acute valvular insufficiency, removes infected foreign bodies, and eliminates recalcitrant infection is associated with significantly improved survival.
A poor prognosis is associated with heart failure, old age, aortic or multiple valve involvement, large vegetations, polymicrobial bacteremia, antimicrobial resistance, delay in initiating therapy, prosthetic v infections, mycotic aneurysms, valve ring abscess, and major embolic events. After cardiac surgery, th mortality rate is higher in early-onset than in late-onset infective endocarditis and in fungal endocarditi
Prophylaxis
(See Tables 270-1 and 270-2 for prophylaxis in children.)
Although its effectiveness is unproved, antimicrobial prophylaxis is usually recommended for patients predisposed to infective endocarditis who are undergoing procedures associated with bacteremias and possible subsequent infective endocarditis (see Table 208-1). Persons at high risk of endocarditis are with prosthetic heart valves (bioprosthetic, homograft), a previous history of endocarditis, complex cya congenital heart disease, or surgically constructed systemic pulmonary shunts or conduits. Persons at moderate risk are those with most other congenital cardiac malformations, acquired valvular insufficien hypertrophic cardiomyopathy, and mitral valve prolapse with murmur or thickened valve leaflets. Curre recommendations for endocarditis prophylaxis from the American Heart Association are summarized i 208-2 and 208-3.
Prophylaxis against S. aureus and S. epidermidis during cardiac valvular surgery usually consists of ce 2 g IV during initiation of anesthesia with 2 g IV q 8 h for 3 to 6 doses. Other antimicrobial drugs may b necessary if postoperative infections with cefazolin-resistant organisms are frequent.
Treatment
Successful treatment requires maintenance of high serum levels of an effective antibiotic and surgical management of mechanical complications and resistant organisms.
Antibiotic regimens: Penicillin-susceptible streptococci (penicillin G MIC <= 0.1 g/mL) include m viridans streptococci, microaerophilic and anaerobic streptococci, and nonenterococcal group D strept Penicillin G 12 to 18 million U/day IV administered continuously or q 4 h and procaine penicillin G 1.2 m IM q 6 or 12 h for 4 wk have equivalent results. When gentamicin 1 mg/kg IM (up to 80 mg) q 8 h is administered concurrently, treatment should be reduced to 2 wk. Patients allergic to penicillin may be cautiously given ceftriaxone if there is no history of penicillin anaphylaxis or, alternatively, vancomycin. Ceftriaxone 2 g once daily IV for 4 wk through a central line is convenient and effective as outpatient treatment. Oral treatment programs are less reliable and should not be used without close monitoring levels to ensure adequate GI absorption.
Penicillin-resistant streptococci (penicillin G MIC > 0.1 g/mL) include enterococcal and some othe streptococcal strains (including fastidious pyridoxal-requiring viridans streptococci), which are relatively resistant to penicillin G and require a penicillin or vancomycin combined with an aminoglycoside. Abou enterococcal strains demonstrate resistance to streptomycin and should be treated with penicillin plus gentamicin. Gentamicin resistance is an increasing therapeutic problem in nosocomial enterococcal endocarditis. Penicillin G 18 to 30 million U/day IV or ampicillin 12 g/day IV administered continuously
Penicillin-resistant streptococci (penicillin G MIC > 0.1 g/mL) include enterococcal and some othe streptococcal strains (including fastidious pyridoxal-requiring viridans streptococci), which are relatively resistant to penicillin G and require a penicillin or vancomycin combined with an aminoglycoside. Abou enterococcal strains demonstrate resistance to streptomycin and should be treated with penicillin plus gentamicin. Gentamicin resistance is an increasing therapeutic problem in nosocomial enterococcal endocarditis. Penicillin G 18 to 30 million U/day IV or ampicillin 12 g/day IV administered continuously should be given concurrently with gentamicin 1 mg/kg IV (based on ideal rather than actual body weig obese persons) q 8 h for 4 to 6 wk. Patients with enterococcal infections lasting > 3 mo with large vege or with vegetations on prosthetic valves should be treated for 6 wk. Persons allergic to penicillin may b desensitized or treated with vancomycin 15 mg/kg IV (up to 1 g) q 12 h and gentamicin.
Pneumococcal or group A streptococcal endocarditis should be treated with penicillin G 10 to 20 m U/day IV for 4 wk. S. aureus endocarditis should be treated with penicillin G 15 to 24 million U/day IV i strain does not produce -lactamase. Ninety-five percent of strains are penicillin-resistant and should be with a penicillinase-resistant penicillin (oxacillin or nafcillin) 2 g IV q 4 h for 4 to 6 wk. Staphylococcal s resistant to the penicillinase-resistant penicillins are also resistant to the cephalosporins, although resi may be difficult to demonstrate with routine testing. Oxacillin-resistant or nafcillin-resistant staphylococ should be treated with vancomycin 15 mg/kg IV q 12 h. Oxacillin-susceptible or nafcillin-susceptible inf in penicillin-allergic patients may be cautiously treated with cefazolin 2 g IV q 8 h if there is no history o penicillin anaphylaxis, or with vancomycin.
Because S. epidermidis endocarditis occurs most often in patients with prosthetic valves, patients may antimicrobial drugs and surgery. Penicillin-susceptible or oxacillin-susceptible strains should be treated outlined above for S. aureus, but for 6 to 8 wk. Oxacillin or nafcillin should be combined with rifampin 3 po every 8 h and gentamicin 1 mg/kg IV every 8 h. Oxacillin-resistant strains should be treated with vancomycin 15 mg/kg IV q 12 h plus gentamicin 1 mg/kg IV every 8 h and rifampin 300 mg po q 8 h fo wk.
HACEK microorganisms (Haemophilus parainfluenzae, H. aphrophilus, Actinobacillus actinomycetemc Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) should be treated with ceftriaxone 2 g for 4 wk or ampicillin plus gentamicin for 4 wk using the same doses given for enterococcal infections. bacillary infections often show antimicrobial resistance and should be treated for >= 4 wk with a sensitivity-proven -lactam antimicrobial drug plus an aminoglycoside.
Cardiac valve surgery: Cardiac valve surgery (debridement and/or replacement of the valve) is frequ required to eradicate infection that is uncontrolled medically, particularly in early-onset PVE. The timin surgical intervention requires experienced clinical judgment. If heart failure caused by a correctable les worsening (particularly when the organism is S. aureus, a gram-negative bacillus, or a fungus), surger required urgently, but an optimal antibiotic regimen is given for 24 to 72 h before surgery.
Response to treatment: Patients with penicillin-susceptible streptococcal infective endocarditis usual better and have a reduction in fever within 3 to 7 days of starting therapy. However, fever may persist reasons other than continued active infection (eg, drug allergy, phlebitis, infarction from emboli). Staphylococcal infective endocarditis often responds more slowly. Sterile emboli and valve rupture ma up to 1 yr after successful antimicrobial therapy. Relapse usually occurs within 4 wk; antibiotic retreatm be effective, but surgery may also be required. Recrudescence of infective endocarditis after 6 wk in p without prosthetic valves usually is a new infection rather than a relapse.
Section 16. Cardiovascular Disorders Chapter 200. Orthostatic Hypotension And Sync Topics
Orthostatic Hypotension Syncope
Orthostatic Hypotension
An excessive fall in BP (typically > 20/10 mm Hg) on assuming the upright posture.
Orthostatic hypotension is not a specific disease but rather a manifestation of abnormal BP regulation various causes.
The gravitational stress of sudden standing normally causes pooling of blood in the venous capacita vessels of the legs and trunk. The subsequent transient decrease in venous return and cardiac output in reduced BP. Baroreceptors in the aortic arch and carotid bodies activate autonomic reflexes that rap normalize BP by causing a transient tachycardia. These changes reflect primarily the sympathetic med increase in catecholamine levels, which augments vasomotor tone of the capacitance vessels, increas rate and myocardial contractility, and thereby enhances cardiac output; arterial and venous vasoconst are mediated by similar mechanisms. Vagal inhibition also increases the heart rate. With continued sta ADH secretion and activation of the renin-angiotensin-aldosterone system cause Na and water retenti expansion of the circulating blood volume.
When afferent, central, or efferent portions of the autonomic reflex arc are impaired by diseases or d myocardial contractility or vascular responsiveness is depressed, hypovolemia is present, or hormona responses are faulty, these homeostatic mechanisms may be inadequate to restore the lowered BP. T manifestations of decreased tissue perfusion are the effects of impaired cerebral blood flow; however, BP changes do not reliably reflect cerebral hypoperfusion.
Hypovolemia is the most common cause of symptomatic orthostatic hypotension. Hypovolemia is ofte induced by excessive use of diuretics (eg, loop diuretics such as furosemide, bumetanide, and ethacry acid); relative hypovolemia is due to vasodilator therapy with nitrate preparations and Ca blockers (ver nifedipine, diltiazem, amlodipine) or with ACE inhibitors. The hypovolemia and diminished vasomotor t caused by protracted bed rest are also often a cause of orthostatic hypotension. Orthostatic hypotensi more frequent in diabetic than nondiabetic patients treated with antihypertensive drugs and also occur
Hypovolemia is the most common cause of symptomatic orthostatic hypotension. Hypovolemia is ofte induced by excessive use of diuretics (eg, loop diuretics such as furosemide, bumetanide, and ethacry acid); relative hypovolemia is due to vasodilator therapy with nitrate preparations and Ca blockers (ver nifedipine, diltiazem, amlodipine) or with ACE inhibitors. The hypovolemia and diminished vasomotor t caused by protracted bed rest are also often a cause of orthostatic hypotension. Orthostatic hypotensi more frequent in diabetic than nondiabetic patients treated with antihypertensive drugs and also occur secondary to vasodilation during febrile illnesses.
Acute or subacute severe hypovolemia caused by disease may produce orthostatic hypotension due t decrease in cardiac output despite intact autonomic reflexes. Hemorrhage, severe vomiting or diarrhea excessive sweating, or the osmotic diuresis in uncontrolled diabetes mellitus may lead to volume deple dehydration, and orthostatic hypotension unless fluid or electrolyte replacement is adequate. Hypokale impairs the reactivity of vascular smooth muscle and may limit the increase in peripheral vascular resis on standing. The adrenocortical hypofunction of Addison's disease may lead to hypovolemic orthostat hypotension in the absence of adequate salt intake. The effects of diuretics and vasodilators are discu below.
Drugs that impair autonomic reflex mechanisms and reduce BP on standing, eg, excessive doses antihypertensive drugs (methyldopa, clonidine, reserpine, ganglionic blocking drugs) and multiple drug also frequent causes. -Adrenergic blockers are a rare cause, but -adrenergic blockers such as prazosi be causative, especially at the initiation of therapy (first-dose effect). Drugs that provoke postural hypo should be initiated in small doses with gradual upward titration. Other drugs that reversibly impair auto reflexes and reduce BP on standing (an important adverse effect) include many of those used to treat psychiatric disorders, such as monoamine oxidase inhibitors (isocarboxazid, phenelzine, tranylcyprom used to treat depression; tricyclic antidepressants (nortriptyline, amitriptyline, desipramine, imipramine protriptyline) or tetracyclic antidepressants; and phenothiazine antipsychotic drugs (chlorpromazine, promazine, thioridazine). Quinidine, levodopa, barbiturates, and alcohol may also produce orthostatic hypotension. The antineoplastic drug vincristine may produce severe long-lasting orthostatic hypotens to neurotoxicity.
Neurologic disorders that involve the autonomic nervous system interrupt the sympathetic reflex impair normal adrenergic responses to standing. This is common with diabetic neuropathy, amyloidosi porphyria, tabes dorsalis, syringomyelia, spinal cord transection, pernicious anemia, alcoholic neuropa Guillain-Barr syndrome (postinfectious polyneuropathy), and Riley-Day syndrome (familial dysautono Surgical sympathectomy, vasospastic disorders, or peripheral venous insufficiency (particularly severe varicose veins) may result in orthostatic hypotension. The postural hypotension of Parkinson's disease aggravated by treatment with levodopa. Orthostatic hypotension may be a component of the vasomoto response in the postgastrectomy dumping syndrome.
Shy-Drager syndrome and idiopathic orthostatic hypotension are two possibly related primary neu disorders commonly associated with severe orthostatic hypotension (see also Ch. 179). In patients wit Shy-Drager syndrome, plasma norepinephrine does not increase on standing; in those with idiopathic orthostatic hypotension, norepinephrine appears to be depleted from the sympathetic nerve endings. I conditions, widespread lesions affect the sympathetic and parasympathetic nervous systems, basal ga and spinal tracts, with resultant widespread autonomic dysfunction in addition to failure of arteriolar an venous vasoconstriction; loss of sweating; bowel, bladder, and stomach atony; impotence; decreased salivation and tearing; mydriasis; and impaired visual accommodation. Paradoxically, BP may be eleva the supine position, even when severe postural hypotension is present, because of loss of parasympa well as sympathetic, regulation of the cardiovascular system. Orthostatic hypotension is accentuated in early morning due to overnight natriuresis and may also be more prominent postprandially and after ex
In many causes of secondary systemic arterial hypertension, in which BP is not controlled by the u homeostatic mechanisms, assuming the upright posture may cause orthostasis; this is prominent in m patients with pheochromocytoma and also occurs in patients with primary hyperaldosteronism, who,
well as sympathetic, regulation of the cardiovascular system. Orthostatic hypotension is accentuated in early morning due to overnight natriuresis and may also be more prominent postprandially and after ex
In many causes of secondary systemic arterial hypertension, in which BP is not controlled by the u homeostatic mechanisms, assuming the upright posture may cause orthostasis; this is prominent in m patients with pheochromocytoma and also occurs in patients with primary hyperaldosteronism, who, paradoxically, have hypertension in the supine position as well as orthostatic hypotension.
Cardiac causes of sudden-onset postural hypotension include unrecognized MI or cardiac arrhythmia cardiac causes of postural hypotension reflecting inability to increase cardiac output include severe dil cardiomyopathy, aortic stenosis, constrictive pericarditis, and advanced heart failure of any cause.
In the elderly, decreased baroreceptor responsiveness, coupled with decreased arterial compliance, a for frequent orthostatic hypotension. The decreased baroreceptor responsiveness delays the tachycar response. Although postural hypotension is described in about 20% of unselected elderly persons, its prevalence is much lower in healthy community-dwelling elderly. Coexistent multiple abnormalities ofte cardiovascular homeostasis in institutionalized elderly.
Faintness, light-headedness, dizziness, confusion, or visual blurring is evidence of a mild to moderate reduction in cerebral blood flow. With more severe cerebral hypoperfusion, syncope or generalized se may supervene (see also Syncope, below). Exercise or a heavy meal may exacerbate symptoms. Oth associated phenomena usually relate to the underlying cause.
Orthostatic hypotension is diagnosed when symptoms suggestive of hypotension and a marked reduc measured BP are provoked by standing and relieved by lying down. An underlying cause must be sou based on the patient's presenting circumstances and associated phenomena (eg, as described above Shy-Drager syndrome).
Prognosis depends on the underlying cause. Orthostatic hypotension due to hypovolemia or drug exce rapidly reversed by correcting these problems. Anemia and electrolyte imbalance can be specifically tr The orthostasis of protracted bed rest can be lessened by having patients sit up each day. Elderly pati should maintain adequate fluid intake, limit or avoid alcohol, and exercise regularly when feasible. The in patients with a chronic underlying disorder is determined by the management of that disease; eg, po hypotension appears to indicate a poor prognosis in diabetic patients with hypertension.
When the causative disease cannot be improved, management is designed to produce peripheral vasoconstriction and/or increase cardiac output. Often, this allows BP to be maintained at an asympto (although reduced) level in the standing position. However, in advanced stages of Shy-Drager syndrom idiopathic orthostatic hypotension, pharmacotherapy is often inadequate, and some mechanical form o counterpressure or a counterpulsation device may be needed. If orthostatic hypotension is related to v pooling in the legs, fitted elastic hose may enhance the cardiac output and BP on standing. In more ad cases, inflatable aviator-type antigravity suits, although often poorly tolerated, may be needed to produ sufficient leg and abdominal counterpressure.
With mild orthostasis, the peripheral adrenergic drug ephedrine 25 to 50 mg po q 3 to 4 h, when the pa awake, may maintain adequate BP. Phenylephrine has also been used. An alternative or concurrent th expansion of plasma volume, initially by increasing Na intake and subsequently by administering Na-re hormones. In the absence of heart failure, Na intake can be increased 5 to 10 g above the usual dieta by liberally salting food or taking sodium chloride tablets. 9--Fludrocortisone 0.1 to 0.5 mg/day po impr
With mild orthostasis, the peripheral adrenergic drug ephedrine 25 to 50 mg po q 3 to 4 h, when the pa awake, may maintain adequate BP. Phenylephrine has also been used. An alternative or concurrent th expansion of plasma volume, initially by increasing Na intake and subsequently by administering Na-re hormones. In the absence of heart failure, Na intake can be increased 5 to 10 g above the usual dieta by liberally salting food or taking sodium chloride tablets. 9--Fludrocortisone 0.1 to 0.5 mg/day po impr peripheral vasoconstrictor response to sympathetic stimulation but is effective only when Na ingestion adequate and weight gain of 1.3 to 2.2 kg (3 to 5 lb) occurs due to Na retention and expansion of the intravascular fluid volume. The risk of this management, particularly in elderly patients or those with im myocardial function, is the development of heart failure; dependent edema alone, in the absence of he failure, does not contraindicate continued therapy. An important complication is hypokalemia due to th K-wasting effect of mineralocorticoid administration accompanied by a high Na intake; K supplements needed. Supine hypertension is an added risk.
Propranolol therapy has been reported to enhance the beneficial effects of Na and mineralocorticoid th -Blockade with propranolol, leading to unopposed -adrenergic peripheral vascular vasoconstriction, pre vasodilation that occurs in some patients on standing. The risk is reduction of Na excretion with develo of heart failure.
Dihydroergotamine, a selective constrictor of peripheral capacitance vessels, has shown only short-ter benefit; the risks include supine hypertension and extremity gangrene. NSAIDs may cause renal Na re and inhibit prostaglandin-induced vasodilation; indomethacin 25 to 50 mg po tid may be beneficial in in peripheral vascular resistance. However, these drugs may cause GI symptoms and unwanted vasopre reactions (described in patients who received indomethacin and sympathomimetic drugs concurrently) Metoclopramide may inhibit the natriuretic and vasodilator effects of dopamine excess (a rare cause o orthostatic hypotension) but may exacerbate parkinsonism. Rapid atrial pacing has had limited succes particularly in patients with slow heart rates. Midodrine may be tried in patients with severe orthostasis unresponsive to other drugs. However, its benefit/risk profile has not been established.
Elderly patients should be encouraged to change posture slowly; sleeping with the head of the bed rai relieve symptoms by promoting Na retention and reducing nocturnal diuresis. They should also avoid prolonged standing. Regular modest-intensity exercise promotes overall vascular tone and reduces ve pooling.

Section 16. Cardiovascular Disorders Chapter 209. Pericardial Disease Topics
[General] Pericarditis
[General]
Congenital anomalies of the pericardium include pericardial cysts and absence of the parietal pericar Pericardial cysts tend to occur at the junction of pericardium and diaphragmatic pleura, more common right. Absence of the parietal pericardium is usually well tolerated but may simulate pulmonary artery s enlargement due to a shift of the heart to the left on chest x-ray. Rarely, partial absence of the left pari pericardium causes strangulation of the circulation due to herniation of the heart through the defect.
Acquired disorders of the pericardium (eg, infection, inflammation, trauma, neoplasms) largely result pericarditis.

Section 16. Cardiovascular Disorders Chapter 201. Arteriosclerosis Topics
[General] Atherosclerosis Nonatheromatous Arteriosclerosis
[General]
Arteriosclerosis: A generic term for several diseases in which the arterial wall becomes thickened and elasticity.
Vascular disease, which affects the brain, heart, kidneys, other vital organs, and extremities, is the lea cause of morbidity and mortality in the USA and in most Western countries. There were almost 1 millio deaths due to vascular disease in the USA in 1994 (twice as many as from cancer and 10 times as ma from accidents). Although prevention and treatment of coronary artery disease (CAD) resulted in a 28. reduction in age-adjusted death rates between 1984 and 1994, CAD and ischemic stroke combined ar number one killer in industrialized Western countries and are of increasing prevalence in the rest of th
The death rate from CAD among white men aged 25 to 34 is about 1/10,000; at age 55 to 64, it is nea 1/100. This age relationship may be due to the time required for lesions to develop or to the duration o exposure to risk factors. The death rate from CAD among white men aged 35 to 44 is 6.1 times that am age-matched white women. For unknown reasons, the sex difference is less apparent in nonwhites. Atherosclerosis is the most common and serious vascular disease. Nonatheromatous forms include arteriolosclerosis and Mnckeberg's arteriosclerosis.

Section 16. Cardiovascular Disorders Chapter 210. Cardiac Tumors Topics
[General] Benign Cardiac Tumors Malignant Cardiac Tumors
[General]
Primary cardiac tumors are rare, found in < 1/2000 persons at autopsy; secondary tumors are 30 to 40 more common. Tumors may be epicardial, myocardial, or endocardial, and their symptoms and signs have localizing features. However, they mimic other heart diseases and can easily be misdiagnosed. T development of cardiac symptoms and signs in a patient with an extracardiac malignancy suggests ca metastases.

Section 16. Cardiovascular Disorders Chapter 202. Coronary Artery Disease Topics
[General] Prevention Of Coronary Artery Disease Angina Pectoris Myocardial Infarction
[General]
Most coronary artery disease (CAD) is due to subintimal deposition of atheromas in the large and medium-sized arteries serving the heart. Risk factors and the pathogenesis of atherosclerotic lesions a are discussed in Chs. 15 and 201. Less often, CAD is due to coronary spasm, which is usually idiopat or without associated atheroma) or may be due to drugs such as cocaine. Rare causes include an em the coronary artery, Kawasaki syndrome (see Ch. 265), and vasculitis (eg, in SLE).
Coronary atherosclerosis is characteristically insidious in onset, is often irregularly distributed in differe vessels, and can abruptly interfere with blood flow to segments of the myocardium, most often due to of an eccentric atheromatous plaque with consequent intraluminal thrombosis.
The major complications of CAD are angina pectoris, unstable angina, MI, and sudden cardiac death d arrhythmias. In the USA, CAD is the leading cause of death in both sexes, accounting for about one th deaths each year.
Although the precise pathogenesis of CAD is unclear, the risk factors are well known: high blood levels density lipoprotein cholesterol (LDL-C) and lipoprotein a, low blood levels of high density lipoprotein ch (HDL-C) and serum vitamin E, and poor physical fitness. High blood levels of triglycerides and insulin insulin resistance may be risk factors, but the data are less clear. CAD risk is increased by tobacco us high in fat and calories and low in phytochemicals (found in fruits and vegetables), fiber, and vitamin E or, at least in some persons, diets with relatively low levels of omega-3 polyunsaturated fatty acids (PU poor stress management; and inactivity. Several systemic diseases (eg, hypertension, diabetes, hypothyroidism) are also associated with increased CAD risk.
Recent studies have shown an association between CAD and a common variant of the platelet fibrinog receptor (PlA2), found in 20% of Americans. The presence of this variant may be as strong a predictor as cigarette smoking and hypertension. Whether giving antiplatelet therapy to persons with this varian prevent CAD remains to be established.
Recent studies have shown an association between CAD and a common variant of the platelet fibrinog receptor (PlA2), found in 20% of Americans. The presence of this variant may be as strong a predictor as cigarette smoking and hypertension. Whether giving antiplatelet therapy to persons with this varian prevent CAD remains to be established.
Homocysteine has recently been identified as a risk factor for coronary, peripheral, and cerebral vascu disease. Patients with homocystinuria, a rare recessive disease, have plasma homocysteine levels 10 times above normal (hyperhomocysteinemia) and accelerated, premature vascular disease. Homocys a direct toxic effect on endothelium and promotes thrombosis and oxidation of LDL. Normal values ran about 4 to 17 mol/L. Modest elevations of total plasma homocysteine have multiple causes, including levels of folic acid, vitamins B 6 and B12, renal insufficiency, certain drugs, and genetically controlled va in homocysteine metabolic enzymes. Patients with homocysteine values in the top 5% have a 3.4 grea of MI or cardiac death than those in the lower 90% after adjustment for other risk factors. Increased homocysteine levels are associated with increased risk regardless of etiology. Recent studies suggest graded risk even in normal-range homocysteine; thus, reduction of normal plasma levels may be advantageous. The most simple and effective way to reduce plasma homocysteine is administration o acid 1 to 2 mg/day, which has essentially no side effects except in untreated vitamin B12 deficiency. M authorities recommend that patients with CAD be screened for plasma homocysteine levels and, unles values are in the lower normal range, treatment be initiated with folic acid. (See also Hyperhomocyste Ch. 132.)
Patients with CAD undergoing atherectomy have biologic markers suggesting coronary artery localizat Chlamydia infection. The role of this and other putative infectious agents in the genesis of CAD is bein investigated.
Section 16. Cardiovascular Disorders Chapter 211. Diseases Of The Aorta And Its Bran Topics
Aneurysms Aortic Dissection Inflammation Of The Aorta Occlusion Of The Abdominal Aorta And Its Branches
Aneurysms
Localized dilation of a blood vessel, particularly the aorta or a peripheral artery.
Aneurysms are thought generally to result from localized weakening of the vessel wall. Specific cause arteriosclerosis, cystic medial necrosis, syphilitic or mycotic infection, aortitis, and trauma. There may familial tendency, particularly for some aortic aneurysms.
AORTIC ANEURYSMS
Aortic aneurysms can develop anywhere along the length of the aorta, but 3/4 are located in the abdom aorta. Thoracic aortic aneurysms, including those that extend from the descending thoracic aorta into upper abdomen (thoracoabdominal aneurysms), account for 1/4 of aortic aneurysms.
Aortic aneurysms may be fusiform or, less commonly, saccular. Fusiform aneurysms are characterized circumferential widening of the aorta, whereas saccular aneurysms represent localized outpocketings aortic wall. Laminated thrombus often lines the walls of aortic aneurysms.
Etiology
Arteriosclerosis, the most common disease associated with aortic aneurysms, may weaken the aortic causing it to expand. Hypertension and cigarette smoking contribute to the degenerative process. Trau arteritis, and mycotic aneurysms are less frequent causes. Mycotic aneurysms occur at sites of localiz bacterial or fungal infections in the aortic or arterial walls. These sites of infection usually are the resul metastatic infection from septicemia, most commonly caused by infectious endocarditis. Infection may spread to blood vessel walls locally, and preexisting aortic or arterial aneurysms may become infected from bloodstream seeding. Although virtually any bacterial or fungal pathogen may infect aneurysms, Salmonella sp show a proclivity for vascular tissues.
causing it to expand. Hypertension and cigarette smoking contribute to the degenerative process. Trau arteritis, and mycotic aneurysms are less frequent causes. Mycotic aneurysms occur at sites of localiz bacterial or fungal infections in the aortic or arterial walls. These sites of infection usually are the resul metastatic infection from septicemia, most commonly caused by infectious endocarditis. Infection may spread to blood vessel walls locally, and preexisting aortic or arterial aneurysms may become infected from bloodstream seeding. Although virtually any bacterial or fungal pathogen may infect aneurysms, Salmonella sp show a proclivity for vascular tissues.
Abdominal Aortic Aneurysms

Of abdominal aortic aneurysms (AAAs), 90% begin below the renal arteries, commonly extending dista either or both iliac arteries.
AAAs may cause pain, which is typically deep, boring, and visceral, felt most prominently in the lumbo region. The pain is usually steady. The patient may present with an awareness of an abnormally prom abdominal pulsation. However, aneurysms often become huge, and may rupture, without antecedent symptoms.
Thorough palpation often reveals an abnormally wide pulsation of the abdominal aorta (typically on bo of the midline). However, even large aneurysms may be very difficult to detect on physical examination especially in obese persons. Rapidly enlarging aneurysms with imminent rupture are frequently tender may be heard over the aneurysm.
Cross-sectional ultrasonography is the most cost-effective noninvasive method of evaluation. It usually clear picture of the extent and size of an aneurysm. CT of the abdomen, particularly if performed with contrast medium, or MRI can also determine aneurysmal size and anatomy but is more costly. MRI is necessary. A plain abdominal x-ray, particularly in a lateral position, may reveal calcification of the ane wall. Abdominal aortography indicates the extent of the aneurysm and outlines other major blood vess are compromised. Aortography is indicated if extension of the aneurysm above the renal arteries (pres about 10% of cases) is suspected. Because aortography outlines only the aortic lumen, the true size o aneurysm may be underestimated if thrombus lines the aneurysmal wall.
Because many patients with AAAs have generalized arteriosclerosis, cardiovascular status should be assessed before surgery. Myocardial scintigraphy using thallium-201 imaging after exercise or in respo IV dipyridamole has been particularly helpful in screening for high-risk cardiac patients who might need attention to coronary artery problems before AAA surgery.
Rupture of an AAA is usually preceded by the onset of excruciating pain in the lower abdomen and ba tenderness of the aneurysm. Depending on the severity of bleeding, hypovolemic shock and death ma follow. Rupture or threatened rupture is a surgical emergency. The operative risk for a ruptured aneury about 50%; postoperative renal failure portends a poor prognosis.
The natural history of AAAs is closely related to size. Rupture is uncommon if aneurysms are < 5 cm w dramatically more common if > 6 cm. Thus, elective surgical repair is usually recommended for all ane > 6 cm unless surgery is contraindicated. In patients who are good surgical risks, elective repair is gen recommended for aneurysms between 5 and 6 cm (mortality, about 2 to 5%). Surgical repair consists excision of the aneurysm and replacement with a synthetic conduit; the graft may have to be carried in
The natural history of AAAs is closely related to size. Rupture is uncommon if aneurysms are < 5 cm w dramatically more common if > 6 cm. Thus, elective surgical repair is usually recommended for all ane > 6 cm unless surgery is contraindicated. In patients who are good surgical risks, elective repair is gen recommended for aneurysms between 5 and 6 cm (mortality, about 2 to 5%). Surgical repair consists excision of the aneurysm and replacement with a synthetic conduit; the graft may have to be carried in or both iliac arteries if the aneurysm involves them. Extension of the aneurysm above the renal arterie necessitates their reimplantation onto the synthetic graft or creating bypass grafts to them.
Treatment of a mycotic aneurysm consists of vigorous antibiotic therapy directed at the specific organi followed by excision of the aneurysm. Early diagnosis and treatment favorably influence outcome.
Thoracic Aortic Aneurysms
Congenital connective tissue disorders (eg, Ehlers-Danlos syndrome, Marfan's syndrome--see Inherite Disorders of Connective Tissue in Ch. 270) typically give rise to cystic medial necrosis, which affects th proximal aorta and may result in aneurysms (typically fusiform).
A common form of thoracic aortic aneurysm involves widening of the proximal aorta and the aortic roo causing aortic insufficiency (annuloaortic ectasia). About 50% of patients with annuloaortic ectasia hav Marfan's syndrome or a variant form of that disease; the condition is idiopathic in the rest.
Tertiary syphilis is an uncommon cause of aneurysms (see also Syphilis in Ch. 164). Aneurysms caus syphilis are typically found in the aortic root and ascending aorta.
Traumatic aneurysms most frequently follow blunt chest trauma and are typically located in the descen thoracic aorta where it becomes fixed to the posterior thoracic cage. However, these are usually false aneurysms, ie, they contain hematomas resulting from blood that has leaked through the torn aortic w often appear on chest x-rays late after severe blunt chest injuries.
Symptoms and Signs
Symptoms relate to pressure against or erosion of adjacent structures by the enlarging aorta, such as (especially in the back where the aneurysm contacts the spine or thoracic cage); cough, wheezing, or hemoptysis from tracheal or bronchial compression or erosion; dysphagia from esophageal compressi hoarseness from compression of the left recurrent laryngeal nerve. Horner's syndrome, a tracheal tug, deviation, and abnormal chest wall pulsations may be signs of thoracic aneurysms. However, as with A thoracic aneurysms may become huge while remaining asymptomatic.
Aortic insufficiency and inflammatory stenosis of the coronary artery ostia are common sequelae of sy aneurysms of the aortic root, and calcification in the wall of the aneurysm is often heavy.
Diagnosis
Thoracic aortic aneurysms can usually be seen on chest x-ray. CT and MRI are particularly helpful in documenting their extent and size. Transthoracic ultrasonography is accurate in sizing aneurysms of th ascending but not the descending aorta, whereas transesophageal ultrasonography appears accurate aneurysms of both. Contrast or magnetic resonance aortography is indicated for most thoracic aneury being evaluated for surgical resection.
With syphilitic aneurysms, serologic tests, especially the fluorescent treponemal antibody absorption a
documenting their extent and size. Transthoracic ultrasonography is accurate in sizing aneurysms of th ascending but not the descending aorta, whereas transesophageal ultrasonography appears accurate aneurysms of both. Contrast or magnetic resonance aortography is indicated for most thoracic aneury being evaluated for surgical resection.
With syphilitic aneurysms, serologic tests, especially the fluorescent treponemal antibody absorption a Treponema pallidum immobilization tests, are most often positive.
The mortality for the elective repair of thoracic aneurysms ranges from 10 to 15%, although the risk inc significantly in complicated aneurysms (eg, those involving the aortic arch or thoracoabdominal aorta).
Thoracic aneurysms generally should be resected if >= 6 cm. However, aneurysms in patients with Ma syndrome are prone to rupture, so elective surgical repair is recommended for aneurysms 5 to 6 cm. S repair consists of resection of the aneurysm and replacement with a synthetic conduit. The Bentall rep consists of resection of the dilated ascending aorta down to the aortic annulus, with excision of the cor arteries around a button of aortic wall. A composite graft (a synthetic conduit into which a prosthetic ao valve may be inserted at one end) is sewn into place between the transected aorta distally and the aor annulus proximally. The coronary arteries are then reimplanted into the graft. Some surgeons use a ho of the proximal aorta and aortic valve instead of synthetic materials.
Patients with a syphilitic aneurysm should undergo surgical repair of the aneurysm and the aortic insuf and be given benzathine penicillin 2.4 million U/wk for 3 wk. If the patient is allergic to penicillin, tetracy erythromycin 500 mg qid for 30 days is most effective. Traumatic aneurysms are prone to rupture and should be repaired surgically.
POPLITEAL, ILIAC, AND FEMORAL ANEURYSMS
The most common peripheral arterial aneurysms are those of the popliteal arteries. Aneurysms at this bilateral in 50% of cases and are frequently associated with AAAs. Although popliteal aneurysms rarel rupture, they may serve as a focus for abrupt thrombotic occlusion of the involved popliteal artery, jeop the foot on the affected side. Thrombus within the aneurysms may lead to distal embolism.
Popliteal aneurysms are usually detected on physical examination and confirmed by ultrasonography o Arteriography can also confirm the diagnosis and assess the circulation distal to the aneurysm.
Surgical resection of popliteal aneurysms with graft replacement of the excised segment is advisable. Aneurysms of the iliac and femoral arteries should also be repaired when they are twice normal size o symptomatic.
UPPER EXTREMITY ANEURYSMS
Upper extremity aneurysms are rare. Aneurysms of the subclavian artery are sometimes associated w cervical ribs. After the cervical rib is removed, the aneurysm is resected and replaced with a graft.
UPPER EXTREMITY ANEURYSMS SPLANCHNIC ARTERY ANEURYSMS
Upper extremity aneurysms are rare. Aneurysms of the subclavian artery are sometimes associated w cervical ribs. After the cervical rib is removed, the aneurysm is resected and replaced with a graft.
Splanchnic artery aneurysms are infrequent. They most commonly involve the splenic artery and less commonly the hepatic and superior mesenteric arteries. Splanchnic artery aneurysms are usually not diagnosed until they rupture, although they may be found incidentally on x-rays if calcified, by CT, or in course of mesenteric angiography. Symptomatic aneurysms should be repaired, whereas the decision asymptomatic aneurysms is based on patient age, surgical risks, and size and location of the aneurys
INTRACRANIAL ANEURYSMS
Congenital saccular aneurysms of the intracranial arteries, particularly the circle of Willis (berry aneury may occur alone or with other congenital anomalies (eg, coarctation of the aorta, polycystic kidneys). T important causes of serious subarachnoid intracerebral hemorrhages (see Ch. 174).
Mycotic aneurysms of the cerebral arteries are particularly hazardous complications of infective endoc often resulting in intracranial hemorrhages. They can usually be sterilized by intensive antibiotic therap generally, they must be resected.

Section 16. Cardiovascular Disorders Chapter 203. Heart Failure Topics
[General] Cardiomyopathy Cor Pulmonale
[General]
(For heart failure in children, see Ch. 261.)
Heart failure (congestive heart failure): Symptomatic myocardial dysfunction resulting in a characterist of hemodynamic, renal, and neurohormonal responses.
No definition of heart failure (HF) is entirely satisfactory. Congestive heart failure (CHF) develops when volume increases and fluid accumulates in the lungs, abdominal organs (especially the liver), and peri tissues.
Physiology
At rest and during exercise, cardiac output (CO), venous return, and distribution of blood flow with O2 to the tissues are balanced by neurohumoral and intrinsic cardiac factors. Preload, the contractile state afterload, the rate of contraction, substrate availability, and the extent of myocardial damage determin ventricular (LV) performance and myocardial O2 requirements. The Frank-Starling principle, cardiac re and the oxyhemoglobin dissociation curve play a role.
Preload (the degree of end-diastolic fiber stretch) reflects the end-diastolic volume, which is influence diastolic pressure and the composition of the myocardial wall. For clinical purposes, the end-diastolic p especially if above normal, is a reasonable measure of preload in many conditions. LV dilatation, hype and changes in myocardial distensibility or compliance modify preload.
The contractile state in isolated cardiac muscle is characterized by the force and velocity of contracti which are difficult to measure in the intact heart. Clinically, the contractile state is often expressed as t ejection fraction (LV stroke volume/end-diastolic volume).
Afterload (the force resisting myocardial fiber shortening after stimulation from the relaxed state) is de
The contractile state in isolated cardiac muscle is characterized by the force and velocity of contracti which are difficult to measure in the intact heart. Clinically, the contractile state is often expressed as t ejection fraction (LV stroke volume/end-diastolic volume).
Afterload (the force resisting myocardial fiber shortening after stimulation from the relaxed state) is de by the chamber pressure, volume, and wall thickness at the time of aortic valve opening. Clinically, aft approximates systemic BP at or shortly after aortic valve opening and represents peak systolic wall str heart rate and rhythm also influence cardiac performance. Reduced substrate availability (eg, of fatty acid or glucose), particularly if O2 availability is reduced, impair the vigor of cardiac contraction and myocardial performance.
Tissue damage (acute with MI or chronic with fibrosis due to various diseases) impairs local myocard performance and imposes an additional burden on viable myocardium.
The Frank-Starling principle states that the degree of end-diastolic fiber stretch (preload) within a ph range is proportional to the systolic performance of the ensuing ventricular contraction (Fig. 203-1). Th mechanism operates in HF, but, because ventricular function is abnormal, the response is inadequate Frank-Starling curve is depressed, fluid retention, vasoconstriction, and a cascade of neurohumoral re lead to the syndrome of CHF. Over time, LV remodeling (change from the normal ovoid shape) with di and hypertrophy further compromises cardiac performance, especially during physical stress. Dilatatio hypertrophy may be accompanied by increased diastolic stiffness.
Cardiac reserve (unused ability of the resting heart to deliver O 2 to the tissues) is an important compo cardiac function during emotional or physical stress. Its mechanisms include increases in heart rate, s and diastolic volume, stroke volume, and tissue extraction of O2. For example, in well-trained young ad during maximal exercise, heart rate may increase from 55 to 70 at rest to 180 beats/min; CO (stroke v heart rate) may increase from its normal resting value of 6 to >= 25 L/min; and O 2 consumption can in from 250 to >= 1500 mL/min. In the normal young adult at rest, arterial blood contains about 18 mL O2 blood, and mixed venous or pulmonary artery blood contains about 14 mL/dL. The arteriovenous O2 d (A-VO2 ) is thus about 4.0 0.4 mL/dL. Even maximal CO during exercise is insufficient to meet tissue metabolic needs; hence, the tissues extract more O 2, and mixed venous blood O2 content falls consid A-VO2 may increase to about 12 to 14 mL/dL. Increased A-VO2 due to lower venous O 2 content is a c adaptive mechanism in HF.
The oxyhemoglobin dissociation curve (see Fig. 203-2) influences O2 availability to the tissues and provide another reserve mechanism in HF. The position of this curve is frequently expressed as P50 (t pressure of O2 in blood at 50% oxyhemoglobin saturation). An increase in the normal P 50 (27 2 mm indicates a rightward shift of the oxyhemoglobin dissociation curve (decreased affinity of Hb for O2). Fo given PO2, less O2 is combined with Hb, and the saturation is lower; thus, at the capillary level, more O released and available to the tissues. Increased hydrogen ion concentration (reduced pH) shifts the cu the right (Bohr effect), as does increased concentration of 2,3-diphosphoglycerate in RBCs, which alte spatial relationships within the Hb molecule.
In many forms of heart disease, the clinical manifestations of HF may reflect impairment of the left or r ventricle.
In many forms of heart disease, the clinical manifestations of HF may reflect impairment of the left or r ventricle.
Left ventricular (LV) failure characteristically develops in coronary artery disease, hypertension, and forms of cardiomyopathy and with congenital defects (eg, ventricular septal defect, patent ductus arter with large shunts).
Right ventricular (RV) failure is most commonly caused by prior LV failure (which increases pulmona venous pressure and leads to pulmonary arterial hypertension) and tricuspid regurgitation. Mitral steno primary pulmonary hypertension, multiple pulmonary emboli, pulmonary artery or valve stenosis, and R infarction are also causes. Volume overload and increased systemic venous pressure may also occur polycythemia or overtransfusion, acute renal failure with overhydration, and obstruction of either vena simulating HF. In these conditions, myocardial function may be normal.
HF is manifest by systolic or diastolic dysfunction, or both. Combined systolic and diastolic abnorm are common.
In systolic dysfunction (primarily a problem of ventricular contractile dysfunction), the heart fails to prov tissues with adequate circulatory output. A wide variety of defects in energy utilization, energy supply, electrophysiologic functions, and contractile element interaction occur, which appear to reflect abnorm intracellular Ca++ modulation and cyclic adenosine monophosphate (cAMP) production. Systolic dysfu has numerous causes; the most common are coronary artery disease, hypertension, and dilated cong cardiomyopathy. There are many known and probably many unidentified causes for dilated myocardio More than 20 viruses have been identified as causal. Toxic substances damaging the heart include alc variety of organic solvents, certain chemotherapeutic drugs (eg, doxorubicin), -blockers, Ca blockers, a antiarrhythmic drugs.
Diastolic dysfunction (resistance to ventricular filling not readily measurable at the bedside) accounts f 40% of cases of HF. It is generally associated with prolonged ventricular relaxation time, as measured isovolumic relaxation (the time between aortic valve closure and mitral valve opening when ventricular pressure falls rapidly). Resistance to filling (ventricular stiffness) directly relates to ventricular diastolic pressure; this resistance increases with age, probably reflecting myocyte loss and increased interstitia collagen deposition. Diastolic dysfunction is presumed to be dominant in hypertrophic cardiomyopathy circumstances with marked ventricular hypertrophy (eg, hypertension, advanced aortic stenosis), and infiltration of the myocardium.
High output failure is HF associated with a persistent high CO that eventually results in ventricular dysfunction. Conditions associated with high CO include anemia, beriberi, thyrotoxicosis, pregnancy, a Paget's disease, and arteriovenous fistula. CHF may develop in high-output states but is often reversib treating the underlying cause. CO is elevated in various forms of cirrhosis, but the onset of congestion cardiac and hepatic mechanisms of fluid retention.
Pathophysiology
In LV failure, CO declines and pulmonary venous pressure increases. Elevated pulmonary capillary pr to levels that exceed the oncotic pressure of the plasma proteins (about 24 mm Hg) leads to increased water, reduced pulmonary compliance, and a rise in the O 2 cost of the work of breathing. Pulmonary v hypertension and edema resulting from LV failure significantly alter pulmonary mechanics and, thereb ventilation/perfusion relationships. Dyspnea correlates with elevated pulmonary venous pressure and resultant increased work of breathing, although the precise cause is debatable. When pulmonary veno
In LV failure, CO declines and pulmonary venous pressure increases. Elevated pulmonary capillary pr to levels that exceed the oncotic pressure of the plasma proteins (about 24 mm Hg) leads to increased water, reduced pulmonary compliance, and a rise in the O 2 cost of the work of breathing. Pulmonary v hypertension and edema resulting from LV failure significantly alter pulmonary mechanics and, thereb ventilation/perfusion relationships. Dyspnea correlates with elevated pulmonary venous pressure and resultant increased work of breathing, although the precise cause is debatable. When pulmonary veno hydrostatic pressure exceeds plasma protein oncotic pressure, fluid extravasates into the capillaries, t interstitial space, and the alveoli. Pleural effusions characteristically accumulate in the right hemithora later bilaterally. Lymphatic drainage is greatly enhanced but cannot overcome the increase in lung wat Unoxygenated pulmonary arterial blood is shunted past nonaerated alveoli, decreasing mixed pulmona capillary PO 2. A combination of alveolar hyperventilation due to increased lung stiffness and reduced P characteristic of LV failure. Thus, arterial blood gas analysis reveals an increased pH and a reduced P (respiratory alkalosis) with decreased saturation reflecting increased intrapulmonary shunting. Typicall is reduced also. A PaCO2 above normal signifies alveolar hypoventilation possibly due to respiratory m failure and requires urgent ventilatory support.
In RV failure, systemic venous congestive symptoms develop. Moderate hepatic dysfunction common in CHF secondary to RV failure, with usually modest increases in conjugated and unconjugated bilirub prothrombin time, and hepatic enzymes (eg, alkaline phosphatase, AST, ALT). However, in severely compromised circulatory states with markedly reduced splanchnic blood flow and hypotension, increas to central necrosis around the hepatic veins may be severe enough to suggest hepatitis with acute live Reduced aldosterone breakdown by the impaired liver further contributes to fluid retention.
In systolic dysfunction, inadequate ventricular emptying leads to increased preload, diastolic volume, a pressure. Sudden (as in MI) and progressive (as in dilated cardiomyopathy) myocyte loss induces ven remodeling, resulting in increased wall stress accompanied by apoptosis (accelerated myocardial cell and inappropriate ventricular hypertrophy. Later, the ejection fraction falls, resulting in progressive pum failure. Systolic HF may primarily affect the LV or the RV (see above), although failure of one ventricle lead to failure of the other.
In diastolic dysfunction, increased resistance to LV filling as a consequence of reduced ventricular com (increased stiffness) results in prolonged ventricular relaxation (an active state following contraction) a the pattern of ventricular filling. Ejection fraction may be normal or increased. Normally, about 80% of stroke volume enters the ventricle passively in early diastole, reflected in a large e wave and smaller a pulsed-wave Doppler echocardiography. Generally, in diastolic LV dysfunction the pattern is reversed, accompanied by increased ventricular filling pressure and a-wave amplitude.
Whether the failure is primarily systolic or diastolic and regardless of which ventricle is affected, variou hemodynamic, renal, and neurohumoral responses may occur.
Hemodynamic responses: With reduced CO, tissue O2 delivery is maintained by increasing A-VO2. Measurement of A-VO2 with systemic arterial and pulmonary artery blood samples is a sensitive index cardiac performance and reflects, via the Fick equation (VO2 = CO A-VO2), CO (inversely related) an body's O2 consumption (VO2--directly related).
Increased heart rate and myocardial contractility, arteriolar constriction in selected vascular beds, venoconstriction, and Na and water retention compensate in the early stages for reduced ventricular performance. Adverse effects of these compensatory efforts include increased cardiac work, reduced perfusion, increased cardiac preload and afterload, fluid retention resulting in congestion, myocyte los increased K excretion, and cardiac arrhythmia.
Renal responses: The mechanism by which an asymptomatic patient with cardiac dysfunction develo
venoconstriction, and Na and water retention compensate in the early stages for reduced ventricular performance. Adverse effects of these compensatory efforts include increased cardiac work, reduced perfusion, increased cardiac preload and afterload, fluid retention resulting in congestion, myocyte los increased K excretion, and cardiac arrhythmia.
Renal responses: The mechanism by which an asymptomatic patient with cardiac dysfunction develo CHF is unknown, but it begins with renal retention of Na and water, secondary to decreased renal perf Thus, as cardiac function deteriorates, renal blood flow decreases in proportion to the reduced CO, th falls, and blood flow within the kidney is redistributed. The filtration fraction and filtered Na decrease, b tubular resorption increases.
Neurohumoral responses: Increased activity of the renin-angiotensin-aldosterone system influences and peripheral vascular response in HF. The intense sympathetic activation accompanying HF stimula release of renin from the juxtaglomerular apparatus near the descending loop of Henle in the kidney. P decreased arterial systolic stretch secondary to declining ventricular function also stimulates renin sec Reflex and adrenergic stimulation of the renin-angiotensin-aldosterone system produces a cascade of potentially deleterious effects: Increased aldosterone levels enhance Na reabsorption in the distal nep contributing to fluid retention. Renin produced by the kidney interacts with angiotensinogen, producing angiotensin I from which is cleaved the octapeptide angiotensin II by ACE. Angiotensin II has various e believed to enhance the syndrome of CHF, including stimulation of the release of arginine vasopressin which is antidiuretic hormone (ADH); vasoconstriction; enhanced aldosterone output; efferent renal vasoconstriction; renal Na retention; and increased norepinephrine release. Angiotensin II is also belie be involved in vascular and myocardial hypertrophy, thus contributing to the remodeling of the heart an peripheral vasculature, which contributes to HF in various myocardial and other heart diseases.
Plasma norepinephrine levels are markedly increased, largely reflecting intense sympathetic nerve stim because plasma epinephrine levels are not increased. High plasma norepinephrine levels in patients w are associated with a poor prognosis.
The heart contains many neurohormonal receptors (1, 1, 2, 3, adrenergic, muscarinic, endothelin, serot adenosine, angiotensin II). In patients with HF, 1 receptors (which constitute 70% of cardiac receptors) the other adrenergic receptors, are down-regulated, potentially adversely affecting myocardial function down-regulation, which is probably a response to intense sympathetic overdrive, has been detected ev asymptomatic patients with the early stages of HF. Altered myocardial stimulator or receptor functions various other neurohormonal factors may adversely influence myocyte performance in HF.
Serum levels of atrial natriuretic peptide (released in response to increased atrial volume and pressure and brain natriuretic peptide (released from the ventricle in response to ventricular stretch) are marked increased in patients with CHF. These peptides enhance renal excretion of Na, but, in patients with CH effect is blunted by decreased renal perfusion pressure, receptor down-regulation, and perhaps enhan enzymatic degradation. Serum atrial natriuretic peptide appears to be important for diagnosis and prog CHF and correlates well with functional impairment.
AVP is released in response to a fall in BP or ECF volume and by the effects of various neurohormona An increase in plasma AVP diminishes excretion of free water by the kidney and may contribute to the hyponatremia of HF. AVP levels in CHF vary, but experimental AVP blockers have increased water ex and serum Na levels.
Other sequelae: Protein-losing enteropathy characterized by marked hypoalbuminemia, ischemic bow infarction, acute and chronic GI hemorrhage, and malabsorption may result from severe chronic venou hypertension. Peripheral gangrene in the absence of large vessel occlusion or chronic irritability and decreased mental performance may result from chronic markedly reduced PO2, reflecting severely red cerebral blood flow and hypoxemia.
Other sequelae: Protein-losing enteropathy characterized by marked hypoalbuminemia, ischemic bow infarction, acute and chronic GI hemorrhage, and malabsorption may result from severe chronic venou hypertension. Peripheral gangrene in the absence of large vessel occlusion or chronic irritability and decreased mental performance may result from chronic markedly reduced PO2, reflecting severely red cerebral blood flow and hypoxemia.
Cardiac cachexia (loss of lean tissue >= 10%) may accompany severely symptomatic HF. The failing h produces tumor necrosis factor-, which is a key cytokine in the development of catabolism and possibl cardiac cachexia. Marked anorexia is characteristic of the syndrome. Restoring cardiac function to nor reverse cardiac cachexia.
Symptoms and Signs
HF may be predominantly right-sided or left-sided and may develop gradually or suddenly (as with acu pulmonary edema).
Cyanosis may occur with any form of HF. The cause may be central and may reflect hypoxemia. A pe component due to capillary stasis with increased A-VO2 and resultant marked venous oxyhemoglobin unsaturation may also be present. Improved color of the nail bed with vigorous massage suggests per cyanosis. Central cyanosis cannot be altered by increasing local blood flow.
LV failure: Pulmonary venous hypertension may become apparent with tachycardia, fatigue on exertio dyspnea on mild exercise, and intolerance to cold. Paroxysmal nocturnal dyspnea and nocturnal coug the redistribution of excess fluid into the lung with the recumbent position. Occasionally, pulmonary ve hypertension and increased pulmonary fluid manifest as bronchospasm and wheezing. Cough may be prominent, and pink-tinged or brownish sputum due to blood and the presence of HF cells is common. hemoptysis due to ruptured pulmonary varices with massive blood loss is uncommon but may occur. S chronic LV failure include diffuse and laterally displaced apical impulse, palpable and audible ventricul and atrial gallops (S4), accentuated pulmonic second sound, and inspiratory basilar rales. Right-sided effusion is common.
Acute pulmonary edema is a life-threatening manifestation of acute LV failure secondary to sudden o pulmonary venous hypertension. A sudden rise in LV filling pressure results in rapid movement of plas through pulmonary capillaries into the interstitial spaces and alveoli. The patient presents with extreme dyspnea, deep cyanosis, tachypnea, hyperpnea, restlessness, and anxiety with a sense of suffocation and diaphoresis are common. The pulse may be thready, and BP may be difficult to obtain. Respiratio labored, and rales are widely dispersed over both lung fields anteriorly and posteriorly. Some patients marked bronchospasm or wheezing (cardiac asthma). Noisy respiratory efforts often render cardiac auscultation difficult, but a summation gallop, merger of S3 and S4, may be heard. Hypoxemia is sever retention is a late, ominous manifestation of secondary hypoventilation and requires immediate attenti
RV failure: The principal symptoms include fatigue; awareness of fullness in the neck; fullness in the abdomen, with occasional tenderness in the right upper quadrant (over the liver); ankle swelling; and, advanced stages, abdominal swelling due to ascites. Edema over the sacrum is likely in supine patien include evidence of systemic venous hypertension, abnormally large a or v waves in the external jugul an enlarged and tender liver, a murmur of tricuspid regurgitation along the left sternal border, RV S3 a and pitting edema of the lowest parts of the body.
Diagnosis
Although symptoms and signs (eg, exertional dyspnea, orthopnea, edema, tachycardia, pulmonary ral
and pitting edema of the lowest parts of the body.
Diagnosis
Although symptoms and signs (eg, exertional dyspnea, orthopnea, edema, tachycardia, pulmonary ral third heart sound, jugular venous distention) have a diagnostic specificity of 70 to 90%, the sensitivity a predictive accuracy are low.
Recommended laboratory tests include CBC, blood creatinine, BUN, electrolytes (eg, Mg, Ca), gluco albumin, and liver function tests. Thyroid function test results should be assessed in patients with atria fibrillation and in selected, especially older, persons. In patients with suspected coronary artery diseas testing with radionuclide or ultrasound imaging or coronary angiography may be indicated. Endocardia is of limited usefulness.
ECG should be performed in all patients with HF, although findings are not specific; ambulatory ECG i generally useful. Various abnormalities (eg, of ventricular hypertrophy, MI, or bundle branch block) ma provide etiologic clues. Recent onset of rapid atrial fibrillation may precipitate acute LV or RV failure. F premature ventricular contractions may be secondary and may subside when the HF is treated.
Chest x-ray should be performed in all patients. Pulmonary venous congestion and interstitial or alveo edema are characteristics of pulmonary edema. Kerley B lines reflect chronic elevation of left atrial pre and chronic thickening of the intralobular septa from edema. Microvascular volume increases, most st dependent areas, ie, the bases in upright posture. Careful examination of the cardiac silhouette, evalu chamber enlargement, and a search for cardiac calcifications may reveal important etiologic clues.
Echocardiography can help evaluate chamber dimensions, valve function, ejection fraction, wall moti abnormalities, and LV hypertrophy. Doppler or color Doppler echocardiography accurately detects per effusion, intracardiac thrombi, and tumors and recognizes calcifications within the cardiac valves, mitra annulus, and the wall of the aorta. Underlying coronary artery disease is strongly suggested by localize segmental wall motion abnormalities. Doppler studies of mitral and pulmonary venous inflow are often identifying and quantitating LV diastolic dysfunction.
Treatment
Even in the most urgent situation, the cause of HF must be determined. Correctable conditions require immediate treatment, which usually begins before the etiologic evaluation is completed. For patients re hospitalization, initial nonspecific treatment includes bed rest with the head elevated or chair rest with dependent, nasal O2 (often at 3 L/min for 24 to 36 hr), and sedation as needed.
Drug treatment of systolic dysfunction: Drug treatment of systolic dysfunction primarily involves diu ACE inhibitors, digitalis, and -blockers; most patients are treated with at least two of these classes.
Diuretics (see Table 203-1) may improve ventricular function even in asymptomatic patients. Loop diu are preferred; the most commonly used is IV or po furosemide. IV doses (usually 20 to 40 mg, increas 320 mg if needed) are often used initially because of quick onset and peak action in about 30 minutes resistant cases, chlorothiazide 250 mg IV; bumetanide 0.5 to 2 mg po, 0.5 to 1.0 mg IV; or metolazone (dosage varies with formulation) may have an additive effect. Overdosage of loop diuretics may cause hypovolemia, hyponatremia, hypomagnesemia and profound hypokalemia, so close electrolyte monito essential. Diuretics may also induce renal failure and enhance the intense sympathetic stimulation characteristic of HF. K-sparing drugs may be used to offset the K-losing effects of loop diuretics, but hyperkalemia may complicate their use. Nonetheless, adding spironolactone to ACE inhibitor or other may improve cardiac function and prognosis. Thiazide diuretics are not usually effective in patients wit
resistant cases, chlorothiazide 250 mg IV; bumetanide 0.5 to 2 mg po, 0.5 to 1.0 mg IV; or metolazone (dosage varies with formulation) may have an additive effect. Overdosage of loop diuretics may cause hypovolemia, hyponatremia, hypomagnesemia and profound hypokalemia, so close electrolyte monito essential. Diuretics may also induce renal failure and enhance the intense sympathetic stimulation characteristic of HF. K-sparing drugs may be used to offset the K-losing effects of loop diuretics, but hyperkalemia may complicate their use. Nonetheless, adding spironolactone to ACE inhibitor or other may improve cardiac function and prognosis. Thiazide diuretics are not usually effective in patients wit advanced symptoms of CHF.
The clinical efficacy of diuretics depends on dietary Na restriction using a stepped approach: eliminatin the table and avoiding heavily salted foods; eliminating salt from cooking and consuming about 1.2 to g/day of Na +; and, in the most severely ill, consuming < 1 g/day of Na through restriction to low-Na foo log of daily weight should be maintained by the patient to enhance ambulatory care of HF and to help recurrent hospitalizations by detecting early evidence of Na+ and water accumulation.
ACE inhibitors cause peripheral arterial and venous vasodilatation, sustained decreases in LV filling at rest and on exercise due to venodilation, decreased systemic vascular resistance, favorable effects remodeling, possible improved diastolic function, probable reduced loss of myocardial cells, and a neg inotropic effect on the failing heart. Various ACE inhibitors enhance survival in HF and reduce the incid recurrent angina and MI in coronary artery disease. Volume expansion and renal failure reduce their u benefit. Side effects include a decrease in BP (sometimes severe) in almost all patients, especially tho hyponatremia. Moderate renal insufficiency may result from vasodilation of the efferent glomerular arte retention may occur due to reduced aldosterone effect, especially in patients receiving K supplements occurs in 5 to 20% of patients, probably due to accumulation of bradykinin as a result of reduced brea inactive metabolites. Occasionally, rash or dysgeusia occurs. Angioneurotic edema is rare but can be threatening.
ACE inhibitors are started in small doses, which are gradually increased, then continued indefinitely; d should be adjusted upward as tolerated. Usual doses are captopril 25 to 50 mg/day, enalapril and lisin to 5 mg/day, and quinapril 10 mg/day. Although an early effect may be observed, the full drug effect is not seen for 2 to 4 wk or considerably longer. Large doses produce a similar frequency of side effects doses but are more effective (studies showing survival and other benefits have generally used large do
The dose of a coadministered diuretic may frequently be reduced, especially if ACE inhibitor-induced r insufficiency occurs. Aspirin may reduce the effect of ACE inhibitors in HF, possibly because it inhibits effects of kinins.
The angiotensin II receptor blocker losartan 25 to 50 mg/day has effects similar to those of ACE inh although comparative trials have not been reported. Theoretically, cough should not occur because los does not influence kinins.
Digitalis preparations have many actions, including weak inotropism; blockade of the atrioventricular n thus slowing the ventricular rate in atrial fibrillation or prolonging PR time in sinus rhythm; weak vasoconstriction; and improved renal blood flow. The drug is widely prescribed in the USA, although its continues to be debated and its usefulness in HF in the absence of atrial fibrillation is controversial.
Digoxin is the most commonly prescribed digitalis preparation. It is excreted by the kidney with an elim half-life of 36 to 48 h in patients with normal renal function. Patients with reduced renal function requir doses. Oral bioavailability of digoxin tablets is around 65 to 75%. Digitoxin, an alternative in patients w known or suspected renal disease, is largely excreted in the bile and is thus not influenced by abnorm function.
Digoxin modestly improves LV function, allows reduced diuretic dosage, and reduces the need for hospitalization. Unlike ACE inhibitors, digoxin does not improve exercise tolerance. When digoxin is w
doses. Oral bioavailability of digoxin tablets is around 65 to 75%. Digitoxin, an alternative in patients w known or suspected renal disease, is largely excreted in the bile and is thus not influenced by abnorm function.
Digoxin modestly improves LV function, allows reduced diuretic dosage, and reduces the need for hospitalization. Unlike ACE inhibitors, digoxin does not improve exercise tolerance. When digoxin is w in HF, the hospitalization rate and symptoms increase, although digoxin does not appear to influence m Thus, digoxin is useful in symptomatic HF when used with diuretics and an ACE inhibitor. Digoxin is m effective in patients with large LV end-diastolic volumes and a third heart sound.
Digoxin (0.25 to 0.50 mg/day depending on body size) in patients with normal renal function will achiev digitalization in about 1 wk (5 half-lives). Digoxin 1 mg IV administered as 0.5 mg initially, then 0.25 mg and 16 h (or 1.25 mg po administered as 0.5 mg initially, then 0.25 mg at 8, 16, and 24 h), should ach adequate levels in tissue and plasma in the absence of toxicity. These doses are followed by 0.125 to mg/day depending on body size; the elderly rarely need > 0.125 mg/day. Patients with reduced renal f require lower doses.
Digoxin (and all digitalis glycosides) has a narrow therapeutic-toxic threshold. About 80% of the therap effect can be achieved with serum levels of 1.0 to 1.5 ng/mL, generally well below the toxic threshold o ng/mL. In the management of atrial fibrillation, moderately low doses of digoxin may be combined with -blockers or Ca blockers (eg, verapamil, diltiazem), which have a significant atrioventricular blocking e control ventricular rate at rest or during exercise.
Digoxin prolongs conduction in the atrioventricular node. First-degree heart block is common and, if no progressive, digoxin dosage need not be adjusted. Wenckebach phenomenon may occur. The most im toxic effects of digitalis are life-threatening arrhythmias due to complete heart block or ventricular arrhy Digitalis increases the automaticity of Purkinje's fibers and may enhance reentry, resulting in coupled extrasystoles, ventricular fibrillation, or ventricular tachycardia. Bidirectional ventricular tachycardia is pathognomonic of digitalis toxicity. Nonparoxysmal junctional tachycardia in the presence of atrial fibril a serious sign of digitalis toxicity but is frequently overlooked.
Hypokalemia and hypomagnesemia (often caused by diuretics) potentiate the capacity of digoxin to in malignant ventricular arrhythmia or heart block. Recognition and treatment of electrolyte depletion are mandatory in patients taking diuretics and digoxin, except in the presence of atrioventricular block, in w temporary pacemaker must be functioning prior to correcting the electrolyte abnormality.
Other manifestations of digitalis toxicity include nausea, vomiting, anorexia, diarrhea, confusion, ambly and rarely xerophthalmia.
The first step in treating digitalis toxicity is to discontinue the drug. The ECG should be closely monitor if serum K is low, 80 mEq of potassium chloride IV should be given in 1 L 5% D/W at 6 mL/min (0.5 m Low serum Mg is treated with magnesium sulfate 1 g q 6 h for four doses IM or IV if mild or 5 g/h in 5% over 3 h (28 mg/min). Administration of digoxin immune Fab (if available) is better than administration another antiarrhythmic drug. Ventricular arrhythmias are treated with lidocaine or phenytoin. Heart bloc slow ventricular rate is best treated with a temporary perivenous pacemaker. Isoproterenol is contraind because of the increased tendency to ventricular arrhythmia.
Several inotropic drugs have been evaluated in the treatment of HF, but, except for digoxin, preparat have shown increased mortality.
With careful administration of -blockers, some patients, especially those with idiopathic dilated cardiomyopathy, will improve clinically and may have reduced mortality. Therapy must be initiated with using 1/4 to 1/10 of the standard daily dose, with a very gradual increase to the standard dose, if tolera over several weeks.
have shown increased mortality.
With careful administration of -blockers, some patients, especially those with idiopathic dilated cardiomyopathy, will improve clinically and may have reduced mortality. Therapy must be initiated with using 1/4 to 1/10 of the standard daily dose, with a very gradual increase to the standard dose, if tolera over several weeks.
After initial treatment of HF by -blockers, heart rate falls, stroke volume and filling pressure are unchan and myocardial O2 consumption falls. With the slower heart rate, diastolic function improves. Ventricul returns to a more normal pattern (increasing in early diastole) that appears less restrictive. Improved myocardial function is measurable after 6 to 12 mo, with an increase in ejection fraction, a fall in LV fill pressure, and an increase in CO. Functionally, exercise capacity appears to improve.
Carvedilol, a 3rd-generation nonselective -blocker, is also a vasodilator with blockade and an antioxida Randomized controlled trials have shown significant reduction in all-cause mortality and cardiac event patients with mildly symptomatic CHF and ejection fraction <= 0.35. Ventricular function is significantly improved. In a patient taking stable doses of diuretics, ACE inhibitors, and digoxin, the recommended dose of carvedilol is 3.125 mg bid for 2 wk with cautious upward titration by doubling the dose every 2 the highest level tolerated to a maximum of 25 mg bid for those weighing < 85 kg and 50 mg bid for th weighing >= 85 kg.
Vasodilators improve ventricular function by reducing systolic ventricular wall stress, aortic impedanc ventricular chamber size, and valvular regurgitation. An improved balance between myocardial O 2 sup demand results. Acutely ill patients with severe pulmonary congestion and deteriorating ventricular fun may respond to IV nitroglycerin or nitroprusside.
Addition of hydralazine and isosorbide dinitrate to standard triple therapy of HF may improve hemodyn and exercise tolerance and reduce mortality in refractory patients. Hydralazine is initiated at 25 mg 4 ti and increased every 3rd day to a maximum of 300 mg/day, although most patients with refractory HF c tolerate dosages > 200 mg/day without developing hypotension. Isosorbide dinitrate is administered at or 4 times/day and increased to a maximum of 160 mg/day. Patients must be carefully monitored for hypotension as the dosage is increased; hospitalization may be required. Benefit may not be evident f several weeks. Except in acutely ill or refractory cases of HF, vasodilators have been replaced by ACE inhibitors, which are easier to use and usually better tolerated.
The use of Ca blockers in patients with reduced LV function causing HF has been disappointing. Sev blockers have shown a deleterious effect (nifedipine, diltiazem, verapamil) or lack of evidence of clinic hemodynamic improvement (nisoldipine, nicardipine, felodipine).
Amlodipine is well tolerated in CHF. It significantly reduces mortality in patients with idiopathic dilated cardiomyopathy. Amlodipine (or another long-acting vasoselective Ca blocker such as felodipine) may useful in patients with cardiomyopathy whose HF is insufficiently controlled by diuretics, ACE inhibitors digitalis, and -blockers. Amlodipine may also be useful in treating associated angina or hypertension.
Drug treatment of diastolic dysfunction: Patients with diastolic dysfunction may not tolerate reduce plasma volume. Thus, diuretics and vasodilators are usually contraindicated. But ACE inhibitors and angiotensin II receptor blockers may reduce LV mass and stiffness and may prove to be of value. Trea HF in hypertrophic cardiomyopathy (see below) with a -blocker, verapamil, or disopyramide aims to red cardiac contractility; thus, digoxin is also contraindicated. Successful treatment of hypertension or valv replacement for aortic stenosis will decrease LV hypertrophy and reduce ventricular stiffness. General treatment of dominant systolic dysfunction will improve diastolic dysfunction. Management of patients extensive ventricular infiltration (eg, in amyloid) remains unsatisfactory. Slowing the heart rate with a -b prolongs diastole, possibly improving ventricular relaxation and allowing a more normal ventricular fillin pattern.
HF in hypertrophic cardiomyopathy (see below) with a -blocker, verapamil, or disopyramide aims to red cardiac contractility; thus, digoxin is also contraindicated. Successful treatment of hypertension or valv replacement for aortic stenosis will decrease LV hypertrophy and reduce ventricular stiffness. General treatment of dominant systolic dysfunction will improve diastolic dysfunction. Management of patients extensive ventricular infiltration (eg, in amyloid) remains unsatisfactory. Slowing the heart rate with a -b prolongs diastole, possibly improving ventricular relaxation and allowing a more normal ventricular fillin pattern.
Drug treatment of arrhythmia: Sinus tachycardia is common in HF but generally subsides with effect treatment of the HF. If tachycardia is persistent, associated causes should be sought (eg, overactive th pulmonary emboli, fever, anemia), and cautious treatment with a -blocker may be considered. Uncontr atrial fibrillation may contribute importantly to LV dysfunction. Some patients have well-controlled ventr rates at rest that become very rapid during minimal emotional or physical stress. Judicious treatment w digoxin, -blockers, or Ca blockers (eg, verapamil, diltiazem) alone or in combination is often effective. Occasionally, dosages that control the tachycardia induce periods of asystole. Insertion of a pacemake maintenance on large doses of drugs that block atrioventricular conduction or complete or partial ablat the atrioventricular node may be required. Ventricular extrasystoles are common in HF. They are gene ignored in the absence of sustained ventricular tachycardia because most subside with successful trea HF.
Amiodarone, a vasodilator, has antiarrhythmic effects and direct negative inotropic action and is anti-is However, in HF, amiodarone 200 to 300 mg/day po improves LV function, possibly because its vasodi effect overcomes its negative inotropic action. Some studies suggest improved survival in cardiomyop especially hypertrophic obstructive cardiomyopathy or when of ischemic origin. Paradoxically, treatmen ventricular arrhythmia with other antiarrhythmics except -blockers in HF has not reduced mortality.
Treatment of arrhythmia in HF may be difficult because antiarrhythmic drugs other than amiodarone a -blockers have adverse proarrhythmic effects in the presence of LV dysfunction. If rapid atrial fibrillatio not respond to therapy with digoxin, -blockers, or Ca blockers, nonpharmacologic treatment with perm pacemaker insertion and complete or partial atrioventricular node ablation should be considered.
Treatment of acute pulmonary edema includes administration of O2 by mask, the upright position if to morphine IV 1 to 5 mg once or twice, and IV furosemide 0.5 to 1.0 mg/kg. If hypoxia is severe (pulse o or CO2 retention is evident (arterial blood gas), tracheal intubation and assisted ventilation may be req Rapid evaluation of the cause of HF by history, physical examination, ECG, and, if indicated, echocard should be undertaken. Specific treatment depends on etiology: a vasodilator for severe hypertension; antiarrhythmic or cardioversion for supraventricular or ventricular tachycardia; and an IV Ca blocker, IV -blocker, IV digoxin, or cardioversion to slow the ventricular rate in paroxysmal atrial fibrillation.
Acute MI is the commonest cause of acute LV failure. If BP is maintained, treatment is as above, addi sublingual nitroglycerin 0.4 mg, repeated in 5 min, followed by IV nitroglycerin 10 to 100 g/min. A thro drug should be administered, if indicated. Because fluid status before onset of acute HF is usually nor patients, diuretics are less useful and may precipitate hypotension. If BP falls or shock develops, IV dobutamine and intra-aortic balloon pump (counterpulsation) may be required. Emergency coronary angiography and evaluation for PTCA or bypass surgery may be undertaken in patients who fail to imp
Treatment of refractory HF: Various factors may cause a failure to respond to appropriate treatment gradual loss of effective response after an initial favorable result. Causes include suboptimal quadrupl therapy, deteriorating renal function, occult thyroid disease, anemia, treatment-induced hypotension, supervening arrhythmia (eg, atrial fibrillation with rapid ventricular response, intermittent ventricular tachycardia), alcohol consumption, and the adverse effects of concomitant drug administration (espec NSAIDs). If treatable causes are not found, additional medical therapy or referral for surgery can be considered.
therapy, deteriorating renal function, occult thyroid disease, anemia, treatment-induced hypotension, supervening arrhythmia (eg, atrial fibrillation with rapid ventricular response, intermittent ventricular tachycardia), alcohol consumption, and the adverse effects of concomitant drug administration (espec NSAIDs). If treatable causes are not found, additional medical therapy or referral for surgery can be considered.
Surgery: Heart transplantation is the only treatment that potentially alters the natural history of HF lon Currently, 1- and 3-yr survival are about 82 and 75%; however, mortality while waiting for a donor is 12 Dynamic cardiomyoplasty has been used experimentally to boost LV function by wrapping the latissim muscle around the heart and stimulating this skeletal muscle repetitively. Functional status has been r to improve in about 80% of patients. Another experimental procedure attempts to relieve wall tension b removing ventricular strips and reducing LV volume, but outcome data are limited. Several implantable ventricular assist devices are being evaluated. Ventricular assist with an external power source has be successful in supporting selected patients with refractory HF before heart transplantation. Newer devic which the power source is inserted wholly within the body, thus reducing the major complication of infe are also being evaluated.
End-of-life care: Death is inevitable in patients with progressive disease who are not transplant candi and whose severe symptoms cannot be controlled. Care must focus on relief of pain and suffering (se 294). Back to top of page
Section 16. Cardiovascular Disorders Chapter 212. Peripheral Vascular Disorders Topics
[General] Peripheral Arterial Occlusion Thromboangiitis Obliterans Raynaud's Disease and Phenomenon Acrocyanosis Erythromelalgia Venous Thrombosis Varicose Veins Arteriovenous Fistula Lymphedema Lipedema
[General]
Peripheral vascular disorders: Disorders affecting the arteries, veins, and lymphatics of the extremities
Peripheral vascular disorders may be arterial (occlusive or functional), venous, combined arteriovenou arteriovenous fistula), or lymphatic. Occlusive arterial disease includes peripheral arterial occlusion an thromboangiitis obliterans. Functional arterial disorders may be vasospastic (Raynaud's phenomenon disease, acrocyanosis) or vasodilatory (erythromelalgia); may be secondary to a local fault in the blood or to disturbances in sympathetic nervous system activity; or may accompany organic vascular diseas Venous diseases include venous thrombosis and varicose veins, combined arteriovenous disorders in arteriovenous fistula, and lymphatic disorders include lymphedema and lipedema.

Section 16. Cardiovascular Disorders Chapter 204. Shock Topics
[General]
[General]
Shock: A state in which blood flow to and perfusion of peripheral tissues are inadequate to sustain life of insufficient cardiac output or maldistribution of peripheral blood flow, usually associated with hypote and oliguria.
Shock may be due to hypovolemia, vasodilation, or cardiogenic causes (poor cardiac output) or a com The fundamental defect in shock is reduced perfusion of vital tissues due (usually) to hypotension, so delivery or uptake is inadequate for aerobic metabolism, resulting in a shift to anaerobic respiration wit increased production and accumulation of lactic acid. When shock persists, impaired organ function is by irreversible cell damage and death. The degree of systemic hypotension necessary to cause shock and often is related to preexisting vascular disease. Thus, a modest degree of hypotension that is tole well by a young, relatively healthy person might result in severe cerebral, cardiac, or renal dysfunction patient who has significant arteriosclerosis.
Hypovolemic shock: Hypovolemic shock is associated with inadequate intravascular volume (absolu relative), which produces diminished ventricular filling and reduced stroke volume. Unless compensate increased heart rate, it results in decreased cardiac output.
A common cause is acute hemorrhage (eg, from trauma, peptic ulcer, esophageal varices, or aortic aneurysm). Hemorrhage may be apparent (eg, hematemesis or melena) or concealed (eg, ruptured ec pregnancy).
Hypovolemic shock may also follow increased losses of body fluids other than blood (see Table 204-1 Hypovolemia usually takes several hours to develop and may be associated with a rising Hb or Hct (du hemoconcentration).
Hypovolemic shock may be due to inadequate fluid intake, resulting in dehydration, often with increase loss. Frequently, because of neurologic or physical disability, patients cannot respond to thirst by incre fluid intake. In hospitalized patients, hypovolemia can be compounded if early signs of circulatory insu are incorrectly ascribed to heart failure and fluids are withheld or diuretics given.
Hypovolemic shock may be due to inadequate fluid intake, resulting in dehydration, often with increase loss. Frequently, because of neurologic or physical disability, patients cannot respond to thirst by incre fluid intake. In hospitalized patients, hypovolemia can be compounded if early signs of circulatory insu are incorrectly ascribed to heart failure and fluids are withheld or diuretics given.
Vasodilatory shock: Vasodilatory shock results from a relative inadequacy of intravascular volume ca vasodilation. Circulating blood volume is normal but insufficient for adequate cardiac filling. Various co may cause widespread venous or arteriolar dilation; eg, severe cerebral trauma or hemorrhage (neuro shock), liver failure, or ingestion of certain drugs or poisons. Shock associated with bacterial infection (bacteremic or septic shock--see Ch. 156) may be partly due to the vasodilatory effects of endotoxin o chemical mediators on resistance vessels, thereby decreasing vascular resistance. In addition, some p with acute MI and shock appear to have inadequate compensatory vasoconstriction in response to de cardiac output. If cardiac output does not increase commensurate with the reduction in vascular resist arterial hypotension develops. Below a critical systemic BP, vital organs will be inadequately perfused. Myocardial dysfunction secondary to inadequate coronary perfusion or other mechanisms (eg, release myocardial depressant factor or other toxic substances) may complicate shock due to vasodilation.
Cardiogenic shock: A relative or absolute reduction in cardiac output due to factors other than inade intravascular volume may result in shock. Causes are described in Table 204-2.
Symptoms and Signs
Symptoms and signs may be due to shock itself or to the underlying disease process. Mentation may preserved, but lethargy, confusion, and somnolence are common. The hands and feet are cold, moist, often cyanotic and pale. Capillary filling time is prolonged, and, in extreme cases, a bluish reticular pat appear over large areas. The pulse is weak and rapid unless heart block or terminal bradycardia is pre sometimes, only femoral or carotid pulses can be felt. Tachypnea and hyperventilation are present, bu may be a terminal event when the respiratory center fails due to inadequate cerebral perfusion. BP tak cuff tends to be low (< 90 mm Hg systolic) or unobtainable, but direct measurement by intra-arterial ca often gives significantly higher values.
In septic shock, a type of vasodilatory shock (see also Ch. 156), fever, usually preceded by chills, is g present. Elevated cardiac output is associated with diminished total peripheral resistance, possibly accompanied by hyperventilation and respiratory alkalosis. Thus, early symptoms may include a shaki a rapid rise in temperature, warm flushed skin, a bounding pulse, and falling and rising BP (hyperdyna syndrome). Urinary flow is decreased despite the high cardiac output. Mental status is usually impaired mental confusion may be a premonitory sign preceding hypotension by >= 24 h. However, these findin and may not be apparent even in patients whose markedly increased cardiac output and reduced vasc resistance are confirmed by direct hemodynamic measurement. In later stages, hypothermia may occu causes of vasodilatory shock (eg, anaphylaxis) may present with findings that are similar to septic sho
Complications
Pulmonary complications that often coexist or develop in patients with shock must not be overlooked. Pulmonary edema after hypovolemia usually is caused by excessive fluid infusion during resuscitation although it may be confused with pneumonia due to unrecognized sepsis or aspiration of gastric conte to transient CNS depression. Pulmonary edema in septic shock usually results from increased permea the pulmonary capillary and alveolar epithelium resulting in increased fluid exudation into the lungs. Th complication (adult respiratory distress syndrome) is very serious. Hydrostatic pulmonary edema often complicates cardiogenic shock because of the marked increase in pulmonary capillary wedge pressure (PCWP).
to transient CNS depression. Pulmonary edema in septic shock usually results from increased permea the pulmonary capillary and alveolar epithelium resulting in increased fluid exudation into the lungs. Th complication (adult respiratory distress syndrome) is very serious. Hydrostatic pulmonary edema often complicates cardiogenic shock because of the marked increase in pulmonary capillary wedge pressure (PCWP).
Diagnosis
Diagnosis requires evidence of insufficient tissue perfusion due to reduced cardiac output or inadequa peripheral vasomotor tone. Most consider shock to be present in any patient with predisposing factors develops a significant fall in BP, a urine flow of < 30 mL/h, and a progressive increase in the arterial la concentration or an increased anion gap associated with reduced HCO 3 levels. The diagnosis is supp signs of hypoperfusion of specific organs (obtundation, oliguria, peripheral cyanosis) or signs relating t compensatory mechanisms (tachycardia, tachypnea, diaphoresis). In the earliest stages of shock, man these signs may be absent or undetected if not specifically sought. Thus, treatment might not be initia the shock is advanced. None of these findings alone is specific for shock; each must be evaluated in t overall clinical context.
In any type of shock, manifestations of the underlying disease process may provide important diagnos Acute blood or fluid loss from a ruptured aorta, spleen, or tubal pregnancy or from peritonitis can be su from the physical findings. Signs of generalized dehydration are helpful in recognizing hypovolemia in with neurologic, GI, renal, or metabolic disorders. In septic shock, signs of preexisting pulmonary, GI, o may be present, as may signs of an underlying malignancy or debilitating disease resulting in altered i against infection. In women of childbearing age, toxic shock syndrome due to tampon use may occur ( 157); septic abortion, especially when performed illegally, can also cause septic shock. A systolic murm indicate ventricular septal rupture or mitral insufficiency, either of which may result in shock after acute Pericardial tamponade is suggested by jugular venous distention, muffled heart sounds, a pericardial r a paradoxical pulse. Massive pulmonary embolism is suspected in patients with a parasternal lift; a lou heart sound at the left sternal border increased on inspiration; an accentuated, widely split pulmonary sound; and distended jugular neck veins.
Hypovolemic shock: Normal or reduced ventricular filling pressure with a low cardiac output in a pati shock is diagnostic. A right ventricular filling pressure or central venous pressure (CVP) < 7 cm H 2 O (< Hg) suggests hypovolemia; CVP may be greater than this when hypovolemic shock occurs in patients preexisting pulmonary hypertension. In some patients who have chronic lung diseases or cardiac dysf measurement of the pulmonary end-diastolic pressure or PCWP, both of which are usually closely rela the left ventricular pressure during diastole, is a better test. Pulmonary end-diastolic pressure or PCW mm Hg (or < 18 mm Hg in a patient with acute MI or preexisting left ventricular disease) suggests hypovolemia.
When hypovolemia is suspected, a therapeutic trial of volume loading--rapid infusion (500 mL/15 min) 0.9% NaCl or colloid (see Prognosis and Treatment, below)--may help confirm the diagnosis. Hypovol be assumed when volume loading improves BP and urine flow and reduces the clinical manifestations shock, with small increments in CVP or PCWP. However, low CVP and PCWP also occur in septic sho improvement after volume loading does not rule out sepsis as the cause.
Hypovolemic shock due to hemorrhage is usually associated with falling Hb and Hct. However, becaus may develop within minutes of acute blood loss, a normal Hb and Hct (before homeostatic hemodilutio not rule out hemorrhage. A rising Hct and Hb in hypovolemic shock suggests hemoconcentration due other body fluids.
Vasodilatory shock: Vasodilatory shock should be suspected in patients with cerebral trauma, sepsis intoxication, or heat exposure with vasoregulatory failure and dehydration. Hypovolemia is also freque
may develop within minutes of acute blood loss, a normal Hb and Hct (before homeostatic hemodilutio not rule out hemorrhage. A rising Hct and Hb in hypovolemic shock suggests hemoconcentration due other body fluids.
Vasodilatory shock: Vasodilatory shock should be suspected in patients with cerebral trauma, sepsis intoxication, or heat exposure with vasoregulatory failure and dehydration. Hypovolemia is also freque present.
Cardiogenic shock: Cardiogenic shock is suggested by engorged neck veins, signs of pulmonary con and a gallop rhythm; however, in many patients with cardiogenic shock, these signs are absent. Diagn usually requires demonstration of reduced cardiac output with increased ventricular filling pressure. Pe tamponade, tension pneumothorax, or massive pulmonary embolism can usually be confirmed by echocardiography, chest radiography, or lung scan perfusion, respectively. When myocardial damage acute MI is sufficient to result in shock, the ECG is usually diagnostic (see Myocardial Infarction in Ch. however, prior infarction, left bundle branch block, or atrioventricular block with idioventricular or pacem rhythm may preclude an ECG diagnosis. In this case, the characteristic elevation of creatinine phosph and the myocardial bands in the circulating plasma are helpful. The ECG helps also to identify arrhyth may, in themselves, cause or contribute to shock. Because hypovolemia may coexist with acute MI or preexisting heart disease, the shock cannot be assumed to be due entirely to myocardial damage, esp inferior or posterior infarcts, which may involve the right ventricle or atrium.
Untreated shock is usually fatal. Even when treated, mortality from cardiogenic shock after massive M from septic shock is high. Prognosis depends on the cause, preexisting or complicating illness, time be onset and diagnosis, and adequacy of therapy.
First aid involves keeping the patient warm, with the legs raised slightly to improve venous return. Hemorrhage should be stopped, airway and ventilation checked, and respiratory assistance given if ne Nothing should be given by mouth, and the patient's head should be turned to avoid aspiration if emes occurs. Because tissue hypoperfusion makes absorption unreliable, all drugs should be given IV if pos Narcotics generally should be avoided, but severe pain may be treated with morphine 3 to 5 mg IV giv 2 min and repeated after 15 to 20 min if necessary. Although cerebral hypoperfusion may cause anxie sedatives or tranquilizers should not be given.
Supportive therapy stabilizes vital functions before diagnostic procedures can be carried out. Norepin or dopamine may be needed (see Table 204-3). Supplemental O2 by face mask should be provided immediately. If severe shock is present or ventilatory support is inadequate, endotracheal intubation is necessary to begin assisted ventilation with positive pressure and high O2 concentrations.
Outside the hospital or in the emergency department, a temporary increase in BP may be achieved wi military (or medical) antishock trousers (MAST). However, experience with MAST is required to avoid complications.
A large (16- to 18-gauge) catheter (particularly if hemorrhage is suspected) should be inserted into a p vein (femoral, internal jugular, or antecubital) to infuse blood or other fluids and to administer drugs (se Invasive Procedures in Ch. 198). Direct infusion of fluid into bone marrow provides an alternative eme access to the circulation when veins are collapsed; in children, this route may be particularly useful, al infusion by the femoral vein is preferable if severe hypovolemic shock is present (see also Cardiopulm Resuscitation in Ch. 263).
Giving IV sodium bicarbonate 50 to 100 mL of an 8.4% (1 mEq/mL) solution may help treat metabolic but treatment of the underlying cause of shock (hypovolemia, sepsis, or low cardiac output) is more im
access to the circulation when veins are collapsed; in children, this route may be particularly useful, al infusion by the femoral vein is preferable if severe hypovolemic shock is present (see also Cardiopulm Resuscitation in Ch. 263).
Giving IV sodium bicarbonate 50 to 100 mL of an 8.4% (1 mEq/mL) solution may help treat metabolic but treatment of the underlying cause of shock (hypovolemia, sepsis, or low cardiac output) is more im
Patients in whom shock is not immediately reversed should be considered critically ill, and definitive tre should be continued in a special care area (eg, an ICU, a coronary care unit). Careful monitoring sho include ECG; systemic arterial BP--preferably by direct intra-arterial cannula; respiratory rate and dept flow (usually by indwelling bladder catheter); arterial blood pH, PaO2, and PaCO2; body temperature; a clinical status, including sensorium, pulse volume, skin temperature, and color. Measurement of CVP, and thermodilution cardiac output using a balloon-tipped pulmonary arterial catheter is also helpful in p with shock of uncertain or mixed etiology or with severe shock, especially when accompanied by seve oliguria or pulmonary edema. A well-designed flow sheet is extremely valuable. Serial measurements arterial blood gases, Hct, serum creatinine, and plasma lactate may also be helpful.
Hypovolemic shock: Definitive treatment necessitates restoring intravascular volume and eliminating underlying cause. Overly rapid infusion of fluids may precipitate pulmonary edema; therefore, monitori or PCWP is sometimes helpful. BP and urine flow should also be monitored. Generally, CVP or PCWP not be raised > 12 to 15 mm Hg by fluid replacement. CVP monitoring alone may be misleading in pat with significant preexisting cardiac or pulmonary vascular disease. Care must be taken when interpreti pressures in patients during ventilatory assistance, particularly when end-expiratory pressure levels > H2 O are being used, or in tachypneic patients with large negative pleural pressures. Measurements sh made at the end of expiration, and the transducer should be placed at the atrial level (midchest) and c calibrated. The precise mode and type of fluids to be given are determined by the clinical circumstance are guided by frequent determination of Hct, serum electrolytes, urine flow, and arterial pH (ie, a searc evidence of resolving metabolic acidosis). 0.9% NaCl is as good as other solutions. After about 40 to 5 the calculated blood volume deficit is replaced, whole blood or a colloid solution should be given. Who should be cross-matched, but in an urgent situation, giving 1 to 2 U of O, Rh-negative blood is a good alternative (see Ch. 129). Colloid solutions--6% hetastarch in 0.9% NaCl, plasma (fresh frozen plasma the risk of transmitting infection), or reconstituted 5% human serum albumin--lack RBCs and will dilute Six percent hetastarch in 0.9% NaCl is an osmotic expander that is usually well tolerated but can prolo bleeding time. The usual maximum dosage is 20 mL/kg/24 h, although larger amounts have been use Allergic reactions have been occasionally reported.
Shock unresponsive to volume replacement may be due to insufficient volume administration in the pr of ongoing blood loss or may be due to complicating factors (eg, coexisting cardiogenic shock due to myocardial damage or septic shock). When hypovolemia is not the probable cause or when systemic B not respond promptly to volume administration, a vasopressor drug should be considered (see treatme vasodilatory shock, below).
Vasodilatory shock (for treatment of patients with adrenal insufficiency, see Ch. 9): Fluid resuscitatio 0.9% NaCl is almost always needed to treat the coexisting intravascular volume depletion that occurs increased systemic vascular permeability, especially in sepsis. Vasopressor drugs (eg, dopamine, norepinephrine) are often necessary, particularly in profound hypotension. Dopamine is an inotropic dr in low dosage (2 to 5 g/kg/min) is less vasoconstrictive than norepinephrine but selectively improves mesenteric and renal blood flow; it may have advantages over other vasopressors in selected patients Dobutamine, a more selective -agonist, increases cardiac output without vasoconstriction and thus ma as useful in such patients. Norepinephrine or dopamine given by controlled IV infusion (see Table 204 be used to raise the systolic pressure to between 90 and 100 mm Hg. Once BP is stabilized, efforts sh made to correct associated abnormalities (eg, hypoxemia, acidosis, hypovolemia, sepsis) so that administration of the vasopressor drug can be reduced or discontinued; prolonged vasoconstriction du -receptor stimulation can further impair visceral microcirculation and increase myocardial work and O 2
mesenteric and renal blood flow; it may have advantages over other vasopressors in selected patients Dobutamine, a more selective -agonist, increases cardiac output without vasoconstriction and thus ma as useful in such patients. Norepinephrine or dopamine given by controlled IV infusion (see Table 204 be used to raise the systolic pressure to between 90 and 100 mm Hg. Once BP is stabilized, efforts sh made to correct associated abnormalities (eg, hypoxemia, acidosis, hypovolemia, sepsis) so that administration of the vasopressor drug can be reduced or discontinued; prolonged vasoconstriction du -receptor stimulation can further impair visceral microcirculation and increase myocardial work and O 2 demand. In the presence of heart failure or sepsis, the inotropic and chronotropic effects of norepinep dopamine may improve cardiac output and systemic perfusion. In the absence of adrenal insufficiency corticosteroid therapy is of no benefit. Little can be done when shock follows massive irreversible cere damage.
Cardiogenic shock (see also Complications under Myocardial Infarction in Ch. 202): Cardiogenic sho treated by improving cardiac performance. Shock after acute MI should be treated with O2 inhalation, stabilization of heart rate and rhythm, and volume expansion if associated with a normal PCWP. Shoc right ventricular MI occasionally responds favorably to rapid volume expansion, which should be consi after inferior wall MI when right-sided ventricular filling pressure (CVP) is significantly elevated in the a of markedly elevated left-sided ventricular filling pressure (pulmonary end-diastolic pressure or PCWP However, fluid administration alone will rarely correct the hemodynamic abnormality, and additional tre with vasopressors may be required. Morphine 3 to 5 mg IV given over 2 min may relieve severe chest help reduce elevated catecholamine levels, and reduce preload and afterload on the failing heart; the response must be closely monitored because morphine causes respiratory depression, is a venodilato may cause BP to fall. The initial dose can be repeated after 10 min if there is no evidence of respirator depression or adverse BP response. Atropine 1 mg IV is occasionally effective in treating severe brady (heart rate, < 50 beats/min) and hypotension that frequently occur very early after the onset of sympto particularly in inferior-posterior MI. Norepinephrine or dopamine is used to maintain arterial systolic pre > 90 mm Hg (but not > 110 mm Hg). Because it markedly increases O2 demand, isoproterenol is contraindicated in patients with shock after acute MI unless it is needed temporarily for complete heart
When shock is complicated by bradycardia or advanced atrioventricular block, restoring BP with norepinephrine or dopamine (see above) and correcting acidosis usually result in an adequate ventricu Temporary transvenous pacing may be necessary in patients with evidence of persistent high-grade atrioventricular block or severe sinus node dysfunction. Short-term administration of isoproterenol (2 m mL 5% D/W at 1 to 4 g/min [0.25 to 1 mL/min]) may occasionally be needed before pacing in patients prolonged asystolic periods or recurrent ventricular tachycardia or fibrillation associated with severe bradycardia. Digoxin is not routinely used in shock but may be of value in patients with supraventricula tachycardia. In the absence of severe systemic hypotension, dobutamine infusion or amrinone (0.75 m over 2 to 3 min followed by infusions of 5 to 10 g/kg/min) may be used to improve cardiac output and left ventricular filling pressure. Tachycardia and arrhythmias may occasionally occur during dobutamin administration, particularly at higher doses. Because amrinone is an inotrope and a vasodilator, arrhyt and hypotension may occur during its administration. Amrinone may also cause thrombocytopenia, an platelet count should be monitored. Vasodilators (eg, nitroprusside, nitroglycerin), which increase veno capacitance or lower systemic vascular resistance, reduce the workload on the damaged myocardium may be of value in patients without severe arterial hypotension. Combination therapy (eg, dopamine o dobutamine with nitroprusside or nitroglycerin) may be particularly useful but requires close ECG and pulmonary and systemic hemodynamic monitoring.
Early use of intra-aortic balloon counterpulsation appears to be valuable for temporarily reversing shoc patients with acute MI and should be considered in patients who require vasopressor support (norepin or dopamine) for > 30 min and in those with acute MI complicated by ventricular septal rupture or seve mitral regurgitation. Development of percutaneous techniques for bedside insertion makes balloon counterpulsation available to community hospitals.
Emergency surgical correction of mechanical defects (eg, ruptured intraventricular septum, pseudoane severe mitral regurgitation, large dyskinetic segment) may also be necessary.
or dopamine) for > 30 min and in those with acute MI complicated by ventricular septal rupture or seve mitral regurgitation. Development of percutaneous techniques for bedside insertion makes balloon counterpulsation available to community hospitals.
Emergency surgical correction of mechanical defects (eg, ruptured intraventricular septum, pseudoane severe mitral regurgitation, large dyskinetic segment) may also be necessary.
Emergency percutaneous transluminal coronary angioplasty (PTCA) to open an occluded coronary art performed within a few hours after onset of acute MI, can reverse cardiogenic shock. Use of IV thromb drugs before emergency PTCA is controversial. However, if emergency PTCA or cardiac surgery is no instituted, thrombolytic therapy should be considered as soon as possible, unless contraindicated.
Other considerations: Pericardial tamponade requires pericardiocentesis, and, in life-threatening situ pericardial fluid may have to be removed at the bedside. Under less urgent circumstances, surgical cre a pericardial window or pericardiectomy may be advisable to avoid recurrence. Massive pulmonary em resulting in shock is treated by supportive measures, including supplemental O2, endotracheal intubati assisted ventilation, vasopressor support (norepinephrine, dopamine), and IV heparin to prevent recur thrombosis. In patients who cannot be stabilized with these measures, emergency pulmonary angiogra should be considered. The use of urokinase or streptokinase to lyse clots appears to be of value and i preferable to attempted embolectomy unless contraindicated (eg, because of recent major surgery, es neurosurgical).
When pulmonary edema complicates shock, rapid resolution often results from treatment of coexisting failure with diuretics while administering O2 as well as positive pressure ventilation. Pulmonary edema develops from septic shock should similarly be treated with O2 and positive pressure ventilation with p end-expiratory pressure (see also Ch. 67).

Section 16. Cardiovascular Disorders Chapter 213. Athletic Heart Syndrome Topics
[General]
[General]
Athletic heart syndrome: The constellation of normal anatomic and physiologic adaptations in persons regularly perform strenuous dynamic exercise (eg, endurance-trained athletes).
Resting sinus bradycardia, third and fourth heart sounds, systolic murmurs, a variety of ECG abnorma and cardiac enlargement on chest x-ray are characteristic. This syndrome, which would be considered abnormal in an untrained person, is a successful adaptation to endurance exercise and should not be misdiagnosed as heart disease.
Physiology
Increased cardiac volume and mass occur characteristically with endurance training, whereas skeletal and myocardial hypertrophy occur with strength (isometric) training. In the endurance-trained athlete, d of all four cardiac chambers and increased left ventricular wall thickness increase the pumping capabi heart. Cardiac chamber dimensions rarely exceed the upper limits of normal. The increase in cardiac o results from a substantial increase in maximal stroke volume.
In untrained persons, cardiac output increases in response to exercise primarily by an increase in hea The endurance-trained athlete does so mainly by an increase in stroke volume. Intracardiac pressures are normal in endurance-trained athletes, and intracardiac, pulmonary, and peripheral vascular pressu respond normally to exercise. Ventricular work per minute is also normal.
Increased cardiac output and O2 delivery to the tissues, both at rest and at all levels of exercise, are d primarily to an increase in stroke volume. Increased diastolic filling time with bradycardia further augm stroke volume and the coronary blood flow, which is predominantly a diastolic event. The total Hb and volume of the endurance-trained athlete are also increased, further enhancing O2 transport. The heart both at rest and at all levels of submaximal exercise decreases progressively with endurance training, reflecting augmented vagal tone. However, decreased sympathetic activation and possibly other nona factors that decrease the intrinsic rate of the sinus node also play a role. Despite the increase in left ve stroke work due to the increased ventricular volume, the O2-sparing effect of the bradycardia predomin
stroke volume and the coronary blood flow, which is predominantly a diastolic event. The total Hb and volume of the endurance-trained athlete are also increased, further enhancing O2 transport. The heart both at rest and at all levels of submaximal exercise decreases progressively with endurance training, reflecting augmented vagal tone. However, decreased sympathetic activation and possibly other nona factors that decrease the intrinsic rate of the sinus node also play a role. Despite the increase in left ve stroke work due to the increased ventricular volume, the O2-sparing effect of the bradycardia predomin such that myocardial O2 demand decreases for the same absolute levels of external work. Cardiac enlargement and bradycardia characteristically regress when endurance training is discontinued.
Symptoms and Signs
Sinus bradycardia, often with sinus arrhythmia, or, occasionally, wandering supraventricular pacemake characteristic. First-degree atrioventricular block can occur in up to 1/3 of athletes. Wenckebach (type 2nd-degree atrioventricular block, occasionally present at rest, characteristically resolves with exercise atrial and junctional rhythms may occur. The arrhythmias are typically asymptomatic and characteristic decrease or disappear as the heart rate increases with exercise. QRS and T voltages are increased on ECG, often with a prominent U wave, which may be related to the bradycardia. Repolarization (ST-T) abnormalities are common and usually normalize with exercise-induced sinus tachycardia.
Systemic BP differs little between endurance-trained athletes and normal untrained persons. The caro pulses are hyperdynamic. The left ventricular impulse is displaced, enlarged, and hyperdynamic. A thir sound (due to early diastolic rapid ventricular filling) is frequently present; a fourth heart sound (more e heard with increased diastolic filling time and a thin chest wall) is less common. A left sternal border ej systolic murmur (likely reflecting nonlaminar flow across the aortic and pulmonic valves secondary to t increased stroke volume) often decreases in intensity with change from a supine to an upright posture cardiac silhouette is globular and enlarged on chest x-ray; at fluoroscopy, cardiac pulsations are brisk prominent. At echocardiography, atrial and ventricular cavity dimensions and left ventricular wall thickn increased.
The extent of bradycardia, cardiac enlargement, or ECG abnormality does not directly correlate with th of training or cardiovascular performance. There is no evidence that even the most strenuous physica is deleterious to the cardiovascular function of a person with a normal heart or predisposes to cardiova disease later in life. However, sudden death, both at rest and with exertion, occurs occasionally in app healthy young athletes, probably due to a cardiac arrhythmia; characteristically, undetected cardiac dis the substrate. Although the increased ventricular refractory period with bradycardia theoretically favors occurrence of ventricular ectopic rhythms, sudden death related to arrhythmia in athletes is most frequ due to previously undetected atherosclerotic coronary heart disease, hypertrophic cardiomyopathy, myocarditis, or congenital coronary artery or aortic valve anomalies.

Section 16. Cardiovascular Disorders Chapter 205. Arrhythmias Topics
[General] Atrial Ectopic Beats Atrial Flutter Sustained Atrial Fibrillation Paroxysmal Atrial Fibrillation Chaotic And Multifocal Atrial Tachycardia Regular Narrow QRS Tachycardias Broad QRS Complex Arrhythmias Ventricular Fibrillation His Bundle Arrhythmias Atrioventricular Block Bundle Branch Block Hemiblock Nonspecific Intraventricular Conduction Defects Sick Sinus Syndrome
[General]
Anatomy
Specialized electrical system cells form a small fraction of cardiac mass. At the junction of the superio cava and the high right atrium, a cluster of cells, the sinoatrial or sinus node, forms the primary electric generator (pacemaker) of the normal heart. These cells produce a rhythmic discharge modulated by autonomic innervation and by circulating catecholamines. Sinoatrial node activity is not seen on the su ECG but occurs 80 to 120 msec before the onset of the P wave, which represents depolarization of at myocardial cells. Impulse transmission from the sinoatrial node through the atrium to the atrioventricul appears to be through normal unspecialized myocardial cells. However, a preferential route of conduc dictated by the muscle bundles that form the atrium.
The atria are electrically insulated from the ventricles except by the atrioventricular node, whose tortuo conduction pathway delays impulse transmission. The atrioventricular nodal refractory period usually i than that of other heart tissue, is heart rate dependent, and is modulated by autonomic tone and by catecholamines, adjusting activation of the ventricles relative to the atria to maximize cardiac output fo given heart rate.
The atrioventricular node is on the atrial side of the annulus fibrosus. Specialized conduction tissue, th bundle, runs along the tricuspid valve ring to the valve trigone, penetrating the annulus fibrosus and co
conduction pathway delays impulse transmission. The atrioventricular nodal refractory period usually i than that of other heart tissue, is heart rate dependent, and is modulated by autonomic tone and by catecholamines, adjusting activation of the ventricles relative to the atria to maximize cardiac output fo given heart rate.
The atrioventricular node is on the atrial side of the annulus fibrosus. Specialized conduction tissue, th bundle, runs along the tricuspid valve ring to the valve trigone, penetrating the annulus fibrosus and co through the membranous interventricular septum. Where the membranous septum becomes muscular the His bundle divides. The right bundle branch continues down the right ventricular endocardial surfa reach the anterior and apical muscle of the right ventricle. Impulses are contained within the branch un final ramifications. The main left bundle branch crosses the summit of the muscular interventricular se emerge on the left side of the heart just below the noncoronary cusp of the aortic valve. The left bundl in a variable manner but functionally gives rise to a left posterior fascicle (which innervates the septum left anterior fascicle. Disease affecting these fascicles may produce characteristic ECG changes (see Hemiblock, below). Abbreviations Used in This Chapter AF ICD Atrial fibrillation Implantable cardioverter defibrillator RBBB Right bundle branch block RF t1/2 Radiofrequency Half-life Ventricular ectopic beat Ventricular fibrillation Ventricular tachycardia
ISA
Intrinsic sympathomimetic VEB activity VF Jugular venous pulse VT
JVP
LBBB Left bundle branch block
WPW Wolff-Parkinson-White (syndrome)
LGL
Lown-Ganong-Levine (syndrome)
Physiology of Sinus Rhythm
The sinoatrial node, possibly the atrioventricular node, and most of the specialized conducting tissues capable of automatic (spontaneous) phase 4 diastolic depolarization. The intrinsic pacemaker rate is h the sinoatrial node, which dominates the lower, slower latent cardiac pacemakers. Sinus rhythm varies remarkably on short-term and long-term recordings.
Respiratory sinus arrhythmia, mediated by oscillations in vagal tone, is particularly common in young p The oscillations are dampened but do not entirely disappear with age. Exercise and emotion are poten accelerators of sinus rhythm through sympathetic neural and catecholamine drive. Resting sinus rates 100 beats/min classically represent the limits of normal, but much slower sinus rates occur in young pe particularly those trained as athletes (see Ch. 213). Thus, resting rates < 60 beats/min (sinus bradycar often are not pathologic. Sinus tachycardia describes rates > 100 beats/min. Normal persons have a m diurnal variation in heart rate, with lowest rates just before early morning awakening, when sinus acce is substantial (see Fig. 205-1). Absolute regularity of sinus rhythm is pathologic and occurs with autono denervation (eg, in advanced diabetes).
particularly those trained as athletes (see Ch. 213). Thus, resting rates < 60 beats/min (sinus bradycar often are not pathologic. Sinus tachycardia describes rates > 100 beats/min. Normal persons have a m diurnal variation in heart rate, with lowest rates just before early morning awakening, when sinus acce is substantial (see Fig. 205-1). Absolute regularity of sinus rhythm is pathologic and occurs with autono denervation (eg, in advanced diabetes).
Pathogenesis
Bradyarrhythmias arise through abnormalities of intrinsic automatic behavior or conduction, principally the atrioventricular node and the His-Purkinje's network. Tachyarrhythmias may arise by altered autom reentry, or triggered automaticity, which have been identified electrophysiologically but can rarely be differentiated clinically. Most clinically significant tachyarrhythmias are probably due to reentry.
Some arrhythmias cause few or no symptoms but are associated with an adverse prognosis. Much ev suggests that prognosis is not necessarily improved by their suppression. Other arrhythmias, although symptomatic, are benign. The nature and severity of underlying heart disease are often of greater prog significance than is the arrhythmia itself.
Symptoms and Signs
There is a wide variation in patient awareness of arrhythmias, either as palpitations or through the mor serious symptoms of hemodynamic upset.
Palpitations (awareness of the heartbeat) are often disagreeable and may arise equally from increase of contraction and from rhythm disturbance. They should be investigated to define the cause and to al anxiety.
Arrhythmias that cause hemodynamic upset are usually sustained bradycardias or tachycardias and life threatening. Resulting dizziness and syncope are common and may disqualify patients from driving certain occupations (eg, airline pilot, railroad engineer). These arrhythmias require urgent attention an hospitalization.
Diagnosis
The history usually provides sufficient information for establishing a working diagnosis. Patients are re reliable in their detection of the fast, completely irregular palpitations of paroxysmal atrial fibrillation (A will tap out regular tachyarrhythmias to within 10 beats/min. The history should differentiate brief arrhy episodes (eg, ectopic beats, second-degree atrioventricular block) from sustained events. The onset a characteristics and any other symptoms should be obtained. It is a widely held but erroneous belief tha well-tolerated tachyarrhythmia must be a supraventricular tachycardia rather than a ventricular tachyca (VT) and vice versa.
If examined during an arrhythmia, the peripheral pulse (reflecting ventricular activation) and the jugula pulse (JVP--reflecting atrial and ventricular activation) are important for diagnosis and can positively id (if atrioventricular dissociation is present) from other sustained regular tachycardias, AF, atrial flutter, a ventricular ectopic beats (VEBs), and second-degree and third-degree heart block.
Whereas the history should give a working diagnosis, and pulse and JVP examination during an arrhy may give an accurate diagnosis, the ECG remains the major diagnostic procedure. The surface ECG represents the net electrical forces of myocardial depolarization. Although each cardiac cell oscillates potential difference of about 90 to 100 mV, ECG signals at the body surface are typically only 1 mV in amplitude. Activation of small structures (eg, sinoatrial node, atrioventricular node, His bundle) is not s
ventricular ectopic beats (VEBs), and second-degree and third-degree heart block.
Whereas the history should give a working diagnosis, and pulse and JVP examination during an arrhy may give an accurate diagnosis, the ECG remains the major diagnostic procedure. The surface ECG represents the net electrical forces of myocardial depolarization. Although each cardiac cell oscillates potential difference of about 90 to 100 mV, ECG signals at the body surface are typically only 1 mV in amplitude. Activation of small structures (eg, sinoatrial node, atrioventricular node, His bundle) is not s
The standard 12-lead ECG is crucial for the characterization and diagnosis of the various sustained tachycardias. However, it provides only a brief sample of cardiac rhythm, particularly when recorded b simultaneous multichannel recorders.
Ambulatory ECG monitoring is the most powerful method of capturing arrhythmic events, and its val enhanced by keeping a diary of associated symptoms. ECG recorders are of many types, eg, those th continuous 24 h (Holter 24 h) or those activated by the patient or by automatic detection of an arrhythm episode. Solid-state recorders can eliminate the vagaries of mechanical tape transport systems. Ambu ECG monitoring is less useful when arrhythmias are infrequent. Patients with suspected life-threatenin disturbances should be hospitalized for monitoring to avoid a fatal out-of-hospital event.
Invasive electrophysiologic studies are indicated when spontaneous arrhythmias are infrequent and serious sustained arrhythmia is suspected. Using programmed stimulation techniques, reentrant arrhy can be initiated and terminated (see Fig. 205-2). However, automatic and triggered automatic arrhythm often are unresponsive to these techniques. Most clinical arrhythmias of importance (VT, atrioventricu reentry tachycardia, reciprocating tachycardias of the preexcitation syndromes) are reentrant.
Signal averaging of the surface ECG can noninvasively detect areas of slowed ventricular activation part of the substrate for VT. These are reflected by low-voltage post-QRS potentials. Normally obscure ambient noise, they are exposed by averaging and amplification. Signal-averaged late potentials in su acute MI have been correlated with an increased risk of sudden death and a propensity to VT (see Fig Signal averaging does not help select appropriate therapy but identifies patients who warrant further investigation; it plays no role in the investigation of narrow QRS tachycardias (see below).
Treatment
Reassurance is important. Most cardiac arrhythmias cause no symptoms, have no hemodynamic impo and have no prognostic significance but may cause anxiety in a patient who becomes aware of them. patients with benign arrhythmias remain disabled despite reassurance. Behavior modification therapy helps when reassurance has failed. In rare cases, a precipitating factor may be identified and modified excessive intake of caffeine or alcohol).
Drug treatment: Antiarrhythmic drug therapy is the mainstay of management for most important arrhy There is no universally effective drug; all have important safety limitations and can aggravate or promo arrhythmias (arrhythmogenesis, proarrhythmia). Drug selection is difficult and often involves trial and e
Antiarrhythmic drug actions based on cellular electrophysiologic effects have been classified by Vaugh Williams (see Table 205-1). This classification is recognized internationally and provides a general log grouping drugs, although its usefulness for prescribing is limited.
Class I drugs are Na channel blockers, including older antiarrhythmic drugs (eg, quinidine). All reduce maximal rate of depolarization of the action potential and thereby slow conduction. They are very effec suppressing VEBs but, to a varying degree, depress left ventricular performance, and all have been as with proarrhythmia. They are subclassified based on the kinetics of their receptor effects: class Ia--dru intermediate onset and offset; class Ib--drugs with short effects; and class Ic--drugs with prolonged eff
Class I drugs are Na channel blockers, including older antiarrhythmic drugs (eg, quinidine). All reduce maximal rate of depolarization of the action potential and thereby slow conduction. They are very effec suppressing VEBs but, to a varying degree, depress left ventricular performance, and all have been as with proarrhythmia. They are subclassified based on the kinetics of their receptor effects: class Ia--dru intermediate onset and offset; class Ib--drugs with short effects; and class Ic--drugs with prolonged eff
Quinidine (class Ia) prolongs action potential and refractoriness (seen on ECG as QT prolongation). T broad-spectrum drug is effective for the suppression of VEBs and VT and for the control of narrow QR tachycardias, including atrial flutter and fibrillation. It is one of the few drugs that may convert AF to sin rhythm. Elimination half-life (t1/2) is 6 to 7 h. If an initial test dose of quinidine sulfate is tolerated, the maintenance dosage is usually 200 to 400 mg po q 4 to 6 h. The target plasma concentration is 2 to 6 Dosing should be adjusted so that QRS duration is < 140 msec (unless there is preexisting bundle bra block) and QT is < 550 msec. About 30% of patients develop adverse reactions. GI problems (diarrhea flatulence) are most common, but fever, thrombocytopenia, and liver function abnormalities also occur Quinidine syncope is a potentially dangerous idiosyncratic and unpredictable effect caused by torsade pointes (see below).
Procainamide (class Ia) has much less effect than quinidine on refractoriness. The main metabolite, N procainamide, also has antiarrhythmic effects and contributes to procainamide's efficacy and toxicity. I given cautiously IV as 100 mg over 1 to 2 min repeated q 5 min to a usual maximum total dose of 600 (rarely up to 1 g) while monitoring BP and ECG. Oral procainamide has a short elimination t1/2 (< 4 h), requiring frequent dosing or use of sustained-release preparations. The usual oral dosage is 250 to 62 (rarely up to 1 g) q 3 or 4 h. Target plasma concentrations are 4 to 8 g/mL. QRS widening by 25% and prolongation to 550 msec suggest toxicity. Almost all patients receiving long-term therapy (> 12 mo) de serologic abnormalities (notably a positive antinuclear factor test), and up to 40% have symptoms and hypersensitivity (arthralgia, fever, pleural effusions).
Disopyramide (class Ia) produces little change in the refractory period. It has an elimination t 1/2 of 5 to target plasma concentration is 3 to 6 g/mL. Oral dosing is usually 100 or 150 mg q 6 h. Parenteral do available in the USA, comprises an initial IV dose of 1.5 mg/kg over not less than 5 min, followed by an infusion of 0.4 mg/kg/h. Disopyramide has powerful anticholinergic effects that play only a minor role in arrhythmia management but are responsible for urinary retention and glaucoma; less serious adverse (eg, dry mouth, problems of accommodation, bowel upset) may contribute to noncompliance. Disopyra has negative inotropic effects, particularly when used parenterally, and it should be used cautiously (if patients with markedly impaired left ventricular function.
Lidocaine (class Ib) has substantial first-pass hepatic metabolism. It produces minimal myocardial dep and has little effect on the sinus node, atria, or atrioventricular node but acts powerfully on His-Purkinj ventricular myocardial tissue. It can suppress the ventricular arrhythmias that complicate MI (VEBs, VT reduce the incidence of primary ventricular fibrillation (VF) when given prophylactically in early acute M However, asystolic events are increased, suggesting sinoatrial and atrioventricular nodal effects. Lidoc elimination t1/2 is 30 to 60 min. The target plasma concentration is 2 to 5 mg/L. It is used only parenter usual regimen is 100 mg IV over 2 min followed by 50 mg IV 5 min later if the arrhythmia has not rever infusion of 4 mg/min (2 mg/min in patients > 65 yr) should then be started. If it is continued for > 12 h, levels may be reached. Concomitant -blocker therapy increases the risk of toxicity, and the lidocaine d should be halved. Adverse effects are neurologic (tremor, convulsions) rather than cardiac. Drowsines delirium, and paresthesias may occur with too-rapid administration.
Mexiletine (class Ib) is an analog of lidocaine with similar electrophysiologic actions, but it has little or n first-pass hepatic metabolism. Mexiletine can suppress symptomatic ventricular arrhythmias, including has little or no role in the management of narrow QRS (supraventricular) arrhythmias. Mexiletine's elim t1/2 is 6 to 12 h, and the target plasma concentration is 1 to 2 g/mL. Oral dosing is 200 to 250 mg q 8 slow-release preparation (not available in the USA) may be given as 360 mg q 12 h. IV dosing (also no
Mexiletine (class Ib) is an analog of lidocaine with similar electrophysiologic actions, but it has little or n first-pass hepatic metabolism. Mexiletine can suppress symptomatic ventricular arrhythmias, including has little or no role in the management of narrow QRS (supraventricular) arrhythmias. Mexiletine's elim t1/2 is 6 to 12 h, and the target plasma concentration is 1 to 2 g/mL. Oral dosing is 200 to 250 mg q 8 slow-release preparation (not available in the USA) may be given as 360 mg q 12 h. IV dosing (also no available in the USA) is complicated by mexiletine's large volume of distribution. An initial dose of 2 mg at a rate of 25 mg/min should be followed by a 250-mg infusion over 1 h, a 250-mg infusion over the n and a maintenance infusion of 0.5 mg/min. Mexiletine, similar to lidocaine, has few cardiovascular adv effects, but GI (nausea, vomiting) and CNS (tremor, convulsions) effects may limit its acceptability. Th slow-release preparation (where available) is better tolerated.
Tocainide (class Ib) is another congener of lidocaine, with little or no first-pass hepatic metabolism. Eli t1/2 is 11 to 15 h, and the target plasma concentration is 4 to 10 g/mL. Oral dosing is 400 mg q 8 h. IV not available in the USA, is up to 750 mg infused over 30 min. Continued IV dosing is possible (1200 m 24 h), but early recourse to oral therapy is advised. Tocainide's kinetics and indications for use are sim those of mexiletine, but significant adverse effects (eg, agranulocytosis) are more likely.
Phenytoin is variably classified but probably belongs to class lb. It was used extensively for arrhythmia management, particularly for suppressing the ventricular arrhythmias of digitalis toxicity, until the adve newer drugs and the decline of digoxin toxicity (which may be better treated by digoxin immune Fab). long elimination t1/2 (22 h). Adverse effects include gingival hyperplasia and blood dyscrasias.
Class Ic drugs are among the most powerful antiarrhythmics but have been associated with a significa proarrhythmia and depression of cardiac contractility. These adverse effects are uncommon in patient hemodynamically normal hearts (eg, Wolff-Parkinson-White [WPW] syndrome) but important in patien extensive cardiac damage subject to life-threatening ventricular tachyarrhythmias. Class Ic drugs are u these latter patients only when the arrhythmia is unresponsive to other therapy.
Class Ic drugs are proving highly effective for the medical cardioversion of AF and for the prophylaxis attacks. These indications have become the principal application for these drugs, particularly because proarrhythmic risks in this context seem relatively low.
Flecainide is a powerful class Ic antiarrhythmic. It has a profound effect on the Na channel, so conduc markedly slowed but refractoriness is little affected. Left ventricular performance may be depressed. F can control symptomatic VEBs, VT, and the reciprocating tachycardias of the WPW syndrome. Elimina is 12 to 27 h, and the target plasma concentration is 0.2 to 1 g/mL. Flecainide is given 100 mg po q 8 The initial dose of the parenteral form, not available in the USA, is 150 mg IV over 10 min. Flecainide encainide were associated with increased mortality (presumptively proarrhythmic) in the treatment of asymptomatic and minimally symptomatic VEBs after acute MI. The drug usually is well tolerated, but vision and paresthesia are occasionally reported. QRS prolongation > 25% indicates toxicity.
Propafenone (class Ic) has effects similar to those of flecainide and is probably similarly proarrhythmic elimination t1/2 is 6 to 7 h. The target plasma concentration is 5 to 8 g/mL. Despite low and variable bioavailability, saturable first-pass metabolism, and variable protein binding, dosing is simple (450 to 9 mg/day in divided doses). Initial doses should be small (150 mg tid), and increases should not be > 50 previous dose. Single doses of 450 and 600 mg po have been used for the medical cardioversion of A safety concerns have emerged, but studies have been small, and this approach should be regarded a experimental.
Class II drugs (-blockers) may be the least toxic and most powerful drugs available, yet their antiarrhy effects are often overlooked. Whereas relatively few arrhythmias are primarily caused by sympathetic overactivity, most are modulated by autonomic tone. -Blockers have poor efficacy in conventional
safety concerns have emerged, but studies have been small, and this approach should be regarded a experimental.
Class II drugs (-blockers) may be the least toxic and most powerful drugs available, yet their antiarrhy effects are often overlooked. Whereas relatively few arrhythmias are primarily caused by sympathetic overactivity, most are modulated by autonomic tone. -Blockers have poor efficacy in conventional antiarrhythmic tests (eg, VEB suppression), but they raise the threshold to VF and may be potent prev VF. -Blockers are 1 -selective or nonselective, may have intrinsic sympathomimetic activity (ISA), and a lipophilic or hydrophilic. These differences seem of little antiarrhythmic relevance, although ISA may re antiarrhythmic potency. In general, -blockers are well tolerated but may depress left ventricular functio particularly in antiarrhythmic doses. They are contraindicated in bronchospastic airway disease and sh used cautiously in other lung diseases. GI disturbances, insomnia, and nightmares may occur. Lassitu common on initiating therapy but rarely persists.
Class III drugs interfere with the K channel to alter the plateau phase of the action potential and incre refractoriness. Conduction velocity is little affected, but, theoretically, the discharge rate of automatic f reduced. These drugs can be proarrhythmic.
Amiodarone is a powerful class III antiarrhythmic. It has few cardiovascular adverse effects and, perha through its modest vasodilator action, produces little or no left ventricular depression. Sinoatrial node a little affected. Amiodarone, by prolonging refractoriness, may create homogeneous conditions of repol throughout the heart. The QT interval on ECG is prolonged, and no upper safe limit to this effect has b suggested. The elimination t1/2 is > 50 days, with substantial delay in onset of action. Initial loading do 600 to 1200 mg/day po for 7 to 10 days have been advocated but with little evidence of faster onset. O maintenance doses should be the minimum needed to control arrhythmias, ideally <= 200 mg/day. Fo life-threatening arrhythmias, IV amiodarone may be given in a dose of 3 to 7.5 mg/kg over 1 h. Parent amiodarone dosing has not been researched extensively. Caution is needed. The ECG should be mon continuously, as there is a risk of inducing atrioventricular block.
Cardiovascular toxicity is rare. Amiodarone is too toxic for long-term use, except for serious arrhythmia narrow QRS complex arrhythmias unresponsive to alternate treatment, those causing significant morb Pulmonary fibrosis may occur in up to 5% of patients treated for > 5 yr and may be fatal. Serial pulmon function testing may detect pulmonary fibrosis early, allowing discontinuation of amiodarone. Other complications include photosensitive dermatitis, hepatic abnormalities, peripheral neuropathy, corneal microdeposits (occur in almost all treated patients, do not seriously affect vision, and are reversible on stopping therapy), hypothyroidism (usually not serious; thyroid hormone replacement can be given wh amiodarone dosing continues), and hyperthyroidism (more difficult to manage; usually necessitates sto amiodarone). Torsade de pointes is rarely produced by amiodarone but can be life threatening. Unless alternative exists, amiodarone should not be given to children.
Racemic (D-L) sotalol has class II and III antiarrhythmic properties, but, although measurable class III (QT prolongation, refractory period change) are detectable in clinical use, they are largely masked by t drug's -blocking properties. Most class III activity resides in the D-isomer. Sotalol is given as 80 to 160 12 h. It depresses left ventricular performance and has been associated with proarrhythmia. The usua contraindications for -blockers apply to its use. In studies of D-sotalol, mortality was increased. Only ra sotalol is available for clinical use.
Ibutilide is a newly approved class III drug (prolongs repolarization) that differs markedly from amiodar sotalol. It achieves its effect by activating a slow inward Na current rather than by blocking outward K c Ibutilide can acutely terminate AF (about 40% success) and atrial flutter (about 65% success). Ibutilide IV over 10 min as a 1-mg infusion for patients >= 60 kg or as 0.01 mg/kg for smaller patients. A dose i to the first may be given after 10 min if the first infusion is unsuccessful. Torsade de pointes has devel 2% of patients. Ibutilide should therefore be used in well-monitored situations and by staff familiar with management of torsade de pointes (see below).
sotalol. It achieves its effect by activating a slow inward Na current rather than by blocking outward K c Ibutilide can acutely terminate AF (about 40% success) and atrial flutter (about 65% success). Ibutilide IV over 10 min as a 1-mg infusion for patients >= 60 kg or as 0.01 mg/kg for smaller patients. A dose i to the first may be given after 10 min if the first infusion is unsuccessful. Torsade de pointes has devel 2% of patients. Ibutilide should therefore be used in well-monitored situations and by staff familiar with management of torsade de pointes (see below).
Bretylium also has antisympathetic (class II) and class III actions. It may cause marked hypotension a indicated only for the management of potentially lethal refractory ventricular tachyarrhythmias (intracta recurrent VF). Bretylium usually is effective within 30 min of injection. The target plasma concentration 1.5 g/mL. The initial IV dose is 5 mg/kg, followed by 1 to 2 mg/min as a constant infusion; its ventricu effects may be delayed 10 to 20 min. The initial IM dose is 5 to 10 mg/kg, which may be repeated to a dose of 30 mg/kg; the maintenance dosage is 5 mg/kg IM q 6 to 8 h.
Class IV drugs are Ca blockers (Ca entry blockers). Nifedipine, similar to other dihydropyridines, has no electrophysiologic effects, but verapamil and diltiazem influence atrioventricular nodal electrophysio and may alter that of Ca-dependent ischemic cells.
Verapamil acts principally on the atrioventricular node, slowing conduction. Used IV, it has a place in t management of narrow QRS tachycardias, which involve the atrioventricular node. Reportedly, termina rates approach 100% with doses of 5 to 15 mg IV over 10 min. However, if verapamil is given to patien serious adverse reactions, including VF, intractable hypotension, and death, may occur. Thus, verapa contraindicated for broad QRS tachycardias. Verapamil 40 to 120 mg po tid is widely prescribed for ar prophylaxis, but the substantial first-pass hepatic metabolism may limit its clinical use.
Diltiazem has a similar electrophysiologic profile to verapamil. It has a long t1/2 (making it less accepta therapy for narrow QRS tachycardia) but has little or no first-pass hepatic metabolism, making it better for chronic arrhythmia prophylaxis.
Drugs not covered by the Vaughan Williams classification are also used. Digoxin shortens atrial a ventricular refractory periods and prolongs conduction in the atrioventricular node. The target plasma concentration is 0.8 to 1.6 ng/mL. Part or all of the 1-mg digitalizing dose may be administered slowly under ECG control, with full resuscitative facilities available. Maintenance is 0.125 to 0.25 mg/day po, depending on body weight and renal function. Although uncommon, digoxin toxicity is manifested by a nausea, vomiting, and often serious arrhythmias (VEBs, atrial ectopic beats, occasionally paroxysmal tachycardia with block) or second-degree or third-degree atrioventricular block. Treatment of serious d toxicity using digoxin immune Fab is safer and more logical than using an antiarrhythmic drug; in other situations, stopping therapy for 48 h and resuming with a lower dose is usually satisfactory. Digoxin is contraindicated in patients with antegrade conduction over an accessory pathway (manifest WPW syn because, in the event of AF, excessive ventricular responses may occur through facilitation of the acce pathway. Digoxin can be used prophylactically in infants and children < 10 yr with WPW (see below).
Adenosine is a purine nucleoside that acts through extracellular adenosine receptors to slow or block atrioventricular nodal conduction. It can terminate arrhythmias that involve the atrioventricular node. A may be safer than verapamil for this purpose because of its extremely short duration of action. It is rap metabolized after administration. The dose is 6 mg followed by up to 12 mg by rapid IV injection. Shor adverse effects (dyspnea, chest discomfort, flushing) occur in 30 to 60% of patients. Adenosine may c bronchospasm and should not be used in asthmatic patients.
Pacemakers: Technical advances have been dramatic. Sophisticated pacing modalities and program are common. Low-energy circuitry and new battery designs have increased device longevity. Screenin devices and interference-resistant circuitry have almost eliminated the risk that automobile distributors antennae, microwave devices, and airport security detectors once posed in suppressing pacemaker fu MRI and operative diathermy may, however, interfere with pacemakers and should be avoided. Cellula
Pacemakers: Technical advances have been dramatic. Sophisticated pacing modalities and program are common. Low-energy circuitry and new battery designs have increased device longevity. Screenin devices and interference-resistant circuitry have almost eliminated the risk that automobile distributors antennae, microwave devices, and airport security detectors once posed in suppressing pacemaker fu MRI and operative diathermy may, however, interfere with pacemakers and should be avoided. Cellula telephones are a source of electromagnetic emissions; pacemaker patients should avoid using such d proximity to the pacemaker generator.
Two important pacemaker developments are corticosteroid-eluting leads and mode switching. Use of t former reduces pacing threshold with increased pacemaker longevity. The latter is proving important fo patients with atrioventricular nodal conduction disorders (natural or iatrogenic) in whom occasional disturbances of sinus rhythm occur. A mode-switching DDDR pacemaker (for the international coding pacemakers and implantable devices, see Table 205-2) can detect atrial arrhythmias such as AF and automatically operate as a VVIR pacemaker until sinus rhythm returns.
Antibradycardia pacemakers are important for symptomatic bradyarrhythmias, which may be caused atrioventricular block, sinoatrial node depression, sinoatrial conduction block, or infra-His block. The se depends on the rate and reliability of the escape pacemaker. Dangerous bradycardias are optimally tre with pacemakers. A simple VVI pacemaker may be adequate for transient or infrequent bradyarrhythm frequent or persistent bradyarrhythmia, prolonged dependence on ventricular pacing may warrant use rate-responsive demand unit (VVIR or DDDR) or, if no atrial or sinus node abnormalities are present, a dual-chamber system (DDD).
Antitachycardia pacemakers offer automatic arrhythmia termination by programmed stimulation. The implantable devices, which may be no larger than conventional pacemakers, deliver a series of preprogrammed pacing sequences when an arrhythmia occurs. Current antitachycardia pacemakers s not be used for VT (although it may respond) because they may precipitate VF; units with backup defib capability should be used in this context. Indications include the reciprocating tachycardias of WPW sy preferably when there is slow or no antegrade conduction over the accessory pathway (lest AF be pre and conducted rapidly to the ventricles), and atrioventricular nodal reentry tachycardia (see below). Ot treatment modalities, especially radiofrequency ablation (see below), are superseding antitachycardia therapy.
Implantable cardioverter defibrillators (ICDs) use relatively low energy shocks (< 35 watt-seconds) directly to the heart to stop VF. Available systems automatically deliver > 200 shocks and provide arrh surveillance for >= 5 yr. Implantation formerly involved a limited thoracotomy, but now > 95% of system transvenous electrodes.
In modern ICDs, backup antibradycardia pacing and telemetry facilities are available. Current indicatio ICD use include resuscitated sudden death (except in the first few hours of acute MI) and medically in life-threatening VT. Defibrillators do not prevent symptomatic arrhythmias and may be combined with suppressive antiarrhythmic therapy. Randomized controlled studies of ICD therapy are scarce. Two st involved highly selected high-risk patients (sudden cardiac death survivors); in both, total mortality was reduced with the ICD vs. the best medical therapy. However, the ICD is not without problems: it offers palliation rather than cure. Patients experience shocks, some of which may be inappropriate response other arrhythmias such as AF. ICDs are also expensive and must be used responsibly.
Antitachycardia pacing is a further ICD development. Many episodes of VT are based on reentry and terminated by various overdrive pacing sequences. Until the advent of ICD, which offers backup defibr the event of provoking VF, this therapy had not been exploited. Follow-up and programming these dev require a specialist.
Radiofrequency (RF) ablation: RF ablation has revolutionized the approach to many types of arrhyth
Antitachycardia pacing is a further ICD development. Many episodes of VT are based on reentry and terminated by various overdrive pacing sequences. Until the advent of ICD, which offers backup defibr the event of provoking VF, this therapy had not been exploited. Follow-up and programming these dev require a specialist.
Radiofrequency (RF) ablation: RF ablation has revolutionized the approach to many types of arrhyth RF lesions are created by gentle heating (typically to 60 C [140 F]) of an electrode catheter with a la Typically, lesions are < 1 cm in diameter with tissue penetration of up to 1 cm. For cure, the arrhythmia depend on a discrete generator or pathway that can be destroyed by these RF lesions. RF ablation ha increased interest in the anatomy of all types of narrow and broad QRS tachycardias. Success rates > are expected for accessory pathway tachycardias, para-atrioventricular nodal reentry tachycardia, atria tachycardia, and right ventricular outflow tract tachycardia. Atrioventricular node ablation (used for ven rate control in AF) is possible in > 99% of patients. Success rates of 85% are reported for the cure of a flutter, which involves a line of RF lesions preventing conduction through an important narrow isthmus myocardium near the orifice of the coronary sinus. AF (except atrioventricular node ablation or modific and ischemic VT are the subjects of RF ablation research but are not currently indications for the tech
RF ablation is remarkably safe. Deaths have occurred principally through cardiac perforation and tamp (death, 1/2000; tamponade, 1/2400).
Surgery: The anatomic basis of WPW syndrome and its arrhythmias is well understood. After accurat localization by catheter or epicardial mapping, the accessory pathway may be destroyed by surgery (s > 95%; operative mortality, < 0.1%) using an epicardial or endocardial approach. However, RF ablatio made surgery for WPW almost obsolete.
Postinfarction VT usually originates in the subendocardium, which, when localized by intraoperative m can be removed by procedures such as endocardial resection. Surgery has an operative mortality of 5 depending on preoperative status, but survivors have a 90% arrhythmia-free 1-yr survival.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 49. Approach To The Patient With Joint D Topics
[General]
[General]
Physical Examination
A complete history and physical examination are important in a patient with joint symptoms, which may of localized or systemic disease. Laboratory and x-ray data are usually of only supplementary help.
Each involved joint should be inspected and palpated, and the range of motion measured. This usually determines the presence of joint disease and establishes whether the joint, the adjacent structures, or involved. Involved joints should be compared with their uninvolved opposites or with those of the exam Information is recorded objectively and quantitatively (eg, using a numbered grading system, measurin range of motion in degrees).
Joint motion, generally painful in joint disease, may not be painful in periarticular, bone, or soft tissue Swelling is an important finding. Palpation of swollen joints helps to (1) elicit the presence of fluid; (2) differentiate among simple effusion, synovial thickening, and capsule or bony enlargement; and (3) de whether the swelling is confined to the joint or is periarticular. Tenderness or swelling at only one side may actually arise in adjacent ligaments, tendons, or bursae; findings from several approaches to the substantiate articular involvement. Monarthritis always suggests infection, crystal-induced arthritis, trau rarely, tumor.
Increased heat over the joint should be carefully localized. Many normal joints are actually cooler than adjacent skin. Crepitus may arise from intra-articular structures or from tendons; the crepitus-producin motions should be determined (eg, knee crepitus may arise from patellofemoral grinding or from femo motion).
Small joints (eg, the acromioclavicular near the shoulder, the tibiofibular at the lateral aspect of the kne radioulnar at the elbow) can be the source of pain that was initially believed to arise from the major join Hand: The main differential features of the hand in osteoarthritis and RA are outlined in Table 49-1.
motion).
Small joints (eg, the acromioclavicular near the shoulder, the tibiofibular at the lateral aspect of the kne radioulnar at the elbow) can be the source of pain that was initially believed to arise from the major join
Hand: The main differential features of the hand in osteoarthritis and RA are outlined in Table 49-1. Subluxations producing swan-neck or boutonnire deformities (see Ch. 61) occur in chronic RA. In pso arthritis, the distal interphalangeal (DIP) joints are commonly affected, psoriasis often is evident aroun adjacent nail, and other joint involvement is more asymmetric than in RA. In Reiter's syndrome, synov periarticular, and periosteal changes can be present in a few DIP, proximal interphalangeal, or metacarpophalangeal joints, and there is asymmetric finger joint involvement. Asymmetric DIP joint involvement also occurs in chronic gout, in which irregular joint or extra-articular tophaceous deposits some of which can be seen under the skin as cream-colored aggregates.
Changes in the hand are generalized in the shoulder-hand syndrome (reflex sympathetic dystrophy), w diffuse edema and mottled, mildly cyanotic skin. In progressive systemic sclerosis, there may be initial puffiness, but with time the skin thickens, and flexion contractures often develop; Raynaud's phenome be noted. Findings in hypertrophic pulmonary osteoarthropathy include clubbing of the fingertips and b tenderness of the distal radius and ulna caused by underlying periostitis. Joint synovitis similar to that occurs in SLE and, less often, in dermatomyositis, although arthralgias and sore, painful hands lacking objective joint swelling are more typical of both these disorders. Finger deformities resembling RA can SLE but are caused by soft tissue disease, not advanced erosive arthritis. Raynaud's phenomenon ca present in SLE, and scaling erythema may be found over the extensor joint surfaces in dermatomyosit
Elbow: Synovial swelling and thickening caused by joint disease occur in the lateral area between the head and olecranon, producing a bulge. Fluid or thickening in the olecranon bursa, rheumatoid nodule epitrochlear nodes should also be sought. Full 180 extension of the joint should be attempted. Althou extension is possible with nonarthritic or extra-articular lesions, its loss is an early change in arthritis. In elbow, sharply localized pain is elicited by placing firm pressure over the lateral epicondyle.
Shoulder: Limited motion, weakness, pain, and disturbed mobility can be tested by having the patient to raise both arms above the head. Muscle atrophy and neurologic changes should be sought. Althoug swelling is not common, a bulge in the anterior area of the shoulder is occasionally present in RA as a forward dissection of glenohumeral synovitis. Careful palpation of the relaxed shoulder may identify tenderness caused by inflammation of bursae or tendons, with common conditions occurring primarily subacromial area or in the long head of the biceps tendon. Localization may permit aspiration and inje a corticosteroid-lidocaine solution to relieve acute tendinitis and to confirm the diagnosis.
Foot and ankle: Because weight bearing may elucidate certain abnormalities, the patient should stan of the examination. In the normal ankle joint, 15 dorsiflexion and 40 plantar flexion are possible. Swe below and in front of the malleoli is characteristic of synovial or intra-articular disease. Palpation of suc soft swelling, with pain elicited on extension and flexion of the foot, demonstrates synovitis of the ankle Pain on inversion or eversion suggests subtalar or ligament disease. Ankle edema, which is associate normal ankle joint motion, can be differentiated from true joint swelling by its diffuse, superficial, pitting nontender character. Metatarsophalangeal joints are commonly swollen and tender in RA. Interphalan synovitis, not as common in the feet in RA, may indicate Reiter's syndrome, other reactive arthritis, ps arthritis, or gout. In gout, the first metatarsophalangeal (MTP) or bunion joint is most commonly affecte the midtarsal or ankle areas can also be involved. Diffuse erythema is striking in an acute attack of go metatarsophalangeal pain on motion with crepitus suggests osteoarthritis.
Knee: Gross deformities such as swelling (eg, popliteal cysts), quadriceps muscle atrophy, and joint in may be more obvious when the patient stands and walks. Careful palpation of the knee in a supine pa especially noting the presence of joint fluid, synovial thickening, and local tenderness, helps detect art Tender extra-articular bursae and true intra-articular disturbances should be differentiated.
Knee: Gross deformities such as swelling (eg, popliteal cysts), quadriceps muscle atrophy, and joint in may be more obvious when the patient stands and walks. Careful palpation of the knee in a supine pa especially noting the presence of joint fluid, synovial thickening, and local tenderness, helps detect art Tender extra-articular bursae and true intra-articular disturbances should be differentiated.
Detection of small knee effusions is commonly problematic and is best accomplished using the "bulge The knee is extended and the leg is slightly externally rotated while the patient is supine with muscles The medial aspect of the knee is stroked to express any fluid away from this area. Placement of one h the suprapatellar pouch and gentle stroking or pressing on the lateral aspect of the knee can create a wave or bulge, visible medially when an effusion is present.
Full 180 extension of the knee should be attempted to detect knee flexion contractures. With meniscu or collateral ligament injuries, forceful lateral or medial bending on leg extension produces pain by compressing the meniscus and simultaneously stretching the opposite collateral ligament. The joint lin located by medial and lateral palpation while slowly flexing and extending the knee. A displaced menis painful on firm pressure; a collateral ligament injury is tender longitudinally. The intactness of the cruci ligaments can be determined by grasping the leg with the knee flexed at 90 (best performed with the sitting on a table with legs dangling) and estimating the amount of posterior-anterior movement (which be minimal). The patella should be tested for free, painless motion. To gauge excess knee mobility, es lateral instability, the thigh is firmly fixed and an attempt is made to rock the relaxed, almost extended from side to side.
Hip: A limp is common in patients with significant hip arthritis or disease in other joints of the leg. It ma caused by pain, shortening of the leg, flexion contracture, or muscle weakness. Loss of internal rotatio the earliest change), flexion, extension, or abduction can usually be demonstrated. Placement of one the patient's iliac crest detects pelvic movement that might be mistaken for hip movement. Flexion con can be identified by attempting leg extension with the opposite hip maximally flexed to stabilize the pe Tenderness over the femoral greater trochanter indicates local bursitis rather than arthritis.
Vertebral column: Cervical and lumbar motion should be measured. Inability to reverse the normal lu lordosis on flexion occurs in degenerative arthritis; limited lumbar flexion is also characteristic of ankylo spondylitis. Degenerative arthritis or ankylosing spondylitis also limits neck motion. Either soft tissue d arthritis may cause pain and limited movement. The effect of movement on pain should be noted. Palp and firm percussion over each vertebra and sacroiliac joint may elicit superficial or deep bone tendern should be distinguished from muscle spasm lateral to the spine. Localized bone pain suggests osteom leukemia, primary or metastatic cancer, compression fracture, or herniated disk. Psychogenic ("touchreactions should be noted, as should muscular tender points typical of fibromyalgia. Chest expansion be measured because it is typically impaired in ankylosing spondylitis.
Diagnosis
Conditions easily misinterpreted as arthritis by the patient include phlebitis, arteriosclerosis obliterans, edema, neuropathy, vascular compression syndromes, the stiffness of Parkinson's disease, periarticu fractures, spinal stenosis, myositis, polymyalgia rheumatica, and fibromyositis. These can each be distinguished by their typical features (described elsewhere in The Manual) and by the absence or pau joint findings. Popliteal cysts resulting from knee arthritis can cause local popliteal pain, venous compr or rupture into the calf and can be confused with phlebitis.
Extra-articular findings can be significant in helping to identify the type of arthritis (eg, tophi in gout, no RA, pustular rash in gonococcemia). Coexisting periarticular disease also may facilitate diagnosis. For example, tendinitis commonly coexists with gonococcal arthritis, RA, and other systemic diseases; pro tenderness of bones adjacent to joints and joint effusions occur in sickle cell disease and hypertrophic
or rupture into the calf and can be confused with phlebitis.
Extra-articular findings can be significant in helping to identify the type of arthritis (eg, tophi in gout, no RA, pustular rash in gonococcemia). Coexisting periarticular disease also may facilitate diagnosis. For example, tendinitis commonly coexists with gonococcal arthritis, RA, and other systemic diseases; pro tenderness of bones adjacent to joints and joint effusions occur in sickle cell disease and hypertrophic pulmonary osteoarthropathy; and enthesitis with tenderness and swelling at tendon insertions suggest reactive arthritis.
Often, arthritis is transient and resolves without diagnosis. Arthritis also may not fulfill the criteria for an defined rheumatic disease (see Table 49-2). A tentative diagnosis is made for treatment, with other possibilities kept in mind. Systemic disease should be considered in all atypical and undiagnosed cond Lyme disease and other infections should always be considered early because they may respond to s treatment.
Certain problems require immediate attention and prompt treatment. Acute monarthritis is one exampl joint fluid examination is essential (see below). Hemorrhagic joint fluid suggests fracture, bleeding diat malignancy. Intensely inflammatory effusions suggest pyogenic infection, requiring immediate antibioti therapy and aspiration or other drainage to establish the diagnosis and to prevent joint destruction.
Blood tests are useful in diagnosing some specific types of arthritis (for specific tests, see the chapte each disease). Elevated ESR or C-reactive protein suggests inflammatory disease. Serum uric acid le elevated by diuretics, low doses of aspirin, other drugs, diet, or alcohol and in gout. Latex fixation tests rheumatoid factor are often highly positive in RA but may also be positive in hepatitis, cirrhosis, sarcoid subacute bacterial endocarditis, TB, and other infections and collagen diseases. Antinuclear factors m positive in RA, Sjgren's syndrome, progressive systemic sclerosis, SLE, hepatitis, and other diseases is suspected, anti-double-stranded DNA, anti-Sm, and complement levels may also provide further sup Serum CK and AST are elevated in muscle disease, including certain forms of muscular dystrophy, cru injury, and polymyositis or dermatomyositis. CK can also be elevated in hypothyroidism.
X-rays are important in the initial evaluation of relatively localized, unexplained joint complaints to dete possible primary or metastatic tumors, osteomyelitis, bone infarctions, periarticular calcifications, or ot changes in deep structures that may escape physical examination. Erosions, cysts, and joint space na can occur in chronic RA, gout, and osteoarthritis. X-rays also are especially useful in examination of th but are usually not needed if the problem seems to be simple acute back strain. CT and MRI can help puzzling persistent lesions.
Other useful studies may include needle or surgical synovial biopsy, ultrasound, arthroscopy, arthrogra bone scanning, electromyography, nerve conduction times, thermography, and muscle or bone biopsy Evaluation of synovial fluid is discussed below.
Differentiating Inflammatory and Noninflammatory Joint Disease
Once joint involvement is established, inflammatory and noninflammatory processes must be different Among the typical local signs of inflammation, increased heat and erythema are most helpful in this differentiation. Erythema should not be expected over chronically inflamed joints in RA. ESR and C-re protein tend to elevate and fever often occurs with severe inflammatory arthritis, but these may also be by an inflammatory process elsewhere in the body. Soft-tissue swelling tends to favor an inflammatory process, but aspiration of an effusion is essential to determine its nature. Osteoarthritis of the knee, al primarily degenerative, often causes knee effusions. Preparation for handling the fluid obtained is critic not necessary to perform all tests on each fluid. Synovial fluid measurements allow most effusions to be classified as normal, noninflammatory,
by an inflammatory process elsewhere in the body. Soft-tissue swelling tends to favor an inflammatory process, but aspiration of an effusion is essential to determine its nature. Osteoarthritis of the knee, al primarily degenerative, often causes knee effusions. Preparation for handling the fluid obtained is critic not necessary to perform all tests on each fluid.
Synovial fluid measurements allow most effusions to be classified as normal, noninflammatory, inflammatory, or septic (see Table 49-3). Effusions can also be hemorrhagic. Each type of effusion su certain joint diseases (see Table 49-4). So-called noninflammatory effusions are actually mildly inflam but tend to suggest diseases with less inflammatory mechanisms. If infection is suspected, a portion o synovial fluid sample should be sent to the laboratory for bacteriologic assessment.
Microscopic examination of a wet synovial fluid smear for crystals (only a few drops of fluid or washing joint are needed), using polarized light, is essential for definitive diagnosis of gout, pseudogout, and ot crystal-induced arthropathies (see Ch. 55). Use of an inexpensive polarizer over the light source and a between the specimen and the examiner's eye will visualize crystals with a shiny white birefringence. Compensated polarized light is provided by inserting a first-order red plate, as is found in commercially available microscopes. The effects of a compensator can be reproduced by placing two strips of clear adhesive tape on a glass slide and placing this slide over the lower polarizer. Any such homemade sys should be tested against a commercial polarizing microscope before diagnostic use. If the crystals see not typical, several less common crystals (cholesterol, liquid lipid crystals, cryoglobulins) or artifacts (e corticosteroid crystals) should be considered.
Other synovial fluid findings that may occasionally make or suggest a specific diagnosis include specif organisms (identifiable by Gram or acid-fast stain); spontaneous in vivo-developed LE cells; marrow sp (caused by fracture); Reiter's cells (monocytes that have phagocytized PMN), seen most often in reac arthritis; amyloid fragments (identifiable by Congo red stain); sickled RBCs (caused by sickle cell hemoglobinopathies); and iron in large mononuclear synovial cells (identifiable by Prussian blue stain present especially in hemochromatosis or pigmented villonodular synovitis).
Comparing synovial fluid and serum complement levels may only occasionally help evaluate inflam fluids. The synovial fluid complement level tends to be < 30% of the serum complement level in RA bu higher in gout, Reiter's syndrome, and infectious arthritis. Synovial fluid complement levels are low (ie, in noninflammatory effusions in which little protein is present. Both synovial and serum fluid compleme may be low in SLE. Measurements of rheumatoid factor in synovial fluid can give false-positive or false-negative results and, thus, should not be performed. Extremely low synovial fluid glucose levels i carefully handled specimens in fluoride tubes may favor the presence of infection.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 56. Tumors Of Bones And Joints Topics
[General] Benign Tumors Of Bone Malignant Tumors Of Bone
[General]
The most common problem in diagnosing and treating bone tumors is failure to suspect them. Persiste progressive unexplained pain of the trunk or extremities, particularly if associated with a mass, must b considered to be a tumor until proved otherwise.
Tumorous or tumorlike conditions rarely affect joints, unless by direct extension of an adjacent bone o tissue tumor. However, two conditions--osteochondromatosis and pigmented villonodular synovitis--oc the lining (synovium) of joints.
Osteochondromatosis is characterized by numerous cartilaginous loose bodies, each of which may larger than a grain of rice, in a swollen, painful joint. Surgery is needed to remove the loose bodies alo the synovium of the joint. In pigmented villonodular synovitis, the synovium becomes thickened and contains hemosiderin, which gives the tissue its blood-stained appearance. This tissue tends to invade adjacent bone, causing cystic destruction. The painful process is difficult to control. Surgery is the usu treatment.
Diagnosis
In children, primary bone tumors prevail; metastatic tumors are rare. In adults, metastatic tumors are a times more common than primary malignant tumors.
Certain x-ray signs may help distinguish benign from malignant lesions. Certain tumors have a charac appearance; eg, lymphoma of bone causes a moth-eaten appearance, whereas giant cell tumor appe cystic. X-rays also determine a tumor's location and may narrow diagnostic possibilities; eg, Ewing's tu commonly appears first in the shaft of the long bone, whereas osteosarcoma usually appears in the metaphysis toward the end of a long bone. Giant cell tumor usually affects the epiphyseal end. An ane bone cyst may be seen in any bone but is usually located in the metaphyseal portion of a long bone. C MRI may also help define the location and extent of a lesion but rarely provide a specific diagnosis. X-
appearance; eg, lymphoma of bone causes a moth-eaten appearance, whereas giant cell tumor appe cystic. X-rays also determine a tumor's location and may narrow diagnostic possibilities; eg, Ewing's tu commonly appears first in the shaft of the long bone, whereas osteosarcoma usually appears in the metaphysis toward the end of a long bone. Giant cell tumor usually affects the epiphyseal end. An ane bone cyst may be seen in any bone but is usually located in the metaphyseal portion of a long bone. C MRI may also help define the location and extent of a lesion but rarely provide a specific diagnosis. Xradioisotopic bone scanning should be performed to search for metastatic or multicentric lesions.
Biopsy is essential for diagnosis. However, histopathologic diagnosis of bone tumors is difficult and re sufficient tissue from a representative portion of the tumor. Open incisional biopsy is usually best. How some pathologists are skilled in diagnosing bone tumors from needle biopsies. The pathologist should given pertinent details of the clinical history and x-ray findings. Because almost all bone tumors have s portions, which are the best material to section and examine for diagnosis by fresh-frozen technique, immediate, accurate, definitive diagnosis is possible in > 90% of cases. Permanent histologic sections usually available on the day after biopsy.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 50. Diffuse Connective Tissue Disea Topics
Rheumatoid Arthritis Sjgren's Syndrome Behet's Syndrome Relapsing Polychondritis Systemic Lupus Erythematosus Discoid Lupus Erythematosus Systemic Sclerosis Eosinophilic Fasciitis Polymyositis And Dermatomyositis Polymyalgia Rheumatica Vasculitis Temporal Arteritis Polyarteritis Nodosa Wegener's Granulomatosis Mixed Connective Tissue Disease
Rheumatoid Arthritis
(See also Juvenile Rheumatoid Arthritis in Ch. 270.)
A chronic syndrome characterized by nonspecific, usually symmetric inflammation of the peripheral joi potentially resulting in progressive destruction of articular and periarticular structures, with or without generalized manifestations.
The cause is unknown. A genetic predisposition has been identified and, in white populations, localize pentapeptide in the HLA-DR 1 locus of class II histocompatibility genes. Environmental factors may als role. Immunologic changes may be initiated by multiple factors (see also Autoimmune Disorders unde Disorders with Type III Hypersensitivity Reactions in Ch. 148). About 1% of all populations are affected women two to three times more often than men. Onset may be at any age, most often between 25 and
Prominent immunologic abnormalities that may be important in pathogenesis include immune complex found in joint fluid cells and in vasculitis. Plasma cells produce antibodies (eg, rheumatoid factor [RF]) contribute to these complexes. Lymphocytes that infiltrate the synovial tissue are primarily T helper ce
Disorders with Type III Hypersensitivity Reactions in Ch. 148). About 1% of all populations are affected women two to three times more often than men. Onset may be at any age, most often between 25 and
Prominent immunologic abnormalities that may be important in pathogenesis include immune complex found in joint fluid cells and in vasculitis. Plasma cells produce antibodies (eg, rheumatoid factor [RF]) contribute to these complexes. Lymphocytes that infiltrate the synovial tissue are primarily T helper ce can produce pro-inflammatory cytokines. Macrophages and their cytokines (eg, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor) are also abundant in diseased synovium. Increase adhesion molecules contribute to inflammatory cell emigration and retention in the synovial tissue. Inc macrophage-derived lining cells are prominent along with some lymphocytes and vascular changes in disease.
In chronically affected joints, the normally delicate synovium develops many villous folds and thickens of increased numbers and size of synovial lining cells and colonization by lymphocytes and plasma ce lining cells produce various materials, including collagenase and stromelysin, which can contribute to c destruction; interleukin-1, which stimulates lymphocyte proliferation; and prostaglandins. The infiltratin initially perivenular but later forming lymphoid follicles with germinal centers, synthesize interleukin-2, o cytokines, RF, and other immunoglobulins. Fibrin deposition, fibrosis, and necrosis also are present. Hyperplastic synovial tissue (pannus) may erode cartilage, subchondral bone, articular capsule, and lig PMNs are not prominent in the synovium but often predominate in the synovial fluid.
Rheumatoid nodules occur in up to 30% of patients, usually subcutaneously at sites of chronic irritatio the extensor surface of the forearm). They are nonspecific necrobiotic granulomas consisting of a cen necrotic area surrounded by palisaded mononuclear cells with their long axes radiating from the cente enveloped by lymphocytes and plasma cells. Vasculitis can be found in skin, nerves, or visceral organ severe cases of RA but is clinically significant in only a few cases.
Symptoms and Signs
Onset is usually insidious, with progressive joint involvement, but may be abrupt, with simultaneous inflammation in multiple joints. Tenderness in nearly all inflamed joints is the most sensitive physical fi Synovial thickening, the most specific physical finding, eventually occurs in most involved joints. Symm involvement of small hand joints (especially proximal interphalangeal and metacarpophalangeal), foot (metatarsophalangeal), wrists, elbows, and ankles is typical, but initial manifestations may occur in any
Stiffness lasting > 30 min on arising in the morning or after prolonged inactivity is common; early aftern fatigue and malaise also occur. Deformities, particularly flexion contractures, may develop rapidly; ulna deviation of the fingers with slippage of the extensor tendons off the metacarpophalangeal joints is a t late result. Carpal tunnel syndrome can result from wrist synovitis. Ruptured popliteal cysts can mimic vein thrombosis.
Subcutaneous rheumatoid nodules are not usually an early manifestation. Visceral nodules, vasculitis leg ulcers or mononeuritis multiplex, pleural or pericardial effusions, lymphadenopathy, Felty's syndrom Sjgren's syndrome, and episcleritis are other extra-articular manifestations. Fever may be present an usually low-grade, except in adult-onset Still's disease, a seronegative RA-like polyarthritis with promin systemic features.
Laboratory Findings
Blood tests are helpful. A normochromic (or slightly hypochromic)-normocytic anemia, typical of other diseases, occurs in 80% of cases; the Hb is usually > 10 g/dL but may rarely be as low as 8 g/dL. Superimposed iron deficiency or other causes of anemia should be sought if Hb is < 10 g/dL. Neutrope occurs in 1 to 2% of cases, often with splenomegaly (Felty's syndrome). Mild polyclonal
Laboratory Findings
Blood tests are helpful. A normochromic (or slightly hypochromic)-normocytic anemia, typical of other diseases, occurs in 80% of cases; the Hb is usually > 10 g/dL but may rarely be as low as 8 g/dL. Superimposed iron deficiency or other causes of anemia should be sought if Hb is < 10 g/dL. Neutrope occurs in 1 to 2% of cases, often with splenomegaly (Felty's syndrome). Mild polyclonal hypergammaglobulinemia and thrombocytosis may be present.
The ESR is elevated in 90% of cases. Antibodies to altered -globulin, so-called rheumatoid factors (RF detected by agglutination tests (eg, the latex fixation test uses human IgG adsorbed to particulate late show IgM RF, occur in about 70% of cases. Although RFs are not specific for RA and are found in ma diseases (eg, granulomatous diseases, chronic infections, hepatitis, sarcoidosis, subacute bacterial endocarditis), a high RF titer helps confirm the diagnosis. In most laboratories, a latex fixation tube dilu of 1:160 is considered the lowest value favoring a diagnosis of RA. RF titers are also often measured nephelometry (< 20 IU/mL is considered negative). A very high RF titer suggests a worse prognosis an often associated with progressive disease, nodules, vasculitis, and pulmonary involvement. The titer c influenced by treatment and often falls as inflammatory joint activity decreases.
The synovial fluid, abnormal during active joint inflammation, is cloudy but sterile, with reduced visco usually 3,000 to 50,000 WBCs/L. Of these cells, PMNs typically predominate, but > 50% may be lym and other mononuclear cells. WBC cytoplasmic inclusions may be seen on a wet smear but are also p other inflammatory effusions. Synovial fluid complement is often < 30% of the serum level. Crystals ar absent.
On x-ray, only soft tissue swelling is seen in the first months of disease. Subsequently, periarticular osteoporosis, joint space (articular cartilage) narrowing, and marginal erosions may be present. The ra deterioration, seen on x-ray and clinically, is highly variable, but erosions as a sign of bony damage m within the first year.
Diagnosis
The American College of Rheumatology has developed simplified criteria for the classification of RA (s Table 50-1). Primarily intended as a communication aid for those in clinical research, these criteria can help guide clinical diagnosis.
Almost any other disease that causes arthritis must still be considered. Some patients with crystal-indu arthritis meet these new criteria; synovial fluid examination often helps exclude these cases. However, diseases causing arthritis can very occasionally coexist. When diagnosis is in doubt, unexplained subcutaneous nodules can be aspirated or biopsied to differentiate gouty tophi, amyloid, and other cau
SLE may mimic RA. SLE usually can be distinguished by the characteristic skin lesions on light-expos areas, temporal-frontal hair loss, oral and nasal mucosal lesions, nonerosive arthritis, joint fluid with of 2000 WBCs/L (predominantly mononuclear cells), positive antibodies to double-stranded DNA, renal and low serum complement levels (see Systemic Lupus Erythematosus, below). Positive antinuclear antibodies and some features of SLE may occur along with otherwise typical RA, giving rise to the term "overlap syndrome." Some of these patients may have severe RA; others have associated SLE or oth collagen disease. Polyarteritis, progressive systemic sclerosis, dermatomyositis, and polymyositis may features that resemble RA.
Other systemic diseases may cause symptoms similar to RA. Sarcoidosis, amyloidosis, Whipple's di and other systemic diseases may involve joints; tissue biopsy sometimes helps differentiate these con Acute rheumatic fever is differentiated by a migratory pattern of joint involvement and evidence of ante streptococcal infection (culture or changing antistreptolysin-O titer). Changing heart murmurs, chorea,
features that resemble RA.
Other systemic diseases may cause symptoms similar to RA. Sarcoidosis, amyloidosis, Whipple's di and other systemic diseases may involve joints; tissue biopsy sometimes helps differentiate these con Acute rheumatic fever is differentiated by a migratory pattern of joint involvement and evidence of ante streptococcal infection (culture or changing antistreptolysin-O titer). Changing heart murmurs, chorea, erythema marginatum are much less common in adults than in children. Infectious arthritis usually is monarticular or asymmetric (see Ch. 54). Diagnosis depends on identification of the causative agent. I can be superimposed on a joint affected by RA. Gonococcal arthritis usually presents as a migratory a that involves tendons around the wrist and ankle and finally settles in one or two joints. Lyme disease occur without the classic history of tick bite and rash; it can be screened for serologically (see Ch. 157 are most commonly involved. Reiter's syndrome (reactive arthritis) is characterized by evidence of ant urethritis or diarrhea; asymmetric involvement of the heel, sacroiliac joints, and large joints of the leg; u conjunctivitis; iritis; painless buccal ulcers; balanitis circinata; or keratoderma blennorrhagicum on the and elsewhere (see Ch. 51). Serum and joint fluid complement levels are often elevated. Psoriatic arth tends to be asymmetric and is not usually associated with RF, but differentiation may be difficult in the absence of characteristic nail or skin lesions (see Ch. 51). Distal interphalangeal joint involvement and mutilans can be suggestive.
Ankylosing spondylitis may be differentiated by its predilection for males, spinal and axial distribution o involvement, absence of subcutaneous nodules, and negative RF test (see Ch. 51). Gout may be mon or polyarticular, with complete recovery between acute attacks early in the disease. Chronic gout may RA (see Ch. 55). Typical needlelike or rodlike birefringent monosodium urate crystals with negative elo are present in the synovial effusion and can be seen by compensated polarized light (see also Ch. 49 Calcium pyrophosphate dihydrate crystal deposition disease may produce monarticular or polyarticula or chronic arthritis (see Ch. 55). However, the presence of weakly birefringent rodlike or rhomboid calc pyrophosphate dihydrate crystals with positive elongation in joint fluid and x-ray evidence of articular c calcification (chondrocalcinosis) differentiate this condition.
Osteoarthritis often involves the proximal and distal interphalangeal joints, first carpometacarpal and metatarsophalangeal joints, knee joints, and spine (see Ch. 52). Symmetry of involvement, prominent swelling (mostly caused by bony enlargement) with some signs of inflammation, joint instability, and subchondral cysts on x-ray may be confusing; the absence of significant amounts of RF, rheumatoid n and systemic involvement along with the characteristic osteoarthritis pattern of joint involvement with s fluid WBC counts < 1000 to 2000/L permit differentiation from RA.
Treatment
As many as 75% of patients improve symptomatically with conservative treatment during the first year disease. However, >= 10% are eventually severely disabled despite full treatment. The disease greatly the lives of most RA patients.
Rest and nutrition: Complete bed rest is occasionally indicated for a short period during the most act painful stage of severe disease. In less severe cases, regular rest should be prescribed. Splints provid joint rest. Joint range of motion and exercise as tolerated must be continued (see below). An ordinary diet is generally sufficient. Rarely, patients have food-associated exacerbations. Food and diet quacke common and should be discouraged. However, fish or plant oil supplements may partially relieve symp because they can decrease production of prostaglandins.
Nonsteroidal anti-inflammatory drugs and salicylates: NSAIDs provide important symptomatic relie may be adequate as simple therapy for mild RA, but they do not appear to alter the long-term course o disease.
because they can decrease production of prostaglandins.
Nonsteroidal anti-inflammatory drugs and salicylates: NSAIDs provide important symptomatic relie may be adequate as simple therapy for mild RA, but they do not appear to alter the long-term course o disease.
Salicylates are relatively safe, inexpensive, analgesic, and anti-inflammatory and can still be a corners drug therapy. Aspirin (acetylsalicylic acid) is begun with 0.6 to 1.0 g (two to three 300-mg tablets) quid meals and with a bedtime snack. Dosage may be increased as needed until a maximally effective or m toxic dose (eg, tinnitus, diminished hearing) is achieved. The final dose may vary from 3 to 6.0 g/day ( to 20 300-mg tablets). The average daily dose required in active RA is 4.5 g (15 tablets). Antacids, suc or H2 blockers between meals can be taken for mild GI symptoms without discontinuing the aspirin. Enteric-coated tablets may offer some advantage because they are less locally irritating in patients wit concomitant dyspepsia from gastritis or hiatus hernia. However, absorption may not be as reliable, and systemic actions still affect the gastric mucosa. Misoprostol 100 to 200 g bid to qid as tolerated used aspirin (and with the NSAIDs described below) may decrease the chance of erosion and a bleeding ga ulcer in high-risk patients, but it may cause abdominal cramps and diarrhea and does not relieve naus epigastric pain. Proton pump inhibitors also appear to decrease the risk of ulcers. Sustained-release a provides longer relief for some patients and may be useful at bedtime, although patients awakened at pain may need a second dose. Nonacetylated salicylates (eg, salsalate, choline magnesium salicylate to offer better GI tolerance than aspirin and do not impair platelet adhesiveness, but they may not be a effective as anti-inflammatory agents.
Other NSAIDs are available for patients who cannot tolerate sufficient aspirin to obtain a good effect o whom less frequent dosing offers a major advantage (see Table 50-2); these drugs are widely used. U only one such NSAID should be given at a time. Doses of all drugs with flexible dosing can be increas 2 wk until response is maximal or maximum dosage is reached. Drugs should be tried for >= 2 to 3 wk assuming inefficacy.
Although often less irritating to the GI tract than high-dose aspirin, these other NSAIDs can also produ gastric symptoms and GI bleeding. They should be avoided during active ulcer disease. Other possible effects include headache, confusion and other CNS symptoms, worsening of hypertension, edema, an decreased platelet adhesiveness. As with aspirin, liver enzymes can be mildly elevated. Creatinine lev rise because of inhibited renal prostaglandins; less frequently, interstitial nephritis can occur. Patients urticaria, rhinitis, or asthma from aspirin can have the same problems with these other NSAIDs. Agranulocytosis has been reported.
NSAIDs act by inhibiting cyclooxygenase enzymes and thus inhibit prostaglandins. Some prostaglandi cyclooxygenase-1 (COX-1) control have important effects in many parts of the body (eg, they provide protection to renal blood flow and the gastric mucosa). Other prostaglandins are induced by inflammat are produced by COX-2. Drugs that may inhibit only or predominantly COX-2 (eg, celecoxib, rofecoxib avoid many of the side effects that result from drugs that also inhibit COX-1.
Slow-acting drugs: The optimal time to add slow-acting drugs to therapy has been re-evaluated, with consensus that early use is indicated in persistent disease. Generally, if pain and swelling persist after mo of disease despite treatment with aspirin or other NSAIDs, the addition of a slow-acting or potentia disease-modifying drug (eg, gold, hydroxychloroquine, sulfasalazine, penicillamine) should be conside Methotrexate, an immunosuppressive drug (see below), is now increasingly also used very early as on second-line potentially disease-modifying drugs.
Gold compounds usually are given in addition to salicylates or other NSAIDs if the latter do not suffic relieve pain or suppress active joint inflammation. In some patients, gold may produce clinical remissio decrease the formation of new bony erosions. Parenteral preparations include gold sodium thiomalate thioglucose (aurothioglucose) IM at weekly intervals: 10 mg the first week, 25 mg the second, and 50 m
second-line potentially disease-modifying drugs.
Gold compounds usually are given in addition to salicylates or other NSAIDs if the latter do not suffic relieve pain or suppress active joint inflammation. In some patients, gold may produce clinical remissio decrease the formation of new bony erosions. Parenteral preparations include gold sodium thiomalate thioglucose (aurothioglucose) IM at weekly intervals: 10 mg the first week, 25 mg the second, and 50 m thereafter until a total of 1 g has been given or significant improvement is apparent. When maximum improvement is achieved, dosage is gradually decreased to 50 mg every 2 to 4 wk. Relapse commonl in 3 to 6 mo if no gold is given after remission. Improvement often can be sustained for several years w prolonged maintenance administration.
Gold compounds are contraindicated in patients with significant hepatic or renal disease or with blood dyscrasia. Before initiating gold therapy, a urinalysis, Hb level, total and differential WBC count, and p count should be obtained. These tests should be repeated before each injection during the first month before every one to two injections thereafter. Presence of HLA-DR3 or HLA-B8 may predict an increas of renal and possibly other side effects from both gold and penicillamine. Possible toxic reactions to go include pruritus, dermatitis, stomatitis, albuminuria with or without a nephrotic syndrome, agranulocyto thrombocytopenic purpura, and aplastic anemia. Less common side effects include diarrhea, hepatitis pneumonitis, and neuropathy. Eosinophilia > 5% and pruritus may precede appearance of a rash and danger signals. Dermatitis usually is pruritic and ranges in severity from a single eczematous patch to generalized and, very rarely, fatal exfoliation.
Gold should be discontinued when any of the above manifestations appear. Minor toxic manifestations mild pruritus, minor rash) may be eliminated by temporarily withholding gold therapy, then resuming it cautiously about 2 wk after symptoms have subsided. However, if toxic symptoms progress, gold shou withheld and the patient given a corticosteroid. A topical corticosteroid or oral prednisone 15 to 20 mg/ divided doses is given for mild gold dermatitis; larger doses may be needed for hematologic complicat gold chelating drug, dimercaprol 2.5 mg/kg IM, may be given up to four to six times/day for the first 2 d bid for 5 to 7 days after a severe gold reaction.
A transient nitritoid reaction with flushing, tachycardia, and faintness can occur several minutes after in of gold sodium thiomalate, particularly if the gold is not stored out of direct light. If these reactions occu aurothioglucose can be used, as this does not seem to cause nitritoid reactions.
An oral gold compound, auranofin, 3 mg bid or 6 mg once daily, may be tried for >= 6 mo and, if neces and tolerated, increased to 3 mg tid for 3 mo more. If the response is not favorable, auranofin should b discontinued. Unlike with injectable gold, diarrhea and other GI symptoms are prominent side effects. and mucocutaneous side effects are fewer than with IM gold, but auranofin does not seem to be as ef as the parenteral gold. Urinalysis, hemoglobin, and the WBC, differential, and platelet counts should b performed at least monthly.
Hydroxychloroquine can also control symptoms of mild or moderately active RA. Toxic effects usuall mild and include dermatitis, myopathy, and generally reversible corneal opacity. However, irreversible degeneration has been reported. Ophthalmologic testing of visual fields using a red test object is recommended before and every 6 mo during treatment. The initial dosage of 200 mg po bid (with brea and dinner) is continued for about 6 to 9 mo. The drug should be discontinued if the patient shows no improvement after 6 to 9 mo. If definite improvement is achieved, the dosage can sometimes be decre 200 mg/day and continued as long as effective. Frequent eye examinations must be continued.
Sulfasalazine, long used for ulcerative colitis, is now increasingly used for RA (for which it was develo is usually given as enteric-coated tablets, starting with 500 mg/day and increasing 500 mg at weekly in to 2 to 3 g/day. Benefit should occur within 3 mo. Toxic effects may include gastric symptoms, neutrop hemolysis, hepatitis, and rash. Monitoring with CBCs and serum chemistries is important while increas dose and occasionally throughout use.
Sulfasalazine, long used for ulcerative colitis, is now increasingly used for RA (for which it was develo is usually given as enteric-coated tablets, starting with 500 mg/day and increasing 500 mg at weekly in to 2 to 3 g/day. Benefit should occur within 3 mo. Toxic effects may include gastric symptoms, neutrop hemolysis, hepatitis, and rash. Monitoring with CBCs and serum chemistries is important while increas dose and occasionally throughout use.
Oral penicillamine may have a benefit similar to gold and may be used in some cases if gold fails or p toxicity in patients with active RA. Side effects are minimized by starting with low dosages. A dosage o mg/day is given for 30 to 90 days; the dosage is increased to 500 mg/day for another 30 to 90 days an definite improvement does not occur, may be increased to 750 mg/day for 60 days. When the patient respond, the dose should not be further increased but kept to the minimally effective level. Before and to 4 wk during therapy, platelets must be checked and urinalysis and CBC performed. Side effects req discontinuation are more common than with gold and include marrow suppression, proteinuria, nephro other serious toxic effects (eg, myasthenia gravis, pemphigus, Goodpasture's syndrome, polymyositis, lupuslike syndrome), rash, and a foul taste. The drug should be given by, or with guidance from, one experienced with its use, and its effects must be monitored closely.
Combinations of slow-acting drugs may be more effective that a single drug. In a recent trial, hydroxychloroquine, sulfasalazine, and methotrexate together were more effective that methotrexate a the other two together.
Corticosteroids: Corticosteroids are the most dramatically effective short-term anti-inflammatory drug however, their clinical benefit for RA often diminishes with time. Corticosteroids do not predictably prev progression of joint destruction, although a recent report suggested that they may slow erosions. Furth severe rebound follows the withdrawal of corticosteroids in active disease. Because of their long-term effects, many recommend that corticosteroids should be given only after a careful and usually prolong of less hazardous drugs. Relative contraindications to corticosteroid use include peptic ulcer, hyperten untreated infections, diabetes mellitus, and glaucoma. TB should be ruled out before corticosteroid the begun.
Corticosteroids promptly suppress clinical manifestations for many patients and may be used for disea exacerbations to maintain joint function and to allow continued performance of customary duties, but t patient should be cautioned about complications with long-term use. Prednisone dosage should not ex 7.5 mg/day, except in patients with severe systemic manifestations of RA (eg, vasculitis, pleurisy, peric Large loading doses followed by rapid dose reduction are not generally recommended (although they been used), nor is alternate-day therapy, because RA usually is too symptomatic on the days corticost are not given.
Intra-articular injections of corticosteroid esters may temporarily help control local synovitis in one or tw particularly painful joints. Triamcinolone hexacetonide may suppress inflammation for the longest time depot corticosteroids, including prednisolone tertiary-butylacetate, also are effective. The soluble 21-phosphate preparations of prednisolone or dexamethasone are not recommended because of rapi clearance from the joint and very short duration of action. Overuse of the recently injected, less painfu may accelerate joint destruction. Because corticosteroid esters are crystalline, local inflammation trans increases within a few hours in about 2% of injections.
Cytotoxic or immunosuppressive drugs: These drugs (eg, methotrexate, azathioprine, cyclosporine increasingly used in management of severe, active RA. They can suppress inflammation and may allo reduction of corticosteroid doses. However, major side effects can occur, including liver disease, pneu bone marrow suppression, and, after long-term use of azathioprine, malignancy. Patients should be fu informed of these potential side effects, and supervision by a specialist is generally advised.
In the course of severe active disease, methotrexate may be used reasonably early (benefit often occu to 4 wk). It can be given 2.5 to 20 mg in a single dose once weekly, starting at 7.5 mg/wk and graduall
reduction of corticosteroid doses. However, major side effects can occur, including liver disease, pneu bone marrow suppression, and, after long-term use of azathioprine, malignancy. Patients should be fu informed of these potential side effects, and supervision by a specialist is generally advised.
In the course of severe active disease, methotrexate may be used reasonably early (benefit often occu to 4 wk). It can be given 2.5 to 20 mg in a single dose once weekly, starting at 7.5 mg/wk and graduall increased as needed. It should be avoided in heavy drinkers and diabetics. Liver function must be mon and a liver biopsy may be needed if liver function tests are abnormal and the patient needs to continue this drug. Clinically significant liver fibrosis is uncommon. CBCs should be performed regularly. Pneum a rare fatal complication. Severe relapses of arthritis can occur after withdrawal. Azathioprine should b initiated at about 1 mg/kg/day (50 to 100 mg) as a single oral dose or bid; dosage can be increased by mg/kg/day after 6 to 8 wk at 4-wk intervals to a maximum of 2.5 mg/kg/day. Maintenance should be at lowest effective dose. Cyclosporine is effective in treatment of RA and may be especially useful in com with other slow-acting drugs. Dosages generally should not exceed 5 mg/kg/day to minimize toxic effe BP and renal function. Although not approved for RA in the USA, cyclophosphamide also is effective b used less often because of greater risks of toxicity.
Etanercept is a tissue necrosis factor antagonist that can be given twice weekly (25 mg sc) to patients have had an inadequate response to one or more disease-modifying drugs. Experimental therapies (e interleukin-1 receptor antagonists) are being studied and have potential but are not yet available.
Exercise, physiotherapy, and surgery: Flexion contractures can be prevented and muscle strength most successfully after inflammation begins to subside. Joint splinting reduces local inflammation and relieve severe local symptoms. Before acute inflammation is controlled, passive exercise to prevent contracture is given carefully and within the limits of pain. Active exercise (including walking and speci exercises for involved joints) to restore muscle mass and preserve the normal range of joint motion is important as inflammation subsides but should not be fatiguing. Established flexion contractures may intensive exercise, serial splinting, or orthopedic measures. Orthopedic or athletic shoes with good hee arch support can be modified using inserts to fit individual needs and are frequently helpful; metatarsa placed posteriorly to painful metatarsophalangeal joints decrease the pain of weight bearing.
Although synovectomy only temporarily relieves inflammation, arthroscopic or surgical synovectomy m preserve joint function if drugs have been unsuccessful. Arthroplasty with prosthetic replacement of jo is indicated if joint damage severely limits function: Total hip and knee replacements are the most con successful. Prosthetic hips and knees cannot be expected to tolerate resumption of vigorous activities competitive athletics). Excision of subluxated painful metatarsophalangeal joints may greatly aid walkin Thumb fusions may provide stability for pinch. Neck fusion may be needed for C1-2 subluxation with c compression or severe pain. Surgical procedures must always be considered in terms of the total dise Deformed hands and arms limit crutch use during rehabilitation; seriously affected knees and feet prev benefit from hip surgery. Reasonable objectives for each patient must be determined, and function mu considered before appearance. Surgery may be performed while the disease is active. Self-help devic enable many patients with severe debilitating RA to perform activities of daily living.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 57. Osteoporosis Topics
[General]
[General]
Osteoporosis: A generalized, progressive diminution of bone density (bone mass per unit volume), cau skeletal weakness, although the ratio of mineral to organic elements is unchanged.
In normal bone, bone formation and bone resorption are closely coupled. In osteoporosis, the net rate resorption exceeds the rate of bone formation, resulting in a decrease in bone mass without a defect i mineralization. In women, osteoclast activity is increased because of decreased estrogen; as men and age > 60 yr, osteoblast activity drops off. Men with prematurely decreased testosterone may have incr osteoclast activity. These changes result in further net loss of bone. The amount of bone available for mechanical support of the skeleton eventually falls below the fracture threshold, and the patient may s fracture with little or no trauma. Bone loss affects both cortical and trabecular bone. Histologically, ther reduction in cortical thickness and in the number and size of trabeculae of cancellous bone, with norm of the osteoid seams. Trabecular bone loss predominates in typical postmenopausal osteoporosis. A d mineralization (osteomalacia) and osteoporosis can coexist.
Peak bone mass in men and women occurs by the middle of the third decade of life and plateaus for a years, during which turnover of bone is constant, with bone formation approximately equaling bone res This is followed by net bone loss of about 0.3 to 0.5%/yr. Beginning with menopause, women experien accelerated bone loss (may be increased tenfold at the rate of 3 to 5%/yr) for about 5 to 7 yr.
The major clinical manifestations of osteoporosis are bone fractures, which cause chronic pain. Howev everyone with low bone mass will experience fracture. The quantity of bone defined as bone density c measured and is predictive of future fracture; however, without bone biopsy, predicting the quality of b important component of bone strength) is difficult. Falls add additional risk. Many elderly persons are a falls because of poor coordination, poor vision, muscle weakness, confusion, and use of hypnotics or medications that alter the sensorium. The use of hip pads by elderly patients can reduce the incidence fracture despite continued falls. Increasing physical activity may increase bone mineral density and lea increased stability and muscle strength.
Classification, Etiology, and Incidence
falls because of poor coordination, poor vision, muscle weakness, confusion, and use of hypnotics or medications that alter the sensorium. The use of hip pads by elderly patients can reduce the incidence fracture despite continued falls. Increasing physical activity may increase bone mineral density and lea increased stability and muscle strength.
Classification, Etiology, and Incidence
Osteoblasts (cells that make the organic matrix of bone and then mineralize bone) and osteoclasts (ce resorb bone) are controlled by systemic hormones, cytokines, and other local factors (eg, parathyroid [PTH], calcitonin, estrogen, 25-hydroxyvitamin D). Estrogen deficiency is a significant cause of acceler bone loss in the perimenopausal state and affects circulating levels of specific cytokines (eg, interleuk tumor necrosis factor-, granulocyte-macrophage colony-stimulating factor, interleukin-6). Levels of the cytokines rise with the loss of estrogen and enhance bone resorption through increased recruitment, differentiation, and activation of osteoclasts. Although calcitonin levels are decreased in women comp men, calcitonin deficiency does not appear to be important in age-related osteoporosis.
Physical stress tends to increase bone mass, whereas immobilization furthers bone loss. Obesity is as with higher bone mass; patients with osteoporosis tend to weigh less and have less muscle mass. Insu dietary intake of Ca, P, and vitamin D is associated with age-related bone loss. The body's acid-base b is also important; for example, the alkalization of the blood with HCO3 retards bone loss. Late menarch early menopause, nulliparity, caffeine ingestion, alcohol use, and cigarette smoking are also important determinants of decreased bone mass. Blacks and Hispanics (Americans of Latin-American descent) higher bone mass than whites and Asians, and men have higher bone mass than women. Thus, altho blacks and Hispanics can develop osteoporosis, they generally do so at a later age than whites and As Genetic factors are important in the development of osteoporosis; postmenopausal women with a fam history of fractures will probably encounter future problems.
Primary osteoporosis: Three types of primary osteoporosis exist. Idiopathic osteoporosis is uncom occurs in children and young adults of both sexes with normal gonadal function.
Type I osteoporosis (postmenopausal osteoporosis) occurs between ages 51 and 75 yr. Although times more common in women, it also occurs in men after castration or with low levels of serum testos and is directly related to the loss of gonadal function. Estrogen loss leads to elevated serum levels of interleukin-6 and perhaps other cytokines, which are thought to lead to increased recruitment and responsiveness of osteoclast precursors in trabecular (cancellous) bone, resulting in increased bone resorption. Type I is largely responsible for fractures in which trabecular bone is predominant, such as vertebral crush fractures and Colles' (distal radius) fractures.
Type II osteoporosis (involutional or senile osteoporosis) is associated with normal processes of a with a gradual decline in the number and activity of osteoblasts and not primarily with an increase in os activity. It typically occurs in patients > 60 yr and is twice as common in women as in men. Type II affe trabecular and cortical bone, often resulting in fractures of the femoral neck, vertebrae, proximal hume proximal tibia, and pelvis. It may result from age-related reduction in vitamin D synthesis or resistance vitamin D activity (possibly mediated by decreased or unresponsive vitamin D receptors in some patie older women, types I and II often occur together.
Secondary osteoporosis: Secondary osteoporosis accounts for < 5% of osteoporosis cases. Causes endocrine disease (eg, glucocorticoid excess, hyperparathyroidism, hyperthyroidism, hypogonadism, hyperprolactinemia, diabetes mellitus), drugs (eg, glucocorticosteroids, ethanol, dilantin, tobacco, barb heparin), and miscellaneous conditions (eg, immobilization, chronic renal failure, liver disease, malabs syndromes, chronic obstructive lung disease, RA, sarcoidosis, malignancy, prolonged weightlessness in space flight).
Symptoms and Signs
hyperprolactinemia, diabetes mellitus), drugs (eg, glucocorticosteroids, ethanol, dilantin, tobacco, barb heparin), and miscellaneous conditions (eg, immobilization, chronic renal failure, liver disease, malabs syndromes, chronic obstructive lung disease, RA, sarcoidosis, malignancy, prolonged weightlessness in space flight).
Symptoms and Signs
Patients with uncomplicated osteoporosis may be asymptomatic or may have pain in the bones or mu particularly of the back. Vertebral crush fractures may develop with minimal or no trauma, usually in weight-bearing vertebrae (T-8 and below); isolated fractures of T-4 or above suggest malignancy. Whe symptomatic, the pain is of acute onset, usually does not radiate, is aggravated by weight bearing, ma associated with local tenderness, and generally begins to subside in 1 wk. However, residual pain may 3 mo. Multiple compression fractures eventually may cause dorsal kyphosis with exaggerated cervical (dowager's hump). Abnormal stress on the spinal muscles and ligaments may cause chronic, dull, ach particularly prominent in the lower thoracic and lumbar area. Fractures at other sites, commonly the hi distal radius, usually result from a fall.
Diagnosis
Serum Ca and P levels, serum protein electrophoresis, and ESR are normal in primary osteoporosis; s alkaline phosphatase is usually normal but may be slightly elevated by a recent fracture or substantiall elevated by multiple recent fractures. PTH levels are normal or low in type I patients and increased in Ca absorption is decreased or if there is inappropriate hypercalciuria. About 20% of postmenopausal osteoporotic women have significant hypercalciuria, which may lead to elevations in serum PTH. Indic bone turnover may be increased (eg, urinary excretion of hydroxyproline-containing peptides, urinary pyridinium peptide, or serum osteocalcin; uptake of technetium-99m methylene diphosphonate). Othe abnormal biochemical findings suggest secondary osteoporosis.
On x-ray, vertebrae and other bones show decreased radiodensity from loss of trabecular structure. H subjective impressions of bone density may be misleading because osteoporosis cannot be diagnosed x-ray (as radiolucency) until > 30% of bone has been lost. A loss of horizontally oriented trabeculae inc the prominence of the cortical end plates and of the remaining vertically oriented, weight-bearing trabe Anterior wedging in the thoracic region and ballooning of the vertebral interspaces in the lumbar region characteristic of vertebral fractures. Although the cortices of long bones may be thin because of exces endosteal resorption, the periosteal surface remains smooth (in contrast to the irregular cortical outline by subperiosteal resorption in hyperparathyroidism). Glucocorticosteroid-induced osteoporosis is likely produce radiolucency of the skull, rib fractures, and exuberant callus formation at sites of healing fract Osteomalacia (see Vitamin D Deficiency and Dependency in Ch. 3) may be confused with osteoporos x-ray but can be distinguished by abnormal serum biochemical findings and by bone biopsy.
Single and dual photon absorptiometry, dual x-ray absorptiometry (DXA), and quantitative CT m bone density of the lumbar spine, hip, and distal radius or ulna and are useful in diagnosis and in follo treatment response. The WHO defines osteoporosis by the DXA results: > 1 standard deviation from t average value in 35-yr-old sex- and race-matched control subjects is defined as osteopenia and sugge osteoporosis; > 2.5 is diagnostic. DXA studies usually are performed at the spine. DXA study of the hip generally better than that of the spine because it is thought to give some information about cortical and trabecular bone, but study of the spine is easier to perform and probably faster.
Prevention and Treatment
The goals of management of osteoporosis are to prevent fractures, to decrease pain when present, an maintain function. Pharmaceutical agents are used to minimize further bone loss. The risk of fracture i
The goals of management of osteoporosis are to prevent fractures, to decrease pain when present, an maintain function. Pharmaceutical agents are used to minimize further bone loss. The risk of fracture i reduced by nonpharmaceutical measures, including maintenance of adequate body weight, increased and other weight-bearing exercises, avoidance of long-acting benzodiazepines, minimal caffeine and a intake, decreased smoking, and treatment of impaired visual function. Educating patients about the ris falls and developing individualized programs to increase physical stability are important.
Women should be advised to consume >= 1000 mg of elemental Ca in their daily diet, but if a strong history of osteoporosis is present or if osteoporosis has already been diagnosed, total Ca intake shoul 1500 mg/24 h. Typically, a small daily supplement of vitamin D (400 IU) is recommended, unless the p hypercalciuric or has abnormal levels of vitamin D. Calcium carbonate tablets 600 mg four to six times (equivalent to 1 to 1.5 g/day of Ca) may be given, but calcium citrate is better absorbed in achlorhydric and may have fewer GI side effects.
Osteoporotic men are given Ca supplements, 1 to 1.5 g/day. When there is evidence of decreased Ca absorption (assessed by urinary Ca levels < 100 mg/day [2.5 mmol/day]), supplements may be increa 3 g/day, and vitamin D 50,000 IU po may be given once or twice weekly. Serum and urine Ca should b monitored closely at these dosages to avoid hypercalcemia, hypercalciuria, and renal failure. 25-Hydroxyvitamin D facilitates Ca absorption in some patients.
Women should consider hormone replacement therapy with estrogen, with or without progestin, in ad Ca; eg, conjugated estrogen 0.625 to 1.25 mg/day, omitting the dosage for 5 consecutive days each m help prevent uterine endometrial hyperplasia, or progestin as described below (see also discussion un Menopause in Ch. 236). Estrogen may arrest or decrease disease progression. It is most effective if s within 4 to 6 yr of menopause, but it may slow bone loss and reduce fractures even when started muc Estrogen produces withdrawal bleeding in about half of postmenopausal women and may increase the endometrial cancer (a progestin, such as medroxyprogesterone acetate 5 to 10 mg/day, for the last 10 the cycle decreases the risk of endometrial cancer but increases the occurrence of withdrawal bleedin produces a more unfavorable serum lipid profile). Estrogen also increases risk of biliary disease but m prevent heart disease and stroke. Risk of breast cancer may be slightly increased. Raloxifene, an estr drug, decreases bone loss without measurable effects on the uterus, decreases serum LDL levels, an not increase serum HDL; its effects on the breast are still unknown.
Bisphosphonates inhibit osteoclast-mediated bone resorption; alendronate has been approved for osteoporosis. Therapy with 10 mg/day decreases the risk of fracture at the vertebrae and hip in postmenopausal women with osteoporosis and increases bone mineral density over at least 4 yr of co therapy. In addition, in patients who are postmenopausal without osteoporosis, alendronate 5 mg/day bone loss. A patient who is resistant to Ca supplementation and who will not or cannot take hormone replacement therapy should consider alendronate therapy alone. The drug must be taken on an empty stomach with a full glass of water, and the patient must remain upright for >= 30 min afterwards to dec the risk of esophageal irritation. Other bisphosphonates are also in development.
Women who are unable to tolerate estrogen because of side effects, or in whom estrogen therapy is contraindicated, can be given salmon calcitonin, which is available in parenteral and nasal spray form parenteral dose is 100 IU sc daily or every other day, whereas the nasal spray dose is 200 U/day in al nostrils (one spray); both formulations require adequate vitamin D and Ca supplementation. Salmon c may be helpful as an antiresorptive agent and as a short-term analgesic (< 3 mo) after an acute fractu
Combined therapy with sodium fluoride 50 mg/day and >= 1 g of supplemental Ca appears to increa mass, but the bone is abnormal (increased trabecular but decreased cortical bone density) and more f
parenteral dose is 100 IU sc daily or every other day, whereas the nasal spray dose is 200 U/day in al nostrils (one spray); both formulations require adequate vitamin D and Ca supplementation. Salmon c may be helpful as an antiresorptive agent and as a short-term analgesic (< 3 mo) after an acute fractu
Combined therapy with sodium fluoride 50 mg/day and >= 1 g of supplemental Ca appears to increa mass, but the bone is abnormal (increased trabecular but decreased cortical bone density) and more f Thus, fluoride is not recommended. Slow-release fluoride is reportedly beneficial; however, the long-te benefit of this therapy is unknown.
There is significant investigation on the use of growth factors as stimulants to produce new bone. Sm intermittent, daily doses of PTH stimulate bone formation without stimulating bone resorption.
Acute back pain from a vertebral crush fracture should be treated with an orthopedic support, analges (when muscle spasm is prominent) heat and massage. Salmon calcitonin therapy also has analgesic properties. Chronic backache may be relieved by an orthopedic garment or, more physiologically, by hyperextension exercises to strengthen paravertebral muscles. Avoiding heavy lifting and falls is impo However, immobilization should be minimized and consistent weight-bearing exercise encouraged.
In severe, uncontrolled fractures caused by osteoporosis, short-term androgens (< 3 mo) can be cons for women when all else fails. Stanozolol and nandrolone increase bone density in women, but their us limited because they lower serum concentrations of high density lipoprotein, cause virilization, and risk hepatotoxicity. Men with osteoporosis also require evaluation for androgen deficiency, for which replac therapy may be considered.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 51. Arthritis Associated With Spondyl Topics
Ankylosing Spondylitis Reiter's Syndrome Psoriatic Arthritis
Ankylosing Spondylitis
(Marie-Strmpell Disease)
A systemic rheumatic disorder characterized by inflammation of the axial skeleton and large periphera
Ankylosing spondylitis (AS) is categorized with Reiter's syndrome (venereal and dysenteric), psoriasis, arthritis, ulcerative colitis, and Crohn's disease, which constitute the seronegative (ie, negative rheuma factor) spondyloarthropathies.
AS is three times more frequent in men than in women and begins most often between the ages of 20 It is 10 to 20 times more common in first-degree relatives of AS patients than in the general population increased prevalence of HLA-B27 tissue antigen in whites or HLA-B7 in blacks supports a genetic predisposition, although environmental factors may contribute. The risk of AS in persons with HLA-B27 about 20%.
Symptoms and Signs
The most frequent presentation is back pain, but disease can begin atypically in peripheral joints, espe children and women, and rarely with acute iritis (anterior uveitis). Additional early symptoms and signs diminished chest expansion from diffuse costovertebral involvement, low-grade fever, fatigue, anorexia loss, and anemia. Recurrent back pain--often nocturnal and of varying intensity--is an eventual compla morning stiffness typically relieved by activity. A flexed or bent-over posture eases back pain and para muscle spasm; thus, some degree of kyphosis is common in untreated patients.
Systemic manifestations occur in 1/3 of patients. Recurrent, usually self-limited, acute iritis (anterior uv rarely is protracted and severe enough to impair vision. Neurologic signs can occasionally result from compression radiculitis or sciatica, vertebral fracture or subluxation, and cauda equina syndrome (whic consists of impotence, nocturnal urinary incontinence, diminished bladder and rectal sensation, and ab of ankle jerks). Cardiovascular manifestations can include aortic insufficiency, angina, pericarditis, and
Systemic manifestations occur in 1/3 of patients. Recurrent, usually self-limited, acute iritis (anterior uv rarely is protracted and severe enough to impair vision. Neurologic signs can occasionally result from compression radiculitis or sciatica, vertebral fracture or subluxation, and cauda equina syndrome (whic consists of impotence, nocturnal urinary incontinence, diminished bladder and rectal sensation, and ab of ankle jerks). Cardiovascular manifestations can include aortic insufficiency, angina, pericarditis, and conduction abnormalities. A rare pulmonary finding is upper lobe fibrosis, occasionally with cavitation t be mistaken for TB and can be complicated by infection with Aspergillus.
AS is characterized by mild or moderate flares of active spondylitis alternating with periods of almost o inactive inflammation. Proper treatment in most patients results in minimal or no disability and in full, productive lives despite back stiffness. Occasionally, the course is severe and progressive, resulting in pronounced incapacitating deformities. The prognosis is bleak for patients with refractory iritis and for patient with secondary amyloidosis.
Diagnosis
The ESR and other acute-phase reactants (eg, C-reactive protein and serum Ig levels) are mildly eleva most patients with active AS. Tests for IgM rheumatoid factor and antinuclear antibodies are negative. positive test for HLA-B27 is usual but not invariable and not specific (a negative test is more useful in h to exclude AS than a positive test is in diagnosing it). This test is not necessary in patients with typical
Diagnosis must be confirmed by x-ray. The earliest abnormalities (pseudo-widening from subchondral erosions, sclerosis or later narrowing) occur in the sacroiliac joints. Early changes in the spine are upp lumbar vertebral squaring and demineralization, spotty ligamentous calcification, and one or two evolv syndesmophytes. The classic bamboo spine with prominent syndesmophytes and diffuse paraspinal ligamentous calcification is not useful for early diagnosis; these changes develop in a minority of patie an average period of 10 yr.
A herniated intervertebral disk is limited to the spine and has no systemic manifestations (eg, fatigu anorexia, weight loss). Laboratory tests, including the ESR, are normal. If necessary, this is confirmed myelography, CT, or MRI. Disease of a single sacroiliac joint should raise concern about infection. Tuberculous spondylitis is discussed under Tuberculosis of Bones and Joints in Ch. 157.
Diffuse idiopathic skeletal hyperostosis (DISH) syndrome is more difficult to differentiate. It occurs primarily in men > 50 yr and may resemble AS clinically and on x-ray. Patients may have some spinal stiffness, and insidious loss of motion. X-ray findings include large ligamentous ossifications bridging s vertebrae and usually affecting the cervical and lower thoracic spine. However, the sacroiliac and spin apophyseal joints are not eroded, stiffness is not accentuated in the morning, the ESR is normal, and no link to HLA-B27.
Treatment
Joint discomfort must first be relieved with drugs. Treatment plans must address prevention, delay, or correction of the deformity and psychosocial and rehabilitation needs. For proper posture and joint mo daily exercise and other supportive measures (eg, postural training, therapeutic exercise) are vital to strengthen muscle groups that oppose the direction of potential deformities (ie, strengthen the extenso than flexor muscle groups). Reading while lying prone and thus extending the neck may help keep the flexible.
correction of the deformity and psychosocial and rehabilitation needs. For proper posture and joint mo daily exercise and other supportive measures (eg, postural training, therapeutic exercise) are vital to strengthen muscle groups that oppose the direction of potential deformities (ie, strengthen the extenso than flexor muscle groups). Reading while lying prone and thus extending the neck may help keep the flexible.
NSAIDs facilitate exercise and other supportive measures by suppressing articular inflammation, pain muscle spasm. Most NSAIDs are of proven value in AS, but tolerance and toxicity, rather than margina differences in efficacy, dictate drug choice. Patients should be monitored and warned of potential adve reactions. The daily dose of NSAIDs should be as low as possible, but maximum doses of a drug such indomethacin may be needed with active disease. Drug withdrawal should be attempted only slowly, a systemic and articular signs of active disease have been suppressed for several months. Several new NSAIDs, referred to as COX-2 drugs because they inhibit cyclooxygenase-2, show promise of providin effectiveness to drugs that inhibit COX-1 with less chance of adverse effects on the gastric mucosa an possibly also the kidney. (See also the NSAID discussion under Rheumatoid Arthritis in Ch. 50.)
Corticosteroids have limited therapeutic value; long-term use is associated with many serious advers effects, including osteoporosis of the stiff spine. For acute iritis, topical corticosteroids (and mydriatics) are adequate; oral corticosteroids are rarely indicated. Intra-articular corticosteroids may be beneficial, particularly when one or two peripheral joints are more severely inflamed than others, thereby compro exercise and rehabilitation.
Most slow-acting (remitting) drugs for RA (eg, gold given IM) either have not been studied or are no effective for AS. Sulfasalazine may be helpful, particularly when the peripheral joints are involved. Dos should be started at 500 mg/day and increased by 500 mg/day at 1-wk intervals to 1 g bid maintenanc also Rheumatoid Arthritis in Ch. 50). The most common side effect is nausea, which is mainly central, enteric-coated tablets are better tolerated. Dose reduction may help.
Narcotics, other strong analgesics, and muscle relaxants lack anti-inflammatory properties and should prescribed only short-term as adjuncts to help control severe back pain and spasm.
Radiotherapy to the spine, although effective, is recommended as a last resort because it increases t acute myelogenous leukemia tenfold.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 58. Paget's Disease Of Bone Topics
[General]
[General]
Etiology and Incidence
Paget's disease of bone (osteitis deformans): A chronic disorder of the adult skeleton in which localize of bone become hyperactive, with replacement of the normal matrix with softened and enlarged bone.
The cause is unknown. The appearance of a fingerprint pattern in pagetic osteoclastic nuclei on electr microscopy of involved bone suggests a viral infection. Paget's disease sometimes is familial, but a sp genetic pattern is unclear. About 3% of persons > 40 yr have Paget's disease, with a 3:2 male predom The disease is more common in Eastern and Western Europe, England, Australia, and New Zealand.
Pathophysiology
Bone turnover is hyperactive at involved sites. Any bone can be involved; most commonly affected, in decreasing order, are the pelvis, femur, skull, tibia, vertebrae, clavicle, and humerus. Excessively activ osteoclasts are often large and contain many nuclei. Osteoblastic repair is also hyperactive, producing coarsely woven thickened lamellae and trabeculae. The mosaic layering of collagen results in structura enlarged and weakened bone, although heavily calcified. Abnormal remodeling with change in the sha bone may cause nerve compression. Osteoarthritis may develop in joints contiguous to pagetic bone.
Symptoms and Signs
The disorder usually is asymptomatic. Onset of symptoms is usually insidious, with pain, stiffness, fatig bone deformity, headaches, decreasing auditory acuity, and increasing skull size. Pagetic bone pain is deep, and occasionally severe, sometimes accentuated at night. Pain also may arise from compressio neuropathy or associated osteoarthritis. Signs may be bitemporal skull enlargement with frontal "bossing," dilated scalp veins, nerve deafness
The disorder usually is asymptomatic. Onset of symptoms is usually insidious, with pain, stiffness, fatig bone deformity, headaches, decreasing auditory acuity, and increasing skull size. Pagetic bone pain is deep, and occasionally severe, sometimes accentuated at night. Pain also may arise from compressio neuropathy or associated osteoarthritis.
Signs may be bitemporal skull enlargement with frontal "bossing," dilated scalp veins, nerve deafness both ears, angioid streaks in the fundus of the eye, a short kyphotic trunk with simian appearance, hob gait, and anterolateral bowing of the thigh or leg with warmth and periosteal tenderness. Spinal stenos paresis, or paraplegia may reflect spinal cord compression. Pagetic lesions are metabolically active an vascular and may lead to high-output heart failure. Deformities may develop from bowing of the long b osteoarthritis of adjacent joints. Pathologic fractures may be the presenting finding. Of patients, < 1% sarcomatous degeneration, often suggested by increasingly severe pain.
Diagnosis
Paget's disease may be confused with hyperparathyroidism, bone metastasis (especially from prostati breast carcinoma), multiple myeloma, and fibrous dysplasia.
Paget's disease is often discovered incidentally on x-ray or laboratory tests performed for other reason Characteristic x-ray findings include increased bone density, abnormal architecture, cortical thicken bowing, and overgrowth. Microfractures in the tibia or femur may be seen. Characteristic findings on laboratory studies include elevated serum alkaline phosphatase (or bone-specific alkaline phosphata increased urinary excretion of pyridinoline cross-links. Serum calcium and phosphorus levels usually a normal, but serum calcium may increase during bed rest. Radionuclide bone scans using technetium phosphonates show increased nuclide localization to the pagetic sites and can be a useful screen for e disease.
Treatment
Localized, asymptomatic disease requires no treatment. Salicylates and other NSAIDs may reduce pa Orthotics help correct abnormal gait caused by bowed lower extremities. Some patients require orthop surgery (eg, to replace a diseased hip or knee, to decompress a stenosed spinal canal or other nerve entrapment).
Drug therapy influences mineral ion fluxes and suppresses bone cell activity. It is indicated (1) when p clearly related to the pagetic process and not to another source (eg, osteoarthritis); (2) to prevent or re bleeding during orthopedic surgery; and (3) to prevent or retard progression of complications (eg, para or paraplegia related to vertebral Paget's disease in a poor surgical candidate, other neurologic deficit
Several biphosphonates are available: Treatment with etidronate disodium 5 to 10 mg/kg once daily fo may be repeated after a 3- to 6-mo interim, if needed; higher doses (20 mg/kg/day po for 3 mo) may b required in markedly active disease. Alendronate 40 mg/day po for 6 mo is taken as a single dose on r the morning and at least 30 min before eating. Pamidronate 30 to 90 mg/day IV is used in a 4-h infusio consecutive days (higher doses can be used in patients with very active disease). Tiludronate is admin as 400 mg/day po for 3 mo. Synthetic salmon calcitonin 50 to 100 IU (0.25 to 0.5 mL)/day sc or IM ma tapered to 50 IU every other day and perhaps to twice or once weekly after the initial response (often a mo of therapy). Calcitonin may also be given as a nasal spray in patients who have received no pain th
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 52. Osteoarthritis And Neurogenic Arthro Topics
Osteoarthritis Neurogenic Arthropathy
Osteoarthritis
(Degenerative Joint Disease; Osteoarthrosis; Hypertrophic Osteoarthritis)
An arthropathy with altered hyaline cartilage and characterized by loss of articular cartilage and hypert bone, producing osteophytes.
Osteoarthritis (OA), the most common articular disorder, begins asymptomatically in the 2nd to 3rd de and is extremely common by age 70. Almost all persons by age 40 have some pathologic change in weight-bearing joints, although relatively few have symptoms. Men and women are equally affected, b is earlier in men.
OA occurred in ancient animals, fish, amphibians, reptiles (dinosaurs), birds, mammoths, and cave be affects almost all vertebrates, suggesting that it appeared with the evolutionary arrival of the bony skel occurs in whales, dolphins, and porpoises, which are supported by water, but not in bats and sloths, w hang upside down. This suggests that OA is an ancient Paleozoic mechanism of repair and remodelin than a disease in the usual sense.
Classification
OA is classified as primary (idiopathic) or secondary to some known cause. Primary generalized OA in the distal and proximal interphalangeal joints (producing Heberden's and Bouchard's nodes), 1st carpometacarpal joint, intervertebral disks and zygapophyseal joints in the cervical and lumbar vertebr metatarsophalangeal joint, hip, and knee. Subsets of primary OA include erosive, inflammatory OA an destructive OA of shoulders and less often of hips and knees in the elderly. Diffuse idiopathic skeletal hyperostosis is a syndrome involving large OA-like spinal osteophytes but little or no loss of articular c Chondromalacia patellae--a mild OA of patellar cartilage in young people--may also occur.
Secondary OA appears to result from conditions that change the microenvironment of the chondrocyte include congenital joint abnormalities; genetic defects; infectious, metabolic, endocrine, and neuropath diseases; diseases that alter the normal structure and function of hyaline cartilage (eg, RA, gout,
hyperostosis is a syndrome involving large OA-like spinal osteophytes but little or no loss of articular c Chondromalacia patellae--a mild OA of patellar cartilage in young people--may also occur.
Secondary OA appears to result from conditions that change the microenvironment of the chondrocyte include congenital joint abnormalities; genetic defects; infectious, metabolic, endocrine, and neuropath diseases; diseases that alter the normal structure and function of hyaline cartilage (eg, RA, gout, chondrocalcinosis); and trauma (including fracture) to the hyaline cartilage or surrounding tissue (eg, f prolonged overuse of a joint or group of joints associated with occupations such as foundry work, coal and bus driving).
Pathophysiology
Normal joints have a low coefficient of friction and do not wear out with typical overuse and trauma. Hy cartilage is avascular, aneural, and alymphatic. It is 95% water and extracellular cartilage matrix and chondrocytes. Chondrocytes have the longest cell cycle in the body (similar to CNS cells and muscle c Cartilage health and function depend on compression and release of weight bearing and use; ie, comp pumps fluid from the cartilage into the joint space and into capillaries and venules, whereas release al cartilage to reexpand, hyperhydrate, and absorb necessary nutrients.
The pathophysiologic process of OA is progressive. Triggered by a change in the microenvironment, th chondrocytes undergo mitosis and increase synthesis of proteoglycans and type II collagen (the princi structural elements of cartilage). Then synthesis of bone by subchondral osteoblasts increases, presu prompted by intercellular communication by cytokines between chondrocyte and osteoblast. With incre bone formation in the subchondral area, physical properties change; the bone becomes stiffer with de compliance, and microfractures occur, followed by callus formation, more stiffness, and more microfra Metaplasia of the peripheral synovial cells results in periarticular formation of osteophytes (or, more co osteochondrophytes, consisting of bone and a mixture of connective tissues with a coating of fibrocart sometimes islands of hyaline cartilage within the osteophyte). The degree of formation of these spurs among joints, in proportion to the underlying cause. Finally, bony cysts (pseudocysts) form in the marr below the subchondral bone. Bony cysts result from extrusion of joint fluid through the hyaline cartilag into the marrow, with a fibroblastic and osteoblastic cellular reaction.
Gross pathology includes roughening, pitting, and irregularities of the hyaline cartilage surface, procee gross ulceration with focal and then diffuse areas of complete loss of cartilage, leaving only eburnated surfaces. By the time symptoms appear, synovial proliferation and some mild synovitis are virtually alw present.
Symptoms and Signs
Onset is gradual, usually involving one or only a few joints. Pain is the earliest symptom and is usually worsened by exercise and relieved by rest. Morning stiffness follows inactivity but lasts < 15 to 30 min lessens with movement. As OA progresses, joint motion diminishes, tenderness and crepitus or gratin sensations appear, and flexion contractures may develop. Proliferation of cartilage, bone, ligament, te capsules, and synovium, along with varying amounts of joint effusion, ultimately produces the joint enlargement characteristic of OA. Acute and severe synovitis is not expected but may occur in patient other diseases (eg, gout, pseudogout) that are the primary initiating mechanism of OA.
OA of the cervical and lumbar vertebrae may lead to myelopathy or radiculopathy. However, the clinica of the former are usually mild. At the disk level, marked thickening and proliferation of the anterior long ligaments result in transverse bars encroaching on the anterior spinal cord; hypertrophy and hyperplas ligamenta flava often compress the posterior cord. Radiculopathy is less frequent because the anterio posterior nerve roots, ganglia, and common spinal nerve are well protected in the intervertebral forami where they occupy only 25% of the available and well-cushioned space.
OA of the cervical and lumbar vertebrae may lead to myelopathy or radiculopathy. However, the clinica of the former are usually mild. At the disk level, marked thickening and proliferation of the anterior long ligaments result in transverse bars encroaching on the anterior spinal cord; hypertrophy and hyperplas ligamenta flava often compress the posterior cord. Radiculopathy is less frequent because the anterio posterior nerve roots, ganglia, and common spinal nerve are well protected in the intervertebral forami where they occupy only 25% of the available and well-cushioned space.
Functional compromise of the vertebral arteries, infarction of the spinal cord, and esophageal compres osteophytes occasionally occur. Symptoms and signs may also derive from ligamentous structures, ca muscles, tendons, disks, and periosteum, all of which are pain sensitive. Venous pressure increases w subchondral bone marrow, also a source of pain.
Hip OA is characterized by gradually increasing rigidity and loss of range of motion. Pain may be felt in inguinal area or referred to the knee. As cartilage is lost in knee OA (medial loss occurs in 70% of cas ligaments become lax, and the joint becomes less stable, with local pain arising from the ligaments an tendons. Tenderness on palpation and pain on passive motion are relatively late signs. Muscle spasm contracture add to the pain. Mechanical block by osteophytes or loose bodies (ossified fragments float the joint space) can occur and cause locking or catching. Deformity and subluxations result from lost c volume, subchondral bone collapse, osteophytes, muscle atrophy, and pseudocysts.
Diagnosis
Although diagnosis is usually straightforward, other common rheumatic diseases must be considered seronegative spondyloarthropathies, pseudogout). OA involvement outside the usual joints suggests secondary OA and requires further consideration regarding etiology (eg, endocrine, metabolic, neoplas biomechanical disorders affecting bone and joints).
Diagnosis is usually based on symptoms and signs or on x-ray in asymptomatic patients. The ESR is n only moderately increased. Blood studies may help rule out identifiable causes of arthritis (eg, gout, R Synovial fluid analysis often discloses clear, viscous joint fluid characteristic of OA (see Tables 49-3 a X-ray generally reveals narrowing of the joint space (predominantly unilateral in early knee OA), increa density of the subchondral bone, formation of osteophytes at the periphery of the joints, and formation pseudocysts in the subchondral marrow.
The pathophysiologic process of OA is usually progressive but occasionally, with no predictability, stop reverses. Treatment includes rehabilitation techniques, which are focused on preventing dysfunction, attempting to begin management before disability develops, and decreasing the severity or duration of disability (see Ch. 291). Primary treatment considerations are the stage and magnitude of tissue chang number of joints involved, the pain cycle, the cause of pain (biomechanical defects or inflammation), a patient's lifestyle. Treatment also includes patient education regarding the nature of the problem (phys and biomechanics), the prognosis (usually benign), the necessity for cooperation, and optimal physica Activities of daily living should receive attention. A patient with hip or knee OA should be instructed to soft deep chairs and recliners from which arising is difficult. The regular use of pillows under the knees encourages contractures and should also be avoided. Patients should sit in straight chairs without slum sleep on a firm bed with a bed board; use a car seat designed for comfort; perform postural exercises; well-supported shoes or athletic shoes; and continue employment and physical activity.
Exercise (range of motion, isometric, isotonic, isokinetic, postural, strengthening) maintains healthy ca and range of motion and develops stress-absorbing tendons and muscles. Daily stretching exercises a utmost importance. Immobilization for relatively short periods can accelerate and worsen the clinical co Arrest and occasionally reversal of hip and knee OA can occur using well-planned exercise as therapy
well-supported shoes or athletic shoes; and continue employment and physical activity.
Exercise (range of motion, isometric, isotonic, isokinetic, postural, strengthening) maintains healthy ca and range of motion and develops stress-absorbing tendons and muscles. Daily stretching exercises a utmost importance. Immobilization for relatively short periods can accelerate and worsen the clinical co Arrest and occasionally reversal of hip and knee OA can occur using well-planned exercise as therapy 4 to 6 h in the daytime to allow rehydration of cartilage) must be balanced with exercise and use.
There is no evidence that widely used NSAIDs have any long-term benefit on OA. Acetaminophen in d up to 1 g qid is a useful analgesic and is generally safer than NSAIDs. In patients with refractory pain o more signs of inflammation, aspirin or other NSAIDs may be used and may provide better relief of sym under Rheumatoid Arthritis in Ch. 50). COX-2 inhibitors (eg, celecoxib, rofecoxib) control inflammation decrease pain with fewer gastrointestinal side effects. Muscle relaxants (usually in low doses) occasio provide temporary benefit when pain arises from muscles strained by attempting to support OA joints. corticosteroid therapy usually is not indicated. Intra-articular depot corticosteroids are helpful when eff signs of inflammation are present; these drugs usually are needed only intermittently and should gene used as infrequently as possible. Drug therapy is the least important aspect of optimum management, 15% of a total program. Hyaluronic acid, a normal physiologic component of synovial fluid, has proven effective in the management of OA of the knee. Commercial preparations, Hyalgan and ARTZ, by inje resulted in measurable improvement using clinical, radiologic, and laboratory criteria.
Laminectomy, osteotomy, and total joint replacement should be considered when conservative therap spinal, knee, or 1st carpometacarpal OA, various supports can provide relief, but they should be follow specific exercise programs. Other adjuncts to therapy are transcutaneous electrical nerve stimulation a rubs (eg, with capsaicin). Experimental therapies that may preserve cartilage or allow chondrocyte gra being studied.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 59. Nonarticular Rheumatism Topics
Spasmodic Torticollis Low Back Pain Bursitis Tendinitis And Tenosynovitis Fibromyalgia Baker's Cyst
Spasmodic Torticollis
Prevalence and Etiology
Involuntary tonic contractions or intermittent spasms of the neck muscles, causing rotational (torticollis (laterocollis), forward (anterocollis), or backward (retrocollis) tilting of the head.
Focal dystonias (of which torticollis is the most common) occur in > 3/10,000 persons; torticollis per se can pull the chin to either shoulder, has a prevalence of about 3/10,000 persons. Congenital torticoll under Spinal Abnormalities in Ch. 261) is rare. It is believed to be caused by unilateral injury to the sternocleidomastoid muscle at birth, which transforms it into a fibrous cord that cannot lengthen with th growing neck. Minimal deformity may be seen in neonates; within a few weeks, a firm swelling occurs sternocleidomastoid muscle, which then contracts. Neck muscle contraction in children may also be se to ocular muscle imbalance or deformities of the cervical spine or musculature. Adult-onset torticollis much more common. About 5% of patients have a positive family history. Tardive dyskinesia, hyperthy basal ganglia disease, CNS infections, or tumors in the bones or soft tissues of the neck may occasion mimic this syndrome, but the cause of spasmodic torticollis is unknown.
Symptoms, Signs, and Course
Dystonias are sustained muscle contractions that can lead to repetitive twisting movements and abnor postures. Torticollis is a chronic, focal dystonia that is different from wryneck, an active, painful, self-lim neck spasm.
Onset may occur at any age but is most frequent in adults between the third and sixth decades. Fema more commonly affected (1.4:1). Symptoms usually begin gradually but may be sudden. Painful tonic
Dystonias are sustained muscle contractions that can lead to repetitive twisting movements and abnor postures. Torticollis is a chronic, focal dystonia that is different from wryneck, an active, painful, self-lim neck spasm.
Onset may occur at any age but is most frequent in adults between the third and sixth decades. Fema more commonly affected (1.4:1). Symptoms usually begin gradually but may be sudden. Painful tonic contractions or intermittent spasms of the sternomastoid, trapezius, and other neck muscles usually oc unilaterally and cause abnormal head position. Sternomastoid muscle contraction causes rotation of th to the opposite side and lateral flexion of the neck to the same side.
Torticollis ranges from mild to severe disease. It may persist for life and can result in restricted movem postural deformity. Usually, the disease slowly progresses for 1 to 5 yr, then plateaus. About 10 to 20% recover spontaneously within 5 yr of onset (usually milder cases of younger onset). One third of cases evidence of dystonia elsewhere (eg, eyelids, face, jaw, hand). Involuntary movements (ie, active spasm disappear during sleep.
Diagnosis
In infants, the neck should be inspected for asymmetry, abnormal structures, or masses. A hematoma sternomastoid muscle may appear several days after birth (usually breech) and may become fibromat subsequent months. Similarly, other pathologic processes in the neck must be ruled out by history of t encephalitis, or evidence of extrapyramidal disease; by examination for any dysfunction; and by x-ray, MRI of the cervical spine if an abnormality is suspected. Electromyographic, neurologic, and psycholog studies usually are negative.
Congenital torticollis should be treated within the first few months of life, initially with intensive physi therapy, including daily passive stretching of the shortened muscle for >= 1 yr. If physical therapy is st later or is not successful, operative division of the contracted sternocleidomastoid muscle and surroun tissues may be indicated.
In adult-onset torticollis, prognosis is good for correctable orthopedic deformities in the neck, but sec spasms from neurologic disorders or the idiopathic processes are more difficult to treat and may persis indefinitely. The spasm can sometimes be temporarily inhibited by physical therapy and massage, eg, tactile pressure to the jaw on the same side as the head rotation (sensory biofeedback techniques). D effectively suppress dystonic movements in only about 25 to 33% of cases but more effectively relieve Anticholinergics (eg, trihexyphenidyl, benztropine) and benzodiazepines (particularly clonazepam) are Muscle relaxants (eg, baclofen) and tricyclic antidepressants (eg, amitriptyline) are usually of limited effectiveness. All drugs should be started in low doses and titrated to an effective or tolerable level wit attention to side effects, particularly in older patients.
Multiple injections of botulinum toxin type A (Botox) into the dystonic muscles of the neck have improv position of the head and reduced painful muscle spasms for 1 to 3 mo in about 70% of patients. Such is also available in the USA for blepharospasm and strabismus. The treatment may lose effectiveness antibodies develop against the toxin. Thalamic surgical procedures are no longer recommended. Sele denervation of the neck muscles is the most successful surgical approach. Nerves to affected neck mu are severed, permanently weakening or paralyzing them. However, focal muscles are involved, and ex weakness is not typically a problem when this procedure is performed at centers with extensive experi Rarely, psychiatric treatment is indicated if an emotional problem is evident; prognosis is best if onset relates to exogenous stress.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 53. Avascular Necrosis Topics
[General]
[General]
Avascular necrosis (osteonecrosis; ischemic necrosis of bone; aseptic necrosis; osteochondritis dissec Focal bone infarction, which may be secondary to various conditions or idiopathic.
Pathologic changes are characterized by cell death in bone resulting from compromised blood supply. magnitude of avascular necrosis is a function of the degree of circulatory compromise. The femoral he is most commonly involved; the femur at the knee and the humeral head (shoulder) are frequently invo the body of the talus, carpal scaphoid, and navicular bone are less commonly involved.
Epidemiology
In the USA, 5% of cases of osteoarthritis of the hip requiring hip replacement are caused by avascular necrosis. The peak incidence is between ages 30 and 60. Idiopathic avascular necrosis of the femoral has a male:female ratio of 4 to 5:1. In 33 to 72% of patients, the disease is bilateral. Legg-Calv-Perth disease of the apophyses and epiphyses in children and adolescents and other osteochondroses have thought to be caused by avascular necrosis, although this is now less certain (see The Osteochondros Ch. 270).
Etiology
Various primary diseases have been associated with avascular necrosis; some are more clearly estab causative (see Table 53-1).
The most common sites of posttraumatic avascular necrosis are the femoral and humeral heads, the b the talus, and the carpal scaphoid. Posttraumatic avascular necrosis develops when blood supply is im and is thus a function of the relative contributions of arteries to the femoral or humeral head and the e anastomoses between them, which varies among persons.
Hip dislocation may tear the ligamentum teres and the joint capsule, compromising vessels lying in the
The most common sites of posttraumatic avascular necrosis are the femoral and humeral heads, the b the talus, and the carpal scaphoid. Posttraumatic avascular necrosis develops when blood supply is im and is thus a function of the relative contributions of arteries to the femoral or humeral head and the e anastomoses between them, which varies among persons.
Hip dislocation may tear the ligamentum teres and the joint capsule, compromising vessels lying in the capsular reflections. Of hips that remain dislocated longer than 12 h, 52% develop avascular necrosis 22% of those reduced within 12 h. In postfracture fixation, the incidence of avascular necrosis and bon collapse ranges from 11 to 45% and does not seem related to the surgeon's skill or fixation device.
Avascular necrosis of other causes most often occurs at the hip, followed by the humeral head. Two m theories on the mechanism of action are intraluminal obliteration of end vessels (eg, by fat emboli, sick or nitrogen bubbles in decompression sickness of deep-sea divers) or extraluminal obliteration caused increased marrow pressure by Gaucher cell proliferation or increased marrow fat. There is also an idio avascular necrosis at the knee occurring most often in elderly women.
Symptoms and Signs
For some patients, pain starts suddenly--patients remember the day and hour when they first perceive sudden, severe, incapacitating pain--presumably at the time of initial vascular obliteration and before a collapse. For other patients, the initial insult is asymptomatic. Most later develop mechanical pain as th femoral head (or other involved bone) collapses. Such pain is induced by standing, walking, moving, c or other mechanical stress and is largely relieved by rest. Patients with advanced disease have pain a
In fracture patients, symptoms that may indicate avascular necrosis are increased pain and limp at ab postevent. Symptoms tend to be nonspecific.
Avascular necrosis of the femoral head presents as groin pain that intermittently radiates down the anteromedial thigh. Patients may demonstrate an antalgic gait, gluteus minimus limp, or limited range motion, especially in flexion, abduction, and internal rotation, with a distinct click elicited by external ro the flexed abducted hip, particularly when moving from a sitting position.
Avascular necrosis of the knee in the elderly is almost always associated with sudden atraumatic on severe constant pain localized to the medial aspect of the knee, accompanied by tenderness over the femoral condyle and, in 1/3 of patients, mild to moderate effusion.
Avascular necrosis of the humeral head may long go undetected because the shoulder is not a weight-bearing joint and symptoms may be transient or mild. Pain commonly radiates to the deltoid tub of the humerus. Active motion is limited very early, but passive motion is preserved. Avascular necrosi humeral head without other sites of involvement is rare.
Diagnosis
Early diagnosis requires a high index of suspicion in patients presenting with pain, particularly of the h knees, or shoulders.
Diagnostic testing depends on the stage of the disease. MRI is the most sensitive and specific techniq should be used for very early diagnosis, when collapse of the femoral head or other bone may be prev If duration of disease is not clear, an x-ray or CT scan should be obtained to rule out advanced diseas scanning is more sensitive than x-ray but is nonspecific and is used less often than MRI.
X-ray findings may not become apparent for months to up to 5 yr after symptom onset. Characteristics
Diagnostic testing depends on the stage of the disease. MRI is the most sensitive and specific techniq should be used for very early diagnosis, when collapse of the femoral head or other bone may be prev If duration of disease is not clear, an x-ray or CT scan should be obtained to rule out advanced diseas scanning is more sensitive than x-ray but is nonspecific and is used less often than MRI.
X-ray findings may not become apparent for months to up to 5 yr after symptom onset. Characteristics x-ray begin with subtle sclerosis of bone. At the femoral head, this is followed by a characteristic subch lucency (the crescent sign). This is followed by collapse of the bone (flattening of the femoral head) an by narrowed joint space and osteoarthritic changes in the opposing bones of the joint.

Prevention is obviously preferable to treatment. Following rules in deep-sea diving can prevent the decompression illness (see Ch. 285). Minimizing corticosteroid doses should also decrease risk.
Conservative management often includes analgesics and non-load bearing in lower extremity joints i attempt to prevent collapse during unassisted healing, although the efficacy of this has been difficult to Range-of-motion exercise should be performed.
Early surgical intervention may offer the best chance of preventing serious joint dysfunction in the hi knees (less so in the shoulders). Disease is generally irreversible by the time it is apparent on x-ray.
Cortical bone grafts may provide mechanical support to subchondral bone and articular cartilage to att prevent collapse as the femoral head revascularizes. Crutches must be used for months after such gra Core decompression involves drilling the neck and head of the femur to remove the central portion of b reducing intraosseous pressure. In some centers, this has been highly successful. In early cases, hip relieved, and up to 75% of patients avoid later joint replacement. Osteotomy has also been used to alt mechanics of the joint and redistribute the maximal load-bearing forces to prevent collapse and deform the femoral head. Crutch use is required for 6 to 12 mo. Surgical hip (or knee) replacement is effective usually reserved for severe refractory pain and secondary osteoarthritis. Caution is warranted when pe this operation in young patients, who often want to persist in vigorous physical activities, which limit the joint implants.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 60. Common Foot And Ankle Disorde Topics
[General] Ankle Sprains Disorders Associated With Heel Pain Disorders Associated With Metatarsalgia
[General]
Diagnosis and management of foot and ankle disorders depend on whether the problem is articular or extra-articular (tendon, nerve, ligament, or bone). Problems may be local (eg, trauma, abnormal foot s or function) or a sign of systemic disease.
The ankle is examined for tenderness: Certain areas of the foot are normally tender (eg, sinus tarsi, d aspect of the ball between the metatarsals). The foot is also inspected for edema and skin changes. Superficial peroneal nerve injury (sensory branches) and entrapment may be evaluated by tapping, wh elicit pain or tingling (Tinel's sign). Veins and tendons are inspected and palpated while moving the an joints are evaluated with deep palpation on movement for swelling, range of motion, and tenderness. S below and anterior to the lateral malleolus occurs in synovial effusion from intra-articular disease (eg, Tender swelling over the anterior talofibular mortise suggests injury of the anterior talofibular ligament. firm, symmetric bilateral swellings over this area suggest juxtamalleolar lipomas, which are common in menopausal women. These swellings may be painful because of nerve entrapment. Swelling behind o both malleoli, usually painful, suggests tenosynovitis.
The heel is examined by placing the foot close to a right angle with the leg. The bottom of the heel and margins should be palpated with firm pressure. The presence of heat and swelling should be noted (se Disorders Associated With Heel Pain, below).
The midfoot is located between the ankle and heel area and the toes. The dorsal and plantar portions midfoot should be examined. Both feet should be compared.
Diffuse unilateral swelling with pain limited to the midfoot can be caused by arthritis or a fractured met (eg, march fracture). Diffuse swelling (which may involve the ankle) that pits on pressure and extends
The midfoot is located between the ankle and heel area and the toes. The dorsal and plantar portions midfoot should be examined. Both feet should be compared.
Diffuse unilateral swelling with pain limited to the midfoot can be caused by arthritis or a fractured met (eg, march fracture). Diffuse swelling (which may involve the ankle) that pits on pressure and extends toes bilaterally may be caused by venous disease, congestive heart failure, or renal disease. Edema t accumulate at the ankle because of shoe compression. Unilateral or bilateral swelling that does not pit pressure indicates the presence of lymphedema. A painful, hot swelling suggests gout or dorsal venou phlebitis. Localized firm circumscribed swellings usually located at the dorsolateral aspect of the foot a commonly caused by ganglion cysts (which must be differentiated from the muscle belly of the extenso digitorum). Joint disease should be assessed through palpation and range of motion. Examination for of the tendons inserting in and traversing the midfoot should be carried out by placing the tendon unde consideration in a contracted position and testing for pain and strength against resistance. MRI is usef demonstrating tendon ruptures and occult inflammation. Plantar flexion and inversion of the foot will accentuate the cutaneous branches of the superficial peroneal nerve, which should always be evaluat source of dorsal foot pain. Tapping of the nerves will elicit pain (Tinel's sign) when these nerves are irr
Examination of the plantar aspect of the midfoot should begin with the plantar fascia. The fascia is exa with the foot placed close to a right angle to the leg (dorsiflexion); firm pressure should then be applied the course of the inner border of the fascia to test for the presence of pain (plantar fasciitis). Palpation fascia may detect the presence of nodules (plantar fibromatosis).
The forefoot is the area primarily composed of the metatarsophalangeal joints, interdigital nerves, and The examiner should palpate each of the metatarsophalangeal joints by placing the thumb under the a joint and the index finger above. If firm pressure elicits pain, a joint disorder is suggested. The presenc pain with heat and swelling suggests inflammatory synovitis. Range of motion should be evaluated in t joints by flexing and extending the joints. Limited range of motion with pain commonly occurs in the big joint (hallux limitus). The ball and sole of the foot should be examined for corns, calluses, or warts. The interdigital nerves should be examined for neuralgia or neuroma by placing firm pressure with the thum between the metatarsal heads.
Firm isolated swellings of the digits can be caused by soft tissue problems, such as infection (eg, ingro toenail or underlying osteomyelitis, especially in a diabetic patient). Malignant melanoma should be co in any long-standing paronychia, especially in the elderly. Other causes of digital swellings include soli osteochondroma (the most common benign bone tumor of the phalanges), psoriatic arthritis (sausage associated with heat and redness, and, less commonly, tumor (eg, fibroma of the tendon sheath). Fluc soft swellings involving the toes are commonly caused by digital myxoid cysts.
Treatment With Injectable Corticosteroids
Soluble corticosteroids have a rapid onset of action with minimal effect on fibroconnective tissue, wher insoluble corticosteroids are long acting and decrease soft tissue fibrosis. Insoluble corticosteroids mu injected with caution, especially if given in a series, because of the paucity of fibroconnective tissue on dorsum of the foot, especially over the toes, and in the tarsus and retrocalcaneal space. Low doses an infrequent injections should be used to avoid skin and soft tissue damage (eg, depigmentation, atroph ulceration), especially in the elderly and in those with peripheral vascular disease and when injecting s joints of the foot. Insoluble corticosteroids should be given deep into the foot in the heel pad, tarsal ca metatarsal interspaces, or ankle joint. When injecting tendons of the foot with insoluble corticosteroids area should be immobilized (injection directly into the Achilles tendon should be avoided). Soluble and insoluble corticosteroids can be combined for rapid onset with long-acting effects. The usual dose is 1 dexamethasone phosphate (4 mg/mL) mixed with 0.125 to 0.25 mL triamcinolone acetonide (40 mg/m 1.5 mL 2% lidocaine in 1:100,000 epinephrine.
metatarsal interspaces, or ankle joint. When injecting tendons of the foot with insoluble corticosteroids area should be immobilized (injection directly into the Achilles tendon should be avoided). Soluble and insoluble corticosteroids can be combined for rapid onset with long-acting effects. The usual dose is 1 dexamethasone phosphate (4 mg/mL) mixed with 0.125 to 0.25 mL triamcinolone acetonide (40 mg/m 1.5 mL 2% lidocaine in 1:100,000 epinephrine.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 54. Infections Of Bones And Joints Topics
Infectious Arthritis Osteomyelitis
Infectious Arthritis
The incidence varies worldwide: < 200/100,000 in the USA, lower in European countries (< 5/100,000 Sweden), but much higher in Africa, Latin America, and Asia.
Inflammation in a joint resulting from bacterial, fungal, or viral infection of synovial or periarticular tissu
Risk factors are listed in Table 54-1. Comorbidity may increase not only the risk of infectious arthritis b disease severity. Patients with RA are at particularly increased risk for bacterial arthritis (prevalence, 0 3.0%; annual incidence, 0.5%). Functional outcome is poor, and the mortality rate is high (25% vs. 9% patients without RA). RA patients frequently have additional risk factors for infectious arthritis (eg, chro medical illness, corticosteroid treatment). Risk of joint infection is substantially increased in patients wi in others with a past history of joint infection or with a prosthetic joint implant.
About 50% of children with joint infection are < 2 yr of age. Of these cases, 93% are monarticular and involve the large joints of the lower extremities: knee (39%), hip (26%), ankle (13%). Sources of infecti include otitis media, umbilical catheters, central lines, femoral venipunctures, meningitis, and adjacent osteomyelitis.
Etiology
Acute infectious arthritis: Acute infectious arthritis (95% of cases) is caused by bacteria or viruses.
Neisseria gonorrhoeae is the most common bacterial cause in adults. It spreads from infected mucosa surfaces (cervix, rectum, pharynx) to the small joints of the hands, wrists, elbows, knees, and ankles b to axial skeletal joints.
Nongonococcal arthritis is usually caused by Staphylococcus aureus (45%); streptococci (9%); or gram-negative organisms, such as Enterobacter, Pseudomonas aeruginosa (40%), and Serratia marc
Neisseria gonorrhoeae is the most common bacterial cause in adults. It spreads from infected mucosa surfaces (cervix, rectum, pharynx) to the small joints of the hands, wrists, elbows, knees, and ankles b to axial skeletal joints.
Nongonococcal arthritis is usually caused by Staphylococcus aureus (45%); streptococci (9%); or gram-negative organisms, such as Enterobacter, Pseudomonas aeruginosa (40%), and Serratia marc (5%). Gram-negative bacterial infections tend to occur in young or elderly patients, those with severe t serious underlying medical illness (renal failure or transplantation, prosthetic joints, SLE, RA, diabetes malignancy), and IV drug users. Infections commonly begin in the urinary tract or skin. In 80% of patie nongonococcal arthritis is monarticular (knee, hip, shoulder, wrist, ankle, elbow). Polyarticular bacteria usually occurs in patients with an underlying chronic arthritis (eg, RA, osteoarthritis) or a joint prosthes Borrelia burgdorferi, an agent of Lyme disease (see Ch. 157), can cause acute migratory polyarthralgi fever, headache, fatigue, and skin lesions or a more chronic intermittent monarthritis or oligoarthritis.
S. aureus and group B streptococci are the most common organisms in neonates and children > 2 yr. kingae appears to be the most common cause in children < 2 yr. Although Haemophilus influenzae typ the most common cause of bacterial arthritis in children aged 6 mo to 2 yr, immunization has reduced incidence by 95% in children aged < 5 yr. In children, N. gonorrhoeae causes < 10% of bacterial arthri is the most common cause of polyarticular infection.
Anaerobic joint infections are often mixed infections with facultative or aerobic bacteria (5 to 10% of ca such as S. aureus, Staphylococcus epidermidis, and Escherichia coli. The predominant anaerobic org are Propionibacterium acnes, Peptostreptococcus magnus, Fusobacterium sp, Clostridium sp, and Bacteroides sp. P. acnes causes infections in joints with prostheses, trauma, or prior surgery. Factors predisposing to anaerobic infection include penetrating trauma, arthrocentesis, recent surgery, joint pr contiguous infection, diabetes, and malignancy.
Joint infections resulting from human bites are caused by the gram-negative organism Eikenella corro group B streptococci, or oral anaerobes (eg, Fusobacterium sp, peptostreptococci, Bacteroides sp). An bites may give rise to joint infections typically caused by S. aureus or organisms of the oral flora comm the animal. Pasteurella multocida causes half the infections resulting from dog or cat bites. Dog and ca also cause infection with Pseudomonas sp, Moraxella sp, and Haemophilus sp. Rat bites cause infect Streptobacillus moniliformis or Spirillum minus.
Joint infections in HIV-infected patients are usually caused by S. aureus, streptococci, and Salmonella HIV-infected patients may have Reiter's syndrome, reactive arthritis, and HIV-related arthritis and arth As HIV-infected patients survive longer, more indolent infections with mycobacteria, fungi, and unusua opportunistic organisms are being detected.
Viral causes of acute arthritis include parvovirus B19, hepatitis B, hepatitis C, rubella virus (active infec after immunization), and togavirus. Varicella; mumps (in adults); adenovirus; coxsackieviruses A9, B2, and B6; and Epstein-Barr virus mononucleosis are also associated with arthralgias and arthritis. These more likely than bacteria to cause polyarthritis.
Chronic infectious arthritis: Chronic infectious arthritis (5% of cases) is caused by mycobacteria, fun some bacteria with low pathogenicity. Examples are Mycobacterium tuberculosis, Mycobacterium mari Mycobacterium kansasii, Candida sp, Coccidioides immitis, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Sporothrix schenckii, Aspergillus fumigatus, Actinomyces israe Brucella sp.
Two thirds of prosthetic joint infections occur within 1 yr of surgery and are caused by intraoperative inoculations of bacteria into the joint or by postoperative bacteremia resulting from skin infection, pneu dental infection, or UTI. Early prosthetic joint infections are caused by S. aureus in 50% of cases, mixe
neoformans, Blastomyces dermatitidis, Sporothrix schenckii, Aspergillus fumigatus, Actinomyces israe Brucella sp.
Two thirds of prosthetic joint infections occur within 1 yr of surgery and are caused by intraoperative inoculations of bacteria into the joint or by postoperative bacteremia resulting from skin infection, pneu dental infection, or UTI. Early prosthetic joint infections are caused by S. aureus in 50% of cases, mixe infections in 35%, gram-negative organisms in 10%, and anaerobes in 5%.
Pathogenesis
Infection in a joint produces an inflammatory reaction (arthritis) that is an attempt to kill the infecting or but that damages joint tissues.
Infectious agents reach joints by (1) direct penetration (trauma, surgery, bites, injection); (2) extension joint from an adjacent infection (eg, osteomyelitis, a soft tissue abscess, an infected wound); and (3) d to the synovial tissue via the bloodstream (bacteremia) from a remote site of infection (skin; respiratory urinary, or GI tract).
Infecting organisms multiply in the synovial fluid and synovial lining tissue. Virulence factors known as adhesins, which permit localization of bacteria in joint tissues, may be produced by some bacteria (eg, aureus). Other bacterial products, such as endotoxin (lipopolysaccharide) from gram-negative organis wall fragments, exotoxins from gram-positive organisms, and immune complexes formed by bacterial a and antibody, augment the inflammatory reaction. PMNs migrate into the joint and phagocytose the in organisms. Phagocytosis of bacteria also results in PMN autolysis with release of lysosomal enzymes joint, which cause synovial, ligament, and cartilage damage. Therefore, PMNs are both the major host system and the cause of joint damage in acute bacterial arthritis. Next, in chronic infections (eg, in RA synovial membrane can proliferate (forming a pannus) and can erode articular cartilage and subchond Inflammatory synovitis may persist even after the infection has been eradicated by antibiotics. It has b theorized that infection alters cartilage, causing it to become antigenic and, together with the adjuvant of bacterial components, results in immune-mediated, "sterile" inflammatory synovitis.
Symptoms and Signs

Joint infections may be acute, with sudden onset of joint pain and swelling, or chronic, with insidious development of milder symptoms.
Acute bacterial arthritis: Onset is rapid (a few hours to a few days) with moderate to severe joint pai warmth, tenderness, and restricted motion. The patient may have no other symptoms of serious infect which can delay diagnosis, thereby reducing the likelihood of a successful outcome. Children with infe arthritis may present with limited spontaneous movement of a limb (pseudoparalysis), irritability, and lo or no fever. In adults, acute bacterial arthritis is classified as gonococcal or nongonococcal, because t clinical features and responses to treatment are quite different.
Gonococcal arthritis, caused by N. gonorrhoeae, is most often seen with a distinctive dermatitis-polyarthritis-tenosynovitis syndrome. Disseminated gonococcal infection is characterized by 7-day history of fever; shaking chills; multiple skin lesions (petechiae, papules, pustules, hemorrhagic necrotic lesions) on mucosal surfaces, the trunk, and lower extremities; migratory arthralgias; and tenosynovitis, which evolves into persistent inflammatory arthritis in one or a few joints. However, sym mucosal infection may not be present. Neisseria meningitidis produces a similar arthritis-dermatitis syn accompanied by a relatively mild upper respiratory tract infection or by severe clinical illness with shoc meningoencephalitis.
necrotic lesions) on mucosal surfaces, the trunk, and lower extremities; migratory arthralgias; and tenosynovitis, which evolves into persistent inflammatory arthritis in one or a few joints. However, sym mucosal infection may not be present. Neisseria meningitidis produces a similar arthritis-dermatitis syn accompanied by a relatively mild upper respiratory tract infection or by severe clinical illness with shoc meningoencephalitis.
Nongonococcal arthritis usually involves a single joint with progressive moderate to severe pain that markedly worsened by movement or palpation so that joint function is impaired. Most infected joints ar swollen, red, and warm to the touch. Fever may be absent or low grade in up to 50% of patients; 20% patients report a shaking chill.
Most cases of anaerobic joint infection are monarticular and involve the hip or knee (in 50%). Extrasites of anaerobic infection include the abdomen, genitalia, periodontal abscesses, sinuses, ischemic and decubiti.
Joint infection associated with IV drug use occurs predominantly in the axial skeleton (sternoclavic costochondral, hip, shoulder, vertebrae, symphysis pubis, and sacroiliac joints) but may infect the peri joints. Gram-negative joint infections tend to be more indolent and difficult to diagnose than the more f staphylococcal joint infections.
Joint infections caused by human bites are often indolent, requiring 1 wk to become manifest. Dog bites produce marked erythema, pain, and swelling in the small joints of the hand within 24 h. Rat bite produce fever, rash, and joint pain with regional adenopathy (2- to 10-day incubation).
Prosthetic joint infection causes prosthesis loosening, failure, and sepsis with significant morbidity a mortality. In prosthetic joint infections occurring within 1 yr of surgery, there is usually a history of a postoperative wound infection that appears to resolve, satisfactory postoperative recovery for many m and then development of persistent joint pain at rest and on weight bearing. One third of prosthetic join infections occur >= 1 yr after surgery when extra-articular infections (eg, pneumonia, UTIs, skin infecti bacterial seeding from dental procedures or invasive instrumentation) produce intermittent bacteremia 25% of patients have reported injury from a fall within 2 wk of the onset of pain, and about 20% have h surgical revisions. Patients may not have fever or leukocytosis, but most have an elevated ESR.
Chronic bacterial arthritis: Onset is indolent, with gradual swelling; mild warmth; minimal or no redne the joint area; and aching pain, which may be mild.
Diagnosis
Diagnosis of infectious arthritis usually requires a high index of suspicion, particularly if the source of in is extra-articular, because symptoms may mimic other forms of arthritis. Diagnosis may be suggested clinical picture and by recovering an organism from a remote site of infection. A blood sample usually WBC elevation in about 1/2 of cases and ESR and C-reactive protein elevation.
Synovial fluid from the swollen joint usually reveals a WBC count > 20,000/L (often > 100,000/L) c of > 95% PMNs in acute infections. Viscosity and glucose concentration are usually decreased. Gram synovial fluid reveals organisms in 50 to 75% of infected joints and distinguishes gram-positive from gram-negative organisms but not staphylococci from streptococci. Fluid should be cultured aerobically anaerobically. Foul-smelling synovial fluid and air within the joint or surrounding soft tissue on x-ray su anaerobic infection.
Disseminated gonococcal infection should be suspected in a sexually active person with a typical clinic history, especially if gonorrhea is found elsewhere. Culture of gonococcus is difficult because the orga very sensitive to drying. If disseminated gonococcal infection is likely, blood and synovial fluid samples
anaerobically. Foul-smelling synovial fluid and air within the joint or surrounding soft tissue on x-ray su anaerobic infection.
Disseminated gonococcal infection should be suspected in a sexually active person with a typical clinic history, especially if gonorrhea is found elsewhere. Culture of gonococcus is difficult because the orga very sensitive to drying. If disseminated gonococcal infection is likely, blood and synovial fluid samples be immediately plated on nonselective chocolate agar, and specimens from urethra, endocervix, rectu pharynx on selective Thayer Martin medium. Blood cultures are positive in 60 to 75% of cases during t week and may be the only method by which to identify the causative organism; cultures from joints wit tenosynovitis are often negative. Synovial fluid cultures from joints with frank purulent arthritis are usua positive, and fluid from skin lesions may be positive.
The only x-ray abnormalities early in acute bacterial arthritis are soft tissue swelling and signs of syn effusions. After 10 to 14 days of bacterial infection, destructive changes of joint space narrowing (refle cartilage destruction) and erosions or foci of subchondral osteomyelitis become evident. Gas formation the joints suggests infection with E. coli or anaerobes. In chronic bacterial arthritis, joint space is prese longer, and marginal erosions and bony sclerosis occur.
Technetium-99m methylene diphosphonate bone scans are usually abnormal in infectious arthritis especially helpful in evaluating axial skeleton joints. The scans show increased uptake with increased flow in inflamed synovial membrane and in metabolically active bone and are thus positive in septic an aseptic arthritis. However, the scans are only 77% accurate because vasospasm, abscess formation, vascular thrombosis may offset the increased uptake caused by the infection. Gallium-67 citrate has accuracy of 91%, but the radiation dose is higher. Very early in infection, scans may show cold spots i of ischemia. Gallium scans (and scans with indium-labeled WBC or IgG) show uptake in purulent syno fluid; they are much more sensitive in acute than in chronic infections. In prosthetic joint infections, gal scans have a low sensitivity, and the usefulness of indium-WBC scans has not been established.
Treatment
Initial antibiotic selection depends on age, past history, extra-articular infection, and comorbidity factor together with synovial fluid Gram stain findings. The regimen should be adjusted when the results of c (24 to 48 h) and susceptibility testing (3 or 4 days) are available.
In suspected nongonococcal gram-positive infections, the initial choice should be a semisynthetic pen nafcillin), a cephalosporin, vancomycin (if methicillin resistance is common [eg, with S. aureus]), or clindamycin. In suspected gram-negative infections, a third-generation cephalosporin and an aminogly (if infection is severe) should be given parenterally until the results of antibiotic sensitivity testing are a
Parenteral antibiotics should be continued until significant clinical improvement occurs (usually 2 wk), antibiotics should be given at several times the usual dose for 2 to 6 wk according to the clinical respo Infections caused by streptococci and Haemophilus can usually be eradicated in 2 wk. Staphylococcal infections require at least 3 wk and often 6 wk or longer, especially in patients with prior arthritis.
In addition to antibiotics, acute nongonococcal bacterial arthritis requires large-bore needle aspiration intra-articular pus at least once/day, tidal irrigation lavage, arthroscopic lavage, or arthrotomy for debri Infected rheumatoid joints should also undergo early aggressive surgical debridement and drainage. J should be splinted for the first few days to reduce pain, followed by passive and active range-of-motion exercises with muscle strengthening as soon as tolerated.
Treatment of disseminated gonococcal infection is the same regardless of stage. Empirical treatment recommendations change frequently because the epidemiology of antibiotic-resistant gonococcus is e Disseminated gonococcal infection rarely requires surgical debridement and drainage and usually doe
should be splinted for the first few days to reduce pain, followed by passive and active range-of-motion exercises with muscle strengthening as soon as tolerated.
Treatment of disseminated gonococcal infection is the same regardless of stage. Empirical treatment recommendations change frequently because the epidemiology of antibiotic-resistant gonococcus is e Disseminated gonococcal infection rarely requires surgical debridement and drainage and usually doe produce permanent joint damage. Coexistent genital infection with Chlamydia trachomatis, which may 50% of cases, must also be treated, and sexual contacts of the patient should be evaluated (see Ch. 1
Prosthetic joint infections require prolonged treatment. Treatment options include (1) long-term supp of infection with antibiotics in patients not fit for surgery; (2) excision arthroplasty with or without fusion patients with uncontrolled infection and insufficient bone stock); (3) arthrotomy for prosthesis removal, meticulous debridement of all cement, abscesses, and devitalized tissues, followed by prolonged antib and (4) immediate or delayed (1 to 3 mo) implantation of a new prosthesis using antibiotic-impregnate cement. The reinfection rate is high (38%) in new implants, whether replaced immediately or after 2 to antibiotic therapy.
Human bites should be treated with amoxicillin or trimethoprim-sulfamethoxazole for 3 to 5 days. Infe with P. multocida resulting from animal bites is usually sensitive to penicillin, but joint infections shoul be surgically debrided. Rat bites that result in infection with S. moniliformis or S. minus usually respond penicillin.
There is no specific treatment of viral arthritis. Mycobacterial and fungal joint infections require prolong treatment, usually with multiple antibiotics, depending on sensitivity testing of the isolated organism.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 61. Common Hand Disorders Topics
Deformities Neurovascular Syndromes Trauma Infections Congenital Deformities Tendon Problems
Deformities
MALLET FINGER
Once hand deformities become relatively established, they cannot be significantly altered by splinting, exercise, or other nonoperative treatment.
A flexion deformity of the terminal interphalangeal joint in which the fingertip droops and extension is n possible.
This deformity may result from a tendon injury or bony avulsion, causing a flexion lag at the distal interphalangeal (DIP) joint (see Fig. 61-1). Closed injuries may be treated with splinting that holds the in extension and leaves the proximal interphalangeal (PIP) joint free. Avulsion fractures are usually un 6 wk, but pure tendon injuries require approximately 8 to 10 wk for collagen to heal sufficiently.
SWAN-NECK DEFORMITY
Metacarpal flexion, hyperextension of the PIP joint, and flexion of the DIP joint.
Although a characteristic finding in RA, swan-neck deformity has several causes, including untreated m deformity, volar plate laxity, spasticity, ligamentous laxity, and malunion of a fracture of the middle pha The inability to overcome hyperextension of the PIP joint makes finger closure impossible and can cau severe disability. True swan-neck deformity does not affect the thumb, which is "missing" a phalangea However, severe hyperextension of the interphalangeal joint of the thumb with flexion of the
Although a characteristic finding in RA, swan-neck deformity has several causes, including untreated m deformity, volar plate laxity, spasticity, ligamentous laxity, and malunion of a fracture of the middle pha The inability to overcome hyperextension of the PIP joint makes finger closure impossible and can cau severe disability. True swan-neck deformity does not affect the thumb, which is "missing" a phalangea However, severe hyperextension of the interphalangeal joint of the thumb with flexion of the metacarpophalangeal (MCP) joint is called a duck bill, Z (zigzag) type, or 90 angle deformity. If assoc with thumb instability, swan-neck deformity can interfere greatly with prehension (pinch). This deformit usually be corrected by interphalangeal arthrodesis.
Treatment is aimed at correcting the underlying cause when possible (ie, correcting the mallet deformi bony misalignment, rebalancing the extensor mechanism, releasing spastic intrinsic muscles).
BOUTONNIRE DEFORMITY
(Buttonhole Deformity)
Fixed flexion of the PIP joint accompanied by hyperextension of the DIP joint.
This may result from lacerations, dislocation, fracture, osteoarthritis, or RA. Classically, the deformity i by disruption of the central slip attachment base of the middle phalanx extensor tendon, creating a sobuttonholing of the proximal phalanx between the lateral bands of the extensor tendon. Surgical recon after fixed deformities develop is often found to be unsatisfactory.
EROSIVE (INFLAMMATORY) OSTEOARTHRITIS
A clinical form of osteoarthritis of genetic predisposition that, in the hand, primarily affects the DIP joint PIP joints, and the first carpometacarpal joints, with extensive synovitis and cyst formation.
Bony enlargement of the DIP joints (Heberden's nodes) and bony overgrowth of the PIP joints (Boucha nodules) are present, often without significant soft tissue swelling. The MCP joints and wrists are usua spared in erosive osteoarthritis. On x-ray, erosions appear subchondral rather than marginal (as is usu seen in RA). The thumb base (carpometacarpal joint) frequently is involved, with a squared-off appear Unlike in RA, the ESR and CBC are usually normal, regardless of disease severity. Treatment can inc range-of-motion exercises in warm water, intermittent splinting to prevent deformity, use of analgesics NSAIDs, and occasional intra-articular injections of depot corticosteroids for acutely symptomatic joint relieve pain and prevent limited motion.
DUPUYTREN'S CONTRACTURE
(Palmar Fibromatosis)
Progressive contracture of the palmar fascial bands, producing flexion deformities of the fingers.
Dupuytren's contracture is common; the incidence is higher in men and increases after age 45. This a dominant condition with variable penetrance occurs more commonly in patients with diabetes, alcoholi epilepsy. However, the factor that causes the palmar fascia to thicken and contract is unknown. Some are familial.
Progressive contracture of the palmar fascial bands, producing flexion deformities of the fingers.
Dupuytren's contracture is common; the incidence is higher in men and increases after age 45. This a dominant condition with variable penetrance occurs more commonly in patients with diabetes, alcoholi epilepsy. However, the factor that causes the palmar fascia to thicken and contract is unknown. Some are familial.
Symptoms, Signs, and Course
The earliest manifestation is usually a tender nodule in the palm (most often at the third or fourth finge followed by formation of a superficial pretendinous cord, which leads to contracture of the MCP joints a interphalangeal joints of the fingers. The nodule may initially cause discomfort but becomes painless a matures. Eventually, the contracture worsens, and the hand becomes arched. The disease occasiona associated with fibrous thickening of the dorsum of the PIP joints (Garrod's pads), Peyronie's disease fibromatosis) in about 7 to 10% of patients, and rarely nodules on the plantar surface of the feet (plant fibromatosis).
Treatment
Treatment, if during the incipient phase, includes local injection of a corticosteroid suspension into the which helps local tenderness and possibly delays progression of fibrotic changes. Surgery is usually in when the hand cannot be placed flat on a table or when significant contracture develops at the PIP joi limiting hand function. Excision of the diseased fascia must be meticulous because it surrounds neuro bundles and tendons. Incomplete excision or new disease will result in recurrent contracture, especiall patients with young onset, family history, Garrod's pads, Peyronie's disease, or plantar foot involveme PIP joint is particularly recalcitrant to correction, and early surgery is advised when PIP joint contractur occurs. Otherwise, management consists of watchful waiting. High-dose vitamin E has been recomme lessen progression of the disease, although data to support this recommendation are lacking.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 55. Crystal-Induced Conditions Topics
Gout Idiopathic Hyperuricemia Calcium Pyrophosphate Dihydrate Crystal Deposition Disease Basic Calcium Phosphate And Other Crystal Disorders
Gout
Pathophysiology
A recurrent acute or chronic arthritis of peripheral joints that results from deposition in and about the jo tendons of monosodium urate crystals from supersaturated hyperuricemic body fluids.
Plasma is saturated with uric acid > 7.0 mg/dL, or 0.41 mmol/L (pH, 7.4; normal sodium concentration [98.6 F]). Urate solubility at 30 C (86 F) is only 4 mg/dL (0.24 mmol/L), so needle-shaped monosodi (MSU) crystals are deposited in avascular tissues (eg, cartilage) or relatively avascular tissues (eg, ten ligaments) around cooler distal peripheral joints and cooler tissues (eg, ears). In severe, long-standing disease, MSU crystals may be deposited in larger central joints and in the parenchyma of organs such kidney.
Tophi are MSU crystal aggregates. They are large enough to first be seen on x-rays of the joints as punched-out lesions and later seen or felt as subcutaneous nodules. At the acid pH of urine, uric acid precipitated readily as small platelike crystals that may aggregate to form gravel or stones, which may obstructive uropathy.
Sustained hyperuricemia is usually caused by decreased renal clearance of urate, especially in patien receiving chronic diuretic therapy and in patients with primary renal diseases that decrease GFR. The the degree and duration of hyperuricemia, the greater the chance of crystal deposition and of acute at gout. However, many hyperuricemic persons never develop gout.
Increased purine synthesis may occur as a primary abnormality or may be caused by increased nucleo turnover in hematologic conditions (eg, lymphoma, leukemia, hemolytic anemia) and in conditions with increased rates of cellular proliferation and cell death (eg, psoriasis). The reason for increased uric ac synthesis de novo in most cases of gout is unknown, but a few cases are attributable to a deficiency o
gout. However, many hyperuricemic persons never develop gout.
Increased purine synthesis may occur as a primary abnormality or may be caused by increased nucleo turnover in hematologic conditions (eg, lymphoma, leukemia, hemolytic anemia) and in conditions with increased rates of cellular proliferation and cell death (eg, psoriasis). The reason for increased uric ac synthesis de novo in most cases of gout is unknown, but a few cases are attributable to a deficiency o hypoxanthine-guanine phosphoribosyltransferase or to overactivity of phosphoribosylpyrophosphate synthetase. The former enzyme abnormality is associated with kidney stones, nephropathy, and sever an early age and, in cases of complete deficiency, with neurologic abnormalities, such as choreoathet spasticity, mental retardation, and compulsive self-mutilation (Lesch-Nyhan syndrome). Dietary purine contribute to serum uric acid. Marked rises in uric acid often follow consumption of purine-rich foods, e with alcoholic beverages. Ethanol induces nucleotide catabolism in the liver and increases the formatio lactic acid, which, similar to other organic acids, blocks urate secretion by the renal tubules. A strict low diet, however, only lowers baseline serum urate by about 1 mg/dL (0.06 mmol/L).
The serum urate level reflects the size of the extracellular miscible urate pool, which normally turns ov every 24 h; 1/3 of the urate is excreted in the feces, and 2/3 in the urine. Normal 24-h urinary uric acid excretion is 300 to 600 mg after 3 days on a low-purine diet or about 600 to 900 mg on a regular diet. Therefore, food intake accounts for about 450 mg of uric acid daily. Hyperuricemia and gout are comm complications in patients receiving cyclosporine for organ transplants. Mean urate levels in premenopa women are about 1 mg/dL (0.6 mmol/L) lower than those in men, but after menopause the levels appr those of men.
Symptoms and Signs
Acute gouty arthritis starts without warning. It may be precipitated by minor trauma, overindulgence purine-rich food or alcohol, surgery, fatigue, emotional stress, or medical stress (eg, infection, vascula occlusion). Acute monarticular or, less often, polyarticular pain, often nocturnal, is usually the first sym The pain becomes progressively more severe and is often excruciating. Signs resemble an acute infec with swelling, warmth, redness, and exquisite tenderness. The overlying skin is tense, warm, shiny, an purplish. The metatarsophalangeal joint of the great toe is most often involved (podagra), but the inste ankle, knee, wrist, and elbow are also common sites. Fever, tachycardia, chills, malaise, and leukocyto occur.
The first few attacks usually affect only a single joint and last only a few days, but later attacks may aff several joints simultaneously or sequentially and persist for weeks if untreated. Local symptoms and s eventually regress, and normal joint function returns. Asymptomatic intervals vary but tend to become as the disease progresses. Without prophylaxis (see Treatment, below), several attacks may occur ea and chronic joint symptoms may develop with permanent erosive joint deformity. Limitation of motion o involves multiple joints of the hands and feet; rarely, the shoulder, sacroiliac, and sternoclavicular joint cervical spine is involved. Urate deposits are common in the walls of bursae and tendon sheaths. Enla tophi on the hands and feet may erupt and discharge chalky masses of urate crystals. Gout caused by cyclosporine often starts in the larger central joints, such as the hip and sacroiliac, as well as in the ha further damages renal tubules.
Diagnosis
Acute gouty arthritis has such distinctive clinical features that it can usually be tentatively diagnosed by and physical examination. Elevated serum urate (> 7 mg/dL [> 0.41 mmol/L]) supports the diagnosis b specific. About 30% of patients have a normal serum urate at the time of the acute attack. Demonstrat tissue or synovial fluid of needle-shaped urate crystals that are free in the fluid or engulfed by phagocy pathognomonic. The appearance of MSU crystals on compensated polarized light microscopy is descr Table 55-1.
Acute gouty arthritis has such distinctive clinical features that it can usually be tentatively diagnosed by and physical examination. Elevated serum urate (> 7 mg/dL [> 0.41 mmol/L]) supports the diagnosis b specific. About 30% of patients have a normal serum urate at the time of the acute attack. Demonstrat tissue or synovial fluid of needle-shaped urate crystals that are free in the fluid or engulfed by phagocy pathognomonic. The appearance of MSU crystals on compensated polarized light microscopy is descr Table 55-1.
A dramatic response often follows within 24 h of colchicine therapy. However, not all gouty attacks res dramatically, and a dramatic response may occur in pseudogout, calcific tendinitis, or other conditions diagnostic approach is now obsolete.
X-rays may show punched-out lesions in subchondral bone, commonly in the first metatarsophalangea Tophi must reach 5 mm in diameter before becoming visible as bony lesions on x-ray. Such detectable lesions are not specific or diagnostic but nearly always precede the appearance of subcutaneous toph
In calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (see below), weakly positively birefringent CPPD crystals cause acute synovitis; in addition, radiopaque deposits are present in fibroc or in hyaline articular cartilage (particularly the knee), and the clinical course is usually milder than in g acute septic joint may be confused with an acute gouty joint, but culture of the synovial fluid demonstra bacteria. Acute rheumatic fever with joint involvement and juvenile RA may simulate gout but occurs m young persons, who rarely get gout. Palindromic rheumatism (ie, acute attacks of inflammation in one joints) is common, especially in middle-aged or elderly men; onset is often even more sudden than in g the pain can be as severe. Attacks spontaneously subside completely after 1 to 3 days. Such attacks m herald the onset of RA, and rheumatoid factor tests are often positive (these tests are positive in 10% patients also). Such attacks are associated with local fibrin deposition. Joint fluid is rarely obtainable b the attacks generally involve extra-articular tissues. Osteoarthritic Heberden's nodes may be the site o tophi, especially in elderly women taking diuretics.
Prognosis
Current therapy permits most patients to live a normal life if the disease is diagnosed early and medica is followed. For patients with advanced disease, tophi can be resolved, joint function improved, and re dysfunction arrested. Gout is generally more severe in patients whose initial symptoms appear before About 20% of patients with gout develop urolithiasis with uric acid or calcium oxalate stones. Complica include obstruction and infection, with secondary tubulointerstitial disease. Untreated progressive rena dysfunction, usually related to coexisting hypertension, diabetes mellitus, or some other cause of neph leads to further impairment in the excretion of urate, accelerating the pathologic process in the joints, a the greatest threat to life.
Treatment
Objectives are (1) termination of the acute attack with NSAIDs, (2) prevention of recurrent acute attack frequent) with daily colchicine, and (3) prevention of further deposition of MSU crystals and resolution existing tophi by lowering the urate concentration in extracellular body fluid. A preventive program sho to avert both the disability resulting from erosion of bone and joint cartilage and the renal damage. Spe treatment depends on the stage and severity of the disease. Coexisting hypertension, hyperlipidemia, obesity should be treated.
Treatment of acute attacks: The response to colchicine is usually dramatic. Joint pains generally beg subside after 12 h of treatment and cease within 36 to 48 h. The dose of colchicine is 1 mg po q 2 h un
to avert both the disability resulting from erosion of bone and joint cartilage and the renal damage. Spe treatment depends on the stage and severity of the disease. Coexisting hypertension, hyperlipidemia, obesity should be treated.
Treatment of acute attacks: The response to colchicine is usually dramatic. Joint pains generally beg subside after 12 h of treatment and cease within 36 to 48 h. The dose of colchicine is 1 mg po q 2 h un response is obtained or until diarrhea or vomiting occur. Severe episodes may require 4 to 7 mg (aver mg). No more than 7 mg should be taken in 48 h. Treatment often causes diarrhea. Colchicine may al given IV if the GI tract is intolerant of oral medication. Colchicine 1 mg is diluted with 0.9% sodium chlo 20 mL and injected slowly (over 2 to 5 min); no more than 2 mg is given in 24 h. Severe bone marrow suppression and death may occur in patients receiving prophylactic oral colchicine when also given IV of this drug. Severe electrolyte imbalance can accompany colchicine-induced diarrheal episodes with disastrous consequences, especially in elderly patients.
NSAIDs are effective in acute attacks of established gout. Daily doses are usually taken with food for 2 days. NSAIDs may cause many complications, including GI upset, hyperkalemia (in patients whose re flow is prostaglandin E2 -dependent), and fluid retention. Elderly and dehydrated patients are at particu especially if there is a history of renal disease.
Gouty attacks also may be treated by aspiration of affected joints, followed by instillation of corticoster esters. Prednisolone tebutate 10 to 50 mg can be used, with doses depending on the size of the affec Single-dose ACTH 80 U IM is very effective treatment and, like colchicine IV, may be especially useful treating gouty attacks in postoperative patients who cannot take oral medications. Prednisone may als used in short courses, for example, 20 to 30 mg/day for polyarticular attacks. Rarely, several of these must be used in combination.
In addition to specific therapy, rest and abundant fluid intake to combat dehydration and to decrease u crystal precipitation in the kidneys are indicated. To control pain, narcotics (eg, codeine 30 to 60 mg) m needed. Splinting of the inflamed joint may be helpful. Treatment with drugs that lower the serum urate concentration should be deferred until acute symptoms have been completely controlled.
Treatment of chronic disease: The frequency of acute attacks is reduced by one to three 0.6-mg tab colchicine daily (depending on tolerance and severity). An extra 1 or 2 mg of colchicine taken at the fir suggestion of an attack usually aborts flares. A neuropathy or myopathy can develop during chronic co ingestion.
Colchicine does not retard the progressive joint damage produced by tophi. Such damage can be prev however, and many tophaceous deposits resolved by lowering the serum urate concentration to the no range and maintaining it indefinitely, either by increasing uric acid excretion with a uricosuric drug or b blocking uric acid production with allopurinol or, in severe tophaceous gout, with both types of drugs to Hypouricemic therapy is indicated for gouty patients with tophaceous deposits, a serum urate concent consistently > 9 mg/dL (> 0.53 mmol/L), persistent joint symptoms despite only a modest increase in s urate, or impaired renal function.
Because acute attacks tend to develop during the first few weeks of treatment of hyperuricemia, contro hyperuricemia should be started in conjunction with daily colchicine or NSAID treatment during a quies phase. Periodic determination of serum urate concentration is a helpful guide to effectiveness of hypo drug therapy. The dosage and selection of the drug should be adjusted to achieve a significant reducti serum urate concentration. Resolution of tophi may take months or years and may require maintenanc serum urate level < 4.5 mg/dL (< 0.26 mmol/L).
In uricosuric therapy, either 500-mg tablets of probenecid or 100-mg tablets of sulfinpyrazone are give dose is adjusted to maintain the serum urate concentration in the normal range. The starting dose sho one-half tablet bid, gradually increasing up to four tablets/day. Sulfinpyrazone has a greater uricosuric
serum urate concentration. Resolution of tophi may take months or years and may require maintenanc serum urate level < 4.5 mg/dL (< 0.26 mmol/L).
In uricosuric therapy, either 500-mg tablets of probenecid or 100-mg tablets of sulfinpyrazone are give dose is adjusted to maintain the serum urate concentration in the normal range. The starting dose sho one-half tablet bid, gradually increasing up to four tablets/day. Sulfinpyrazone has a greater uricosuric than probenecid, but it is more toxic. Salicylates antagonize the uricosuric effect of both drugs and sho avoided. Acetaminophen provides comparable analgesia without interfering with the uricosuric drug ac
Allopurinol, 200 to 600 mg/day, in divided doses inhibits uric acid synthesis and thus controls serum u concentration. As with uricosurics, the initial dose is usually low and is increased until urate levels are 4.5 mg/dL (0.26 mmol/L). In addition to blocking the enzyme responsible for uric acid formation (xanth oxidase), this drug corrects excessive purine synthesis de novo. It is especially helpful in treating patie repeatedly pass uric acid or calcium oxalate renal calculi or who have severe renal dysfunction. Estab uric acid renal stones dissolve during allopurinol treatment. Adverse effects of allopurinol include mild distress and potentially dangerous skin rash, hepatitis, vasculitis, and leukopenia.
Other therapeutic interventions: Fluid intake >= 3 L/day is desirable for all gouty patients, especially those who chronically pass uric acid or calcium oxalate renal calculi. Alkalization of urine with sodium bicarbonate or trisodium citrate 5 g tid is also sometimes recommended. Acetazolamide 500 mg at be an excellent way to alkalize the concentrated nocturnal urine. Care must be taken not to alkalize the u vigorously, as this will favor deposition of calcium oxalate crystals. Drugs are so effective in lowering th urate concentration that rigid restriction of dietary purines is rarely necessary. Obese patients should b encouraged to lose weight during a quiescent phase of the disease. Large tophi in areas with healthy be removed surgically; all others should slowly resolve under adequate serum urate-lowering therapy. Extracorporeal shock wave lithotripsy may be considered to disintegrate renal calculi.
Section 5. Musculoskeletal And Connective Tis Disorders Chapter 62. Common Sports Injuries Topics
[General] Metatarsal Stress Fracture Shin Splints Popliteus Tendinitis Achilles Tendinitis Patellofemoral Pain Posterior Femoral Muscle Strain Piriformis Syndrome Lumbar Strain Lateral Epicondylitis Medial Epicondylitis Rotator Cuff Tendinitis
[General]
(See also discussions of plantar fasciitis under Calcaneal Spur Syndrome under Disorders Associated Heel Pain in Ch. 60. Head injury is discussed in Chs. 170 and 175; head injury in children, under Injuri 263. Trauma to other parts of the body is discussed elsewhere in The Manual. For further discussion o traumatic musculoskeletal conditions, see Ch. 59.)
More than 10 million sports injuries are treated each year in the USA. Athletes and nonathletes share similar injuries. For example, lateral and medial epicondylitis (tennis elbow) can be caused by carrying suitcase, turning a screwdriver, or opening a stuck door, and patellofemoral pain (runner's knee) can b caused by excessive pronation while walking. Thus, principles of sports medicine can be applied to the treatment of all musculoskeletal injuries.
Etiology
All persons have tissues susceptible to injury because of inherent weakness or biomechanical factors. example, patients with exaggerated lumbar lordosis are at risk of back pain when they swing a baseba and patients with excessive pronation of the feet are at risk of knee pain when they run long distances correction, the risk of chronic injury is high because specific motions are performed repeatedly in all sp Pain usually ceases when activity is stopped but recurs each time the same workload is reached.
Overuse: The most common cause of muscle or joint injury is overuse. Continuing to exercise when s
example, patients with exaggerated lumbar lordosis are at risk of back pain when they swing a baseba and patients with excessive pronation of the feet are at risk of knee pain when they run long distances correction, the risk of chronic injury is high because specific motions are performed repeatedly in all sp Pain usually ceases when activity is stopped but recurs each time the same workload is reached.
Overuse: The most common cause of muscle or joint injury is overuse. Continuing to exercise when s pain occurs exacerbates injury. Overuse may result from not allowing >= 48 h recovery after an intens workout, regardless of fitness.
Every time muscles are stressed, some fibers are injured, and some use up the available glycogen. Be only uninjured fibers or those with adequate glycogen function properly, vigorous exercise demands th work from fewer fibers, increasing the likelihood of injury. It takes >= 48 h for fibers to heal and longer glycogen to be replaced. Exercisers who work out daily should stress different parts of the body.
Most training methods emphasize the hard-easy principle, ie, exercising intensely on one day (eg, run 5-min/mile pace) and at a more relaxed pace on the next (eg, a 6- to 8-min/mile pace). If an athlete tra twice/day, each intense workout should be followed by at least three easy ones. Only swimmers can to an intense and an easy workout each day. Presumably, the buoyancy of the water helps protect their m and joints.
Biomechanical factors: Muscles, tendons, and ligaments may be injured when they are too weak for exercise (they can be strengthened by resistance exercises, using progressively heavier weights). Bon be weakened by osteoporosis. Joints are more likely to be damaged if supporting muscles and ligame weak.
Structural abnormalities can place uneven stress on body parts (eg, unequal leg lengths). Running on tracks or crowned roads places greater stress on the hip of the leg that strikes higher ground, increasin risk of pain or injury at this site.
The biomechanical factor that most commonly causes foot, leg, or hip injury is excessive pronation (ro the feet after they strike the ground) while running. After pronation, the foot rolls toward the lateral plan aspect (supination), then raises on the toes before stepping off the ground and shifting weight to the o Pronation helps prevent injury by distributing the force of impact with the ground. Excessive pronation cause injury through exaggerated medial twisting of the lower leg, resulting in foot, leg, hip, and knee p ankles are so flexible that, during walking or running, the arches touch the ground and thus appear to shallow or absent.
A cavus foot has a very high arch. Many people who appear to have a cavus foot have normal arches ankles, so they pronate very little. Their feet usually are poor shock absorbers, increasing the risk of st fracture in the bones of the feet and legs.
Diagnosis
After a physical examination and a history (eg, acute or subacute onset; position of applied forces; cha training, equipment, surface) have been performed, referral to a specialist for various carefully selecte (eg, plain x-ray, bone scan, strain x-ray under general anesthesia, CT, MRI, arthroscopy, electromyogr computer-aided physiologic tests) may be considered.
Prevention
Warming up involves exercising muscles at a relaxed pace for a few minutes before an intense worko minutes of exercise can raise muscle temperature to about 38 C (101 F), making the muscle more p
Prevention
Warming up involves exercising muscles at a relaxed pace for a few minutes before an intense worko minutes of exercise can raise muscle temperature to about 38 C (101 F), making the muscle more p stronger, and resistant to injury. Active warm-up by exercise prepares muscles for an intense workout effectively than passive heating with warm water, a heating pad, an ultrasound, or an infrared lamp.
Stretching does not prevent injury but can improve performance, elongating muscles so they can dev greater torque. Stretching should be performed after a warm-up or after exercise. To avoid direct injury athletes should never stretch further than they can hold for 10 sec.
Cooling down (gradually slowing down before stopping exercise) can prevent dizziness and syncope person who exercises vigorously and stops suddenly, blood can pool in the dilated leg veins, causing d and even fainting (see also Ch. 200). Cooling down maintains increased circulation and helps clear lac from the bloodstream. It does not prevent next-day muscle soreness, which is caused by damage to th muscle fibers.
Treatment
Acute aspects of the injury should be addressed first, including pain management (see Ch. 167) and r the injured part (eg, by splinting).
RICE: Immediate treatment for almost all acute athletic injuries is RICE (Rest, Ice, Compression, Elev Rest is instituted immediately to minimize hemorrhage, injury, and swelling. Ice limits inflammation and reduces pain. Compression and elevation limit edema.
The injured part should be elevated. A bag that is chemically cooled or filled with chipped or crushed ic conforms better than ice cubes to body contours) should be placed on a towel over the injured part. An bandage should be wrapped over the ice bag and around the injured part, loosely enough to permit blo After 10 min, the ice bag and bandage are removed, but the injured part is kept elevated. Ten minutes and without the ice bag and bandage should be alternated for 60 to 90 min several times during the fir
Rebound vasodilation occurs about 9 to 16 min after ice is applied and lasts 4 to 8 min after its remova Therefore, ice should be removed if vasodilation occurs or after 10 min, but it can be reapplied 10 min removal.
Local corticosteroid injections: Peri- or intra-articular corticosteroid injections can relieve pain and r swelling and are a useful adjunct to analgesics and rest. However, they also inhibit fibroblast function collagen deposition and thus can delay healing. Corticosteroid injections markedly reduce tendon bloo supply, which can cause necrosis, increasing the risk of rupture. Injection should be close to, not into, tendon. Injected weight-bearing tendons are weaker than noninjected tendons for as long as 15 mo. R intra-articular injections can cause cartilage to lose its hyaline luster and become soft and fibrillated; occasional injections may avoid this.
Alternative sports: The patient should avoid the activity or sport until healing occurs. An alternative s does not stress the injured part or cause pain should be encouraged (see Table 62-1). Such exercise prevent loss of fitness. Every week of rest usually requires >= 2 wk of exercise to reach preinjury fitnes The injured patient should restore flexibility, strength, and endurance before returning to full athletic ac
Orthotics: Excessive pronation is often treated with orthotics (shoe inserts). They can be flexible, sem
Alternative sports: The patient should avoid the activity or sport until healing occurs. An alternative s does not stress the injured part or cause pain should be encouraged (see Table 62-1). Such exercise prevent loss of fitness. Every week of rest usually requires >= 2 wk of exercise to reach preinjury fitnes The injured patient should restore flexibility, strength, and endurance before returning to full athletic ac
Orthotics: Excessive pronation is often treated with orthotics (shoe inserts). They can be flexible, sem rigid and can extend proximal to the metatarsal heads or proximal to or beyond the toes. Most orthotic runners are semirigid and extend proximal to the toes. Good running shoes should have a rigid heel co control the rearfoot, a saddle to prevent the foot from slipping medially over the orthotic and pronating excessively, and a padded collar to restrict the ankle from rolling inward excessively. They must allow for the orthotic, which usually reduces shoe width by one letter grade.
Section 17. Genitourinary Disorders Chapter 214. Clinical Evaluation Of Genitourinary D Topics
[General]
[General]
Normally, adults void about 4 to 6 times/day, mostly in the daytime, totaling 700 to 2000 mL/day.
Genitourinary disorders may present nonspecifically but usually do so as abnormal clinical or laborator manifestations suggesting a primary renal abnormality or a systemic disease associated with renal pat
Symptoms and Signs
Asymptomatic patients with renal disease may have hypertension or abnormal blood or urine findings. may have a family history of renal disorders (eg, polycystic disease, hereditary nephropathy). Routine antenatal ultrasonography may detect fetal renal abnormalities.
In symptomatic patients, fever, weight loss, and malaise are common findings with renal carcinoma, a renal failure, and UTI. Typically, renal symptoms include changes in micturition, urinary output, or app hematospermia in men; or pain, edema, and nonspecific symptoms and signs related to renal insuffici
Frequent micturition without an increase in urine volume is a symptom of reduced bladder filling cap Infection, foreign bodies, calculi, or tumors may injure the bladder mucosa or underlying structures, lea inflammatory infiltration and edema. Mild stretching of the bladder, reduced bladder elasticity, a pelvic a gravid uterus functionally reduces bladder capacity, resulting in pain and urgency (a compelling need urinate). Incontinence may occur if voiding is not immediate. Urine volume is usually small, and the de urinate may be almost constant until the irritative process resolves.
Polyuria (> 2500 mL/day voided) may be caused by increased water intake (eg, compulsive water drin osmotic diuresis (eg, glycosuria from uncontrolled diabetes mellitus), decreased vasopressin release d hypothalamic or posterior pituitary disease, or decreased renal tubular response to ADH from hyperca K deficiency, or congenital or acquired nephrogenic diabetes insipidus (NDI).
Oliguria (< 500 mL/day voided in adults or < 24 mL/kg body weight/day in young children) tends to be and caused by decreased renal perfusion (prerenal factors), ureteral or bladder outlet obstruction (pos
osmotic diuresis (eg, glycosuria from uncontrolled diabetes mellitus), decreased vasopressin release d hypothalamic or posterior pituitary disease, or decreased renal tubular response to ADH from hyperca K deficiency, or congenital or acquired nephrogenic diabetes insipidus (NDI).
Oliguria (< 500 mL/day voided in adults or < 24 mL/kg body weight/day in young children) tends to be and caused by decreased renal perfusion (prerenal factors), ureteral or bladder outlet obstruction (pos factors), or primary renal disease. Uremia may occur.
Anuria (< 100 mL/day voided in adults), although rare, may signal acute renal failure, the end stage o progressive renal insufficiency, or, rarely, renal infarction or cortical necrosis. It may also be due to rev urinary obstruction. Prolonged anuria inevitably results in uremia.
Nocturia (voiding during the night) is an abnormal but nonspecific symptom. It may occur without dise due to excessive fluid intake in the late evening. It may result from urine retention secondary to bladde obstruction (eg, prostatism). Less commonly, nocturia may reflect early renal disease and polyuria from decrease in concentrating capacity or heart and liver failure without evidence of intrinsic urinary system disease.
Enuresis (bed-wetting) is physiologic during the first 2 or 3 yr of life but later becomes an increasing p (see under Behavioral Problems in Ch. 262). It may be caused by delayed neuromuscular maturation lower urinary tract or organic disease; eg, infection or distal urethral stenosis in girls, posterior urethral in boys, or neurogenic bladder in either sex.
Dysuria (painful urination) suggests irritation or inflammation in the bladder neck or urethra, usually du bacterial infection. Persistent symptoms without such infection require careful evaluation of the bladde urethra (see also Ch. 215).
Obstructive symptoms (hesitancy, straining, decrease in force and caliber of the urinary stream, term dribbling) are commonly due to obstruction distal to the bladder. In men, such obstruction is usually du prostatic obstruction or less often to urethral stricture or posterior urethral valves (which may be conge boys). Similar symptoms may suggest meatal stenosis in either sex.
Urinary incontinence (an uncontrollable loss of urine) may be caused by exstrophy of the bladder, epispadias, vesicovaginal fistula, ectopic ureteral orifices, congenital or acquired neurogenic (peripher neuropathy, stroke, dementia) bladder dysfunction, or injuries due to prostatectomy or childbirth (see a 215). In women, incontinence with mild physical stress (eg, coughing, laughing, running, lifting) is com due to urethral atrophy from a lack of estrogen or to a cystocele as a result of aging or stretching of the floor muscles during childbirth. Loss of urine due to bladder outlet obstruction or a flaccid bladder may overflow incontinence when the intravesicular pressure exceeds outlet resistance. Residual urine is alw present with overflow incontinence.
Pneumaturia (the passage of gas in the urine) is rare. It usually indicates a fistula between the urinary and the bowel and may be a complication of diverticulitis, with abscess formation, enterocolitis, colon c or vesicovaginal fistula. Rarely, pneumaturia may be due to gas formation from bacteriuria alone.
Abnormal color or appearance of urine has many causes. Urine may be clear during water diuresis o a deep yellow color when maximally concentrated due to chromogens (eg, urobilin). If excretion of foo pigments (usually red urine) or drugs (brown, black, blue, green, or red) can be excluded, non-yellow u suggests the presence of hematuria, hemoglobinuria, myoglobinuria, pyuria, porphyria, or melanoma. urine is commonly due to precipitated amorphous phosphate salts in an alkaline urine; less frequently, suggests pyuria due to a UTI. Milky urine may be caused by precipitated phosphates in an alkaline uri dust urine usually is produced by precipitated urates in an acid urine. Urine microscopy and chemical a usually identify the cause.
pigments (usually red urine) or drugs (brown, black, blue, green, or red) can be excluded, non-yellow u suggests the presence of hematuria, hemoglobinuria, myoglobinuria, pyuria, porphyria, or melanoma. urine is commonly due to precipitated amorphous phosphate salts in an alkaline urine; less frequently, suggests pyuria due to a UTI. Milky urine may be caused by precipitated phosphates in an alkaline uri dust urine usually is produced by precipitated urates in an acid urine. Urine microscopy and chemical a usually identify the cause.
Hematuria (blood in the urine) can produce red to brown discoloration depending on the amount of bl present and the acidity of the urine. Slight hematuria may cause no discoloration and may be detected microscopy or chemical analysis. Hematuria without pain usually is due to renal, vesical, or prostatic d In the absence of RBC casts (which usually indicate glomerulonephritis--see Table 214-1), silent hema may be caused by bladder or kidney tumor. Such tumors usually bleed intermittently, and complacenc not occur if the bleeding stops spontaneously. Intermittent, recurrent hematuria may also occur in IgA nephropathy. Other causes of asymptomatic hematuria include calculi, polycystic disease, renal cysts, cell disease, hydronephrosis, and benign prostatic hyperplasia. Hematuria accompanied by excruciatin (renal colic) suggests passage of a ureteral calculus or a clot from renal bleeding. Hematuria with dysu also associated with bladder infections or lithiasis.
Chyluria (lymph in the urine) is produced by rupture of a lymph vessel, chiefly due to abnormal conne between obstructed retroperitoneal lymphatics and the renal collecting system or to filariasis, lymphom occult neoplasm.
Hematospermia (bloody semen) occurs in < 2% of urologic referrals. Most patients have recurrent hematospermia, although some experience it just once. It is usually idiopathic. Seminal vesiculopathy unidentified infection or vascular congestion may be causal. It may also be associated with prolonged abstinence or with frequent or interrupted coitus. The disorder is usually benign and is rarely associate malignancy or serious infection. Such patients should, however, be evaluated for prostatic infection or strictures. Occasionally, hematospermia is due to a bleeding disorder. Treatment is empiric, unless a c found. Some urologists advocate a 5- to 7-day trial of tetracycline 250 mg qid followed by gentle prosta massage.
Kidney pain usually is felt in the flank or back between the 12th rib and the iliac crest, with occasiona radiation to the epigastrium. Stretching of the pain-sensitive renal capsule is the probable cause and m occur in any condition producing parenchymatous swelling (eg, acute glomerulonephritis, pyelonephrit ureteral obstruction). There is often marked tenderness over the kidney in the costovertebral angle for the 12th rib and the lumbar spine. Inflammation or acute distention of the renal pelvis or ureter causes the flank and hypochondrium, with radiation into the ipsilateral iliac fossa and often into the upper thigh testicle, or labium. The pain is intermittent but does not completely remit between waves of colic. Chro obstruction is usually asymptomatic.
Bladder pain is most commonly caused by bacterial cystitis; it is usually suprapubic and referred to th urethra during urination. Acute urinary retention causes agonizing pain, whereas chronic urinary retent to bladder neck obstruction or neurogenic bladder usually causes little discomfort.
Prostate pain due to prostatitis may be felt as a vague discomfort or fullness in the perineal or rectal a prostatic disease is generally painless. Testicular pain due to trauma or infection usually is severe.
Edema usually represents excessive extracellular water and Na due to abnormal renal excretion, but i also be caused by heart or liver disease. Initially, edema may be evident only by weight gain but later b overt. Edema associated with kidney disease is sometimes noted first as facial puffiness rather than s dependent or lower parts of the body. If fluid retention continues, anasarca (generalized edema) with f transudates (effusions) in the pleural and peritoneal cavities may occur; it is most frequently associate
Edema usually represents excessive extracellular water and Na due to abnormal renal excretion, but i also be caused by heart or liver disease. Initially, edema may be evident only by weight gain but later b overt. Edema associated with kidney disease is sometimes noted first as facial puffiness rather than s dependent or lower parts of the body. If fluid retention continues, anasarca (generalized edema) with f transudates (effusions) in the pleural and peritoneal cavities may occur; it is most frequently associate continuous, heavy proteinuria (nephrotic syndrome).
Uremia (a toxic condition associated with excessive accumulation in the blood of protein metabolism by-products) occurs when GFR declines to < 10% of normal, with resultant disturbances of multiple or systems. Weight loss, weakness, fatigue, dyspnea, anorexia, nausea and vomiting, itching, failure to g tetany, peripheral neuropathy, pericarditis, and convulsions are the usual symptoms and signs; most c ameliorated or reversed by dialysis or renal transplantation and appropriate diet.
Hypertension may be secondary to renal disease (eg, vascular anomalies or occlusion, glomerulonep progressive renal failure). However, <= 5% of adult hypertension is due to renovascular causes (with m renal artery or segmental artery obstruction and demonstrable increased renin secretion from the obst side).
Skin changes may include pallor, suggesting anemia, commonly associated with renal disease; exco suggesting pruritus; and infections (eg, carbuncles, cellulitis), which may be due to glomerulonephritis. lesions from vasculitis or endocarditis may suggest a possible cause of renal disease. Retinal abnormalities on ophthalmoscopy may include hemorrhages, exudates, and papilledema as cerebral edema associated with malignant hypertension or metabolic abnormalities.
Other abnormalities suggesting urinary system disease include stomatitis; an ammoniacal breath od enlargement of the kidneys, bladder, or prostate on palpation.
Laboratory Findings
Blood studies: Hematologic assessment may suggest renal disease. Anemia (particularly normocyt normochromic from a lack of erythropoietin) may be a clue to renal failure, but many other causes (eg, neoplasia, systemic inflammatory diseases) must be excluded. Polycythemia may occur in renal cell c or polycystic disease, but more common causes should be considered first.
Serum chemistries often are abnormal in renal dysfunction, but changes are nonspecific. For examp hypernatremia (see Ch. 12) is most frequently due to lack of adequate water intake in an obtunded pa can be produced by excessive water loss from a renal concentrating defect due to tubulointerstitial dis (eg, NDI, hypercalcemic or K depletion nephropathy). Serum HCO3 may be reduced by metabolic acid to renal disease, by lactic acidosis, or by ketoacidosis. In the absence of acute muscle damage, a pers increase in serum creatinine is highly specific for renal dysfunction (see Measurement of renal function below).
Urinalysis: Urinalysis is the best guide to intrinsic GU disease and includes microscopic examination sediment and qualitative evaluation of protein, glucose, ketones, blood, nitrites, and WBC esterase. U standardized conditions, the solute concentration of urine (osmolality or sp gr) or urine pH may have d significance. Routine urinalysis in asymptomatic patients is infrequently positive and rarely leads to ad testing or changes in therapy. Only in pregnant women is there good reason to screen for bacteriuria ( prevent serious fetal and maternal sequelae) and proteinuria (to detect preeclampsia). However, routin urinalysis misses about 2% of patients with bacteriuria, and quantitative urine cultures are recommend instead. A useful and economic means of following women later in pregnancy after a negative culture
standardized conditions, the solute concentration of urine (osmolality or sp gr) or urine pH may have d significance. Routine urinalysis in asymptomatic patients is infrequently positive and rarely leads to ad testing or changes in therapy. Only in pregnant women is there good reason to screen for bacteriuria ( prevent serious fetal and maternal sequelae) and proteinuria (to detect preeclampsia). However, routin urinalysis misses about 2% of patients with bacteriuria, and quantitative urine cultures are recommend instead. A useful and economic means of following women later in pregnancy after a negative culture repeat nitrite testing of first-morning voided specimens.
Particulate elements in urine, which can be separated and concentrated by forcing urine through a me filter, require special microscopy staining techniques but provide a permanent record. More commonly 15 mL of freshly voided urine is centrifuged for 5 min at a slow speed (1500 rpm) and the supernatant decanted. The residue at the bottom of the centrifuge tube is best visualized in a special glass chambe fixed volume, but an ordinary glass slide and coverslip will suffice. Using reduced light with the low-pow objective, several fields are scanned. The light is increased and, with the high-power objective, specifi and casts are identified (see Table 214-2). A semiquantitative estimation of these formed elements is a high-power or low-power field count (eg, 10 to 15 WBCs/high-power field).
Normal urine contains a few cells and other formed elements shed from the entire urinary tract. With d these cells are increased and may help localize the site and type of injury. Voided urine in women con genital tract cells. Urinary system disease is suggested in a male by > 1 WBC, RBC, or epithelial cell/high-power field (400), ie, > 1000 cells/mL, or in a female by > 4 WBCs/high-power field, ie, > 40 cells/mL in centrifuged urine. Excessive WBCs may indicate infection or other inflammatory diseases. symptomatic patients, the finding of > 10 WBCs/L strongly suggests significant bacteriuria. Occasion bacteria in a centrifuged urine sediment do not necessarily indicate UTI. However, bacteria in an unce fresh urine sample together with urine cultures of > 10 5 colony-forming units (CFU)/mL of voided urine UTI rather than contamination.
Excessive RBCs may indicate infection, tumor, calculi, or inflammation anywhere in the kidney or urina When >= 80% of the RBCs are dysmorphic (wide range of morphologic variation), hematuria is likely t glomerular in origin (see Ch. 224). In some clinical conditions, analysis of RBC morphology may be un For example, isomorphic erythrocyturia can be found in forced diuresis, in glomerulonephritis with gros hematuria, or in renal insufficiency. A mixed morphologic pattern of urinary RBCs may occur in IgA ne frequent cause of glomerular hematuria. Recent identification of acanthocytes (ring-formed RBCs with more protrusions of different shapes and sizes) is a more specific marker of glomerular bleeding. Stud suggest that if 5% of the total urinary RBCs are acanthocytes, then an underlying glomerular disease c diagnosed with high sensitivity (71%) and specificity (98%).
Crystals of various salts (eg, oxalate, phosphate, urate) or drugs (eg, sulfonamides) may be found whe concentrations and urinary pH exceed the limits of their solubility.
Casts (cylindric masses of mucoprotein in which cellular elements, protein, or fat droplets may be entr in urine sediment are most important in distinguishing primary renal disease from diseases of the lowe (see Table 214-1).
Proteinuria is simply and rapidly detectable by commercially available dipsticks. This technique is sen as little as 5 to 20 mg/dL of albumin, the predominant protein in most renal diseases, but is less sensit globulins and mucoproteins and may be negative in the presence of Bence-Jones proteins. Electropho immunoelectrophoresis, and radioimmunoassays can also separate or quantitate various urinary prote
The major mechanisms producing proteinuria are elevated plasma concentrations of normal or abnorm proteins (overflow proteinuria; eg, lysozymuria in myelomonocytic leukemia, Bence-Jones proteinuria); increased tubular cell secretion (TammHorsfall proteinuria); decreased tubular resorption of normal filt proteins; and an increase of filtered proteins caused by altered glomerular capillary permeability.
The major mechanisms producing proteinuria are elevated plasma concentrations of normal or abnorm proteins (overflow proteinuria; eg, lysozymuria in myelomonocytic leukemia, Bence-Jones proteinuria); increased tubular cell secretion (TammHorsfall proteinuria); decreased tubular resorption of normal filt proteins; and an increase of filtered proteins caused by altered glomerular capillary permeability.
In adults, proteinuria is usually found incidentally during a routine physical examination. Proteinuria ma intermittent, orthostatic (occurring only when upright), or constant (persistent). Most patients with interm orthostatic proteinuria do not show any deterioration of renal function, and in about 50% the proteinuri after several years. Constant proteinuria is more serious. Although the course is indolent without other indicators of renal disease (eg, microscopic hematuria), most patients demonstrate proteinuria over m years; many develop an abnormal urine sediment and hypertension; and a few progress to renal failur
Measurements of protein excretion are useful for diagnosis and follow-up, especially in constant prote 24-h measurement of total protein excretion (normal, < 150 mg/day) may be done. Alternatively, in a ra sample of urine, the protein:creatinine ratio (normally < 0.2) is measured. Heavy proteinuria (> 2 g/m2/ protein:creatinine ratio > 2) is found in patients with glomerulopathy producing the nephrotic syndrome Ch. 224).
Proteinuria usually is minimal, intermittent, or absent in diseases primarily involving the tubulointerstitia (eg, pyelonephritis, analgesic nephropathy, benign nephrosclerosis, nephropathies of hypercalcemia a depletion).
Exercise proteinuria sometimes occurs in joggers, marathon runners, and boxers. It is accompanied b elevation of catecholamines and may be associated with hemoglobinuria, hematuria, or even myoglob
For glucosuria, testing by dipstick is specific and very sensitive, detecting as little as 100 mg/dL (5.5 m of glucose. The most common cause of glucosuria is diabetic hyperglycemia with normal renal glucose transport. However, if glucosuria persists with normal blood glucose concentrations, renal tubular dysf should be considered.
For ketonuria, the dipstick reagent is more sensitive to acetoacetic acid than to acetone and does not with -hydroxybutyric acid. Ketonuria usually is nonspecific, and acetoacetic acid, acetone, and -hydrox acid are excreted in the urine. Finding any of these three compounds in urine generally is satisfactory diagnosis of ketonuria. Ketonuria offers clues to the causes of metabolic acidosis. It is present in starv uncontrolled diabetes mellitus, and occasionally in ethanol intoxication. It is not specific for intrinsic uri system disease.
For hematuria, the dipstick reagent is sensitive to free Hb and myoglobin. A positive test in the absen RBCs on microscopic examination suggests hemoglobinuria or myoglobinuria--an important etiologic c the patient with acute renal failure.
For nitrituria, the dipstick test depends on the conversion of nitrate (derived from dietary metabolites) by the action of certain bacteria in the urine. Normally no detectable nitrite is present. When bacteriuri significant, the test will be positive in 80% of cases in which the urine has incubated for >= 4 h in the b Thus, a positive test is a reliable index of significant bacteriuria. However, a negative test does not exc bacteriuria. Reasons for a negative test in the presence of bacteriuria include insufficient bladder incub time for conversion of nitrate to nitrite, low urinary excretion of nitrate, absence in some urinary pathog the enzymes to convert nitrate to nitrite, and reduction of nitrates to nitrogen by bacterial enzymes.
WBC esterase is found in azurophilic or primary neutrophil granules. Its detection, indicating the prese WBCs, is a surrogate for bacteriuria, but it actually suggests the presence of inflammation from any so bacterial infection being the most common. False-negative results may occur in the presence of very concentrated urine, glycosuria, urobilinogen, phenazopyridine, nitrofurantoin, rifampin, and large amou
time for conversion of nitrate to nitrite, low urinary excretion of nitrate, absence in some urinary pathog the enzymes to convert nitrate to nitrite, and reduction of nitrates to nitrogen by bacterial enzymes.
WBC esterase is found in azurophilic or primary neutrophil granules. Its detection, indicating the prese WBCs, is a surrogate for bacteriuria, but it actually suggests the presence of inflammation from any so bacterial infection being the most common. False-negative results may occur in the presence of very concentrated urine, glycosuria, urobilinogen, phenazopyridine, nitrofurantoin, rifampin, and large amou vitamin C.
Osmolality is the total concentration of solutes in urine, expressed as mOsm/kg (mmol/kg) of urine wa best determined by an osmometer. Normal urine osmolality is 50 to 1200 mOsm/kg depending on the circulating titer of vasopressin and the rate of urinary solute excretion. Although loss of urinary concen capacity is a sensitive test of renal dysfunction, measurement of urine osmolality (or sp gr) in a random voided urine sample is only helpful when it is > 700 mOsm/kg (sp gr > 1.020), which excludes significa tubulointerstitial disease. Lower osmolality values may be normal or abnormal depending on the prior hydration.
Urinary sp gr is measured by a urinometer or estimated by refractive index (refractometer) or a sp gr strip method. Although the correlation with osmolality is not linear, it is satisfactory for clinical use, exc large amounts of glucose or high mol wt solutes such as protein or organic iodides (radiocontrast agen present. Unlike the urinometer and refractometer, which give abnormally high values in contrast to the osmolality values, the sp gr reagent strip does not require correction for the presence of these compou
Urinary pH is measured by a dipstick impregnated with various dyes that change color when the pH is Although this test is done routinely, it does not identify or exclude patients with urinary system disease However, it often helps identify various crystals that may be found in urine on microscopy. Testing of u a pH meter is critical in diagnosing the distal type of renal tubular acidosis, which is suggested by a uri 5.5 after an acid load. The urinary pH in patients with other types of renal disease usually varies relativ normally, although the capacity to excrete titratable acid and ammonia may be reduced.
Quantitative urine cultures: A culture sample that reflects bladder urine must be obtained without u contamination from other sources. This can be achieved directly by urethral catheter or suprapubic ne aspiration of the bladder. Noninvasive techniques using clean midstream-voided urine collection and quantitative culture methods usually give adequate information without the hazards of instrumentation Interpretation of urinary CFU levels must consider the patient's clinical presentation (see Table 214-3).
Localization studies (see Table 214-4) are based on the hypothesis that bacteria coming from the ur suggest renal infection (see also Ch. 227). Most patients with UTI have bladder bacteriuria without evi tissue invasion, which readily responds to appropriate antimicrobial treatment (unless there is urinary t obstruction); localization studies are not indicated. However, for a patient with frequent relapsing infec localization studies may help uncover the cause and lead to different therapy. The bladder washout m probably the most benign localization procedure, because it avoids cystoscopy and ureteral catheteriz
Measurement of renal function: Renal function tests (see Table 214-5) are useful in evaluating the s of kidney disease and in following its progress.
Serum creatinine can be used as an index of renal function because creatinine production and excre reasonably constant in the absence of muscle disease. Serum concentration of creatinine varies inver the GFR and therefore is a useful index of the GFR if production (related to muscle mass and age) an metabolism (increased in uremia) are considered. The upper limit of serum creatinine concentration in with normal GFR is 1.2 mg/dL (110 mol/L); in women, 1 mg/dL (90 mol/L).
Creatinine clearance in men is 140 to 200 L/day (70 14 mL/min/m2) and in women, 120 to 180 L/da 10 mL/min/m2). The creatinine clearance (Clcreat) can be calculated from the serum creatinine concen
the GFR and therefore is a useful index of the GFR if production (related to muscle mass and age) an metabolism (increased in uremia) are considered. The upper limit of serum creatinine concentration in with normal GFR is 1.2 mg/dL (110 mol/L); in women, 1 mg/dL (90 mol/L).
Creatinine clearance in men is 140 to 200 L/day (70 14 mL/min/m2) and in women, 120 to 180 L/da 10 mL/min/m2). The creatinine clearance (Clcreat) can be calculated from the serum creatinine concen men as: In women, the calculated values are multiplied by 0.85.
Creatinine clearance is not useful for detecting early kidney damage due to hypertrophy of residual glo After loss of 50 to 75% of the normal glomerular filtration surface, a decrease in creatinine clearance i detectable. Thus, a normal creatinine clearance cannot exclude the presence of mild renal disease.
BUN, in contrast to serum creatinine, is unsuitable as a single measure of renal function because it is influenced by variations in urine flow rate and by the production and metabolism of urea. The BUN:cre ratio often is used to differentiate prerenal, renal, or postrenal (obstructive) azotemia. A ratio > 15 is ab and suggests prerenal or postrenal azotemia. The BUN:creatinine ratio also is elevated whenever urea production is increased by diet, TPN, or glucocorticoid therapy; with some neoplasms and antibiotics; excessive protein catabolism, as seen in infections and uncontrolled diabetes mellitus. Common cause prerenal azotemia include shock, ECF depletion, massive GI hemorrhage, severe heart and liver failur bilateral tight renal artery stenosis. The BUN:creatinine ratio is normal in renal azotemia. The ratio is lo pregnancy, overhydration, severe liver disease, and malnutrition.
Tests of renal concentrating capacity are simple and diagnostically helpful. A loss of concentrating c in the presence of adequate vasopressin stimulation is associated with tubulointerstitial disease (edem infiltrate, fibrosis), except when NDI is present. The loss of concentrating ability frequently is present lo before a depression of GFR is measurable. Renal concentrating capacity is best tested by water depri for 12 to 14 h and by the response to exogenous vasopressin. After the patient has fasted for 12 to 14 overnight, the osmolality of the initial morning urine and of subsequent hourly samples is measured. W hourly measurements differ < 30 mOsm/kg or sp gr < 0.001, the maximum concentrating capacity has reached with water deprivation. Aqueous vasopressin 5 U sc or desmopressin 10 g by nasal insufflat given, and the urine osmolality is measured after another hour. The results of this type of testing are n Fig. 214-1. (Caution: In patients with renal failure, water deprivation may be harmful and usually is no in diagnosis; the concentrating capacity is always abnormal when the GFR is significantly reduced.) A response to water deprivation or exogenous vasopressin suggests an intrinsic renal concentrating defe may be due to one or more of the following functional tubular impairments: congenital (eg, NDI, Fanco syndrome) or acquired (eg, osmotic diuresis, certain diuretics [furosemide, bumetanide, ethacrynic aci deficiency, hypercalcemia). Otherwise, tubulointerstitial disease should be considered, as in sickle cell disease, toxic nephritis, pyelonephritis, or any renal disease severe enough to produce azotemia. For responses to these tests and their interpretations, see Treatment under Diabetes Insipidus in Ch. 7.
Measurement of the renal plasma flow is no more useful clinically than the GFR but is more difficult a costly.
Additional special tests of renal tubular function usually require research laboratories and are reserve patients with specific problems. However, tests that measure plasma phosphate and urate, urinary am acids, and urine pH are readily available and may prove useful in screening specific clinical problems.
Imaging procedures: Plain x-ray of the abdomen (kidney, ureter, bladder [KUB] film) can demonstra size and location of the kidneys but has been superseded by ultrasonography (US). Because GI and G diseases tend to mimic each other, KUB film may be helpful in the differential diagnosis. However, the outline can be obscured by bowel content, lack of perinephric fat, or a perinephric hematoma or absce
acids, and urine pH are readily available and may prove useful in screening specific clinical problems.
Imaging procedures: Plain x-ray of the abdomen (kidney, ureter, bladder [KUB] film) can demonstra size and location of the kidneys but has been superseded by ultrasonography (US). Because GI and G diseases tend to mimic each other, KUB film may be helpful in the differential diagnosis. However, the outline can be obscured by bowel content, lack of perinephric fat, or a perinephric hematoma or absce difficulty may be overcome by CT. Congenital absence of a kidney may be suggested. If both kidneys unusually large, polycystic kidney disease, multiple myeloma, lymphoma, amyloid disease, or hydrone may be present. If both are small, the end stage of bilateral renal dysplasia or sclerosing disease (eg, glomerulonephritis, tubulointerstitial nephritis, nephroangiosclerosis) must be considered. Unilateral enlargement suggests renal tumor, cyst, or hydronephrosis, whereas a small kidney on one side is com with congenital dysplasia, atrophic pyelonephritis, or an ischemic kidney. Normally, the left kidney is 0. longer than the right.
In 90% of cases, the right kidney is lower than the left because of displacement by the liver. The long a the kidneys are oblique to the spine and tend to parallel the borders of the psoas muscles. If both kidn parallel to the spine, the possibility of horseshoe kidneys should be considered. If only one kidney is d a tumor or cyst may be present.
Because x-ray film is two-dimensional, a calculus in the urinary tract is practically impossible to diagno unless it is a staghorn calculus. However, suspicious opaque bodies may be noted in the region of the kidney, ureter, bladder, or prostate. Oblique and lateral films and visualization of the urinary tract with radiocontrast agents, US, or CT are necessary to place the calcification specifically within these organ
Intravenous urography (IVU; excretory urography; commonly but incorrectly referred to as intravenou pyelography) is often used to visualize the kidney and lower urinary tract. Studies are done by IV infus iodinated benzoic acid derivative. The iodine provides radiopacity, while the benzoic acid is rapidly filte the kidney. A contrast agent, after IV injection, becomes concentrated in the renal tubules in <= 5 min, providing a nephrogram. Renal CT is often performed routinely at this stage to show renal outlines tha otherwise be obscured by overlying gas or bowel content. In addition, cysts frequently can be different from solid neoplasms. Later, the contrast agent appears in the collecting system, outlining the renal pe ureters, and finally the bladder. Visualization depends on the concentration of the contrast agent in the and the urinary collecting system. Therefore, the best radiograms are obtained in patients with a norm who do not actively diurese during contrast agent administration. An adequate study in patients with B mg/dL (> 17.8 mmol urea/L) or plasma creatinine > 3 mg/dL (> 270 mol/L) usually is difficult. For azo patients, another renal imaging technique (eg, US, CT if indicated) is less risky and is preferred.
IVU is indicated when investigating causes for recurrent UTI or when the site of obstruction produces hydronephrosis, vesicoureteral reflux, hypertension, and urolithiasis. If renal injury is suspected, IVU w confirm that the uninjured kidney is normal and will provide functional information about the injured kid However, in urinary system trauma, CT (or sometimes angiography) is preferred.
(Caution: Acute renal failure occasionally occurs [incidence < 0.5%] after radiocontrast procedures in patients. The mechanism is unknown, but concomitant risk factors for contrast-associated nephropath prior renal insufficiency, diabetes mellitus, advanced age, extracellular volume depletion, and multiple myeloma. When contrast studies are done in high-risk patients, adequate extracellular volume expans nonionic contrast, and a reduced contrast dose may reduce the risk.)
In retrograde pyelography, radiopaque agents similar to those used in IVU are introduced directly int urinary tract after cystoscopy and catheterization of the ureter. Retrograde pyelography provides more opacification of the collecting and voiding system when IVU has been unsuccessful because of poor re function, a nonvisualized kidney by IVU, upper urinary tract bleeding with normal IVU, or filling defect i upper urinary tract. Additionally, retrograde evaluation may be indicated to assess the degree, type, ca and length of ureteral obstruction or when the patient is allergic to IV radiocontrast. It is also useful for
In retrograde pyelography, radiopaque agents similar to those used in IVU are introduced directly int urinary tract after cystoscopy and catheterization of the ureter. Retrograde pyelography provides more opacification of the collecting and voiding system when IVU has been unsuccessful because of poor re function, a nonvisualized kidney by IVU, upper urinary tract bleeding with normal IVU, or filling defect i upper urinary tract. Additionally, retrograde evaluation may be indicated to assess the degree, type, ca and length of ureteral obstruction or when the patient is allergic to IV radiocontrast. It is also useful for examination of the pelvicalyceal collecting system, ureters (including suspected ureterovaginal fistula) urinary bladder. Disadvantages are potential infection, distortion of the calyces by overdistention, back phenomena that obscure detail, acute ureteral edema and secondary stricture formation, and the need anesthesia.
In anterograde pyelography, radiocontrast agents are introduced into the renal pelvis by radiographic visualization. This procedure may be indicated when retrograde pyelography cannot be done because inability to catheterize a ureter, severe bladder disease, ectopic or reimplanted ureter, or inability to inj radiocontrast above an obstructed site in a ureter.
Cystography, which is part of IVU, may be unsatisfactory because of poor opacification or incomplete Retrograde cystography (controlled bladder filling using a catheter) is then necessary for adequate visualization. Retrograde cystography is advisable for study of neurogenic bladder, bladder rupture, or recurrent UTIs. Causes such as vesicoureteral reflux or vesical fistulas can be diagnosed by this techn by radionuclide bladder scanning. Films are taken during and after voiding to ensure adequate bladde emptying.
The male urethra may be examined during voiding after the cystogram (voiding urethrocystography). I urethral catheter cannot be inserted, retrograde injection of a contrast agent (retrourethrocystography) delineates urethral pathology.
CT is more expensive than US and IVU. However, CT is most useful in evaluating the character and e renal masses or determining the cause of a retroperitoneal mass distorting the normal urinary tract (eg enlarged abdominal lymph node). Renal cysts are of low density on CT. After IV injection of radiocontr there is no enhancement; the cyst stands out as a prominent lucency against the contrast-containing parenchyma. Renal carcinoma, conversely, generally is isodense on the unenhanced scan and, after administration of IV radiocontrast, shows an increased density due to hypervascularity of the lesion. C enhancement often helps demonstrate necrotic areas within the mass and areas of fat content that su angiomyolipoma. The extent of extrarenal involvement by a tumor often can be determined. When bla carcinoma is suspected or known, CT with sequential intravesical air and radiocontrast is also useful.
Angiography is the most invasive renal imaging procedure and is reserved for special indications. Co agents can be introduced by the retrograde method, in which a catheter is inserted through a peripher (femoral, axillary) and extended to the desired area in the aortic lumen, and by the translumbar metho rarely used, in which percutaneous needle puncture of the aorta is performed. The retrograde method and simplest and provides superior angiograms. In many institutions, conventional arteriography has b replaced by digital subtraction techniques, which are safer because lower contrast loads and smaller c can be used.
Angiography is best reserved for investigating possible vascular lesions (eg, aneurysm); indeterminate mass lesion; embolization of a renal tumor; and inadequate CT visualization of renal veins or the inferi cava. Arteriography for a vascular map occasionally is desirable for bulky tumors. Angiography may al useful for suspected renal hypertension; congenital renal anomalies of structure, position, or vascular persistent unilateral renal bleeding in the presence of a normal IVU; a poorly functioning kidney of rela recent onset when the retrograde pyelogram is normal or if retrograde ureteral catheterization is techn unsuccessful; and cases in which accurate knowledge of blood supply is necessary before an operatio for partial nephrectomy or transplant donors). Complications include injury to the cannulated vessels a neighboring organs, reactions to the radiocontrast, and bleeding.
useful for suspected renal hypertension; congenital renal anomalies of structure, position, or vascular persistent unilateral renal bleeding in the presence of a normal IVU; a poorly functioning kidney of rela recent onset when the retrograde pyelogram is normal or if retrograde ureteral catheterization is techn unsuccessful; and cases in which accurate knowledge of blood supply is necessary before an operatio for partial nephrectomy or transplant donors). Complications include injury to the cannulated vessels a neighboring organs, reactions to the radiocontrast, and bleeding.
In venography, the inferior vena cava is usually visualized for diagnostic purposes by percutaneous p of the femoral vein. Complications have been few and are limited to extravasation of blood and of radiocontrast in the area of injection. Renal vein catheterization provides samples for renal vein renin a for diagnosis of renal vein thrombosis, and for evaluation of the extent of renal malignancy when US o indeterminate.
Ultrasonography (US), a noninvasive, relatively innocuous technique, is advantageous in that visualiz does not depend on function. Nevertheless, some functional information can be inferred, especially in fetus, in whom the kidneys can be identified after about 20 wk gestation, permitting measurement of u production rate by serial estimations of the bladder volume. For neonates, US is the first choice for investigating abdominal masses, UTI, and suspected anomalies of the urinary system because it is atr and yields highly accurate results.
The kidney can be effectively outlined and the pelvicalyceal echo pattern critically examined by scanni multiple positions. US is particularly effective in diagnosing polycystic kidney disease, differentiating re and tumors, detecting hydronephrosis and perirenal fluid collections or intrarenal hemorrhage, estimat size and parenchymal thickness, and locating the optimal site for percutaneous renal biopsy or nephro US is the preferred diagnostic method in a uremic patient when uptake of contrast agent or isotope is US is effective in evaluating renal transplantation for sudden changes in kidney size; in detecting obstr lymphocele, or perirenal hemorrhage; and in detecting retroperitoneal pathology, such as tumor, lymphadenopathy, or hemorrhage. Doppler US may show patency of arteries and veins and the amou speed of blood flow, which is useful in evaluating kidney transplant patients or selected patients with hypertension.
The urine-filled bladder is readily outlined by US. Normally, bladder wall contour changes depend on th amount of urine present. Absence of normal contour changes, distortion of bladder position, or abnorm thickness indicates pelvic or bladder wall pathology. Although bladder tumors may be observed with U a superior technique.
MRI offers information about renal masses that cannot be determined by other techniques. It allows di imaging in the transverse, coronal, and sagittal planes. Morphologic data are obtained from three-dime reconstruction of the tissue. Solid and cystic renal lesions are as readily distinguished by CT, but MRI information about the cyst fluid to help differentiate hemorrhage and infection. In addition, MRI defines vascular and perirenal structures, permitting diagnosis of thrombosis, aneurysm, arteriovenous fistula, neoplastic extension. In the pelvis, MRI shows tissue planes and can demonstrate the seminal vesicle the extent of wall invasion by bladder cancer. MRI is limited by respiratory motion and peristalsis. Intra calcifications are poorly defined because they have few mobile protons.
MRI with contrast using gadolinium pentetic acid administered by bolus injection and rapid sequence i is increasingly used. This technique provides information about GFR and tubular function.
Morphologic procedures: Renal biopsy is performed to establish a histologic diagnosis, help estima prognosis and the potential reversibility or progression of the renal lesion, estimate the value of therap modalities, and determine the natural history of renal diseases. The only absolute contraindication to b uncontrollable bleeding. Biopsy of a solitary native kidney is a relative contraindication to be weighed a the need for information. Biopsies of a single, functioning, transplanted kidney are done frequently to e various types of nephropathy (eg, graft rejection, drug toxicity, recurrence of primary renal disease). C
Morphologic procedures: Renal biopsy is performed to establish a histologic diagnosis, help estima prognosis and the potential reversibility or progression of the renal lesion, estimate the value of therap modalities, and determine the natural history of renal diseases. The only absolute contraindication to b uncontrollable bleeding. Biopsy of a solitary native kidney is a relative contraindication to be weighed a the need for information. Biopsies of a single, functioning, transplanted kidney are done frequently to e various types of nephropathy (eg, graft rejection, drug toxicity, recurrence of primary renal disease). C associated with increased morbidity after biopsy are deemed relative contraindications: eg, renal tumo renal cysts, hydronephrosis, perinephric abscesses, severe reduction in blood or plasma volume, seve hypertension, and advanced renal failure with symptoms of uremia.
Open biopsy is rarely necessary--only when the percutaneous method has been unsuccessful or when visual control of the biopsy is critical. For the percutaneous technique the patient is sedated, and the k visualized by radiography or US. With the patient in the prone position, after the overlying skin and mu the back are anesthetized, the biopsy needle is inserted and tissue is obtained for light, electron, and immunofluorescent microscopy.
Urine cytology is useful in screening for possible urinary tract neoplasia in high-risk populations (eg, petrochemical workers, patients with painless hematuria from nonrenal causes) and in following patien resection of bladder tumors. The initial and several consecutive voidings are examined for abnormal e cells. Cytology is abnormal in 70 to 85% of patients with known urinary tract epithelial neoplasia, but inflammatory or reactive hyperplastic lesions of the urinary tract or cytotoxic drugs for nonurogenital ca may produce false-positive results. In asymptomatic patients, the incidence of carcinoma cells in the u about 0.1%. False-negative findings usually are associated with neoplasia that appears low-grade on histology. Diagnostic accuracy may be increased for bladder neoplasms by vigorous bladder lavage w small volume of 0.9% NaCl solution (50 mL pushed in and then aspirated by syringe through a cathete cells collected in the saline are concentrated and examined. Back to top of page

Section 17. Genitourinary Disorders Chapter 224. Glomerular Diseases Topics
[General] Nephritic Syndrome Nephrotic Syndrome
[General]
Glomerular diseases (glomerulopathies): Diverse disease processes that mainly affect the glomerulus include, but are not limited to, glomerulonephritis.
Glomerular diseases may be primary or secondary to systemic disease. The major pathogenic catego inflammatory (nephritic syndrome) and hemodynamic (nephrotic syndrome). Acute nephritic syndrome synonymously with acute glomerulonephritis (GN). The prototype is poststreptococcal GN. Chronic ne disorders also exist (eg, chronic nephritic-proteinuric syndrome). Nephrotic syndrome is a grouping of symptoms, signs, and laboratory findings due to increased glomerular capillary wall permeability. Man diseases can cause nephrotic syndrome, and nephritic and nephrotic syndromes can occur together.
Structural, functional, and clinical similarities exist within each group because of the few ways that ren responds to injury and the symptoms and signs that renal disease can produce. Although pathologic differences may provide an understanding of glomerular diseases, correlations between morphologic c and clinical features are unreliable predictors of prognosis and response to treatment.
In some patients with glomerular disease, extrarenal manifestations suggest a causative disease (eg, vasculitis, infection). Serologic markers, such as antistreptococcal antibodies, anti-glomerular baseme membrane (GBM) antibodies, antineutrophil cytoplasmic autoantibodies (ANCA), antinuclear antibodie cryoglobulins, C3 nephritic factor, hypocomplementemia, or IgA-fibronectin aggregations, suggest a sp glomerular disease or at least help narrow the differential diagnosis (see Fig. 224-1).

Section 17. Genitourinary Disorders Chapter 215. Urinary Incontinence Topics
[General] Transient Incontinence Established Incontinence
[General]
Urinary incontinence: The involuntary leakage of urine.
Urinary incontinence is abnormal regardless of age, mobility, mental status, or frailty. Incontinent perso frequently embarrassed, isolated, stigmatized, depressed, and regressed; incontinent elderly persons institutionalized because this disorder is a significant burden to caregivers. Incontinence remains large neglected problem despite the fact that it is highly treatable and often curable.
Continence requires integrity of lower urinary tract function as well as adequate mentation, mobility, m and manual dexterity. With age, bladder capacity, the ability to postpone voiding, and the urinary flow decline, and uninhibited bladder contractions become more prevalent. The postvoiding residual volum increases but probably to <= 50 to 100 mL. Maximum urethral closure pressure and urethral length de women, and prostate size increases in most men. Daily ingested fluid is excreted later in the day, into night. These changes enhance the likelihood of incontinence in an older person but alone do not caus
Incontinence can be categorized by duration of symptoms, by clinical presentation, or by physiologic abnormality. Determining whether incontinence is of recent onset (transient) or chronic (established) g the differential diagnosis. It is also useful to categorize the problem as urge, stress, or overflow inconti

Section 17. Genitourinary Disorders Chapter 225. Tubulointerstitial Disease Topics
[General] Acute Tubulointerstitial Nephritis Chronic Tubulointerstitial Nephritis
[General]
Tubulointerstitial abnormalities occur in most renal disorders. Furthermore, more than one condition associated with tubulointerstitial inflammation (eg, diabetes mellitus, UTI) may be present in a patient. selected circumstances, tubulointerstitial nephritis predominates, producing a syndrome with diverse c (see Table 225-1).

Section 17. Genitourinary Disorders Chapter 216. Myoneurogenic Disorders Topics
[General] Neurogenic Bladder Megacystis Syndrome Ureteral Dysfunction
[General]
Normal urinary control and voiding are the result of complex interactions of smooth muscle, skeletal m cerebral control, and the autonomic nervous system. Congenital and acquired disorders of muscle and innervation (see also Ch. 215 and Nocturnal Enuresis under Behavioral Problems in Ch. 262) may res inadequate urinary storage or control, urinary stasis, infection, calculi (see Ch. 221), or renal damage.

Section 17. Genitourinary Disorders Chapter 226. Toxic Nephropathy Topics
[General]
[General]
Etiology
Toxic nephropathy: Any functional or morphologic change in the kidney produced by an ingested, injec inhaled, or absorbed drug, chemical, or biologic agent.
Most of the clinically important drugs and chemicals that produce nephrotoxicity (see Table 226-1) are toxic to cells. Other agents can produce renal injury by indirect mechanisms (see Table 226-2) often n apparent from a knowledge of the biochemistry of the agent. The effects of some antibiotics on variou portions of the nephron are shown in Fig. 226-1. Nephrotoxicity may also occur from normal ions circu abnormal concentrations (eg, from hypokalemia, hyperkalemia, hypomagnesemia, or hyperuricemia).
Drugs that depend primarily on renal elimination (see Table 226-3) must be used carefully in patients w known renal disease. Protein binding substantially affects pharmacokinetics and cell toxicity in many o renal failure, protein binding of acidic drugs is reduced because of loss of plasma protein. Renal failure affects drug oxidation and reduction; glucuronide, sulfate, and glycine conjugation; acetylation; and hy
In hospitals, the leading cause of nephrotoxic renal failure (about 25% of acute renal failure) is use of antibiotics, especially aminoglycosides (streptomycin, kanamycin, neomycin, gentamicin, tobramycin, amikacin, sisomicin). Such drugs bind to cellular anionic phospholipid proximal tubular cells and are transported to anionic protein (megalin); they then undergo endocytic uptake and accumulate within lysosomes, possibly inhibiting their function. Aminoglycosides also increase urinary enzyme and prote and decrease creatinine clearance. Unless toxicity is severe, nonoliguric renal failure usually results. Aminoglycosides appear to be synergistic in toxicity with other directly and predictably nephrotoxic dru polymyxin B, amphotericin B). Because these drugs accumulate, toxicity may be delayed or may occu a repeat course of therapy. Outdated tetracycline may produce a Fanconi-like syndrome. (See also Drug-Induced Tubulointerstitial Nephritis in Ch. 225.)
All radiographic contrast agents are to some extent nephrotoxic, particularly when given intra-arteria Predisposing risk factors are hypoperfusion, cardiogenic shock, ECF volume depletion, existing renal insufficiency, age > 60 yr, solitary kidney, diabetic nephropathy, myeloma, hyperuricemia, heart failure
a repeat course of therapy. Outdated tetracycline may produce a Fanconi-like syndrome. (See also Drug-Induced Tubulointerstitial Nephritis in Ch. 225.)
All radiographic contrast agents are to some extent nephrotoxic, particularly when given intra-arteria Predisposing risk factors are hypoperfusion, cardiogenic shock, ECF volume depletion, existing renal insufficiency, age > 60 yr, solitary kidney, diabetic nephropathy, myeloma, hyperuricemia, heart failure multiple exposures at close intervals.
Analgesics produce about 2 to 5% of cases of end-stage renal disease in the USA and 13 to 20% in A and South Africa. In general, virtually all peripherally acting anti-inflammatory analgesics are potentiall nephrotoxic, and most centrally acting analgesics are not. Salicylates have direct nephrotoxicity in ove and a synergistic role in mixed analgesic nephropathy; they are common components in many drugs. all nonsteroidal anti-inflammatory analgesics (which are, with varying potency, prostaglandin synthetas inhibitors) can produce renal tubular epithelial damage, hypoperfusion, papillary necrosis, and chronic tubulointerstitial nephritis. Many of these drugs are available OTC.
Most heavy metals accumulate in segments of the proximal nephron because transport or binding site as sulfhydryl groups are located there. Toxic effects of lead are caused by pica; industrial exposure; contaminated water, wine, or alcohol; mining; smoke inhalation; or leaded gasoline. Tetraethyl lead pe intact skin and lungs. Chronic lead syndrome includes shrunken kidneys, uremia, hypertension, anem basophilic stippling, encephalopathy, peripheral neuropathy, and Fanconi's syndrome. Acute lead colic occur. Hg, bismuth, and thallium nephrotoxicity are decreasing in incidence, but cadmium, copper, gol uranium, arsenic, and iron nephrotoxicity are prevalent. Iron nephrotoxicity is associated with proximal myopathy in patients with hemochromatosis and other forms of iron overload (see Ch. 128), eg, in dial patients with multiple transfusions and hemolytic anemias (eg, thalassemia).
Solvents that cause nephrotoxicity and drugs that induce immune complex disease are listed in Ta 226-1.
Unusual plant and animal molecules can cause acute tubular necrosis (eg, raw gallbladder of grass sushi--Ctenopharyngodon idella), antigen-nephrotic syndrome (eg, poison ivy, oak), or interstitial fibros antigen-nephrotic syndrome, ochratoxin from fungi and chemical warfare, herbs such as Aristolochia pistolochia).
Pathophysiology
The kidney's many unique features render it susceptible to toxicity. It has the highest blood supply/g (a mL/g/min) of all tissues (about 0.07 mL/g/min for most organs except the lung). Circulating agents are delivered at 50 times the rate as for other tissues. Distribution disorders can accelerate toxicity, eg, thr constriction of a major vascular bed. The kidney has the largest endothelial surface area/g, with two co capillary beds. The first bed (glomerulus) has the highest hydrostatic pressure and greatest filtration fr Nonbound solutes leave the circulation via filtration at >= 100 mL/min, far above the average of most o Thus, a disproportionate sample of absorbed agents is presented to the kidney via arterial circulation.
Physiologic reduction of glomerular filtrate to form concentrated urine may expose the luminal surface to as much as 300 times the plasma concentration for filtered molecules or >= 1000 times for secreted molecules. The surface area exposed is enormous because of a fine brush border on proximal tubular countercurrent flow mechanism increases ionic concentration of the interstitial fluid of the medulla (and increases urine concentration) up to 4 times the plasma concentration; no other tissue fluid reaches su concentrations.
Tubular transport separates drugs from binding proteins, which commonly protect other cells. Transce transport exposes the interior of the cell and its organelles to newly encountered chemicals. Binding si
molecules. The surface area exposed is enormous because of a fine brush border on proximal tubular countercurrent flow mechanism increases ionic concentration of the interstitial fluid of the medulla (and increases urine concentration) up to 4 times the plasma concentration; no other tissue fluid reaches su concentrations.
Tubular transport separates drugs from binding proteins, which commonly protect other cells. Transce transport exposes the interior of the cell and its organelles to newly encountered chemicals. Binding si sulfhydryl groups) may facilitate entry but retard exit (eg, heavy metals). Exit may be reduced by proxim distal reabsorption, or both, of a toxin (eg, ochratoxin A [1/3 distal, 2/3 proximal]). General inhibition (e alkalinization, acidification) may alter transport in either direction. Blockade of transport receptors may tissue exposure (eg, diuresis from blockade of adenosine A receptor). The kidney has the highest O2 glucose consumption/g and is therefore vulnerable to toxins affecting cell energetics.
As the leading site of immune complex deposition, the kidney is uniquely susceptible to immunologic i Two percent of glomerular and 5% of mesangial cells express Ia molecules that complex with antigen activate lymphocytes for cellular immune reactions. The mesangium is a site for invasion of monocyte phagocytes, and other biologically active cells migrating from the blood. Immunologic events in the me also may control physiologic events in the vascular supply; eg, through stimulation of angiotensin rece probably mediated via lymphokines or renin release by juxtaglomerular apparatus.
Diagnosis requires a broad knowledge of drugs and toxicology and of possible exposures to toxic agen work, during recreation and hobbies, from a suicide or homicide attempt, and from food and drink (see 226-4).
For treatment guidelines, see the discussions of syndromes produced by the particular toxic agent (eg and chronic renal failure, nephrotic syndrome, tubular acidosis, tubulointerstitial nephritis) and 23. Ce high-flux dialyzers have been used to remove methotrexate, and special membranes have been used recycled albumin dialysate to remove albumin-bound toxins. Antioxidants have been proposed to treat damage to the kidneys.
General measures include removing the offending agent by emesis, by enhanced excretion (eg, with c or diuretics) while renal function remains, and by direct removal from the bloodstream via the most effi method (usually, hemodialysis with a large-surface dialyzer, hemoperfusion over charcoal or resins, plasmapheresis, or sorbapheresis).
Combination therapy may be indicated; eg, for methanol poisoning, dialysis should be combined with i of ethanol to compete for alcohol dehydrogenase, thus decreasing metabolism of methanol to more da neurotoxins and ocular toxins. HCO3 infusions for acidosis due to the production of formic acid may al indicated. Combination therapy can save life and sight when large amounts of methanol and other solv produce high levels of lactic acidosis.

Section 17. Genitourinary Disorders Chapter 217. Obstructive Uropathy Topics
[General]
[General]
Obstructive uropathy (urinary tract obstruction): Structural or functional changes in the urinary tract tha normal urine flow, sometimes leading to renal dysfunction (obstructive nephropathy).
Obstructive uropathy is common at all ages. Hydronephrosis (a nephropathic consequence) is found a postmortem examination with equal sex distribution in about 4% of patients. Obstructive uropathy is m common in men > 60 yr because of the increased incidence of benign prostatic hyperplasia and prosta cancer. About 2 people per 1000 in the USA are hospitalized for obstructive uropathy.
Obstructive uropathy may be acute or chronic, partial or complete, and unilateral or bilateral. It may oc any level from the renal tubules (casts, crystals) to the external urethral meatus (see Table 217-1) and result in increased intraluminal pressure, urinary stasis, UTI, and calculi formation.
In the male, obstruction of the urethra may result from benign prostatic hyperplasia, prostate cancer, c prostatitis with fibrosis, a foreign body, contracture of the vesical neck, or congenital urethral valves. U strictures and meatal stenosis may be acquired or congenital. In the female, urethral obstruction is rar may occur secondary to tumor, radiotherapy, surgery, or urologic instrumentation (usually repeated dil
Obstructive nephropathy (renal insufficiency, renal failure, or tubulointerstitial damage) may be due to increased intratubular pressure, local ischemia, or, often, associated UTI. Infiltration by inflammatory T and macrophages, an autoimmune response to refluxed urinary Tamm-Horsfall mucoprotein, and vaso hormones may also play a role in renal damage.
Pathologic findings consist of dilation of the collecting ducts and distal tubules and chronic tubular atro little glomerular damage. Obstructive uropathy without dilatation can occur when retroperitoneal tumor fibrosis encases the collecting systems, when obstructive uropathy is mild and renal function is not imp and within 3 days after the onset of obstructive uropathy, when the collecting system is relatively nonc and less likely to dilate. In the 2% of children who develop obstructive uropathy, congenital anomalies urinary tract are usually present.
Pathologic findings consist of dilation of the collecting ducts and distal tubules and chronic tubular atro little glomerular damage. Obstructive uropathy without dilatation can occur when retroperitoneal tumor fibrosis encases the collecting systems, when obstructive uropathy is mild and renal function is not imp and within 3 days after the onset of obstructive uropathy, when the collecting system is relatively nonc and less likely to dilate. In the 2% of children who develop obstructive uropathy, congenital anomalies urinary tract are usually present.
Symptoms and Signs

Symptoms and signs vary with the site, degree, and rapidity of onset of obstructive uropathy.
Pain is common due to distention of the bladder, collecting system, or renal capsule. Upper ureteral or pelvic lesions lead to flank pain or tenderness, whereas lower ureteral obstruction causes pain that ma radiate to the ipsilateral testicle or labia. Pain may be severe with acute complete ureteral obstruction ureteral calculus). Acute dilation from a downwardly displaced kidney or after a fluid load (eg, beer drin osmotic diuresis due to a radiocontrast agent during IVU) produces intermittent pain because urine pro increases to a level greater than the flow rate through the area of obstruction. Pain is typically minimal absent with partial or slowly developing obstructive uropathy (eg, ureteropelvic junction obstruction, pe tumor). Unsuspected ureteropelvic obstruction in an adult may cause hydronephrosis. A flank mass m palpable, particularly in massive hydronephrosis of infancy and childhood.
Anuria is highly suggestive of obstructive uropathy in the absence of shock, hemolytic-uremic syndrom rapidly progressive glomerulonephritis. Although urine volume may be reduced in any renal disease, a most often occurs with complete bilateral obstructive uropathy. Normal or even polyuric urine output do exclude partial obstructive uropathy.
Despite a reduced GFR, nocturia or polyuria may result from impaired renal concentrating capacity an reabsorption. With unilateral obstructive uropathy and a normal contralateral kidney, the plasma creati concentration is usually near normal, and anuria and acute renal failure are rare. Loss of renal function due to vascular or ureteral spasm mediated by autonomic activation.
Other clinical findings include hypertension, hyperkalemia secondary to a form of type 4 renal tubular a and salt wasting that predisposes to ECF volume depletion.
In an asymptomatic patient with long-standing obstructive uropathy, urinalysis may be normal or revea WBCs or RBCs. However, complete or severe partial bilateral obstructive uropathy may produce acute chronic renal failure.
Diagnosis
Obstructive uropathy should be considered in all patients with otherwise unexplained renal insufficienc history may suggest symptoms of benign prostatic hyperplasia or prior malignancy or urolithiasis.
Bladder catheterization should be performed initially if bladder neck obstruction is suggested (eg, by suprapubic pain, a palpable bladder, or unexplained renal failure in an older man). For further examina possible causes and the severity of prostate and bladder pathology, cystourethroscopy is done along w cystourethrography if a urethral obstruction (eg, stricture, valve) is suspected.
Abdominal ultrasonography is the initial test of choice in most patients (see also discussions of urinary evaluation procedures in Ch. 214) because it avoids potential allergic and toxic complications of radioc agents. However, the false-positive rate is 25% if only minimal criteria (visualization of the collecting sy are considered in the diagnosis. The combination of ultrasonography, plain abdominal x-ray, and, if ne
cystourethrography if a urethral obstruction (eg, stricture, valve) is suspected.
Abdominal ultrasonography is the initial test of choice in most patients (see also discussions of urinary evaluation procedures in Ch. 214) because it avoids potential allergic and toxic complications of radioc agents. However, the false-positive rate is 25% if only minimal criteria (visualization of the collecting sy are considered in the diagnosis. The combination of ultrasonography, plain abdominal x-ray, and, if ne CT diagnoses obstructive uropathy in > 90% of patients. Duplex Doppler ultrasonography can usually diagnose unilateral obstructive uropathy by detecting an increased resistive index (a reflection of increased renal vascular resistance) in the affected kidney.
Before IVU, radionuclide renal scanning, or retrograde technique, the patient should undergo diuresis suitable diuretic (eg, furosemide 0.5 mg/kg IV) to assess the degree of hydronephrosis and the compa delay in emptying time.
IVU can identify the site of obstructive uropathy, can detect associated conditions (eg, papillary necros caliceal blunting from previous infection), and has a very low false-positive rate. However, IVU is cumb and requires radiocontrast agents. IVU is primarily used to screen for obstructive uropathy when stagh calculi or multiple renal or parapelvic cysts are present (ultrasonography and CT usually cannot differe cysts or calculi from hydronephrosis), when CT cannot identify the level of obstructive uropathy, and w acute obstructive uropathy is suspected to be caused by calculi, sloughed papilla, or blood clot. Acute obstructive uropathy may not dilate the collecting system, but a mechanical obstruction (eg, calculus) c located, if present.
Antegrade or retrograde pyelography is usually used to relieve rather than diagnose obstructive uropa However, delayed emptying can confirm a functional or anatomic abnormality when the history is highl suggestive, although hydronephrosis may be absent. Dehydration alone may prolong the emptying tim a kidney is assessed as nonfunctioning by pyelography, a radioisotope scan can determine perfusion identify functional renal parenchyma.
If evaluation for back or flank pain reveals hydronephrosis without evident obstructive uropathy, noninv diuretic renography is performed. If the renogram is negative or equivocal but the patient is symptoma perfusion pressure flow study should be performed via percutaneous insertion of a catheter into the di renal pelvis, followed by fluid perfusion into the pelvis at 10 mL/min. If obstructive uropathy is present, marked increase in urine flow should slow the rate of washout of the radioisotope during renal scannin further dilate the collecting system on IVU, or elevate the renal pelvic pressure to > 22 mm Hg during perfusion.
A renogram or perfusion study that causes pain similar to the patient's initial complaint is interpreted a positive. If the perfusion study is negative, the pain probably has a nonrenal cause. False-positive and false-negative results are common for both tests.

Most cases can be corrected; a delay in therapy can lead to irreversible renal damage.
Prognosis varies depending on the underlying pathology responsible for the obstructive uropathy and presence or absence of UTI. In general, acute renal failure due to a ureteral calculus is reversible, with adequate return of renal function. With chronic progressive obstructive uropathy, renal dysfunction ma partial or irreversible. The prognosis for renal function is better when adequate therapy is initiated prom
Treatment consists of elimination of the obstruction by medical therapy (eg, hormonal therapy for pros cancer), instrumentation (eg, endoscopy, lithotripsy), or surgery. Prompt drainage for hydronephrosis i
presence or absence of UTI. In general, acute renal failure due to a ureteral calculus is reversible, with adequate return of renal function. With chronic progressive obstructive uropathy, renal dysfunction ma partial or irreversible. The prognosis for renal function is better when adequate therapy is initiated prom
Treatment consists of elimination of the obstruction by medical therapy (eg, hormonal therapy for pros cancer), instrumentation (eg, endoscopy, lithotripsy), or surgery. Prompt drainage for hydronephrosis i indicated if renal function is compromised, UTI persists, or pain is significant. Temporary drainage may needed in severe obstructive uropathy, UTI, or calculi (for treatment, see also Ch. 221). The percutane technique can be used in most cases. Lower obstructive uropathy may require catheter drainage or ur diversion. Indwelling pigtail ureteral catheters can be placed for acute or long-term drainage in selecte patients. Intensive treatment for UTI and renal failure is imperative.
Surgery should be considered in a patient with pain and a positive diuretic renogram. However, no the necessary in an asymptomatic patient with a positive diuretic renogram but normal renal function or wi negative diuretic renogram.

Section 17. Genitourinary Disorders Chapter 227. Urinary Tract Infections Topics
Bacterial Infections Fungal Infections Parasitic Infections Interstitial Cystitis
Bacterial Infections
(See also Ch. 157.)
The normal urinary tract is sterile and very resistant to bacterial colonization. However, UTI is the mos common bacterial infection in all age groups.
In neonates, UTIs are more common in males than in females and are often associated with bacterem observation presumably relates to the greater frequency of congenital anomalies of the urinary tract in infants. In children aged 1 to 5 yr, the incidence of bacteriuria is about 0.03% in boys and 1 to 2% in g rises to about 5% in girls > 10 yr. Because the incidence is rare in preadolescence, boys with UTIs fre have congenital or acquired urinary tract abnormalities. In children < 10 yr, about 30 to 50% of UTIs ar associated with vesicoureteral reflux (VUR) and renal scarring, which can lead to renal insufficiency if treated (see Chronic pyelonephritis, below). Bacteriuria is rare in adolescent boys. Asymptomatic bact occurs in about 5% of adolescent girls but is not associated with urologic abnormalities.
Among patients aged 20 to 50 yr, UTIs are about fiftyfold greater in women. The incidence increases i and women > 50 yr; the female:male ratio decreases as a result of the increased frequency of prostate disease.
Gram-negative aerobic bacteria (see Table 227-1) cause most bacterial UTIs. A few UTIs are acquired hematogenously, but about 95% occur when bacteria ascend from a colonized vaginal introitus and ur the bladder and, in the case of acute uncomplicated pyelonephritis, up the ureter to the kidney. Esche coli is the most common bacterium isolated and accounts for about 80% of community-acquired infect and Staphylococcus saprophyticus for about 10%. In hospitalized patients, E. coli accounts for about cases; the gram-negative species Klebsiella, Proteus, Enterobacter, and Serratia for about 40%; and t gram-positive bacterial cocci Enterococcus faecalis and Staphylococcus sp (saprophyticus, aureus) fo
hematogenously, but about 95% occur when bacteria ascend from a colonized vaginal introitus and ur the bladder and, in the case of acute uncomplicated pyelonephritis, up the ureter to the kidney. Esche coli is the most common bacterium isolated and accounts for about 80% of community-acquired infect and Staphylococcus saprophyticus for about 10%. In hospitalized patients, E. coli accounts for about cases; the gram-negative species Klebsiella, Proteus, Enterobacter, and Serratia for about 40%; and t gram-positive bacterial cocci Enterococcus faecalis and Staphylococcus sp (saprophyticus, aureus) fo remainder. The nosocomial incidence of bacteremia attributed to UTI is about 73/100,000.
Complicated UTIs occur in the setting of urologic impairment, usually due to instrumentation or obstruc (anatomic abnormalities, neurogenic dysfunction, calculi, catheterization). Although obstruction alone cause UTI, its presence predisposes to UTI and makes UTI more difficult to eradicate with medical the
UTIs in men < 50 yr are often due to urologic abnormalities. However, uncomplicated UTI can occur in men without abnormalities who have unprotected anal intercourse, an uncircumcised penis, unprotect intercourse with a woman whose vagina is colonized with uropathogens, and AIDS (CD4+ T-cell count 200/L).
Among nuns, bacteriuria is significantly less frequent (0.4 to 1.6% from 15 to 54 yr of age) than among sexually active women, suggesting a role for sexual intercourse in the development of acute uncomplic UTI in women. Use of spermicide with a diaphragm is linked to an increased risk of UTI in women, pro because spermicide-induced alterations in vaginal flora permit overgrowth of E. coli.
Bacteriuria is more common in elderly men because of abnormal micturition and significant residual bl urine; poor emptying of the bladder due to uterine prolapse and cystocele formation and soiling of the perineum from fecal incontinence in women; and neuromuscular diseases and increased use of instrumentation and bladder catheters in both sexes. Diabetics who have neurogenic bladders or who been catheterized have an increased incidence and severity of infections. Because pregnancy may ind urinary stasis due to functional and anatomic obstruction of ureters and bladder, UTI during pregnancy be regarded as complicated.
Urethritis: Bacterial infection of the urethra occurs when organisms that gain access to it acutely or ch colonize the numerous periurethral glands in the bulbous and pendulous portions of the male urethra a entire female urethra.
The sexually transmitted pathogens Chlamydia trachomatis, Neisseria gonorrhoeae, and herpes simpl common causes of dysuria in men and women. Nongonococcal urethritis may be associated with infec the scrotal contents (see Epididymitis in Ch. 219).
Cystitis: Bacterial infection of the bladder in men is usually complicated and generally results from as infection of the urethra or prostate or occurs secondary to urethral instrumentation. In women, sexual intercourse usually precedes uncomplicated cystitis.
Prostatitis: Chronic bacterial prostate infection is the most common cause of recurrent UTI in men du reintroduction of infection into the bladder.
Acute pyelonephritis: The term pyelonephritis refers to bacterial infection of the kidney parenchyma should not be used to describe any tubulointerstitial nephropathy unless UTI is documented. About 20 community-acquired bacteremias in women are attributed to pyelonephritis. Pyelonephritis is uncomm men with a normal urinary tract. In patients who have recurrent infections and no structural abnormalit normal host defense mechanisms may be decreased.
In 30 to 50% of women with a normal urinary tract, pyelonephritis occurs by the ascending route despi dynamics of urine flow and the interference of the vesicoureteral junction. Cystitis alone or anatomic d
community-acquired bacteremias in women are attributed to pyelonephritis. Pyelonephritis is uncomm men with a normal urinary tract. In patients who have recurrent infections and no structural abnormalit normal host defense mechanisms may be decreased.
In 30 to 50% of women with a normal urinary tract, pyelonephritis occurs by the ascending route despi dynamics of urine flow and the interference of the vesicoureteral junction. Cystitis alone or anatomic d may produce reflux. This tendency is greatly enhanced when peristalsis is inhibited (eg, during pregna obstruction, by endotoxins of gram-negative bacteria). Although obstruction (strictures, calculi, tumors, prostatic hypertrophy, neurogenic bladder, VUR) predisposes to infection, most women with pyeloneph have no demonstrable functional or anatomic defects of the urinary tract. Pyelonephritis or focal absce be due to hematogenous UTI, which is infrequent and usually results from bacteremia with virulent bac Salmonella organisms, S. aureus). Pyelonephritis is very common in girls or in pregnant women after instrumentation or bladder catheterization.
The kidney usually is enlarged due to inflammatory PMNs and edema. Infection is focal and patchy be in the pelvis and medulla and extending into the cortex as an enlarging wedge. Chronic inflammatory c appear within a few days, and medullary and subcortical abscesses may develop. Parenchymal tissue between foci of infection is common. Arteries, arterioles, and glomeruli are considerably resistant to in Papillary necrosis may be evident in acute pyelonephritis associated with diabetes, obstruction, sickle disease, or analgesic nephropathy. Although acute pyelonephritis is frequently associated with renal s in children, similar scarring in adults is not detectable in the absence of reflux or obstruction.
Chronic pyelonephritis (chronic infective tubulointerstitial nephritis): This chronic patchy, often b pyogenic infection of the kidney produces atrophy and calyceal deformity with overlying parenchymal s It causes end-stage renal failure in about 2 to 3% of patients treated by dialysis or transplantation. Chr pyelonephritis occurs only in patients with major anatomic abnormalities, such as obstructive uropathy calculi, or, most commonly, VUR (in 30 to 45% of young children with symptomatic UTI). VUR is usual congenital defect that results in incompetence of the ureterovesical valve, most often due to a short in segment. VUR can be acquired in patients with a flaccid bladder due to spinal cord injury.
The histologic picture is nonspecific and similar to that of other diseases that produce chronic tubuloin nephropathy. The most specific change is a parenchymal scar associated with retraction of the adjace papilla. The renal scars (also called reflux nephropathy) are primarily induced by the reflux of infected the ureters and into the renal parenchyma via the ducts of Bellini at the papillary tips, spreading outwa the collecting tubules (called intrarenal reflux). In scars that form in utero, concurrent renal dysplasia w perfusion defects may be responsible for the scar formation rather than UTI. Infection without intrarena is unlikely to produce renal injury. The papillary collecting duct orifices are normally wide open at the u lower poles in young children, but normal growth usually results in spontaneous cessation of intrarena by age 6. The net effect is that almost all new scars in children with VUR occur before the age of 8 and virtually only in association with new UTI. In comparison, high-pressure reflux due to obstruction can c scars at any age.
Xanthogranulomatous pyelonephritis is an unusual variant of chronic pyelonephritis that typically oc middle-aged women with a history of recurrent UTIs. It is a complication of obstruction due to renal ca is typically associated with Proteus infections. The kidney is enlarged, and perirenal fibrosis and adhes adjacent retroperitoneal structures are common. The disease is almost always unilateral and appears represent an abnormal immune response to infection with giant cells, lipid-laden macrophages, and ch clefts, which accounts for the yellow color of the infected tissue. Two presentations occur in children. T common affects boys and girls equally and involves the entire kidney. The other form, which is more c in girls, is localized and may mimic a tumor.
Symptoms and Signs

Urethritis: Onset is gradual, and symptoms are mild. Men with urethritis usually present with urethral
common affects boys and girls equally and involves the entire kidney. The other form, which is more c in girls, is localized and may mimic a tumor.
Symptoms and Signs
Urethritis: Onset is gradual, and symptoms are mild. Men with urethritis usually present with urethral discharge, which is purulent when due to N. gonorrhoeae and whitish mucoid when nonspecific (see a 164). Women usually present with dysuria, frequency, and pyuria.
Cystitis: Onset is usually sudden. Cystitis usually produces frequency, urgency, and burning or painfu of small volumes of urine. Nocturia, with suprapubic and often low back pain, is common. The urine is turbid, and gross hematuria occurs in about 30% of patients.
A patient with a neurogenic bladder or an indwelling catheter usually has no symptoms referable to the when invasive UTI occurs but may present with symptoms and signs of pyelonephritis or unexplained (possibly the first sign of sepsis). In the elderly, UTIs are often asymptomatic.
Prostatitis: Acute bacterial prostatitis is characterized by chills, fever, urinary frequency and urgency, and low back pain, varying symptoms of obstruction to voiding, dysuria, nocturia, and sometimes gros hematuria. The prostate gland is tender, focally or diffusely swollen, and indurated.
Chronic prostatitis is more occult than acute prostatitis; the patient usually presents with recurrent bac or variable low-grade fever with back or pelvic discomfort.
Acute pyelonephritis: Typically, symptom onset is rapid and characterized by chills, fever, flank pain, and vomiting. Symptoms of lower UTI (eg, frequency, dysuria) occur concomitantly in about 1/3 of pati abdominal rigidity is absent or slight, a tender, enlarged kidney may sometimes be palpable. Costover tenderness is generally present on the infected side. In children, symptoms often are meager and less characteristic.
Chronic pyelonephritis: Symptoms and signs (eg, fever, flank or abdominal pain) are often vague an inconsistent. In xanthogranulomatous pyelonephritis, presenting symptoms may include flank pain, malaise, anorexia, and weight loss. A unilateral renal mass can usually be palpated on physical exami
Diagnosis
Clinical differentiation between upper and lower UTI is impossible in many patients. Studies using uret catheterization and a bladder washout technique have demonstrated that about 30 to 50% of patients lower UTI symptoms also have silent kidney infection. The best noninvasive technique for differentiatin bladder from kidney infections appears to be the response to a short course of antibiotic therapy (see Treatment, below). IVU may help evaluate recurrent infections in symptomatic males; in women with a of childhood infections, possible nephrolithiasis, or painless hematuria; and in children. Urologic invest not routinely needed in women with recurrent symptomatic or asymptomatic UTI because it does not in therapy.
Urethritis: In women, urethritis and vaginitis account for most urinary symptoms when urine specimen culture-negative for bacteria. Vaginitis associated with Candida albicans, Trichomonas vaginalis, or ba vaginosis may cause dysuria from the passage of urine across an inflamed labia. Although dysuria ma predominant, vaginal discharge, vaginal odor, and dyspareunia also occur in most women. Urethritis c by sexually transmitted disease (STD), such as C. trachomatis, N. gonorrhoeae, or herpes simplex viru causes milder symptoms, is gradual in onset, and produces dysuria without other urinary symptoms. Hematuria is virtually always absent on midstream urinalysis.
culture-negative for bacteria. Vaginitis associated with Candida albicans, Trichomonas vaginalis, or ba vaginosis may cause dysuria from the passage of urine across an inflamed labia. Although dysuria ma predominant, vaginal discharge, vaginal odor, and dyspareunia also occur in most women. Urethritis c by sexually transmitted disease (STD), such as C. trachomatis, N. gonorrhoeae, or herpes simplex viru causes milder symptoms, is gradual in onset, and produces dysuria without other urinary symptoms. Hematuria is virtually always absent on midstream urinalysis.
Cystitis: The presence of gross hematuria strongly suggests bacterial cystitis. Microscopic examinatio urine (for bacteria and WBCs) and urine culture confirms the diagnosis; almost all female patients hav and up to 50% have microscopic hematuria. Culture of a midstream urine sample generally demonstra causative bacteria, but about 30% of patients with similar symptoms of cystitis have insignificant bacte 105 colony-forming units/mL). A negative urinalysis or urine Gram stain result does not rule out acute b cystitis in cases with low colony counts.
In women, the differential diagnosis includes other common genital infections that produce dysuria, su vulvovaginitis (yeast, Trichomonas, bacterial vaginosis) or STDs involving the urethra and cervix (C. trachomatis, N. gonorrhoeae, herpes simplex virus infection).
Prostatitis: Because acute cystitis usually accompanies acute prostatitis, the bacterial pathogen often identified by culture of voided bladder urine. Because of the risk of bacteremia, the physician should n massage an acutely inflamed prostate gland until blood concentration of an appropriate antibacterial d adequate.
Chronic prostatitis may be more occult and usually presents only as recurrent bacteriuria or with low-g fever and back or pelvic discomfort. Chronic prostatitis is the most common cause of recurrent sympto UTI in men due to reintroduction of infection into the bladder. Diagnosis is established by positive cultu prostatic massage. The periurethral area is cleansed, and the patient then voids. The initial 5 to 10 mL and a midstream specimen (VB2) are obtained for quantitative culture. The patient stops voiding befor bladder is empty, and the prostate is massaged. Any expressed prostatic secretions and the first 5 to 1 subsequently voided urine (VB3) are cultured. Interpretation of the test requires that bladder urine (VB 103/mL to allow identification of the frequently small number of organisms from the prostate. Chronic p is suspected when VB3 has > 12 WBCs/high-power field. Cultures of urine or expressed prostatic sec are almost always positive in chronic prostatitis, but negative cultures do not exclude the diagnosis.
Acute pyelonephritis: Typical symptoms and signs of sepsis and pyelonephritis (flank pain, fever, rig dysuria) with findings of leukocytosis, pyuria, and bacilluria on Gram staining of unspun urine strongly the diagnosis (see Table 214-3). Infections of the renal pelvis and parenchyma cannot be differentiate clinically; both sites usually are affected. The finding of neutrophils in a tubule is the pathologic equiva urinary WBC casts. Physical examination sometimes shows some abdominal rigidity, which must be differentiated from that produced by intraperitoneal disease. Special stains are needed to differentiate and renal tubular casts. WBC casts, when seen, are pathognomonic of pyelonephritis, but they are als in glomerulonephritis and noninfective tubulointerstitial nephritis. Urine pH may be alkaline because of urea-splitting organisms; proteinuria is minimal (< 0.6 g/m2 /day, urine protein:creatinine ratio < 0.6).
Acute pyelonephritis must be differentiated from other intra-abdominal conditions (eg, appendicitis, uro that may present with flank pain, fever, rigors, and sometimes symptoms of cystitis. In women, pelvic inflammatory disease, ectopic pregnancy, and ruptured ovarian cyst must also be considered.
Chronic pyelonephritis: A history of UTI and recurrent acute pyelonephritis is helpful but infrequently obtained except in children with VUR. Recurrent UTI and a typical pattern of renal dysfunction occasio occur and strongly suggest the diagnosis, which is primarily established by IVU. Parenchymal scarring irregular renal contour, with partial or almost complete loss of visible parenchyma between the calyces renal capsule. Focal scarring is rarely absent on IVU. Ureteral dilation may be present, reflecting the c
Chronic pyelonephritis: A history of UTI and recurrent acute pyelonephritis is helpful but infrequently obtained except in children with VUR. Recurrent UTI and a typical pattern of renal dysfunction occasio occur and strongly suggest the diagnosis, which is primarily established by IVU. Parenchymal scarring irregular renal contour, with partial or almost complete loss of visible parenchyma between the calyces renal capsule. Focal scarring is rarely absent on IVU. Ureteral dilation may be present, reflecting the c induced by chronic severe reflux. These abnormalities are relatively specific for chronic bacterial pyelonephritis, although not necessarily for infection with common bacteria. Similar changes can occu urinary tract TB (see Genitourinary Tuberculosis in Ch. 157), which is strongly suggested by concurren urinary tract abnormalities (eg, ureteral strictures, a contracted bladder).
A voiding cystourethrogram may not show reflux, which frequently ceases spontaneously (after pubert because of the increased length of the submucosal portion of the terminal ureter. However, cystoscop evidence of previous reflux at most ureteral orifices. Proteinuria is absent, minimal, or intermittent even renal scarring is far advanced. Urinary sediment is usually scant, but renal epithelial cells, granular cas occasionally WBC casts are found. Defects in concentrating ability and hyperchloremic acidosis before azotemia may be found. An abnormal voiding cystourethrogram only suggests the diagnosis in a patie otherwise unexplained proteinuria (occasionally nephrotic range) and renal insufficiency. In such case biopsy will show focal glomerulosclerosis typical of advanced reflux nephropathy.
The course is extremely variable, but the disease typically progresses extremely slowly; most patients adequate renal function for >= 20 yr after onset. Frequent exacerbations of acute pyelonephritis, altho controlled, usually further deteriorate renal structure and function. Continued obstruction predisposes perpetuates pyelonephritis and increases pelvic pressure, which damages the kidney directly.
Renal scarring in utero can be detected by antenatal ultrasonography. In older patients, renal scarring commonly occurs with ischemic injury due to nephrosclerosis. However, the scars are randomly distrib the calyces are normal, not blunted and dilated.
In xanthogranulomatous pyelonephritis, blood tests reveal nonspecific findings including anemia an liver dysfunction. Although urinalysis and urine culture indicate the presence of UTI, diagnosis is confir radiologic examination. An IVU is abnormal but generally not diagnostic, and CT is preferred for evalu suspected xanthogranulomatous pyelonephritis and for excluding renal carcinoma.
Prevention
In women who experience >= 3 UTIs/yr, voiding immediately after sexual intercourse or avoiding use o diaphragm may be helpful. Drinking cranberry juice may reduce pyuria and bacilluria. If these techniqu unsuccessful, low-dose oral antimicrobial prophylaxis virtually eliminates the incidence of recurrent UT trimethoprim-sulfamethoxazole 40/200 mg po daily or thrice weekly, trimethoprim 100 mg daily or thric weekly, or a daily tablet of a fluoroquinolone (eg, ciprofloxacin, norfloxacin, ofloxacin, lomefloxacin, en or nitrofurantoin (macrocrystals) 50 or 100 mg/day. Postcoital trimethoprim-sulfamethoxazole or a fluoroquinolone may be effective. If UTI recurs after 6 mo of this therapy, prophylaxis may be reinstitut or 3 yr.
Effective prophylaxis of UTI in pregnant women is similar to that in nonpregnant women. Appropriate p include those with acute pyelonephritis during a previous pregnancy, patients with bacteriuria during p who have had a posttreatment recurrence, and patients who required prophylaxis for recurrent UTI be pregnancy.
Antimicrobial prophylaxis for postmenopausal women is similar to that described above. Additionally, s or topical estrogen therapy markedly reduces the incidence of recurrent UTI.
who have had a posttreatment recurrence, and patients who required prophylaxis for recurrent UTI be pregnancy.
Antimicrobial prophylaxis for postmenopausal women is similar to that described above. Additionally, s or topical estrogen therapy markedly reduces the incidence of recurrent UTI.
Treatment
Goals for antibiotic use in UTI are eradication of the infective organism, prevention or control of bacter and subsequent systemic complication, and avoidance of recurrent symptomatic UTI. Cost-effectivene the avoidance of serious adverse events are also important.
Obstructive uropathy, anatomic abnormalities, and neuropathic GU lesions may require surgical correc Catheter drainage of an obstructed urinary tract aids in prompt control of UTI. Occasionally, a renal co abscess or perinephric abscess requires surgical drainage. Instrumentation of the lower urinary tract in presence of infected urine should be deferred, if possible. Sterilization of the urine before instrumentat antibiotic therapy for 3 to 7 days after instrumentation can prevent life-threatening urosepsis.
Urethritis and cystitis: Symptoms of urethritis or cystitis may resolve without antimicrobial therapy (s patients self-treat with water-loading only and/or do not see a physician). In men, trimethoprim-sulfamethoxazole or a fluoroquinolone is given for 10 to 14 days because shorter course associated with frequent recurrences. In symptomatic women, a 3-day course of trimethoprim-sulfamethoxazole or a fluoroquinolone effectively treats acute cystitis and eradicates pote bacterial pathogens in vaginal and GI reservoirs. -Lactams less effectively eradicate bacterial pathoge the two reservoirs and are associated with more frequent antimicrobial resistance and higher recurren
The response to a 3-day course of therapy helps determine which patients require additional evaluatio treatment. Single-dose therapy results in higher recurrence rates and is not recommended. Longer co therapy (7 to 14 days) are prescribed for patients with a history of recent UTI or diabetes mellitus or wi symptoms lasting > 1 wk.
Previously healthy women without symptoms of vaginitis are treated as described above and do not ne urinalysis and culture unless symptoms continue after therapy. If urinalysis and culture are negative, n antimicrobial therapy is prescribed. If pyuria but not bacteriuria is present in a sexually active woman, trachomatis urethritis is diagnosed presumptively, and a longer course of a tetracycline or sulfonamide to the patient and her sexual partner. A symptomatic patient with a positive urinalysis and a cultured o sensitive to the 3-day antimicrobial therapy is treated for a kidney infection with a 14-day course of trimethoprim-sulfamethoxazole or a fluoroquinolone. Some patients with low colony counts develop an urethral syndrome due to trauma or inflammation of the urethra, occasionally caused by gonococcus, fungal disease.
Recurrent cystitis associated with pneumaturia (passage of air in the urine) suggests a vesicoenteric fi Changing or multiple organisms are common. The most common cause of recurrent cystitis in men is bacterial prostatitis. Although acute prostatitis may respond to 10 to 14 days of treatment, recurrence i common, possibly due to poor tissue penetration of many antimicrobials and prostatic calculi that can drainage and act as foreign bodies to prevent tissue sterilization.
Many abnormal organisms colonize the vaginal vestibules (apparently due to an inadequate local defe mechanism) for a long time; recurrent cystitis is sometimes secondary to a small and otherwise asymp vesicovaginal fistula. An unusual form of cystitis, cystitis emphysematosa, is characterized by symptom infection plus pneumaturia and is due to infection by gas-forming bacilli involving the submucosal laye bladder wall.
Many abnormal organisms colonize the vaginal vestibules (apparently due to an inadequate local defe mechanism) for a long time; recurrent cystitis is sometimes secondary to a small and otherwise asymp vesicovaginal fistula. An unusual form of cystitis, cystitis emphysematosa, is characterized by symptom infection plus pneumaturia and is due to infection by gas-forming bacilli involving the submucosal laye bladder wall.
Asymptomatic bacteriuria in diabetics, elderly persons, or those with chronic indwelling bladder cathete should ordinarily not be treated with antimicrobial drugs. However, asymptomatic bacteria in pregnant is actively sought and treated as a symptomatic UTI. However, few antibiotics can be safely used. Ora -lactams, sulfonamides, and nitrofurantoin are considered safe in early pregnancy, but sulfonamides s avoided near parturition because of a possible role in the development of kernicterus. Trimethoprim ca fetal toxicity in animal studies; similar evidence in humans is lacking. Fluoroquinolones are avoided be possible damage to fetal cartilage. When pyelonephritis is diagnosed during pregnancy, hospitalization parenteral therapy with a -lactam with or without an aminoglycoside is appropriate.
Treatment may also be indicated in asymptomatic UTI in neutropenic patients, those with recent renal transplants, patients scheduled for instrumentation of the urinary tract (after removal of a bladder cath has been in place for < 1 wk), young children with gross VUR, and patients with a struvite calculus tha be removed and with frequent UTI symptoms. Therapy typically consists of an appropriate antimicrobi basis of culture results for 3 to 14 days or chronic suppressive therapy for untreatable obstructive prob (eg, calculi, reflux).
Prostatitis: Acute infections may respond to 10 to 14 days of treatment with trimethoprim-sulfamethox a fluoroquinolone, but relapses are common because of poor penetration of many antimicrobials and a abnormalities (eg, prostatic calculi). For relapsing or chronic prostatitis, 4 to 12 wk of antimicrobial ther be required. However, failure rates up to 40% may occur, and resistant organisms (eg, E. faecalis, P. aeruginosa) are often found. Treatment at this stage includes prolonged antibiotic suppression, repeat therapy for each recurrence, and surgical removal of the infected prostate gland under antibiotic cover
Acute pyelonephritis: Outpatient treatment with oral antimicrobials (trimethoprim-sulfamethoxazole o fluoroquinolone for 14 days) is possible if the patient has no nausea or vomiting, no signs of volume de a bacterial infection, and no evidence of septicemia and is reliable in following medical advice. Otherw patients should be hospitalized and given parenteral therapy depending on local sensitivity patterns of involved strains. Common regimens include ampicillin plus gentamicin, trimethoprim-sulfamethoxazole fluoroquinolone, and advanced-spectrum cephalosporins (eg, ceftriaxone). Aztreonam, -lactam/-lactam inhibitor combinations (ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin-tazobactam), and imipenem-cilastatin are generally reserved for patients with more complicated pyelonephritis (eg, obstr calculi, resistant bacteria) or recent urinary tract instrumentation. Parenteral therapy is continued until defervescence and other signs of clinical improvement occur. In > 80% of patients, this improvement o within 72 hr. Oral therapy is begun, and the patient can be discharged for the remainder of the 14-day treatment course. For complicated cases, urologic corrections of anatomic defects may be needed alo prolonged antibiotic suppression.
Chronic pyelonephritis: Without demonstrable obstruction or recurrent acute pyelonephritis, asympto renal bacteriuria has not been clearly established as harmful. Therefore, repeated courses of antimicro suppressive therapy are not indicated. Complications of uremia or hypertension must be treated appro If obstruction cannot be eliminated and recurrent UTI is common, long-term therapy with antimicrobials trimethoprim-sulfamethoxazole, trimethoprim, a fluoroquinolone, nitrofurantoin) is useful.
For xanthogranulomatous pyelonephritis, an initial course of antimicrobials should be given to cont infection, followed by en bloc nephrectomy with removal of all involved tissue and closure of any fistula

Section 17. Genitourinary Disorders Chapter 218. Prostate Disease Topics
Benign Prostatic Hyperplasia Prostatitis
Benign Prostatic Hyperplasia

(Benign Prostatic Hypertrophy)
Benign adenomatous hyperplasia of the periurethral prostate gland, causing variable degrees of bladd obstruction.
A major difficulty in establishing prevalence of benign prostatic hyperplasia (BPH) has been the lack o common definition. Based on autopsy studies, the prevalence of histologically diagnosed BPH increas 8% in men aged 31 to 40 yr to 40 to 50% in men aged 51 to 60 yr and > 80% in men older than 80 yr. However, based on clinical criteria in men aged 55 to 74 yr without prostate cancer, the prevalence of 19% using the criteria of a prostate volume > 30 mL and a high International Prostate Symptom score However, the prevalence is only 4% if the criteria are a prostate volume > 30 mL, a high score, a maxi urinary flow rate < 10 mL/sec, and a postvoid residual urine volume > 50 mL.
The etiology is unknown but may involve hormonal changes associated with aging. Multiple fibroadeno nodules occur in the periurethral region of the prostate gland, probably originating within the periurethr glands rather than in the true fibromuscular prostate (surgical capsule), which is displaced peripherally progressive growth of the nodules. The hyperplasia may involve the lateral walls of the prostate (latera hyperplasia) or tissue at the inferior margin of the vesical neck (middle lobe hyperplasia). Histologically tissue is glandular, with varying proportions of fibrous stroma interposed.
As the lumen of the prostatic urethra becomes compromised, urine outflow is progressively obstructed accompanied by hypertrophy of the bladder detrusor, trabeculation, cellule formation, and diverticula. Incomplete bladder emptying causes stasis and predisposes to infection with secondary inflammatory in the bladder (chronic prostatitis, see below) and the upper urinary tract. Urinary stasis predisposes to
tissue is glandular, with varying proportions of fibrous stroma interposed.
As the lumen of the prostatic urethra becomes compromised, urine outflow is progressively obstructed accompanied by hypertrophy of the bladder detrusor, trabeculation, cellule formation, and diverticula. Incomplete bladder emptying causes stasis and predisposes to infection with secondary inflammatory in the bladder (chronic prostatitis, see below) and the upper urinary tract. Urinary stasis predisposes to calculus formation (see Ch. 221). Prolonged obstruction, although incomplete, can produce hydroneph and compromise renal function.
Progressive urinary frequency, urgency, and nocturia are due to incomplete emptying and rapid refillin bladder. Decreased size and force of the urinary stream produce hesitancy and intermittency. Sensati incomplete emptying, terminal dribbling, almost continuous overflow incontinence, or complete urinary retention may ensue. Straining to void can cause congestion of superficial veins of the prostatic urethr trigone, which may rupture and produce hematuria. Acute complete urinary retention may be precipita prolonged attempts to retain urine, immobilization, exposure to cold, anesthetics, anticholinergic and sympathomimetic drugs, or ingestion of alcohol. Symptoms may be quantitated by the seven-question American Urological Association Symptom Score (see Table 218-1).
On rectal examination, the prostate usually is enlarged, has a rubbery consistency, and, frequently, ha the median furrow. However, digital rectal examination of prostate size may be misleading. A small pro rectal examination may be sufficiently large to cause obstruction. The distended urinary bladder may b palpable or percussible on physical examination.
Serum prostate-specific antigen (PSA) is moderately elevated in 30 to 50% of patients with BPH, depe on prostate size and degree of obstruction (see also Prostate Cancer in Ch. 233). Men with mild or mo BPH symptoms usually do not need further testing.
More severe symptoms or the presence of hematuria or UTI warrants further evaluation by a urologist. may disclose upward displacement of the terminal portions of the ureters (fishhooking) and a defect at base of the bladder compatible with prostatic enlargement. With prolonged obstruction, the ureters dila hydronephrosis occurs. Urethral catheterization cystoscopy or ultrasonography after voiding measures urine, and catheterization permits preliminary drainage to stabilize renal function and adequately contr indicated because of an elevated serum PSA, transrectal ultrasonography permits estimation of gland may aid selection of the appropriate surgical approach, and differentiates vesical neck contracture, ch prostatitis, and other obstructive phenomena. Instrumentation should be avoided until definitive therap been decided, because manipulation may increase obstruction, trauma, and infection.
An indurated and tender prostate suggests prostatitis, whereas a stony, hard, nodular prostate usually indicates carcinoma or, occasionally, prostatic calculi.
Treatment
When BPH is associated with UTI or azotemia due to bladder outlet obstruction, initial therapy should medical, directed toward stabilizing renal function, discontinuing anticholinergic and sympathomimetic and eradicating infection. Urethral or suprapubic catheter drainage may be desirable in advanced blad outlet obstruction. The chronically obstructed, distended bladder should be slowly decompressed to he postobstructive diuresis. For some patients with mild to moderate obstructive symptoms, -adrenergic b such as terazosin may improve voiding. The 5-reductase inhibitor finasteride may reduce prostate size improving voiding over time (months), especially in patients with large (> 40 mL) glands. All such patie should avoid anticholinergic and narcotic drugs, which may induce obstruction.
and eradicating infection. Urethral or suprapubic catheter drainage may be desirable in advanced blad outlet obstruction. The chronically obstructed, distended bladder should be slowly decompressed to he postobstructive diuresis. For some patients with mild to moderate obstructive symptoms, -adrenergic b such as terazosin may improve voiding. The 5-reductase inhibitor finasteride may reduce prostate size improving voiding over time (months), especially in patients with large (> 40 mL) glands. All such patie should avoid anticholinergic and narcotic drugs, which may induce obstruction.
Definitive therapy is surgical. Although sexual potency and continence are usually retained, about 5 to patients will experience some postsurgical problems. Transurethral resection of the prostate (TURP) is preferred. Larger prostates (usually > 75 g) may require open surgery using the suprapubic or retropub approach, permitting enucleation of the adenomatous tissue from within the surgical capsule. The inci impotence and incontinence is much higher than after TURP. All surgical methods require postoperati catheter drainage for 1 to 5 days. Alternative surgical approaches include intraurethral stents, microwa thermotherapy, high-intensity focused ultrasound thermotherapy, laser ablation, electrovaporization, a radiofrequency vaporization; their roles are not established.

Section 17. Genitourinary Disorders Chapter 228. Renovascular Disease Topics
[General] Renal Artery Occlusion Renal Arteriole And Microvasculature Occlusion Renal Vein Thrombosis
[General]
(See also Renovascular Hypertension in Ch. 199.)
Vascular disorders of the kidney cause renal dysfunction from reduced blood flow due to partial or com occlusion of large, medium, or small renal vessels (see below). Vascular disease primarily affecting th glomeruli (the most common type of renovascular involvement) is discussed in Ch. 224. Systemic vasc involving the glomeruli (Wegener's granulomatosis, polyarteritis nodosa, hypersensitivity vasculitis [eg Henoch-Schnlein purpura, essential mixed cryoglobulinemia, serum sickness]) and disorders causing vascular obstruction from fibrin strands (eg, thrombotic thrombocytopenic purpura-hemolytic-uremic sy are discussed elsewhere in The Manual.
Section 17. Genitourinary Disorders Chapter 219. Disorders Of The Penis And Scro Topics
[General] Disorders Of The Penis Disorders Of The Scrotum Genital Trauma
[General]
Abnormalities of the external male genitalia are psychologically disturbing and sometimes serious (see and Urethra and Testes and Scrotum under Renal and Genitourinary Defects in Ch. 261).
Section 17. Genitourinary Disorders Chapter 229. Abnormal Renal Transport Syndro Topics
Renal Tubular Acidosis Renal Glucosuria Nephrogenic Diabetes Insipidus Bartter's Syndrome Liddle's Syndrome
Renal Tubular Acidosis

Classification and Pathophysiology
Impaired secretion of hydrogen ions in the distal nephron or resorption of bicarbonate ions (HCO3 -) pro leading to chronic metabolic acidosis, with or without K depletion, nephrocalcinosis, and rickets or osteomalacia.
Type I (distal) renal tubular acidosis (RTA) is usually a sporadic disorder in adults and a familial diso children. Sporadic cases may be primary (nearly always in women) or secondary (eg, to an autoimmun disease with hypergammaglobulinemia, especially Sjgren's syndrome; amphotericin B or lithium thera renal transplantation; nephrocalcinosis; renal medullary sponge kidney; or chronic renal obstruction). F cases may be autosomal dominant and are often associated with hypercalciuria. In type I RTA, the ab develop a hydrogen ion gradient across the distal nephron is impaired so that the urine pH is never < 5
Type II (proximal) RTA accompanies several inherited diseases (eg, Fanconi's syndrome, fructose intolerance, Wilson's disease, Lowe's syndrome), multiple myeloma, vitamin D deficiency, and chronic hypocalcemia with secondary hyperparathyroidism. It may occur after renal transplantation; after intox with heavy metals; and after treatment with certain drugs, including acetazolamide, sulfonamides, outd tetracycline, and streptozocin. In type II RTA, the capacity of the proximal tubules to reabsorb HCO3- is decreased, so that urine pH is > 7 at normal levels of plasma HCO3 - but may be < 5.5 at low levels of HCO 3 -. Type III RTA is a combination of types I and II and is very rare.
Type IV RTA is a sporadic disease associated with mild renal insufficiency in adults with diabetes mel nephropathy, or interstitial renal damage (SLE, obstructive uropathy, sickle cell disease). It also may b
HCO 3 -. Type III RTA is a combination of types I and II and is very rare.
Type IV RTA is a sporadic disease associated with mild renal insufficiency in adults with diabetes mel nephropathy, or interstitial renal damage (SLE, obstructive uropathy, sickle cell disease). It also may b produced by drugs that interfere with the renin-aldosterone-renal tubule axis (eg, NSAIDs, ACE inhibit K-sparing diuretics, trimethoprim). Aldosterone deficiency or unresponsiveness of the distal tubule to aldosterone results in type IV RTA. This reduces K excretion, causing hyperkalemia, which reduces am production and acid excretion by the kidney. Urine pH is usually normal.
Symptoms and Signs
Type I or II RTA is associated with chronic metabolic acidosis, mild volume contraction, and hypokalem Hypokalemia may cause muscle weakness, hyporeflexia, and paralysis. Type I RTA has decreased ci excretion in the urine, increased mobilization of bone Ca, and hypercalciuria, which results in osteopen pain, and Ca calculi in the urine or nephrocalcinosis. Renal parenchymal damage and chronic renal fa may develop. Type IV RTA is usually asymptomatic with only mild acidosis, but cardiac arrhythmias or paralysis may develop if hyperkalemia is extreme.
Diagnosis
Low plasma HCO3- and low blood pH with a normal level of undetermined anions (anion gap) are pres Type I RTA is confirmed by an acid load test: Ammonium chloride 100 mg/kg po normally reduces urin < 5.2 within 3 to 6 h, but in type I RTA, urine pH remains > 5.5. Type II RTA is diagnosed by an HCO 3 test: Sodium bicarbonate is slowly infused IV or given po to raise plasma HCO3-. In type II RTA, HCO3 appear in the urine (urinary pH > 6.5) before plasma HCO 3- reaches the normal range. Type IV RTA h plasma aldosterone levels (or a depressed response to aldosterone) and decreased urinary K and am excretion.
Treatment
Sodium bicarbonate relieves symptoms and prevents or stabilizes renal failure and bone disease. In a with type I RTA, 80 to 200 mg/kg/day (1 to 3 mEq/kg/day) po in divided doses will eliminate acidosis a reduce the occurrence of calculi. In children, the total daily dose may need to be up to 2 to 3 times gre correct the serum HCO3 level. In type II RTA, the plasma HCO3- cannot be restored to the normal ran HCO 3 replacement should exceed the acid load of the diet (1 to 3 mEq/kg/day). Excess HCO 3 replace will increase potassium bicarbonate losses in the urine. Bicitra or Polycitra-K can be substituted for so bicarbonate and may be better tolerated. K supplements or potassium citrate may be required in patie become hypokalemic when given sodium bicarbonate but is not recommended in patients with normal serum K levels. In type IV RTA, the hyperkalemia is treated with volume expansion and occasionally K diuretics. A few patients may need mineralocorticoid replacement therapy.

Section 17. Genitourinary Disorders Chapter 220. Erectile Dysfunction Topics
[General]
[General]
Erectile dysfunction (impotence) :The inability to attain or sustain an erection satisfactory for coitus.
The term impotence has been replaced by the less pejorative erectile dysfunction. An estimated 10 to million men aged > 18 are affected in the USA. The prevalence is 52% in men aged 40 to 70 and incre with age. However, men can enjoy sexual activity throughout life; although the amount and force of eja and muscular tension decrease, erectile dysfunction is not inevitable with aging, even into the 70s and
Etiology
Rarely, erectile dysfunction is primary (the man has never been able to attain or sustain erections), w almost always due to psychologic factors (sexual guilt, fear of intimacy, depression, severe anxiety) an due to biogenic factors (usually associated with low testosterone levels and reflecting disorders of the hypothalamic-pituitary-gonadal axis). Secondary erectile dysfunction occurs when a man who previou attain and sustain erections no longer can. More than 90% of these cases are organic in nature.
The major cause of erectile dysfunction is vascular; other large pathogenic categories include hormon disorders, drug use, and neurologic disorders. Transient erectile dysfunction for any reason may lead secondary psychologic difficulties that compound the problem. Erectile dysfunction may be situational, involving place, time, a particular partner, some perceived competitive defeat, or damaged self-esteem psychologic factors that may accompany organic disorders cannot be overlooked and must be conside every case. They may be the cause or the consequence of erectile dysfunction.
Vascular disorders: The major types of vascular problems that can result in erectile dysfunction are atherosclerotic disease of penile arteries, inadequate impedance of venous outflow (venous leaks), or combination of both. With age and underlying diseases (eg, atherosclerosis, hypertension), dilation of blood vessels and smooth muscle relaxation decrease, diminishing the amount of blood entering the p Venous leaks make it difficult for blood to remain in the penis during erection. Diseases that accelerate atherosclerosis (eg, diabetes, smoking, hypertension) increase the prevalence of erectile dysfunction. knowledge of some of the regulators of vascular tone (eg, nitric oxide) may lead to future treatments.
atherosclerotic disease of penile arteries, inadequate impedance of venous outflow (venous leaks), or combination of both. With age and underlying diseases (eg, atherosclerosis, hypertension), dilation of blood vessels and smooth muscle relaxation decrease, diminishing the amount of blood entering the p Venous leaks make it difficult for blood to remain in the penis during erection. Diseases that accelerate atherosclerosis (eg, diabetes, smoking, hypertension) increase the prevalence of erectile dysfunction. knowledge of some of the regulators of vascular tone (eg, nitric oxide) may lead to future treatments.
Hormonal disorders: Hormonal problems (eg, elevated prolactin, hypothyroidism and hyperthyroidism Cushing's syndrome) may cause erectile dysfunction. Although hypogonadism (low testosterone and l bioavailable testosterone) is associated with a decline in libido, the linkage of testosterone and erectile unclear. Drug use: Drugs cause about 25% of cases (see Table 220-1).
Neurologic disorders: Neurologic disorders (eg, stroke, temporal lobe seizures, multiple sclerosis, se and autonomic dysfunction, spinal cord injuries) are often causally related to erectile dysfunction.
Of men undergoing transurethral resection of the prostate, 40% experience problems with erections. M extensive surgical prostatic resection can be associated with a higher prevalence of erectile dysfunctio Retrograde ejaculation (prostatic fluid reversing flow to the bladder) also commonly follows transurethr resection of the prostate.
Diagnosis
A general medical evaluation includes history of drugs, alcohol, smoking, diabetes, hypertension, and atherosclerosis; examination of the genitalia for fibrous bands or plaques (Peyronie's disease); and ev for signs of vascular, hormonal, or neurologic disorders.
Laboratory procedures should include assessment of plasma glucose, thyroid function, and serum testosterone (total and bioavailable [non-sex hormone binding globulin-bound testosterone]). Luteinizin hormone, follicle-stimulating hormone, and prolactin levels may be helpful; it is difficult to adequately d hypogonadism with just a total testosterone concentration.
When the cause is uncertain, the nocturnal penile tumescence (NPT) test can be of some help, but us in older patients, who may have abnormal NPT but usable erections or normal NPT but unusable erec Episodes of NPT often accompany rapid eye movement (REM) sleep. The patient can be monitored fo nocturnal erections in a special sleep laboratory. Absence of nocturnal erections strongly suggests an basis. However, the presence of nocturnal erections does not necessarily equate to usable erections w awake.
It may be helpful to assess vascular indices. For example, the penile pressure-brachial pressure index BP in the penis divided by systolic BP in the arm) can indicate risk for other major vascular events (eg MI), even in asymptomatic patients.
It is vital to screen for depression, which may not always be apparent. The Beck Depression Scale or t Yesavage Geriatric Depression Scale in older men is simple and easy to administer. Personal relation should also be explored. If conflict is present or communication with a partner is difficult, counseling m beneficial.
Treatment
In cases in which a cause is found (eg, prolactinoma, hypothyroidism), treatment should be directed to
beneficial.
Treatment
In cases in which a cause is found (eg, prolactinoma, hypothyroidism), treatment should be directed to underlying disorder.
Reassurance after careful physical examination and necessary laboratory tests is a key first step. Edu dispel myths and misinformation is important. Every effort should be made to include the patient's part Appropriate options should be presented to the patient such that he and his partner can choose their preference. A constriction ring, which may be a metal or plastic ring or a leather band with snaps (sold paraphernalia stores as cock rings), helps patients with venous leaks. However, these rings are useles patient does not have an erection. Treatment of organic dysfunction may involve a vacuum tumescent that uses negative pressure to draw blood into the penis, with a band or ring placed at the base of the retain the erection; this can be appropriate for patients in a stable relationship who have intercourse on twice/wk. Bruising of the penis, coldness of the tip of the penis, or lack of spontaneity are some drawb this modality.
Penile injection therapy using alprostadil (PGE1) can result in erections with a mean duration of about Risks include bruising of the penis, bleeding into the penis, and priapism (see Ch. 219). The amount o injected material should be dosed to the appropriate level by the physician to minimize priapism; the p can then self-inject at home. The incidence of priapism is less with intraurethral PGE 1 than with penile injections.
Sildenafil is a newly released oral drug. It promotes erection by potentiating the effect of nitric oxide on vascular smooth muscle, thus increasing blood flow to the penis. It creates more normal erectile respo because it only works with concomitant sexual arousal. The drug must be taken 30 to 60 min before se contraindicated in persons taking nitrates; it causes headaches in about 16% of users.
Surgery for a penile prosthesis can result in return of erections but involves the risks of anesthesia, inf and prosthetic malfunction. Drug therapy with the -blocker yohimbine has not proven superior to place some studies. It has been effective in psychogenic erectile dysfunction; however, hypertension and he dysfunction make its use less than ideal.
Testosterone therapy for hypogonadism can result in marked improvement in libido. Injectable or trans forms of testosterone are preferable to oral formulations, which carry a significant risk of hepatic dysfu Adverse effects can include polycythemia (and increased risk of stroke), gynecomastia, prostatic enlar and Na and water retention. Hct should be checked at least every 3 mo, and prostatic examination, prostate-specific antigen assessment, and liver function tests should be periodic. If Hct is >= 54%, testosterone should be discontinued, or the patient should undergo phlebotomy if he wishes to remain testosterone.
Behavioral and other therapies for anxiety and depression and counseling for dysfunctional relationshi should be part of therapy. Partner issues (eg, atrophic vaginitis, safe sex) must be considered. Erectile dysfunction is not inevitable or unalterable.
Section 17. Genitourinary Disorders Chapter 230. Inherited And Congenital Renal Diso Topics
Cystic Nephropathies Noncystic Nephropathies
Cystic Nephropathies
Dysplastic renal malformations with single or multiple cysts < 1 cm to > 10 cm in diameter.
The major groups are shown in Table 230-1. The most common disorders with the greatest clinical im polycystic kidney diseases, nephronophthisis and medullary cystic disease, and medullary sponge kid
POLYCYSTIC KIDNEY DISEASES
Inherited disorders characterized by many bilateral renal cysts that increase renal size but reduce func renal tissue.
Polycystic kidney disease may be autosomal recessive (see under Renal and Genitourinary Defects in 261) or autosomal dominant (ADPKD). Renal involvement is characterized by cystic dilations in all par nephron, including Bowman's space. Cysts are lined by epithelium and contain fluid derived from the glomerular filtrate and modified by the action of the tubular epithelial cells. Mechanisms for the develo polycystic disease and the progressive enlargement of cysts are not well understood. Renal cysts in b may be discovered in utero.
Autosomal Dominant Polycystic Kidney Disease

Symptoms and Signs
The incidence is about 1/1000. Penetrance is essentially complete; all patients >= 80 yr have some sig the disease. About 5 to 10% of patients with end-stage renal disease have ADPKD.
The incidence is about 1/1000. Penetrance is essentially complete; all patients >= 80 yr have some sig the disease. About 5 to 10% of patients with end-stage renal disease have ADPKD.
Symptoms and Signs
ADPKD is often asymptomatic initially but may be discovered by ultrasound in childhood. It is slowly progressive over many years. Clinical onset is in early or middle adult life, although the disease may n discovered until autopsy. Symptoms usually are related to effects of the cysts (eg, lumbar discomfort o hematuria, UTI, colic due to nephrolithiasis) or to a loss of renal function with uremic symptoms. Chron infection frequently is superimposed and contributes to the progressive renal dysfunction. In about 33% cases, cysts occur in the liver, but these do not affect liver function. Hypertension is found in about 50% patients at diagnosis.
Malformations of selected vasculature, including intracranial aneurysms and aortic root dilation, may re altered expression and function of the PKD gene in arterial smooth muscle cells and myofibroblasts. A of young adults and up to 10% of older patients have associated intracranial aneurysms. Rupture of a aneurysm occurs in 65 to 75% of affected patients usually before the age of 50, especially in patients poorly controlled hypertension. Valvular abnormalities (most often mitral valve prolapse and aortic regurgitation) can be detected by cardiac ultrasonography in 25 to 30% of patients with ADPKD. Altho patients are asymptomatic, the cardiac lesions may progress and become severe enough to require va replacement. Antimicrobial prophylaxis may be prudent, particularly in patients with audible murmurs.
Diagnosis
The diagnosis is obvious in advanced cases because the kidneys are grossly enlarged and palpable. Urinalysis shows mild proteinuria and varying degrees of hematuria, but RBC casts are infrequent. Pyu common even without bacterial infection. Episodically, the urine is grossly bloody, apparently because hemorrhage from a ruptured cyst or a dislodged calculus. Azotemia is progressive. The findings on IVU characteristic, with large kidneys showing irregular outlines because of the many cysts, which compres elongate the calyces, infundibula, and pelvis, giving a spidery appearance. Renal and hepatic ultrason and CT show a typical moth-eaten appearance due to cysts that displace functional tissue; these stud be diagnostic in early disease before typical IVU changes are noted. The differential diagnosis include or multiple cysts that do not distort a sufficient portion of the renal parenchyma to cause uremia.
Accurate genetic diagnosis may soon be available. Recombinant DNA technology has localized a gen mutation (PKD1) in about 85% of ADPKD families to the short arm (p) of chromosome 16, specifically markers: the -globin complex and the gene for phosphoglycerate kinase. Most of the remaining familie genetic defect on chromosome 4 (PKD2), but a few families unrelated to either locus have been descr
About 50% of patients with ADPKD1 become uremic between the ages of 55 and 60, compared with a for non-ADPKD1 patients. Uncommonly, ADPKD becomes clinically apparent in young children even t the affected parent has adult-onset disease. As in many other renal diseases, ADPKD has an accelera course in blacks and occurs about 10 yr earlier. Other factors that predict more rapidly progressive ren disease include diagnosis at a younger age, male sex, larger renal volume, and the presence of hyper hepatic cysts (in women), gross hematuria, and UTIs (in men). Without dialysis or transplantation, pati usually die as a result of uremia or complications of hypertension (about 10% die of intracranial hemor from rupture of aneurysms).
Good management of UTIs and secondary hypertension may significantly prolong life. Management o
course in blacks and occurs about 10 yr earlier. Other factors that predict more rapidly progressive ren disease include diagnosis at a younger age, male sex, larger renal volume, and the presence of hyper hepatic cysts (in women), gross hematuria, and UTIs (in men). Without dialysis or transplantation, pati usually die as a result of uremia or complications of hypertension (about 10% die of intracranial hemor from rupture of aneurysms).
Good management of UTIs and secondary hypertension may significantly prolong life. Management o if present, is the same as in other renal diseases (see Ch. 222). With dialysis, patients with ADPKD m higher Hb levels than any other group of renal failure patients. Transplantation is feasible, but the use parental and sibling donors may be impractical in view of the genetic characteristics of the disease. Ge counseling is recommended.
NEPHRONOPHTHISIS AND MEDULLARY CYSTIC DISEASE
A group of genetically determined cystic disorders characterized by cystic involvement of the medulla a insidious onset of uremia.
Nephronophthisis, inherited as an autosomal recessive trait, typically occurs in the first 2 decades of some patients, it is associated with retinal pigment degeneration (the retinal-renal dysplasia syndrom
Medullary cystic disease, inherited as an autosomal dominant trait, is symptomatically similar to nephronophthisis but presents later in life. End-stage renal disease typically occurs between the ages and 50 yr. About 15% of cases involve no family history, suggesting a sporadic new mutation or the occurrence of autosomal recessive disease in an only child. The kidneys in all variants (see Table 230 shrunken, with a thinned cortex and often striking cystic changes in the medulla surrounded by scarrin interstitial fibrosis.
Polyuria due to a vasopressin-resistant renal concentrating defect is often the earliest symptom. Unex uremia is an early clue in some patients. Urinary Na wastage frequently occurs and commonly is seve enough to require Na intake of several hundred mEq/day to prevent extracellular volume depletion. Re growth and evidence of bone disease are common in children. In many patients, these problems deve slowly over years and are so well compensated that they are not recognized as abnormal until significa uremic symptoms appear.
Serum chemistries show chronic renal failure. Proteinuria is minimal or absent, and the urinary sedime unremarkable. Ultrasonography or IVU shows a smooth renal outline and normal-sized or small kidney often, multiple small and occasionally larger cysts at the corticomedullary junction. Thin-section CT is e more sensitive, detecting cysts as small as 5 mm in diameter. Because cysts may be few and small, th be missed by any or all of these imaging studies.
Disease progression varies depending on the degree of renal dysfunction at presentation. Usually, pro is slow but inexorable. When uremia supervenes, its management is the same as for other causes of c renal failure (see Ch. 222). Transplantation may be very successful.
MEDULLARY SPONGE KIDNEY
Congenital dilatation of the renal collecting ducts due to tubular ectasia or dysplasia in the pericalycea of the renal pyramids.
MEDULLARY SPONGE KIDNEY
Congenital dilatation of the renal collecting ducts due to tubular ectasia or dysplasia in the pericalycea of the renal pyramids.
Sponge kidney leads to urinary stasis and nephrocalcinosis. It is more frequent in those with Ehlers-Da syndrome, congenital hemihypertrophy, and Beckwith-Wiedemann syndrome.
The condition usually is asymptomatic unless renal colic due to urolithiasis (the most common present complaint), hematuria, or UTI supervenes. Nephrocalcinosis occurs in > 50% of affected kidneys. The usually evidence of incomplete distal renal tubular acidosis (overt metabolic acidosis is rare) and decre renal concentrating ability without symptomatic polyuria.
The disorder must be differentiated from renal cystic disease, papillary necrosis, pyelonephritic cysts, other conditions causing nephrocalcinosis. Diagnosis can be made by urography, which shows pyram cavities filled with contrast material, resembling "a bouquet of carnations." Intraductal concretions of ca phosphate are also often seen. Ultrasound is not helpful because the cysts are small and located deep medulla.
The long-term prognosis is excellent. Although calculus-induced obstruction can reduce the GFR, this usually transient. Nephrocalcinosis may be progressive, but no specific medical treatment has been adequately assessed. Treatment is only indicated for UTIs (using appropriate antimicrobial therapy) an recurrent calculus formation. As with idiopathic Ca calculi, treatment varies with the underlying metabo abnormality. Frequently, thiazides (eg, hydrochlorothiazide 25 mg bid) and high fluid intake may inhibit formation and reduce obstructive complications.

Section 17. Genitourinary Disorders Chapter 221. Urinary Calculi (Stones; Nephrolithiasis; Urolithiasis) Topics
[General]
[General]
Urinary calculi (stones; nephrolithiasis; urolithiasis). About 1 in 1000 adults is hospitalized annually in t because of urinary calculi, which are also found in about 1% of all autopsies. Calculi vary from microsc crystalline foci to calculi several centimeters in diameter. A large calculus, called staghorn calculus, ma shaped by and virtually fill an entire renal calyceal system.
About 80% of calculi in the USA are composed of Ca, mainly calcium oxalate; 5% are uric acid; 2% ar cystine; and the remainder are magnesium ammonium phosphate (or infection calculi). About 5% of p who form Ca calculi have primary hyperparathyroidism. Other rare causes are sarcoidosis, vitamin D intoxication, hyperthyroidism, renal tubular acidosis, multiple myeloma, metastatic cancer, and primary hyperoxaluria. Uric acid calculi develop with increased urine acidity, which crystallizes undissociated u Cystine calculi are diagnostic of cystinuria (see under Anomalies in Kidney Transport in Ch. 261). Mag ammonium phosphate calculi (struvite) indicate the presence of a UTI caused by urea-splitting bacteri calculi must be treated as infected foreign bodies. Unlike other types of calculi, magnesium ammonium phosphate calculi occur mostly in women.
Pathogenesis relates to factors that increase the supersaturation of urine with calculus-forming salts (e overexcretion of salt, urine acidity, low urine volume); preformed nuclei (eg, uric acid crystallites, other and abnormal crystal growth inhibitors. Idiopathic hypercalciuria (urinary Ca > 300 mg/day [> 7.5 mm in men, > 250 mg/day [> 6.2 mmol/day] in women) is hereditary. It is present in 50% of men and 75% women who form Ca calculi and is the main risk factor for Ca calculi in the USA. Hypocitruria (urinary 350 mg/day [< 1820 mol/day]) alone or with other disorders promotes calculi because citrate normally urinary Ca as a soluble calcium citrate salt.
Hyperoxaluria (urinary oxalate > 40 mg/day [> 440 mol/day]) can be primary or caused by excess in of oxalate-containing foods (eg, rhubarb, spinach, cocoa, nuts, pepper, tea) or by excess oxalate abso due to various enteric diseases (eg, bacterial overgrowth syndromes, chronic pancreatic or biliary dise ileojejunal surgery. The clinical history and amount of oxalate in the urine will help determine the caus
urinary Ca as a soluble calcium citrate salt.
Hyperoxaluria (urinary oxalate > 40 mg/day [> 440 mol/day]) can be primary or caused by excess in of oxalate-containing foods (eg, rhubarb, spinach, cocoa, nuts, pepper, tea) or by excess oxalate abso due to various enteric diseases (eg, bacterial overgrowth syndromes, chronic pancreatic or biliary dise ileojejunal surgery. The clinical history and amount of oxalate in the urine will help determine the caus
In hyperuricosuria (urinary uric acid > 750 mg/day [> 4 mmol/day] in women or > 800 mg/day [> 5 mm in men), uric acid crystals provide a nidus on which calcium oxalate crystals can orient themselves and In these patients, seemingly pure Ca calculi or mixed Ca and uric acid calculi can form because the ur nidus is not measurable by commercial laboratories. Hyperuricosuria is almost always caused by exce of purine (in meat, fish, and poultry).
Symptoms and Signs
Although many calculi are asymptomatic, they commonly cause pain, bleeding, obstruction, and secon infection. Back pain or renal colic may occur when calculi obstruct one or more calyces, the renal pelv ureter. Renal colic is typically excruciating and intermittent, usually originating in the flank or kidney are radiating across the abdomen along the course of the ureter, frequently into the genital region and inn Calculi in the bladder may cause suprapubic pain.
GI symptoms (nausea, vomiting, abdominal distention, the clinical picture of ileus) may obscure the ur origin. Chills, fever, hematuria, and frequent urination are common, particularly as a calculus passes d ureter. The affected kidney may become transiently nonfunctioning in acute renal colic because of a u calculus, even after the calculus has passed spontaneously.
Diagnosis
The patient with a single Ca calculus requires limited evaluation (eg, measurement of plasma Ca conc on two occasions looking for hyperparathyroidism, increased fluid intake to > 2 L/day, IVU for an anato abnormality such as medullary sponge kidney). A careful dietary history looking for reversible predispo factors (eg, a high protein diet, vitamin C or D supplements) may be helpful. Extensive metabolic evalu hypercalciuria, hyperuricosuria, or hypocitraturia is not warranted because specific therapy for one of t metabolic abnormalities should not be instituted in the absence of active calculus disease.
The symptoms along with flank or costovertebral angle tenderness, increased sensitivity in the lumbar groin areas, or genital pain with no obvious localized lesions suggest renal colic from calculi. Differenti diagnosis includes appendicitis, cholecystitis, peptic ulcer, pancreatitis, ectopic pregnancy, and dissec aneurysm.
Urinalysis: Urine may be normal despite multiple calculi. Macroscopic or microscopic hematuria is com Pyuria with or without bacteria may be seen. A calculus may have a characteristic color or appearance various crystalline substances may be identified in the sediment, but the calculus' composition should determined by crystallography. The only exception is the presence of the typical benzene-ring crystals cystine in a concentrated, acidified specimen, which strongly suggests cystinuria.
Imaging: Most urinary calculi are demonstrable on x-ray. However, pure uric acid calculi, rare xanthine some cystine calculi, and some matrix calculi (composed largely of protein matrix) are radiolucent. Pyr Ca deposits within the renal parenchyma are diagnostic of nephrocalcinosis and suggest type I renal t acidosis, sarcoidosis, hypervitaminosis D, Cushing's disease, multiple myeloma, hyperparathyroidism, metastatic neoplasms, or milk-alkali syndrome. Renal ultrasonography may be helpful. Retrograde uro or IVU may show opaque or nonopaque calculi and the extent and degree of obstruction. Noncontrast
Imaging: Most urinary calculi are demonstrable on x-ray. However, pure uric acid calculi, rare xanthine some cystine calculi, and some matrix calculi (composed largely of protein matrix) are radiolucent. Pyr Ca deposits within the renal parenchyma are diagnostic of nephrocalcinosis and suggest type I renal t acidosis, sarcoidosis, hypervitaminosis D, Cushing's disease, multiple myeloma, hyperparathyroidism, metastatic neoplasms, or milk-alkali syndrome. Renal ultrasonography may be helpful. Retrograde uro or IVU may show opaque or nonopaque calculi and the extent and degree of obstruction. Noncontrast CT is useful in the emergency room evaluation of acute flank or abdominal pain to help detect a calcu degree of obstruction, or another cause of the pain (eg, aortic aneurysm, appendicitis).
Prophylaxis
Studies of the natural history of calculus disease have shown that, in a patient who has passed a first calculus, the likelihood of forming a second calculus is 15% at 1 yr, about 40% at 5 yr, and about 50% Measurements of calculus-forming substances in the urine and the clinical history are needed to plan prophylaxis, beginning with recovery and analysis of the calculus. In < 3% of patients, no metabolic abnormality is found. These patients seemingly cannot tolerate normal amounts of calculus-forming sa their urine without crystallization. Thiazide diuretics, potassium alkali, and increased fluid intake may re their calculus production rate.
For patients with hypercalciuria, thiazide diuretics (eg, trichlormethiazide 2 mg bid) lower urine Ca ex and supersaturation with calcium oxalate; calculus production falls dramatically. Patients with calculi a encouraged to increase their fluid intake to >= 3 L/day. K replacement with potassium alkali can be us levels fall to < 3.5 mEq/L. A low Ca diet and sodium cellulose phosphate should be used cautiously be they may produce a chronic negative Ca balance. Oral orthophosphate has not been thoroughly studie patients with hypocitruria, oral alkali (potassium citrate 25 to 50 mEq/L bid) usually increases urinary
Prophylaxis for those with hyperoxaluria varies. Patients with small-bowel disease can be treated with combination of a low-oxalate, low-fat diet; Ca loading; and cholestyramine. Primary hyperoxaluria has responded to pyridoxine 5 to 500 mg/day po, possibly by increasing transaminase activity responsible conversion of glyoxylate, the immediate oxalate precursor to glycine.
In hyperuricosuria, intake of meat, fish, and poultry should be reduced. If the diet cannot be changed allopurinol 300 mg each morning lowers uric acid production. Increasing the urine pH to between 6 an with oral alkalinizing drugs (eg, potassium citrate 40 to 80 mEq/day in 2 or 3 divided doses) and increa water intake are usually effective.
Treatment
Although effective therapies can prevent new calculus formation, medical therapy is only indicated in a with metabolically active disease (formation of new calculi, enlargement of an old calculus, passage of Small solitary calculi, uncomplicated by infection or obstruction, require no specific therapy. Treatment urea-splitting bacteria and any metabolic causes may obviate the need for surgery. If eradication of inf impossible, chronic suppressive therapy may be necessary. Symptoms of colic may be relieved by nar (morphine 10 to 15 mg or meperidine 100 mg IM q 3 to 4 h), but antispasmodics are unsatisfactory.
Shock wave lithotripsy (SWL) can replace open surgery for most symptomatic calculi in the renal pelvi ureter. SWL is the usual monotherapy for symptomatic calculi < 2 cm in diameter. Percutaneous nephrolithotomy or ureteroscopy may be used to remove larger renal or ureteral calculi, respectively. C impacted in the renal pelvis or ureter may require SWL or endoscopic removal, particularly when asso with infection. Calculi along the entire course of the ureter may be approached endoscopically from be (ureteroscopically) or from above (percutaneous approach). If the calculus is small enough to be remo intact, direct-vision basketing under ureteroscopic control may be performed. For larger ureteral calcul of intracorporeal lithotripsy with calculus fragmentation (electrohydraulic lithotripsy, laser lithotripsy, pn
nephrolithotomy or ureteroscopy may be used to remove larger renal or ureteral calculi, respectively. C impacted in the renal pelvis or ureter may require SWL or endoscopic removal, particularly when asso with infection. Calculi along the entire course of the ureter may be approached endoscopically from be (ureteroscopically) or from above (percutaneous approach). If the calculus is small enough to be remo intact, direct-vision basketing under ureteroscopic control may be performed. For larger ureteral calcul of intracorporeal lithotripsy with calculus fragmentation (electrohydraulic lithotripsy, laser lithotripsy, pn lithotripsy) can fragment the calculus into smaller pieces, which can be extracted. Uric acid calculi in th or lower urinary tract occasionally may be dissolved by prolonged alkalinization of the urine, but chemi dissolution of other calculi is not possible.
Section 17. Genitourinary Disorders Chapter 231. Immunologically Mediated Renal Di Topics
[General]
[General]
Immunologically mediated renal disease (immune renal disease): Glomerular, vascular, and tubulointe renal disease mediated by host immune mechanisms.
The cause of immunologically mediated renal disease is antigenic triggering of an immune reaction (se Chs. 146 and 148). The list of associated antigens is extensive and continually expanding (see Table 2 These antigens are categorized as renal or nonrenal (based on their origins within or outside the kidne as self or foreign (ie, endogenous or exogenous to the person). The causative antigen is often unknow
Pathogenesis
To cause immunologically mediated renal disease, an antigen must localize to the kidney and trigger a immune inflammatory response. Renal antigens are inherently localized, being constituent proteins of kidney. Nonrenal antigens require a mechanism for depositing (planting) in the kidney.
Renal antigens serve as fixed targets for antibody binding, as do some nonrenal antigens that circulate deposit (plant) within the kidney. Usually, nonrenal antigens that cause renal disease are bloodborne a attach to a specific antibody, forming immune complexes that circulate to the kidney. Depending on th physical and chemical features, immune complexes have characteristic sites of localization in the kidn glomerular mesangium, glomerular basement membrane (GBM), endothelial cells lining the inside of t epithelial cells lining the outside of the GBM (see Fig. 224-2). For example, in IgA nephropathy (Berge disease), the immune complex contains IgA, and the preferred site of localization is the mesangium be of the large size of the IgA molecule. Bacterial antigens complexed with IgG tend to localize within the on the epithelial side of the GBM because of their smaller sizes.
Once localized, antigens and immune complexes establish and perpetuate immune inflammatory rena usually via one or more of the classic types of immune reactions (see Table 231-2). Rarer types includ IgE-mediated, direct C activation, and immunodeficiency disorders (eg, AIDS, congenital C componen deficiencies). Histopathologic patterns of injury depend on the location and type of immune response.
IgE-mediated (type I, immediate, or anaphylactic hypersensitivity) renal disease (see Table 231-
Once localized, antigens and immune complexes establish and perpetuate immune inflammatory rena usually via one or more of the classic types of immune reactions (see Table 231-2). Rarer types includ IgE-mediated, direct C activation, and immunodeficiency disorders (eg, AIDS, congenital C componen deficiencies). Histopathologic patterns of injury depend on the location and type of immune response.
IgE-mediated (type I, immediate, or anaphylactic hypersensitivity) renal disease (see Table 231IgE-mediated immune response is triggered when allergen-sensitive T cells contact specific allergens the pro-allergic interleukins IL-4 and IL-5, which enhance production of IgE and activate mast cells and basophils. IgE coating of basophils and mast cells in the presence of allergen causes the release of va proteins (eg, histamine) and chemokines (eg, IL-4), which cause vasospasm, prostaglandin synthesis, platelet-mediated coagulation, thrombosis, and fibrin deposition. IgE deposition and eosinophilic infiltra occur in several renal inflammatory diseases. In particular, IgE-mediated hypersensitivity in part under allergic tubulointerstitial renal disease due to penicillins, especially methicillin, which is associated with eosinophilia, eosinophilic infiltration in the kidney, IgE deposition, responsiveness to corticosteroids, a frequently, rapid improvement after discontinuation of the causative drug.
Cytotoxic antibody-mediated (type II hypersensitivity) renal disease: Anti-GBM disease (Goodpas disease) is the prototype. Renal damage is caused by linear deposition of antibody specific for type IV of the GBM. The antibody attaches to its antigen and forms an immune complex that activates the com system--a group of plasma and membrane proteins having enzymatic, chemoattractant, binding, and regulating properties. Activation of C through C1 (classic pathway) or C3 (alternative pathway) forms a called the membrane attack complex (MAC), made up of the C5-9 components of C. MAC can injure t directly by creating membrane channels or indirectly by attracting other inflammatory cells to participat immune response. For example, the C5-7 fragment of C attracts neutrophils to the site of inflammation neutrophils release lysosomes, cause further tissue injury, and can directly injure and penetrate the G Moreover, they produce reactive O2 species (ie, free radicals, superoxide) and eicosanoids and intera platelets to activate the clotting system and stimulate fibrin deposition. Thus, in anti-GBM disease, cyto antibody localizes along the GBM in a linear pattern with C in a similar although more irregular or inter distribution. The histopathology is characterized by necrotizing destruction of the glomerular architectu by fibrin deposition in fibroepithelial crescents.
Antineutrophil cytoplasmic antibodies (ANCA) also cause cytotoxic antibody-mediated immunologically mediated renal disease and play a role in Wegener's glomerulonephritis and other vasculitic renal dise Although characterized as pauci-immune because of the virtual absence of immune components on immunofluorescence, ANCA-associated renal diseases are best classified under immunologically med renal disease because ANCA play a causative role. Although various types of ANCA exist, each recog specific component of the neutrophil cytoplasm (eg, myeloperoxidase; lysozyme; elastase; proteinase lactoferrin; cathepsins B, D, and G), most sera containing ANCA are specific for one antigen. Virtually C-ANCA are specific for proteinase 3, and P-ANCA for myeloperoxidase. Wegener's granulomatosis i prototype of ANCA-mediated renal disease; nearly all cases of Wegener's granulomatosis are associa ANCA.
Although the events initiating ANCA production are unknown, it has been proposed that the action of A neutrophil cytoplasmic antigens activates neutrophils. Cell surface integrins are up-regulated, leading attraction and rolling of neutrophils along the vascular endothelium of the kidney and other organs invo the vasculitic process. Adherence of neutrophils to endothelial cells up-regulates endothelial surface interaction ligands (eg, intracellular adhesion molecule-1, endothelial-leukocyte adhesion molecule-1). ligands strengthen the binding of activated neutrophils to endothelial sites, resulting in various immune inflammatory events, including generation of reactive O2 species, lysosomal degranulation, activation with release of lymphokines, and subsequent damage to endothelial cells.
The glomerular vascular endothelium is particularly vulnerable to injury. Although immunoglobulin dep rarely demonstrated, it has been proposed that ANCA complexed to proteinase 3 or myeloperoxidase to endothelial sites along the GBM because of the cationic charges of the proteinase 3 or myeloperoxi
inflammatory events, including generation of reactive O2 species, lysosomal degranulation, activation with release of lymphokines, and subsequent damage to endothelial cells.
The glomerular vascular endothelium is particularly vulnerable to injury. Although immunoglobulin dep rarely demonstrated, it has been proposed that ANCA complexed to proteinase 3 or myeloperoxidase to endothelial sites along the GBM because of the cationic charges of the proteinase 3 or myeloperoxi autoantigens. The planting of ANCA-antigen immune complexes along the GBM initiates and propaga ANCA-mediated injury. The histopathology of clinical Wegener's granulomatosis features necrotizing r progressive crescentic glomerulonephritis and T-cell-mediated granulomas in the kidney and respirato
Activation of neutrophils by ANCA may also be pathogenic in idiopathic forms of necrotizing glomerulo and rapidly progressive glomerulonephritis (without involvement of the respiratory tract) and in microsc polyarteritis, a common form of renal vasculitis that presents in the small vessels of the kidney (and ot organs) without granulomas or deposition of immunoglobulin.
Immune complex-mediated (type III hypersensitivity) renal disease: Immune complex localizes in mesangium, glomerular capillary wall, or renal interstitium and can often be demonstrated in the circul Renal biopsy demonstrates antibody and C in these locations in a lumpy-bumpy pattern.
The underlying mechanisms may be analogous to those in animal experiments, in which parenteral administration of foreign protein elicits production of antibody that combines with the antigen as immun complexes in the kidney after the antigen has been planted or in the circulation to be subsequently de Planted antigen attracts its antibody from the circulation, and a local immune complex is formed. Altern if circulating immune complexes are formed as antibody production increases, the size of the circulatin immune complex increases, favoring removal from the circulation by reticuloendothelial cells or localiz the mesangium or glomerular capillary wall. Small immune complexes are less likely to be deposited, a immune complexes are preferentially removed by reticuloendothelial organs (spleen, liver, and lympha minimizing localization in the kidney. Various endogenous and exogenous substances may function as in immune complex formation. For example, endogenous nuclear proteins may result in DNA-anti-DNA immune complex in lupus nephritis, or streptococcal cell wall antigens may form immune complex in poststreptococcal glomerulonephritis.
There is growing evidence that immune complexes are planted by a variety of mechanisms. Some ant have specific affinity for the GBM. Other planted antigens may be altered native antigens or viruses th access renal tissues via the circulation. Regardless of the type or source of the antigen, various factor to affect localization, including release of vasoactive substances that enhance vascular permeability; t shape, and antigen:antibody ratio of the immune complex; and the presence of receptors for activated glomerular epithelial cells and for the Fc fragment of IgG on mesangial and interstitial cells.
Immune complexes are deposited in the glomerular capillary wall, predominantly in subepithelial sites; localization of immune complex with activation of C underlies the pathogenesis of immune complex ra progressive glomerulonephritis. C activation stimulates various immune phenomena, including attractio neutrophils with lysosomal release and other lymphocytes with cytokine release. Virtually all types of re pathology can be seen, including minimal change disease and mesangial proliferative, membranous, membranoproliferative, mesangiocapillary, necrotizing, and rapidly progressive glomerulonephritis (see 224).
Cell-mediated (type IV or delayed hypersensitivity) renal disease: The prototype is the renal trans renal transplants from identical twins, the antigens of the graft may be identical to those of the host an immune response is induced. However, in nearly all nontwin transplants, the kidney presents nonself a that trigger an immune (predominantly cell-mediated) response. HLAs on cells of the transplant are pr by monocytes and macrophages, which release interleukin-1 and activate helper T cells. Activated hel cells stimulate other T cells in the presence of interleukin-2, transforming them to cytotoxic T cells that attack foreign antigens of the graft, resulting in cell-mediated immune inflammation. If the host has bee
renal transplants from identical twins, the antigens of the graft may be identical to those of the host an immune response is induced. However, in nearly all nontwin transplants, the kidney presents nonself a that trigger an immune (predominantly cell-mediated) response. HLAs on cells of the transplant are pr by monocytes and macrophages, which release interleukin-1 and activate helper T cells. Activated hel cells stimulate other T cells in the presence of interleukin-2, transforming them to cytotoxic T cells that attack foreign antigens of the graft, resulting in cell-mediated immune inflammation. If the host has bee presensitized to antigens of the renal graft, transplantation may trigger hyperacute rejection (an antibody-mediated attack on renal capillary endothelium), resulting in acute renal ischemia, infarction, transplant loss.
Cell-mediated renal disease appears to play a part in chronic poststreptococcal glomerulonephritis (PS Lymphocytes stimulated by exposure to streptococcal wall antigens may cross-react with renal glomer antigens, resulting in progressive cell death and sclerosis of the renal parenchyma.
Direct C-mediated renal disease: Renal injury may occur in the apparent absence of antigen or antib and properdin are deposited in the mesangium and glomerular capillary wall. Early components of C a immunoglobulin are usually not demonstrable on immunofluorescence. The alternative complement pa may be activated when properdin cleaves C3, using C3 proactivator, C3 proactivator convertase, and C3 as cofactors. These molecules are constituents of normal serum, and alternative pathway activatio proceeds at a controlled rate without excessive deposition of activated C3. The mechanism whereby a becomes disordered, with resultant renal C3 deposition, is unclear. About half of patients who develop immunologically mediated renal disease associated predominantly with C3 deposition have a serum p that can directly cleave C3 to active C3b. This molecule, C3 nephritic factor, is a heat-stable IgG autoa of mol wt 150,000. C3b may deposit in the phagocytic mesangium of the glomerulus, subendothelially along C3b binding sites within the capillary wall, triggering local immune inflammatory injury.
Direct C activation results in disease characterized by proliferation of cellular elements within the rena corpuscle and increased capillary wall thickness. These changes on renal biopsy are called membranoproliferative glomerulonephritis (MPGN), which may be type I, II, or III. Type I is characteriz deposited primarily in subendothelial sites along the capillary wall, and type II is associated primarily w dense intramembranous deposits. Type III is a mixture of types I and II.
HIV: HIV infection may be associated with progressive renal disease. IV drug abuse, a significant risk not present in all cases. Proteinuria with rapidly progressive HIV-associated focal segmental glomerulosclerosis appears to be more likely in male, urban, black IV drug users, whereas a nonprotei more slowly progressive HIV nephropathy occurs predominantly in white, homosexual seropositive pat
The histopathology is characterized early by focal segmental glomerulosclerosis and focal deposition o and C3. Later, renal biopsy tissue shows more extensive collapse of entire glomeruli. The renal interst often infiltrated with many CD8+ CD2+ T cells. The presence of tuboreticular structures within the glom endothelial cells suggests a role for direct viral attack or for viral particles to react as planted antigens causing immunologically mediated renal disease in HIV nephropathy. Additionally, immune complex-ty involvement in patients with HIV probably results from circulation of bacterial, viral, or tumor-associate immune complexes to the kidney, triggering an immune complex-mediated renal disease, and from ex antibody-mediated immunity because polyclonal hypergammaglobulinemia has been described in HIV infection.
Congenital C component deficiencies: Perhaps resulting from impaired handling of circulating autol proteins, these deficiencies are associated with several rare immunologically mediated renal diseases SLE-like syndrome and a hemolytic-uremic syndrome with renal cortical necrosis in patients with facto deficiency have been described. The mechanisms are unclear, but perturbation of the immune system excess or deficiency may be a predisposing factor.
Diagnosis
proteins, these deficiencies are associated with several rare immunologically mediated renal diseases SLE-like syndrome and a hemolytic-uremic syndrome with renal cortical necrosis in patients with facto deficiency have been described. The mechanisms are unclear, but perturbation of the immune system excess or deficiency may be a predisposing factor.
Diagnosis
Renal biopsy and light microscopic examination of stained tissue provide the best method for diagnos immunologically mediated renal disease, assessing prognosis, and selecting treatment. However, bec various immune mechanisms may result in similar morphologic changes, immunofluorescence micros using fluorescein-labeled specific antibodies often is also helpful in characterizing the type and locatio immune components in the kidney.
The type and pattern of C deposition help diagnosis. C deposition usually follows the pattern of immun complex or immunoglobulin deposition or both. However, C3 deposition in the absence of immunoglob Clq, or C4 deposition may occur via alternative pathway activation in type II MPGN. Electron microscopy allows visualization of submicroscopic changes in the thickness and composition glomerular and tubular structures and clarifies the presence and location of immune deposits.
Urinalysis for examining the urine for protein and formed elements is often useful. Nephrotic syndrom Ch. 224) is present in virtually all forms of immunologically mediated renal disease. Abundant protein a frequently lipid-laden modified tubular epithelial cells (oval fat bodies with "Maltese crosses" on polariz microscopy) are found in the urine. Nephrotic-range proteinuria usually suggests an underlying immun mechanism, although nephrotic syndrome may occur in nonimmune renal disease (eg, diabetes mellit
Injury resulting in necrosis, as in acute cytotoxic-type injury of anti-GBM disease, causes significant he Immune complex-type injury (eg, postinfective glomerulonephritis) is associated with hematuria and R casts. Hematuria, leukocyturia, RBC casts, and epithelial cell casts are associated with the active neph SLE and some other collagen-vascular diseases. MPGN and membranous glomerulonephritis are ass with significant proteinuria; MPGN usually produces hematuria, but membranous glomerulonephritis ra does. Minimal-change disease and focal sclerosing glomerulonephritis may produce only proteinuria.
Serologic analyses may detect cytotoxic antibodies in the circulation in cytotoxic antibody-mediated r disease (eg, anti-GBM antibodies, anti-HLA antibodies). Circulating immune complexes may be found various immune complex-mediated renal diseases, as determined by Clq binding or Raji cell assay. Ci ANCA can be detected in ANCA-mediated renal disease (eg, Wegener's granulomatosis).
Altered levels of C proteins often differentiate types of immunologically mediated renal disease. When alternative pathway activation predominates (eg, in MPGN and frequently PSGN), C consumption beg activation of C3; thus, early components of C (Clq, C4, and C2) are not depressed. In classic pathway activation (eg, in SLE), consumption begins with the early components, which are thereby depressed. presence of C3 nephritic factor with depressed C3 but normal Clq, C4, and C2 is virtually diagnostic of with alternative pathway activation.
Other helpful serologic analyses include rising antibody titers to streptococcal antigens in PSGN. Othe postinfective glomerulonephritides can be diagnosed by serologic findings, eg, a positive test for syphi hepatitis-associated antigen, or rising antibody titers to other infective organisms. AIDS may be diagno polymerase techniques showing HIV antibodies or HIV antigen.
Histocompatibility testing may help diagnose some forms of immunologically mediated renal diseas example, PSGN has been associated with HLA-B12, IgA nephropathy with HLA-B35 and HLA-DR4, a anti-GBM or Goodpasture's syndrome with HLA-DR2.
hepatitis-associated antigen, or rising antibody titers to other infective organisms. AIDS may be diagno polymerase techniques showing HIV antibodies or HIV antigen.
Histocompatibility testing may help diagnose some forms of immunologically mediated renal diseas example, PSGN has been associated with HLA-B12, IgA nephropathy with HLA-B35 and HLA-DR4, a anti-GBM or Goodpasture's syndrome with HLA-DR2.
Treatment
Treatment varies depending on pathogenesis. As the immunologic mechanisms become better unders more treatment alternatives are becoming available, but many of these renal diseases remain resistan treatment.
Principles of treatment include modulating host immune mechanisms by removing antigen, antibody, o immune complex; inducing immunosuppression via immunosuppressive drugs; and administering anti-inflammatory drugs and, in some cases, platelet-inhibiting and anticoagulation drugs (see Table 2 the antigen cannot be eradicated, the goal is to reduce the antigen load and create excess antibody to natural reticuloendothelial removal of immune complex. Plasmapheresis is beneficial in anti-GBM dise acute allograft rejection, and SLE. Plasmapheresis must be given with corticosteroids and immunosup drugs for maintenance.
A few diseases (eg, SLE, acute transplant rejection, and possibly membranous glomerulonephritis) res corticosteroids given daily or as large doses (ie, methylprednisolone sodium succinate 10 to 15 mg/kg weekly or monthly). Azathioprine or mycophenolate with corticosteroids may provide additional benefit transplant rejection and SLE. Cyclophosphamide is the drug of choice in Wegener's granulomatosis a possibly, in membranous glomerulonephritis and SLE. Cyclosporine, tacrolimus, and mycophenolate m have been very effective in renal transplantation and have additional applications in other immunologic mediated renal diseases.
Acute renal transplant rejection is treated with monoclonal antibodies to T cells (OKT3 antibody) or an against human T cells raised in animals (ATG).
Platelet inhibitors (dipyridamole, aspirin, and ticlopidine) are the only recommended treatment for type MPGN. In type II MPGN, depressing the level of cytotoxic antibodies is difficult because the stimulatin remains.

Section 17. Genitourinary Disorders Chapter 222. Renal Failure Topics
[General] Acute Renal Failure Chronic Renal Failure
[General]
(See also Renal Disease and Diabetes Mellitus in Ch. 251 and Renal and Electrolyte Abnormalities in

Section 17. Genitourinary Disorders Chapter 232. Trauma To The Urinary Tract Topics
[General] Renal Trauma Bladder Trauma Ureteral Trauma Urethral Trauma
[General]
The GU tract is involved in about 10 to 15% of all abdominal trauma. GU trauma is caused by blunt or penetrating external forces (most commonly, motor vehicle accidents, falls, or gunshot or stab wounds iatrogenic injury. It is often subtle and requires a high index of suspicion for early recognition. The use diagnostic and therapeutic algorithms minimizes complications and preserves organ function.

Section 17. Genitourinary Disorders Chapter 223. Dialysis Topics
[General] Hemodialysis Peritoneal Dialysis Nondialytic Management Considerations Psychosocial Aspects Of Long-Term Dialysis
[General]
Dialysis: The process of removing toxins directly from the blood (hemodialysis) or indirectly via periton (peritoneal dialysis) using diffusion across a semipermeable membrane or ultrafiltration.
Hemofiltration uses convective transport through ultrafiltration across a membrane. Hemodiafiltration c diffusion and convective transport. Hemoperfusion removes toxins by perfusing blood over a bed of ad (usually a resin compound or charcoal) material.
Dialysis and hemofiltration procedures can help manage some derangements of renal failure but not it endocrine deficits (ie, lack of erythropoietin and calcitriol production). Accumulated water and dissolve may be removed by ultrafiltration (hydraulic in hemodialysis and hemofiltration, osmotic in peritoneal d Homeostatic balance of minerals (K, P, Mg, sulfate) and removal of toxic end products of nitrogen met (eg, urea, creatinine, uric acid) may be accomplished by diffusion or convective transport. Metabolic ac corrected by diffusion of HCO3 or HCO3 precursors (acetate, lactate) in dialysis and by infusion of thes materials in hemofiltration.
In oliguric acute renal failure (ARF) due to acute tubular necrosis, dialysis is often used prophylacticall regular basis until the recovery phase when BUN and creatinine spontaneously fall. In chronic renal fa (CRF), dialysis is started when the GFR falls below 10 mL/min/1.73 m2 BSA (15 mL/min/1.73 m2 BSA diabetics) or when the patient cannot maintain normal daily activity. Most physicians agree that uremic symptoms (nausea, vomiting, anorexia, fatigability, diminished sensorium) and signs (pericardial frictio refractory pulmonary edema, metabolic acidosis, foot or wrist drop, asterixis) necessitate urgent dialys indications for dialysis include uremic encephalopathy, pericarditis, intractable metabolic acidosis, fluid overload, and life-threatening hyperkalemia. Diabetic patients appear to develop uremic symptoms an at a lower serum creatinine level.
Accurate measurement of GFR requires inulin or iothalamate clearances, which are difficult to perform expensive, and not widely available. However, the GFR can be approximated in patients with advance
indications for dialysis include uremic encephalopathy, pericarditis, intractable metabolic acidosis, fluid overload, and life-threatening hyperkalemia. Diabetic patients appear to develop uremic symptoms an at a lower serum creatinine level.
Accurate measurement of GFR requires inulin or iothalamate clearances, which are difficult to perform expensive, and not widely available. However, the GFR can be approximated in patients with advance failure by averaging the urea clearance (which alone may underestimate GFR due to resorption) and t creatinine clearance (which alone may overestimate GFR due to tubular secretion). Dialysis may be us sole therapy for CRF or as supportive therapy during renal transplantation.
Patients with stable CRF may not require dialysis. However, if an intercurrent illness (eg, gastroenteriti failure, sepsis, lactic acidosis) produces acute metabolic or circulatory decompensation, deterioration sudden and dialysis needed. Dialysis may also negatively affect quality of life, and some patients choo to undergo it. Psychologic intervention may help both sets of patients cope.
Acute intoxications may require dialysis (see Ch. 307). The decision to institute dialysis depends on th and biochemical characteristics of the poison, the severity of toxicity, the likelihood of impaired excreti poison's ability to be metabolized to a more toxic form (eg, oxidation of ethylene glycol to oxalic acid), relationship between toxicity and blood concentration. Hemoperfusion is more effective than hemodial barbiturate, ethchlorvynol, meprobamate, acetaminophen, paraquat, and glutethimide intoxications.

Section 17. Genitourinary Disorders Chapter 233. Genitourinary Cancer Topics
[General] Renal Cell Carcinoma Secondary Renal Cancer Cancer Of The Renal Pelvis And Ureter Bladder Cancer Prostate Cancer Urethral Cancer Penile Cancer Testicular Cancer
[General]
(See also Ch. 142.)
GU tumors occur at any age and in both sexes. Including prostate cancer, they account for about 42% cancers in the male and 4% in the female.
Section 6. Pulmonary Disorders Chapter 63. Approach To The Pulmonary Patie Topics
[General] Cough Dyspnea Chest Pain Wheeze Stridor Hemoptysis Cyanosis Finger Clubbing
[General]
Diagnosis and management of pulmonary disorders requires a history, a physical examination, and us chest x-rays. Pulmonary function testing, arterial blood gas analysis, chemical or microbiologic tests, o studies (eg, endoscopy, bronchoalveolar lavage, biopsy, radionuclide scanning) may be needed. Thes special tests and techniques are discussed elsewhere in The Manual.
History-taking provides essential information and initiates understanding of the patient as a person and patient's environment, expectations, and fears; it is the best way to develop rapport and collaboration. desired include those relating to occupational or other exposures; family, travel, and contact history; a account of previous illnesses and use of drugs; and test results (eg, from tuberculin skin tests or chest Most important, however, are a clear definition of the present complaint, general symptoms (eg, lassitu weight loss, fever), and the major respiratory symptoms of cough, sputum, dyspnea, chest pain, whee hemoptysis. A parent or guardian can speak for an infant or young child; if an elderly person is demen additional information should be sought from relatives or associates.
Physical examination follows history-taking in importance. Some information (general condition, deme discomfort, anxiety, dyspnea on exertion) is absorbed almost subconsciously as the patient walks from waiting room to the office, whereas other general and respiratory information must be actively sought. sequence of inspection, palpation, percussion, and auscultation should be followed when examining th In some patients, the chest examination may yield no information even when a serious disease is pres others, it yields a pearl (eg, incoordination of respiratory muscle groups, a pleural friction rub, or a loca monophonic wheeze).

Section 6. Pulmonary Disorders Chapter 73. Pneumonia Topics
[General] Pneumococcal Pneumonia Staphylococcal Pneumonia Streptococcal Pneumonia Pneumonia Caused By Gram-Negative Bacilli Pneumonia Caused By Haemophilus influenzae Pneumonia Of Legionnaires' Disease Mycoplasmal Pneumonia Chlamydial Pneumonia Psittacosis Viral Pneumonia Pneumonia Caused By Pneumocystis carinii Fungal Pneumonia Pneumonia In The Compromised Host Postoperative And Posttraumatic Pneumonias Aspiration Pneumonia
[General]
Pneumonia: An acute infection of lung parenchyma including alveolar spaces and interstitial tissue.
Pneumonia (pneumonitis) may affect an entire lobe (lobar pneumonia), a segment of a lobe (segment lobular pneumonia), alveoli contiguous to bronchi (bronchopneumonia), or interstitial tissue (interstitial pneumonia). These distinctions are generally based on x-ray observations. (See also discussions of tu pneumonia under Tularemia and pneumonic plague under Plague in Ch. 157 and rickettsial pneumoni Q Fever in Ch. 159; pneumonias in newborns are discussed in Neonatal Pneumonia in Ch. 260.)
In the USA, about 2 million people develop pneumonia each year and 40,000 to 70,000 die; it ranks si among all disease categories as a cause of death and is the most common lethal nosocomial (hospital-acquired) infection. In developing countries, lower respiratory tract infections are usually the m cause of death, or they rank second only to infectious diarrhea.
Bacteria are the most common cause of pneumonia in adults > 30 yr. Of these, Streptococcus pneum the most common. Other pathogens include anaerobic bacteria, Staphylococcus aureus, Haemophilus
among all disease categories as a cause of death and is the most common lethal nosocomial (hospital-acquired) infection. In developing countries, lower respiratory tract infections are usually the m cause of death, or they rank second only to infectious diarrhea.
Bacteria are the most common cause of pneumonia in adults > 30 yr. Of these, Streptococcus pneum the most common. Other pathogens include anaerobic bacteria, Staphylococcus aureus, Haemophilus influenzae, Chlamydia pneumoniae, C. psittaci, C. trachomatis, Moraxella (Branhamella) catarrhalis, L pneumophila, Klebsiella pneumoniae, and other gram-negative bacilli. Mycoplasma pneumoniae, a bacteria-like organism, is particularly common in older children and young adults, typically in the spring pulmonary pathogens in infants and children are viruses: respiratory syncytial virus, parainfluenza viru influenza A and B viruses. These agents may also cause pneumonia in adults; however, the only com viruses in previously healthy adults are influenza A, occasionally influenza B, and rarely varicella-zoste Among other agents are higher bacteria including Nocardia and Actinomyces sp; mycobacteria, includ Mycobacterium tuberculosis and atypical strains (primarily M. kansasii and M. avium-intracellulare); fun including Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Cryptococcus neof Aspergillus fumigatus, and Pneumocystis carinii; and rickettsiae, primarily Coxiella burnetii (Q fever).
The usual mechanisms of spread are inhaling droplets small enough to reach the alveoli and aspiratin secretions from the upper airways. Other means include hematogenous or lymphatic dissemination an spread from contiguous infections. Predisposing factors include upper respiratory viral infections, alco institutionalization, cigarette smoking, heart failure, chronic obstructive airway disease, age extremes, immunocompromise (as in diabetes mellitus and chronic renal failure), compromised consciousness, dysphagia, and exposure to transmissible agents.
Symptoms
Typical symptoms include cough, fever, and sputum production, usually developing over days and som accompanied by pleurisy. Physical examination may detect tachypnea and signs of consolidation, suc crackles with bronchial breath sounds. This syndrome is commonly caused by bacteria, such as S. pneumoniae and H. influenzae.

Diagnosis is based on the characteristic symptoms combined with an infiltrate on chest x-ray.
About 30 to 50% of patients have no identifiable pathogen despite a clinical impression of bacterial pneumonia. Although the time-honored method of identifying bacterial pathogens is culturing expector sputum, these specimens are often misleading because normal oropharyngeal flora may contaminate during passage through the upper airways. The most reliable specimens are taken from normally steri such as blood in patients with bacteremic pneumonia or pleural fluid in patients with empyema. Specia techniques, special stains, serologic assays, or lung biopsies are required to identify some pathogens: mycobacteria, mycoplasmas, anaerobic bacteria, chlamydiae, viruses, fungi, legionellae, rickettsiae, a parasites.
Treatment consists of respiratory support, including O2 if indicated, and antibiotics, which are selected basis of Gram stain results. If Gram stain is not performed or does not establish a diagnosis, antibiotic selected on the basis of probabilities according to patient age, epidemiology, host risk factors, and sev illness.

Section 6. Pulmonary Disorders Chapter 64. Pulmonary Function Testing Topics
[General]
[General]
Physiology
Pulmonary function testing includes both simple spirometry and sophisticated physiologic testing. Pulm function abbreviations are explained in Table 64-1.
Normally, the volume and pattern of ventilation are initiated by neural output from the respiratory cente brain stem. This output is influenced by input from carotid (PaO2) and central (PaCO2, [H+]) chemorece proprioceptive receptors in muscles, tendons, and joints; and impulses from the cerebral cortex. Nerve impulses travel from the respiratory center via the spinal cord and peripheral nerves to the intercostal a diaphragmatic muscles. Normal gas exchange occurs if inspired gas is transmitted through structurally unobstructed airways to patent, adequately perfused alveoli. Normally, alveolar ventilation (A) and per are well matched and proportional to the metabolic rate, and arterial blood gas tensions are maintaine a narrow range (see also Measurements of Arterial Blood Gases, below).
Static Lung Volumes and Capacities
Static lung volumes (see Fig. 64-1) reflect the elastic properties of the lungs and chest wall. Vital capa or "slow VC") is the maximum volume of air that can be expired slowly after a full inspiratory effort. Sim perform, it is one of the most valuable measurements of pulmonary function. Because VC decreases a restrictive lung disorder (eg, pulmonary edema, interstitial fibrosis) worsens, it can be used along with diffusing capacity to follow the course of such a disorder and its response to therapy. The VC also refl strength of the respiratory muscles and is often used to monitor the course of neuromuscular disorder also the discussions of maximal voluntary ventilation and maximal inspiratory and maximal expiratory pressures, below.)
Forced vital capacity (FVC), similar to VC, is the volume of air expired with maximal force. It is usual measured along with expiratory flow rates in simple spirometry (see Dynamic Lung Volumes and Flow below). The VC can be considerably greater than the FVC in patients with airway obstruction. During t maneuver, terminal airways can close prematurely (ie, before the true residual volume is reached), tra
pressures, below.)
Forced vital capacity (FVC), similar to VC, is the volume of air expired with maximal force. It is usual measured along with expiratory flow rates in simple spirometry (see Dynamic Lung Volumes and Flow below). The VC can be considerably greater than the FVC in patients with airway obstruction. During t maneuver, terminal airways can close prematurely (ie, before the true residual volume is reached), tra gas distally and preventing its measurement by the spirometer. Total lung capacity (TLC) is the total volume of air within the chest after a maximum inspiration.
Functional residual capacity (FRC) is the volume of air in the lungs at the end of a normal expiration all respiratory muscles are relaxed. Physiologically, it is the most important lung volume because it approximates the normal tidal breathing range. Outward elastic recoil forces of the chest wall tend to in lung volume but are balanced by the inward elastic recoil of the lungs, which tends to reduce it; these are normally equal and opposite at about 40% of TLC. Loss of lung elastic recoil in emphysema increa FRC. Conversely, the increased lung stiffness in pulmonary edema, interstitial fibrosis, and other restr disorders decreases FRC. Kyphoscoliosis leads to a decrease in FRC and in other lung volumes beca stiff, noncompliant chest wall restricts lung expansion. Inspiratory capacity is the difference between FRC.
The FRC has two components: residual volume (RV), the volume of air remaining in the lungs at the maximal expiration, and expiratory reserve volume (ERV); ERV = FRC - RV. The RV normally accou about 25% of TLC (see Fig. 64-1). Changes in RV parallel those in the FRC with two exceptions: In re lung and chest wall disorders, RV decreases less than do the FRC and TLC (see Fig. 64-2), and in sm airways disease, premature closure during expiration leads to air trapping, so that the RV is elevated w FRC and FEV1 remain close to normal. In COPD and asthma, the RV increases more than the TLC d resulting in some decrease in the VC (see Fig. 64-3). The characteristic abnormality seen in obesity is decreased ERV, caused by a markedly decreased FRC with a relatively well-preserved RV.
Dynamic Lung Volumes and Flow Rates
Dynamic lung volumes reflect the caliber and integrity of the airways. Spirometry (see Fig. 64-1) record volume against time during an FVC maneuver. Forced expiratory volume in 1 sec (FEV1 ) is the volu air forcefully expired during the first second after a full breath and normally accounts for > 75% of the F This value is recorded both as an absolute value and as a percentage of the FVC (FEV 1 %FVC). The forced expiratory flow during the middle half of the FVC (FEF25-75%) is the slope of the line that interse spirographic tracing at 25% and 75% of the FVC. The FEF25-75% is less effort-dependent than the FEV a more sensitive indicator of early airway obstruction.
Prolongation of expiratory flow rates is increased by bronchospasm (in asthma), impacted secretions ( bronchitis), and loss of lung elastic recoil (in emphysema). In fixed obstruction of the upper airway, flow limited by the caliber of the narrowed segment rather than by dynamic compression, resulting in equal reduction of inspiratory and expiratory flow rates (see Fig. 64-4D).
In restrictive lung disorders, increased tissue elastic recoil tends to maintain the caliber of the larger ai that at comparable lung volumes, flow rates are often higher than normal. (Tests of small airways func however, may be abnormal.)
Retesting pulmonary function after the patient inhales a bronchodilator aerosol (eg, albuterol, ipratropi provides information about the reversibility of an obstructive process (ie, the asthmatic component). Improvement in FVC or FEV1(L) of > 15 to 20% is usually considered a significant response. In patien airway obstruction, absence of a response to a single exposure to a bronchodilator, however, does no
however, may be abnormal.)
Retesting pulmonary function after the patient inhales a bronchodilator aerosol (eg, albuterol, ipratropi provides information about the reversibility of an obstructive process (ie, the asthmatic component). Improvement in FVC or FEV1(L) of > 15 to 20% is usually considered a significant response. In patien airway obstruction, absence of a response to a single exposure to a bronchodilator, however, does no preclude a beneficial response to maintenance therapy. In bronchoprovocation testing, a significant de in flow rates after inhaling methacholine (a cholinergic drug) may indicate asthma.
Maximal voluntary ventilation (MVV) is determined by encouraging the patient to breathe at maxima volume and respiratory rate for 12 sec; the volume of air expired is expressed in L/min. The MVV gene parallels the FEV 1 and can be used to test internal consistency and estimate patient cooperation. The can be estimated from the spirogram by multiplying the FEV1(L) 40.
When the MVV is disproportionately low in a patient who seems to be cooperating, neuromuscular we should be suspected. Except in advanced neuromuscular disease, most patients can generate fairly g single-breath efforts (eg, FVC). Because the MVV is much more demanding, it can reveal the diminish reserves of weak respiratory muscles. The MVV decreases progressively with increasing weakness of respiratory muscles and, along with maximum inspiratory and expiratory pressures (see below), may b only demonstrable pulmonary function abnormality in patients with moderately severe neuromuscular
The MVV is important preoperatively because it reflects the severity of airway obstruction as well as th patient's respiratory reserves, muscle strength, and motivation.
Flow-Volume Loop
The flow-volume loop is generated by continuously recording flow and volume with an electronic spirom during a forced inspiratory and expiratory VC maneuver. The shape of the loop reflects the status of th volumes and airways throughout the respiratory cycle. Characteristic changes occur in restrictive and i obstructive disorders. The loop is especially helpful in detecting laryngeal and tracheal lesions. It can distinguish between fixed obstruction (eg, tracheal stenosis) and variable obstruction (eg, tracheomala vocal cord paralysis) of the upper airway. Fig. 64-4 illustrates some characteristic flow-volume loop abnormalities.
Lung Mechanics
Airway resistance (Raw) can be directly measured with a body plethysmograph, which determines th pressure required to produce a given flow. More commonly, however, Raw is inferred from dynamic lu volumes and expiratory flow rates, which can be obtained more easily.
Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) measure the strength respiratory muscles as the patient forcibly inhales and exhales, respectively, through a closed mouthp attached to a pressure gauge. Like the MVV (see above), maximal pressures are reduced in neuromu disorders (eg, myasthenia gravis, muscular dystrophy, Guillain-Barr syndrome). These pressures, alo the VC, are often measured at the bedside of an intubated patient to predict the success of weaning fr ventilatory support.
Diffusing Capacity
The diffusing capacity for carbon monoxide (DL CO) can be determined from a single breath (DLCOSB). patient inspires a known small amount of carbon monoxide (CO), holds his breath for 10 sec, then exh
ventilatory support.
Diffusing Capacity
The diffusing capacity for carbon monoxide (DL CO) can be determined from a single breath (DLCOSB). patient inspires a known small amount of carbon monoxide (CO), holds his breath for 10 sec, then exh sample of alveolar (end-expired) gas is analyzed for CO, and the amount absorbed during that breath calculated and expressed as mL/min/mm Hg.
A low DLCO probably reflects abnormal ventilation/perfusion ratios (/) in diseased lungs rather than ph thickening of the alveolar-capillary membrane. However, this test relies on the avidity of Hb for CO and affected by the volume of blood and the quantity of desaturated Hb in the lungs at the time of testing. T DLCO is low in processes that destroy alveolar-capillary membranes (eg, emphysema and interstitial inflammatory or fibrotic processes) and in severe anemia, in which less Hb is available to bind the inha The DL CO is artifactually low if the patient's Hb is already occupied by CO (eg, if he smokes within sev hours of the test). The DLCO increases with polycythemia and with increased pulmonary blood flow, as occur in early heart failure.
Small Airways Studies
In the normal lung, bronchi < 2 mm in diameter constitute < 10% of the total airway resistance, but the aggregate surface area is large. Disease affecting primarily the small (peripheral) airways can be exte not affect the Raw or any tests dependent on it (eg, FEV1 ). This is true of early obstructive lung diseas interstitial granulomatous, fibrotic, or inflammatory disorders.
The status of the small airways is reflected by the FEF25-75% and by expiratory flow rates in the last 25 of the FVC, best determined from the flow-volume loop (see Fig. 64-4A). More sophisticated tests of s airways function have been devised--eg, frequency-dependent changes in lung compliance (dynamic compliance), closing volume, and closing capacity. In general, such tests add little to those more read available and have little place in the clinical laboratory.
Monitoring Respiration During Sleep
Central and obstructive sleep apnea can be distinguished by monitoring respiration during sleep (see a Sleep Apnea Syndromes in Ch. 173). An oximeter on the ear or finger monitors O 2 saturation. A cathe placed in a nostril measures end-tidal PCO2 (PETCO2) and monitors airflow. Chest wall motion is mon a strain gauge or impedance electrodes. In obstructive sleep apnea, airflow at the nose ceases despit continued excursion of the chest wall, O2 saturation drops, and PET CO2 increases. In central apnea, c wall motion and airflow cease simultaneously.
Ordering Pulmonary Function Tests
As a general preoperative screen, determination of the FVC, FEV1 , FEV1 %FVC, and MVV usually su Testing should be performed before chest or abdominal surgery in smokers > 40 yr old and in patients respiratory symptoms. In patients with suspected laryngeal or tracheal disorders, a flow-volume loop s requested. If weakness of the respiratory muscles is suspected, the MVV, MIP, MEP, and VC are the appropriate tests.
A complete set of pulmonary function tests should be requested when the clinical picture does not coin
Testing should be performed before chest or abdominal surgery in smokers > 40 yr old and in patients respiratory symptoms. In patients with suspected laryngeal or tracheal disorders, a flow-volume loop s requested. If weakness of the respiratory muscles is suspected, the MVV, MIP, MEP, and VC are the appropriate tests.
A complete set of pulmonary function tests should be requested when the clinical picture does not coin with the data obtained by simple spirometry or when more complete characterization of an abnormal pulmonary process is desired. A complete set includes determination of static and dynamic lung volum DLCO, flow-volume loop, MVV, MIP, and MEP. However, extensive testing is tiring, time-consuming, expensive, and unnecessary for adequate clinical assessment of most patients. Periodic determination and DLCO usually suffice to monitor patients with interstitial lung disease. Tables 64-2 and 64-3 are intended as general guidelines for interpreting pulmonary function tests.
Measurements of Arterial Blood Gases
The PaO2 and Pa CO2 reflect the adequacy and efficiency of gas exchange between the lungs and ven blood. The PaCO2 is normally maintained in the narrow range of 35 to 45 mm Hg. An increase in CO2 production (CO 2) normally results in an appropriate increase in ventilatory drive and in alveolar ventila preventing any increase in PaCO2. The A and Pa CO2 are inversely proportional at any given level of CO PaCO2 = k CO2 ).
The PaO2 is considerably lower than the inspired PO2 (PIO2) and somewhat lower than the PaO2. Fig. shows the changes in PO2 as inspired gas is transported to the alveoli. The PO2 in inspired gas is calc as the fractional percentage of inspired O 2 (FIO2) times barometric pressure (PB). For room air at sea PIO2 = 0.21 760 mm Hg ~= 160 mm Hg. As inspired gas enters the upper airway, it becomes saturat water vapor. At sea level and at normal body temperature (37 C [98.6 F]), water exerts a partial pres 47 mm Hg. After saturation with water vapor, the PO2 is slightly diluted; PO2 = 0.21 (760 - 47) ~= 149 For practical purposes, the PO2 of inspired gas as it enters the alveoli can be approximated by multiply FI O2 7 (eg, for room air, 21 7 = 147 mm Hg; for 40% O2, 40 7 = 280 mm Hg).
Because total gas tension in the alveoli must remain constant, the greater the amount of CO 2 entering alveoli, the lower the PAO2 must be. In a patient on a normal diet, the respiratory quotient (ie, the ratio CO2 /O2) is not unity but is about 0.8, thus every 1 mm PACO2 effectively displaces 1.25 mm PAO2. (Respiratory quotient is affected by the relative quantity of fat and carbohydrate in the diet, increasing 1 with a high-carbohydrate diet and decreasing to about 0.7 with a high-fat diet.) For clinical purposes, PACO2 can be assumed to equal the PaCO2. Thus, the PA O2 can be calculated by the equation PAO2 (PB - PH2O) - 1.25 Pa CO2 (see Fig. 64-5).
For room air, with a Pa CO2 of 40 mm Hg, the PAO2 = 147-50 = 97 mm Hg. Normal A is about 5 L/min, perfusion (). If A and were perfectly matched (ie, / = 1), PAO2 and Pa O2 would be equal. The overall / r normal lungs is, however, about 0.8. This degree of / mismatch results in a PaO2 that is 5 to 15 mm Hg than the PAO2, equivalent to shunting 2% of pulmonary arterial (mixed venous) blood directly into the pulmonary venous circulation without participation in gas exchange. The difference between PA O2 and (A - aDO2) directly reflects the degree of mismatching of and , ie, the severity of intrinsic lung disease.
The PaO2 for a healthy 20-yr-old breathing room air is about 90 mm Hg. The normal PaO2 at age 70 is
than the PAO2, equivalent to shunting 2% of pulmonary arterial (mixed venous) blood directly into the pulmonary venous circulation without participation in gas exchange. The difference between PA O2 and (A - aDO2) directly reflects the degree of mismatching of and , ie, the severity of intrinsic lung disease.
The PaO2 for a healthy 20-yr-old breathing room air is about 90 mm Hg. The normal PaO2 at age 70 is 75 mm Hg. This physiologic decrease in PaO2 with age results from a decrease in lung elastic recoil (s emphysema), leading to closure of small airways in the tidal volume range, with a further decrease in t overall / ratio of the lungs.
The physiologic causes of hypoxemia are listed in Table 64-4. A lower-than-normal PIO2 necessarily le hypoxemia, without any alteration in / relationships and without an increase in the A - aDO2. Passenge of commercial aircraft are pressurized to the equivalent of an altitude of 1500 to 2400 m--similar to bre 17% O2 at sea level. Hypoxemia can be offset somewhat by hyperventilation, but a PaO2 as low as 30 has been reported in patients with COPD during commercial flights (see also Ch. 283).
Hypoventilation alone can lead to hypoxemia, even without intrinsic lung disease. If the PaCO2 increas 40 to 80 mm Hg, as might occur with a sedative overdose, the PaO2 must decrease by 50 mm Hg (ie, 1.25), from 90 to 40 mm Hg. When hypoventilation is identified as the main cause of hypoxemia (ie, hypoxemia with a normal A - aDO2), the diagnoses listed in Table 64-4 should be considered.
By far the most common cause of hypoxemia is / imbalance (see Fig. 64-6). In patients with COPD, lo tissue elastic recoil, bronchospasm, and inspissated secretions combine to worsen / relationships in th Areas with low / ratios result in hypoxemia; areas with high ratios lead to wasted ventilation (dead sp increasing the work of breathing and contributing to hypercapnia. As long as the airways are not totally occluded, hypoxemia is readily corrected with small increments in FIO2, because there is a strong grad diffusion to the areas of alveolar hypoxia. Characteristically, an FIO2 of 24 to 28% is adequate to corre hypoxemia due to / imbalance.
Areas that are not ventilated at all (because the alveoli are totally collapsed or filled with fluid) but that perfused result in right-to-left shunting of blood. Shunting results in hypoxemia that is more refractory t increases in FIO2 because O 2 cannot reach the gas-exchanging surface. Such situations often require mechanical ventilation and positive end-expiratory pressure (PEEP) to increase the FRC and open clo airways (see Ch. 66). Impaired diffusion of O 2 across the alveolar-capillary membrane is probably not a significant cause of hypoxemia, except at high altitude.
Split-Function Ventilation/Perfusion Scanning
Preoperative quantitative ventilation/perfusion lung scanning (split-function scanning) is a noninvasive technique useful for predicting postpneumonectomy lung function. It is most useful in patients with lun who frequently have asymmetric lung function. A radioactive isotope is injected (perfusion) or inhaled (ventilation) as is done for a conventional lung scan. After equilibration, the percentage of isotope in ea is determined, usually in the posterior projection with the patient supine.
Predicted postpneumonectomy FEV1 equals percentage of radionuclide uptake in the noncancerous lu multiplied by preoperative FEV1 (in liters). A value of < 0.8 L (or < 40% of that predicted for the patient indicates serious pulmonary disability and the likelihood of unacceptably high perioperative morbidity a mortality.
Predicted postpneumonectomy FEV1 equals percentage of radionuclide uptake in the noncancerous lu multiplied by preoperative FEV1 (in liters). A value of < 0.8 L (or < 40% of that predicted for the patient indicates serious pulmonary disability and the likelihood of unacceptably high perioperative morbidity a mortality.
Transdiaphragmatic Pressure Measurement
Transdiaphragmatic pressure measurement permits quantitative assessment of the severity of diaphra weakness. This procedure can be used to diagnose bilateral diaphragmatic paralysis. Balloon manom placed in the distal esophagus and in the stomach, and pressure across the diaphragm is measured. T procedure indirectly determines tension in the diaphragm during an inspiratory effort. Normally, the gra across the diaphragm at total lung capacity is > 25 cm of water.
The diagnosis of unilateral paralysis, suggested by asymmetric elevation of the affected hemidiaphrag x-ray, can be confirmed by fluoroscopy. During a forced inspiratory maneuver (the "sniff" test), the una hemidiaphragm descends forcefully, increasing intra-abdominal pressure and pushing the paralyzed hemidiaphragm cephalad (paradoxical motion). However, fluoroscopy is inaccurate for the diagnosis o bilateral paralysis.
Exercise Testing
Repeating physiologic measurements during or after exercise can help determine the relative roles of and lung disorders in the etiology of dyspnea, assist in disability evaluations, and monitor the effective a rehabilitation program. Patients with suspected asthma but normal resting exams and spirometry ma wheeze during exercise, especially when inhaling cooled air. A decrease in VC or FEV1 of > 15% is considered abnormal, indicating hyperactive airways. A decrease in DL CO or oxygenation during exerc indicates abnormal gas exchange and may be the first physiologic indication of pulmonary vascular or interstitial lung disease.
In patients with heart disease, stroke volume may not increase appropriately with exercise. Consequen heart rate increases disproportionately to the O2--a result of increased VD/VT (dead space ventilation) hypoxemia, or fatigue of the respiratory muscles.

Section 6. Pulmonary Disorders Chapter 74. Lung Abscess Topics
[General]
[General]
Lung abscess: A localized cavity with pus, resulting from necrosis of lung tissue, with surrounding pne
A lung abscess may be putrid (due to anaerobic bacteria) or nonputrid (due to anaerobes or aerobes). "Gangrene of the lung" denotes a similar though more diffuse and extensive process in which necrosis predominates.
Lung abscesses are usually due to infected material from the upper airway aspirated when a patient is unconscious or obtunded from alcohol, other drugs, CNS disease, general anesthesia, coma, or exces sedation. The causative organisms are usually anaerobes. Lung abscesses are often associated with periodontal disease, in which anaerobes are prevalent. Bacteria cultured from lung abscesses include common and nasopharyngeal flora, particularly anaerobes, and less often, aerobic bacteria or fungi. Bronchogenic carcinoma is an occasional underlying cause in older smokers. Cavitary TB is not consi lung abscess but must be remembered in the differential diagnosis.
Pneumonia due to Klebsiella pneumoniae (Friedlnder's bacillus), Staphylococcus aureus, Actinomyce israelii, -hemolytic streptococcus, Streptococcus milleri (and other aerobic or microaerophilic streptoco Legionella sp, or Haemophilus influenzae is sometimes complicated by abscess formation. Lung absc the compromised host is usually due to Nocardia sp, Cryptococcus sp, Aspergillus sp, Phycomycetes atypical mycobacteria (primarily Mycobacterium avium-intracellulare or M. kansasii), or gram-negative Blastomycosis, histoplasmosis, and coccidioidomycosis may also cause acute or chronic lung abscess should be suspected in a person who has nonputrid abscesses and who lives in an endemic area. Les common causes of lung abscess include septic pulmonary emboli, secondary infection of pulmonary in and direct extension of amebic or bacterial abscesses from the liver through the diaphragm into the low of the lung.
Single lung abscesses are most common. Multiple abscesses usually are unilateral; they may develop simultaneously or spread from a single focus. In abscesses due to aspiration, the superior segment of lobe and the posterior segment of an upper lobe are affected most often. A solitary abscess secondar
common causes of lung abscess include septic pulmonary emboli, secondary infection of pulmonary in and direct extension of amebic or bacterial abscesses from the liver through the diaphragm into the low of the lung.
Single lung abscesses are most common. Multiple abscesses usually are unilateral; they may develop simultaneously or spread from a single focus. In abscesses due to aspiration, the superior segment of lobe and the posterior segment of an upper lobe are affected most often. A solitary abscess secondar bronchial obstruction or to an infected embolus starts as necrosis of a major portion of the affected bronchopulmonary segment. The base of the segment is usually next to the chest wall, and the pleura in the area is often obliterated by inflammatory adhesions. Embolic spread of infection, most often due aureus with tricuspid endocarditis in IV drug abusers, has become more common and is usually chara by multiple lung lesions in noncontiguous sites. Suppurative venous thrombophlebitis due to aerobic o anaerobic bacteria may also cause embolic lung abscesses.
An abscess usually ruptures into a bronchus, and its contents are expectorated, leaving a cavity filled and air. Occasionally, an abscess ruptures into the pleural cavity, resulting in an empyema, sometimes bronchopleural fistula. Similarly, the rupture of a large abscess into a bronchus or vigorous attempts a drainage may cause widespread bronchial dissemination of pus with diffuse pneumonia and a conditio resembling adult respiratory distress syndrome. (See also discussion of empyema under Pleural Effus Ch. 80.)
Symptoms and Signs
Onset may be acute or insidious. Early symptoms are often those of pneumonia, ie, malaise, anorexia sputum-producing cough, sweats, and fever. Severe prostration and a temperature of 39.4 C (103 F higher may be present. Fever, anorexia, weakness, and debility are sometimes minimal if the infection limited or indolent. Unless the abscess is completely walled off, the sputum is purulent and may be blood-streaked. An abscess may not be suspected until it perforates a bronchus, when a large amoun purulent sputum, putrid or not, may be expectorated over a few hours or several days. The sputum ma contain gangrenous lung tissue. A putrid (penetrating and foul) odor is diagnostic of anaerobic bacteria causation. Putrid sputum occurs in 30 to 50% of all patients with lung abscess, but about 40% of patie abscesses due to anaerobes do not have a putrid sputum, so its absence does not exclude this diagn Chest pain, if present, usually indicates pleural involvement.
Physical signs include a small area of dullness, indicating localized pneumonic consolidation, and us suppressed (rather than bronchial) breath sounds. Fine or medium moist crackles may be present. If t is large (unusual with current therapy), there may be tympany and amphoric breath sounds.
Signs of pulmonary suppuration generally disappear with appropriate antibiotic therapy, but this disapp does not necessarily denote cure. If the abscess becomes chronic, weight loss, anemia, and hypertrop pulmonary osteoarthropathy may occur. Physical examination of the chest may be negative in the chro phase, but rales and rhonchi are usually present.
Diagnosis
Lung abscess is suggested by the symptoms and signs described above. Chest x-rays early in the cou show a segmental or lobar consolidation, which sometimes becomes globular as pus distends it. After abscess ruptures into a bronchus, a cavity with a fluid level appears on x-ray. If chest x-rays suggest a underlying tumor or foreign body or if the presentation is atypical, CT scanning may provide better ana definition.
Sputum should be examined by smear and culture for bacteria, fungi, and mycobacteria. Expectorated is not appropriate because the mouth normally contains anaerobic organisms that contaminate the sp
abscess ruptures into a bronchus, a cavity with a fluid level appears on x-ray. If chest x-rays suggest a underlying tumor or foreign body or if the presentation is atypical, CT scanning may provide better ana definition.
Sputum should be examined by smear and culture for bacteria, fungi, and mycobacteria. Expectorated is not appropriate because the mouth normally contains anaerobic organisms that contaminate the sp during passage through the upper airways. The attribution of disease to anaerobes usually requires a specimen obtained by transtracheal aspiration, transthoracic aspiration, or fiberoptic bronchoscopy wit protected brush and quantitative cultures, but these procedures are not performed often. Such invasiv procedures should be reserved for cases that have an atypical presentation or that are unresponsive t antibiotics; however, once antibiotics are initiated, there is no reliable method for obtaining specimens for bacterial culture. Bronchoscopy is unnecessary if response to antibiotics is adequate and if a foreig or tumor is not suspected.
Lesions that simulate bacterial lung abscess include cavitating bronchogenic carcinoma, bronchiectas empyema secondary to a bronchopleural fistula, TB, coccidioidomycosis and other mycotic lung infect infected pulmonary bulla or air cyst, pulmonary sequestration, silicotic nodule with central necrosis, su or hepatic (amebic or hydatid) abscess with perforation into a bronchus, and Wegener's granulomatos Repeated clinical evaluation and the procedures described above can usually differentiate these disor from simple lung abscess.

Prompt, complete healing of a lung abscess depends on adequate antibiotic treatment. Most patients without surgery.
Antibiotics should be started as soon as sputum and blood have been collected for culture and sensiti preferred drug is clindamycin, initially 600 mg IV tid, then 300 mg po qid. An alternative regimen is IV p G 2 to 10 million U/day, followed by oral penicillin V 500 to 750 mg qid. Antibiotics are changed to oral the patient is afebrile and subjectively improved. Some authorities prefer to combine penicillin with ora metronidazole 500 mg qid. If a gram-negative organism, S. aureus, or other aerobic pathogen is implic the antibiotic chosen depends on the results of sensitivity tests. Treatment should be continued until th pneumonitis has resolved and the cavity has disappeared, leaving only a small stable residual lesion, thin-walled cyst, or clear lung fields. Resolution usually requires several weeks or months of treatment of which is given as oral antibiotics on an outpatient basis.
Postural drainage may be a helpful adjunct, but it may also cause spillage of infection into other bronc extension of the infection or acute obstruction. If the patient is weak or paralyzed, tracheostomy and s may be necessary. Rarely, bronchoscopic aspiration may help facilitate drainage. Surgical drainage is necessary because lesions usually respond to antibiotics. Patients with large cavities who do not respo drugs may be candidates for percutaneous drainage; patients with empyema require it.
Pulmonary resection is the procedure of choice for an abscess resistant to drugs, particularly if bronch carcinoma is suspected. Lobectomy is the most common procedure; segmental resection usually suffi small lesions. Pneumonectomy may be necessary for multiple abscesses or pulmonary gangrene refra medical management. The mortality rate after pneumonectomy is 5 to 10%; after lesser resections, it i lower.

Section 6. Pulmonary Disorders Chapter 65. Special Procedures Topics
[General] Chest Imaging Thoracentesis Percutaneous Needle Biopsy Of Pleura Thoracoscopy Tube Thoracostomy Bronchoscopy Percutaneous Transthoracic Needle Aspiration Mediastinoscopy Mediastinotomy Thoracotomy Tracheal Aspiration Airway Establishment And Control Postural Drainage Pulmonary Rehabilitation Pursed-Lip Breathing
[General]
After the patient's complete history and physical and pulmonary function data are obtained, special pro may be used to help diagnose diseases of the lungs, pleura, chest wall, diaphragm, and mediastinum.

Section 6. Pulmonary Disorders Chapter 75. Occupational Lung Diseases Topics
[General] Diseases Due To Inorganic Dusts Diseases Due To Organic Dusts Diseases Due To Irritant Gases And Other Chemicals Sick Building Syndrome
[General]
Occupational lung diseases: Lung disorders directly related to matter inhaled from the work environme
The effects of an inhaled agent depend on many factors: its physical and chemical properties, the susceptibility of the exposed person, the site of deposition within the bronchial tree, and the dose (see 75-1).
Physical properties include the state of the inhaled agent. An agent can be a particle (solid particulat (liquid particulate), vapor (gaseous form of a substance that is normally a liquid), or gas (substance wi fixed volume). An inhaled particle may be deposited and retained in the lungs. If soluble, it is absorbed bloodstream. Usually, the body's defenses eventually remove insoluble particles and mists.
Susceptibility varies from person to person. For example, the mucociliary escalator removes particles the dead space in the respiratory tract more rapidly in some persons than in others; the clearance rate genetically determined. Immunologic status also affects susceptibility.
The site of deposition of particles governs substantially the lung's response (see Table 75-2). Partic deposited in the respiratory tract mainly as the result of three physical processes: impaction, sediment and diffusion. Large particles (6 to 25 m) are deposited by impaction and sedimentation, usually in th and sometimes in the conducting airways. Particles between 0.5 and 6 m are more prone to being de in the gas-exchanging portions of the lungs through sedimentation. Particles between 1 and 3 m are often involved in the development of pneumoconiosis. Particles < 1 m are mostly deposited in the lun parenchyma through diffusion, but many are exhaled. The smaller asbestos fibers have the greatest penetrability and are most likely to migrate to the pleura and cause benign plaques or malignant mesotheliomas.
Deposition of particles in the nose may lead to rhinitis, hay fever (which may be regarded as occupatio related in an agricultural worker), septal perforation in chrome workers, and nasal cancer in furniture w
parenchyma through diffusion, but many are exhaled. The smaller asbestos fibers have the greatest penetrability and are most likely to migrate to the pleura and cause benign plaques or malignant mesotheliomas.
Deposition of particles in the nose may lead to rhinitis, hay fever (which may be regarded as occupatio related in an agricultural worker), septal perforation in chrome workers, and nasal cancer in furniture w
Deposition of particles in the trachea and bronchi may induce three responses. (1) Bronchoconstriction result from an antigen-antibody reaction, eg, in some forms of occupational asthma; from pharmacolog mechanisms (in byssinosis), in which the deposition of particles causes the mast cells of the airways to produce bronchoconstrictors, such as histamine and slow-reacting substance of anaphylaxis (leukotrie D4 , and E4); or from irritation as a reflex mechanism (eg, in response to sulfites). (2) Bronchitis or muc gland hypertrophy may be induced by long-continued deposition of particles, which may lead to a mino chronic airflow obstruction. (3) Lung cancer may result from deposition of asbestos fibers or dusts with adsorbed radon daughters.
Deposition of organic, antigenic particles in the lung parenchyma may lead to the development of hypersensitivity pneumonitis (extrinsic allergic alveolitis), an acute granulomatous process affecting th and respiratory bronchioles (see Ch. 76). Inorganic particles may cause a fibrotic response that is foca nodular, as in typical silicosis, or diffuse and generalized, as in asbestosis and berylliosis. If particles a (eg, tin oxide), a benign pneumoconiosis without fibrosis develops. Inhalation of certain gases and vap Hg, cadmium, nitrogen dioxide) can cause acute pulmonary edema, acute alveolitis, and bronchiolitis obliterans.

Section 6. Pulmonary Disorders Chapter 66. Respiratory Failure Topics
[General]
[General]
Respiratory failure: Impairment of gas exchange between ambient air and circulating blood, occurring intrapulmonary gas exchange or in the movement of gases in and out of the lungs.
In intrapulmonary gas exchange, O2 is transferred to arterial blood (oxygenation) and CO2 eliminated f Impaired intrapulmonary gas exchange usually results primarily in hypoxemia, because the diffusing c of CO 2 is so much greater than that of O2 and because regional zones of hypoventilation (inadequate ventilation) with poor CO 2 removal can be compensated for by increased ventilation of normal lung un process of moving gases in and out of the lungs may be inadequate (global or generalized hypoventila producing primarily hypercapnia, although hypoxemia occurs as well. Many pathologic processes cau simultaneous failure of both of these functions, but selective or disproportionate impairment of one or is more common.
Hypoxemia
The following mechanisms may act alone or together to cause arterial hypoxemia:
A decrease in the partial pressure of inspired O 2 (PIO2) occurs at high altitude (in response to redu barometric pressure), during toxic gas inhalation, and near fires, which consume O 2.
Hypoventilation causes levels of alveolar O2 (PAO2) and arterial O2 (PaO2) to fall. During the initial ph hypoventilation or apnea, Pa O2 may fall more precipitously than arterial CO2 levels (PaCO2) rise becau stores of O2 are modest while those of CO2 are much greater. However, as the Pa CO2 and PACO2 inc (the PaCO2 increases by 3 to 6 mm Hg/min in a totally apneic patient), the PAO2 must fall because the state concentration of PAO2 has a fixed relationship to PaCO2 , as predicted by the alveolar gas equatio = PIO2 - PaCO2 /R. R is the respiratory exchange ratio (the ratio of CO 2 production to O2 consumption steady state). When intrapulmonary gas exchange is normal, the PAO2/PaO2 gradient remains unchan and the fall in PaO2 approximates the fall in PAO2.
(the PaCO2 increases by 3 to 6 mm Hg/min in a totally apneic patient), the PAO2 must fall because the state concentration of PAO2 has a fixed relationship to PaCO2 , as predicted by the alveolar gas equatio = PIO2 - PaCO2 /R. R is the respiratory exchange ratio (the ratio of CO 2 production to O2 consumption steady state). When intrapulmonary gas exchange is normal, the PAO2/PaO2 gradient remains unchan and the fall in PaO2 approximates the fall in PAO2.
CO2
CO2
Impaired diffusion is produced by physical separation of gas and blood (as in diffuse interstitial lung d or by shortened transit time of RBCs through the capillaries (as in pulmonary emphysema with loss of bed).
Regional ventilation/perfusion (/) mismatching almost always contributes to clinically important hypo Lung units ventilated poorly in relation to perfusion result in desaturation; the effect depends partly on content of mixed venous blood. A reduced venous O2 content worsens the hypoxemia further. The mo common causes are disorders that result in poorly ventilated lung units (eg, airway obstruction, atelect consolidation, or edema of cardiogenic or noncardiogenic origin). The degree of hypoxic pulmonary vasoconstriction, which diverts blood from poorly ventilated lung zones, determines how much a reduc ventilation contributes to hypoxemia. Because the capillary blood that exits from well-ventilated lung un already saturated with O2, hyperventilation with an increase in the PAO2 does not fully compensate for mismatching. However, O 2 supplementation impressively reverses hypoxemia when / mismatching, hypoventilation, or impaired diffusion is the cause, because the PAO2 of even poorly ventilated units in enough to allow full saturation of Hb. When patients breathe 100% O2, only perfused alveoli that are to unventilated (shunt units) contribute to hypoxemia.
Shunt (the direct bypass of systemic venous blood to the arterial circulation) can be intracardiac, as in cyanotic right-to-left congenital heart disease, or can result from blood passing through abnormal vasc channels within the lung (eg, pulmonary arteriovenous fistulae). The most common causes are pulmon diseases that produce regional / mismatching, with regional ventilation being nearly or totally absent.
The admixture of abnormally desaturated venous with arterial blood lowers PAO2 in patients with pulmonary disease and impaired intrapulmonary gas exchange. Mixed venous O 2 saturation (S O2) is d influenced by any imbalance between O 2 consumption and O2 delivery. Thus, anemia uncompensated increased cardiac output or a cardiac output insufficient for metabolic needs can cause SO2 and Pa O2 decrease, even when lung pathology remains unchanged.
Hypercapnia
Major mechanisms that can cause or contribute to hypercapnia are insufficient respiratory drive, a defe ventilatory pump, a workload so great that respiratory muscle fatigue develops, and intrinsic lung disea severe / mismatching. The last two mechanisms often coexist.
Although an increase in the partial pressure of inspired CO2 (eg, in proximity to an indoor fire or with d inhalation of CO 2 ) may occasionally cause hypercapnia, hypercapnia almost always indicates ventilato insufficiency or failure.
The PaCO2 is proportional to CO2 production (CO2) and is inversely proportional to alveolar ventilation according to the standard equation (where k = a constant)
An increase in CO 2 due to fever, seizures, agitation, or other factors is usually compensated for by an
The PaCO2 is proportional to CO2 production (CO2) and is inversely proportional to alveolar ventilation according to the standard equation (where k = a constant)
An increase in CO 2 due to fever, seizures, agitation, or other factors is usually compensated for by an immediate increase in A. Hypercapnia develops only if the increase in A is inappropriately low.
Hypoventilation is the most common cause of hypercapnia. In addition to an elevated PaCO2, respira acidosis is present in proportion to the extent of tissue and renal buffering.
A reduced A can be due to a decrease in total minute ventilation (E)--often called global hypoventilatio an increase in dead space ventilation per minute (D). (E equals exhaled volume per breath [tidal volum respiratory rate per minute.)
A drug overdose with suppression of the brain stem respiratory centers is one cause of global hypoven
Dead space (VD), or wasted ventilation, occurs when lung regions are well ventilated but underperfus conversely, when well-perfused alveoli are ventilated with gas that contains a high fraction of CO2 . Su regions eliminate less than their normal share of CO2. The fraction of each tidal breath not involved in exchange (VD/VT), called the physiologic dead space fraction, can be estimated as follows:
(PECO2 = mixed expired concentration of CO2.) An alternative equation shows how an elevation in dea contributes to hypercapnia; CO2, E, and VT are assumed to be constant.
Etiology
Respiratory failure (resulting in hypoxemia and/or hypercapnia) may be caused by airway obstruction; dysfunction of lung parenchyma but not of the airways; and ventilatory pump failure.
For effective ventilation, negative pleural pressure must be generated by the respiratory muscles actin coordinated fashion on an intact rib cage. Ventilatory pump failure may be caused by primary dysfunct the CNS respiratory centers, dysfunction of the ventilatory neuromuscular apparatus, or structural abnormalities of the chest wall that prevent effective transmission of respiratory muscle forces. The air and lung parenchyma may be anatomically normal. For example, disorders (eg, flail chest, kyphoscolio alter the structure of the chest wall can cause inefficient coupling of muscle contraction and pleural pre generation. Hypoventilation can also occur when the inspiratory muscles of the diaphragm and rib cag contract asynchronously (eg, during diaphragmatic paralysis, quadriplegia, or acute stroke).
Often, the primary reason for pump dysfunction is reduced muscular power. The endurance of muscle determined by the balance of nutritional supply and demand. Therefore, respiratory muscles deprived nutrients because of hypotension or hypoxemia perform inefficiently and become fatigued.
Acute hyperinflation severely reduces the efficiency of the ventilatory pump even when the strength of individual muscle fibers remains normal. Not only are the inspiratory muscle fibers foreshortened so th produce less force, but also the work that the muscles must do is increased because of residual end-e alveolar recoil tension and reduced compliance of the lung's connective tissue at high lung volumes. Furthermore, altered geometry (eg, flattened diaphragm, expanded rib cage) limits the pleural pressur that can be generated during forceful contraction. During positive pressure ventilation, acute hyperinfla associated with a positive end-expiratory difference between alveolar and central airway pressures (auto-PEEP).
alveolar recoil tension and reduced compliance of the lung's connective tissue at high lung volumes. Furthermore, altered geometry (eg, flattened diaphragm, expanded rib cage) limits the pleural pressur that can be generated during forceful contraction. During positive pressure ventilation, acute hyperinfla associated with a positive end-expiratory difference between alveolar and central airway pressures (auto-PEEP).
Symptoms and Signs
The clinical symptoms and signs of respiratory failure are nonspecific and may be minimal even when hypoxemia, hypercarbia, and acidemia are severe. The primary physical signs of ventilatory fatigue ar vigorous use of accessory ventilatory muscles, tachypnea, tachycardia, declining tidal volume, irregula gasping breathing patterns, and paradoxical abdominal motion.
Acute hypoxemia may cause diverse problems, including cardiac arrhythmia and coma. Some alterat consciousness is typical, and confusion is common. Chronic reduction in PaO2 is generally well tolerat patients with adequate cardiovascular reserve. However, alveolar hypoxia (PAO2 < 60 mm Hg) can ind pulmonary arteriolar vasoconstriction and increase pulmonary vascular resistance, leading, over week months, to pulmonary hypertension, right ventricular hypertrophy (cor pulmonale), and eventual right ventricular failure.
Hypercapnia may produce acidemia. Sudden increases in Pa CO2 occur much faster than compensato increases in extracellular buffer base. Acute decreases in cerebral pH increase ventilatory drive; howe time, buffering capacity in the CNS increases, eventually blunting the decrease in cerebral pH and red ventilatory drive.
The effects of acute hypercapnia are much less well tolerated than those of chronic hypercapnia. Acut hypercapnia may cause changes in sensorium ranging from subtle personality changes and headache marked confusion and narcosis. Hypercapnia also causes cerebral vasodilation and increased CSF pr a major problem in patients with acute head injury. Acute CO2 retention causes acidemia, which when (pH < 7.3), contributes to pulmonary arteriolar vasoconstriction, systemic vascular dilation, reduced my contractility, hyperkalemia, hypotension, and cardiac irritability, with the potential for life-threatening arrhythmias.
Diagnosis
Blood gas measurement (PaO2, PaCO2, and pH) is the main tool for diagnosing and judging the severi respiratory failure (see Ch. 64). In many cases, it must be repeated frequently to assess deterioration improvement.
Neuromuscular function is evaluated by observing the ventilatory pattern and measuring vital capacity volume, breathing frequency, and maximal inspiratory pressure. The ratio of breathing frequency to tid volume is particularly helpful; > 100 breaths/min/L indicates severe weakness or fatigue. The intensity ventilatory drive is most practically assessed by looking for signs of patient distress (respiratory rate > vigorous use of accessory ventilatory muscles, paradoxical abdominal motion) and by examining PaCO relation to the expired minute ventilation (E) requirement. For example, if PaCO2 is high (> 45 mm Hg) and breathing frequency are modest or low, drive may be suppressed or mechanics impaired; the pres agitation or distress argues for the latter.
If the cause of ventilatory failure is not obvious, certain bedside measurements help define the respon mechanisms. The workload of breathing is reflected in the E, by the vigor of respiratory muscle activity such indexes of breathing workload as the mean, plateau, and peak inspiratory pressures during pass
and breathing frequency are modest or low, drive may be suppressed or mechanics impaired; the pres agitation or distress argues for the latter.
If the cause of ventilatory failure is not obvious, certain bedside measurements help define the respon mechanisms. The workload of breathing is reflected in the E, by the vigor of respiratory muscle activity such indexes of breathing workload as the mean, plateau, and peak inspiratory pressures during pass machine inflation. Calculating the dead space fraction (VD/VT) and measuring CO2 production may he define factors contributing to the ventilatory requirement. In acute ventilatory failure, impedance of che inflation is difficult to assess precisely, except during mechanical ventilation, when it is best gauged by measures of chest mechanics (eg, airway resistance and respiratory system compliance).
Treatment
The primary aims are to maintain adequate O 2 delivery, to alleviate an excessive breathing workload, establish electrolyte and pH balance while preventing further damage from O2 toxicity, barotrauma, inf or other iatrogenic complications. Atelectasis, fluid overload, bronchospasm, increased respiratory sec and infection yield to specific measures, but treatment of other problems (eg, adult respiratory distress syndrome [ARDS], respiratory muscle fatigue, and structural abnormalities of the lung and chest wall) supportive.
O2 therapy: Increasing the fraction of inspired O 2 (FIO2) increases PaO2 whenever true shunt is not responsible for hypoxemia. Under usual circumstances, the goal is to increase Hb saturation to at leas 90% without causing O2 toxicity. Many patients with chronic hypoxemia tolerate a PaO2 < 55 mm Hg; h whatever the cause for ventilatory failure, a Pa O2 between 60 and 80 mm Hg is usually desirable for a O2 delivery to tissues and for amelioration of pulmonary hypertension induced by hypoxemia. Because sigmoidal nature of the oxyhemoglobin dissociation curve, a Pa O2 > 80 mm Hg does not significantly i the O 2 content of blood. The lowest FIO2 that provides an acceptable PaO2 should be selected. For pa with pulmonary insufficiency caused by / imbalances and diffusion limitation (eg, in obstructive pulmon disease), an FI O2 < 40% usually suffices, with 25 to 35% being adequate for most patients. O 2 toxicity concentration- and time-dependent. Sustained elevations in FI O2 > 60% result in inflammatory change alveolar infiltration, and, eventually, pulmonary fibrosis. An FIO2 > 60% should be avoided unless nece the patient's survival. An FIO2 < 60% is well tolerated for long periods without clinically evident toxicity.
An FIO2 < 40% can be given via nasal cannulas or a face mask. With a face mask, the flow of O 2 requ depends on the FIO2 desired and the mask design. With nasal cannulas, an O2 flow of 2 to 4 L/min ord can raise PaO2 to therapeutic levels. However, the FIO2 delivered to the patient can only be estimated estimates require knowing the total minute ventilation (E) of the patient breathing room air and the dur inspiration and expiration. If the time in both phases of ventilation is equal, only the flow of 100% O2 fr O2 reservoir is delivered to the patient. Thus, for a minute ventilation of 10 L/min with a 4-L/min flow o O2 through a nasal cannula, the FI O2 delivered to the patient is estimated at (2 100%) + (8 21%)/1 37% O2. If minute ventilation rises and O 2 flow is unchanged, the FIO2 decreases. Because of the uncertainties in such estimates (eg, admixture of O2 with room air, mouth breathing, varying respirator the PaO2 or arterial O2 saturation (SaO2), measured by noninvasive oximetry, must be monitored regu
Excessive O 2 administration is a common cause of respiratory depression in the management of CO2 retention. With chronic hypercapnia, the respiratory center may become insensitive to changes in PaC respond primarily to hypoxic stimuli. If Pa O2 is raised excessively, the hypoxic ventilatory drive is oblite and further CO2 retention may ensue with worsening respiratory acidosis. Such a complication is prev
Excessive O 2 administration is a common cause of respiratory depression in the management of CO2 retention. With chronic hypercapnia, the respiratory center may become insensitive to changes in PaC respond primarily to hypoxic stimuli. If Pa O2 is raised excessively, the hypoxic ventilatory drive is oblite and further CO2 retention may ensue with worsening respiratory acidosis. Such a complication is prev judicious use of O2 and is detected at an early stage most effectively by arterial blood gas monitoring. supplying O2 during spontaneous ventilation leads to a rising PaCO2 and acidemia, mechanical assista necessary (see below).
Use of positive pressure: Continuous positive airway pressure (CPAP), bilevel positive airway pressu (BiPAP), positive end-expiratory pressure (PEEP), and specialized techniques for increasing mean alv pressure (eg, inverse ratio ventilation--see below) often reopen closed alveolar units, thereby reducing right-to-left shunt and the need for supplemental O 2 .
CPAP, a nonventilator technique that uses a face mask, recruits lung volume and often improves the PaO2/FIO2 ratio. It is most often used in patients with modest ventilatory requirements and acute atelec pulmonary edema. BiPAP varies airway pressure about two levels, accomplishing both ventilatory ass and higher end-expiratory lung volumes.
PEEP at low levels (3 to 5 cm H2O) can benefit virtually all intubated, mechanically ventilated patients respiratory failure; it helps compensate for the volume loss that accompanies the supine posture and translaryngeal intubation. The optimal level of PEEP to be used is a function of tidal volume; higher lev PEEP are usually required with small tidal volumes (< 7 mL/kg). PEEP may need to be > 15 cm H2 O t acceptable arterial oxygenation at a well-tolerated FIO2. PEEP's volume-recruiting effects and ability to improve the PaO2 can be negated if vigorous expiratory muscle contraction forces lung volume lower t relaxed end-expiratory (equilibrium) position. When this breathing pattern is evident, sedation or paraly help. When pulmonary infiltration is predominantly unilateral, delivering the same level of PEEP to bot may be ineffective, because it diverts blood from the healthy lung to the diseased one. With independe ventilation, the pattern of lung inflation, FI O2, and PEEP may be tailored to each lung.
Specific measures: Some measures can help compensate for impaired O2 exchange. Optimizing Hb concentration can improve O2-carrying capacity, although if the Hct becomes too high, O2 delivery can impaired because of increased blood viscosity. Although controversial, the optimal Hb for most acutely patients with severe hypoxemia may be in the range of 10 to 12 g/dL. Correcting acute alkalemia impr performance.
Reducing tissue O 2 requirements can be as effective as improving O2 delivery. Fever, agitation, overfeeding, vigorous respiratory activity, shivering, sepsis, burns, tissue injury, seizures, and other co clinical conditions increase O2 consumption; aggressive steps should be taken to control them. Sedati pharmacologic paralysis reduce O2 consumption in patients who remain agitated or who fight the vent However, protracted paralysis must be avoided because it silences the cough mechanism, creates a monotonous breathing pattern that encourages secretion retention in dependent regions, and may acc muscle weakness and atrophy.
Maintaining cardiac output by the appropriate use of fluids and inotropic drugs is crucial in the treatm hypoxemia. Because extravascular water accumulates readily in many lung conditions, fluids should b judiciously. A delicate balance must be maintained because severe fluid restriction, although often red lung water and improving O2 exchange, may compromise perfusion of the gut, kidneys, and other vita
Maintaining cardiac output by the appropriate use of fluids and inotropic drugs is crucial in the treatm hypoxemia. Because extravascular water accumulates readily in many lung conditions, fluids should b judiciously. A delicate balance must be maintained because severe fluid restriction, although often red lung water and improving O2 exchange, may compromise perfusion of the gut, kidneys, and other vita
Assisting failing circulation, whether from cardiac or noncardiac causes, may help correct a low Pa O measures include fluid manipulation, pressors, inotropic drugs, and reduction of O2 consumption. In pa with pulmonary edema, diuretics and other measures may help mobilize extravascular lung water, ther increasing lung compliance, reducing cardiac asthma, and lessening the workload of the respiratory m Relieving cardiac ischemia, lessening left ventricular afterload, or using a calcium channel blocker may decrease pulmonary vascular congestion and hypoxemia in patients with diastolic cardiac dysfunction.
Corticosteroids should not be used routinely for diffuse parenchymal pulmonary diseases, pulmonary or ARDS (see Ch. 67); the increased catabolism, protein wastage, and risk of infection far outweigh th potential therapeutic benefit in the first phase of respiratory failure. Nonetheless, certain patients (eg, t with proven vasculitis, fat embolism, acute eosinophilic pneumonia, or allergic reactions that contribute hypoxemia) may benefit. Corticosteroids may help more consistently in the later fibroproliferative stage ARDS. Corticosteroids also benefit patients with acute asthma or an exacerbation of COPD.
Position changes may be beneficial. The change from the supine to upright position produces an inc lung volume equivalent to about 5- to 12-cm H2 O PEEP, depending on thoracic compliance. When po recumbent bedridden patients should be turned often (especially during coma or paralysis). Alternating decubitus positions maximally stretches different regions of the lung and improves secretion drainage. one lung is affected disproportionately, oxygenation may improve dramatically when the good lung is i dependent position. However, care should be taken to ensure that secretions from the infiltrated lung a aspirated into the airways of the other. Furthermore, certain patients with ARDS undergo marked O2 desaturation when repositioned (for reasons that are poorly understood). The prone position is often dramatically effective in the early stages of ARDS. Although the reason for this response is not comple understood, redistribution of resting lung volume with expansion of the dorsal areas is likely to be the p benefit.
Clearing secretions from upper and lower airways is crucial. Parenteral hydration may help keep sec adequately liquefied. Occasionally, mucolytic drugs (eg, potassium iodide preparations, acetylcysteine used if secretions remain tenacious despite adequate hydration and humidification of inspired air. Anti and corticosteroids may help reduce the volume of secretions in selected patients.
If the patient's own coughing efforts are ineffective, chest physiotherapy techniques (positioning, chest percussion) may be helpful. Secretions retained despite these measures must be removed by suctioni Secretions in the lower airways can be sucked out through a catheter introduced past the vocal cords nose. If this method is unsuccessful or the lower airway secretions are too copious, an artificial airway usually required. For short periods, an oral or nasal endotracheal tube can be used; if suctioning is req prolonged periods, a tracheostomy may be necessary (see Ch. 65).
Moistening all inspired gas mixtures delivered to the trachea helps ensure the reduced viscosity of secretions. A heated humidifier moisturizes the inspiratory air stream most effectively; alternatively, hygroscopic disposable humidifiers (artificial noses) can be placed in the common channel of the vent circuit to recover exhaled moisture and return it to inhaled air.
Bronchodilators are indicated when bronchospasm and bronchial edema are factors. Airway resistan be decreased and gas exchange improved by -adrenergic or anticholinergic drugs given as aerosols a theophylline derivatives or corticosteroids given IV or orally (see Asthma in Ch. 68). Nebulizers to deliv aerosols may be attached to a mechanical ventilator or driven by a source of pressurized gas. Metered inhalers can be used with or without a ventilator.
circuit to recover exhaled moisture and return it to inhaled air.
Bronchodilators are indicated when bronchospasm and bronchial edema are factors. Airway resistan be decreased and gas exchange improved by -adrenergic or anticholinergic drugs given as aerosols a theophylline derivatives or corticosteroids given IV or orally (see Asthma in Ch. 68). Nebulizers to deliv aerosols may be attached to a mechanical ventilator or driven by a source of pressurized gas. Metered inhalers can be used with or without a ventilator. Antibiotics are given to control infection.
Precautions to minimize complications: In patients with acute lung injury, positive airway pressure, vasopressors and vasodilators are potentially dangerous. Thus, the need for PEEP, the level of ventila support, and the FIO2 level should be frequently reassessed. Mean intrathoracic pressure can often be reduced by allowing the patient to provide as much ventilatory power as is compatible with comfort, eg intermittent mandatory ventilation.
Often, semiconscious, agitated, confused, or disoriented patients who receive mechanical ventilation m restrained and sedated, because abrupt ventilator disconnection and accidental extubation can rapidly produce lethal bradyarrhythmias, hypoxemia, asphyxia, or aspiration of gastric contents. In patients wi pulmonary edema, the interruption of PEEP for even brief periods (eg, during suctioning or tubing cha may cause profound desaturation that is difficult to reverse as lung volume falls and the airways flood edematous fluid. Paralyzed patients must be carefully monitored because ventilation is totally machine-dependent. Because air swallowing and ileus are common, the stomach should be decompre most recently intubated patients. The clinician must be ready to decompress a lung tension cyst or a pneumothorax immediately.
Mechanical Ventilation
In current practice, positive pressure ventilation (PPV) is the only form of support for acute respiratory Ventilators that apply negative pressure to the chest (tank, cuirass, poncho-wrap) require a rigid struct support for the vacuum compartment that greatly impedes intensive care nursing.
Criteria for intubation and mechanical ventilation include progressive acidemia, hypoxemia, and circula dysfunction. Before instituting mechanical ventilation, the clinician must select the mode of ventilation and frequency of machine-supported cycles), the FI O2 to be delivered, the sensitivity of the machine to efforts, and the applied level of PEEP. Machine cycles can be either pressure- or flow-regulated and e volume-, flow-, time-, or pressure-cycled.
Pressure-cycled ventilators are simple in design and low in cost. However, because the tidal volume delivered during each respiratory cycle depends on the duration of the inspiratory phase and the impe the chest (resistance, compliance), these ventilators do not reliably provide a specified tidal volume or ventilation. Their use is confined to nonintubated patients requiring insufflation of bronchodilators or la volumes to reverse atelectasis.
Volume-cycled ventilation has long been the standard type of ventilatory support for all forms of sev respiratory failure. All modern ventilators can provide it as well as several other modes that vary in ven waveform, cycles, percentage of support provided, and method of terminating the machine-aided cycle many patients with moderate illnesses who can tolerate a pressurized nasal or orofacial mask, ventilat be accomplished without tracheal intubation.
Full ventilatory support is designed to perform the complete work of breathing and attempts to provid adequate tidal volume at a specified frequency. Flow-regulated volume-cycled breaths are the standar clinician selects the desired tidal volume, inspiratory flow waveform (eg, constant or decelerating), and
many patients with moderate illnesses who can tolerate a pressurized nasal or orofacial mask, ventilat be accomplished without tracheal intubation.
Full ventilatory support is designed to perform the complete work of breathing and attempts to provid adequate tidal volume at a specified frequency. Flow-regulated volume-cycled breaths are the standar clinician selects the desired tidal volume, inspiratory flow waveform (eg, constant or decelerating), and flow rate. Once these are selected, peak airway cycling pressure varies depending on inflation impeda end-expiratory alveolar pressure. When the pressure-regulated time-cycled variant (pressure-controlle ventilation) is used, pressure and inspiratory duration are selected and tidal volume is allowed to vary inflation impedance. Either type of cycle can be set to occur at a fixed rate (controlled ventilation) or in response to patient effort (assist/control mode ventilation). A backup frequency rate is specified to trigg machine if the patient does not do so.
Partial ventilatory support is indicated when the patient can comfortably perform a portion of the bre workload, as during the process of machine withdrawal (weaning). Assistance can be provided for eve spontaneous breath with pressure support, a flow-cycled technique that rapidly builds airway pressure fixed level with every breath. High or low levels of assistance can be provided, depending on the press selected. On newer equipment, the shape of the pressure waveform and the flow off-switch criterion c adjusted. Pressure support helps to overcome endotracheal tube resistance, which can be surprisingly during respiratory failure. When the appropriate level of pressure is given, pressure support tends to b comfortable in that the patient has some control over the flow profile and cycle duration. Synchronized intermittent mandatory ventilation uses either flow-regulated, volume-cycled or pressure-regulated, tim breaths to provide the machine support at a frequency determined by the clinician. The level of suppor varied not by adjusting the cycle characteristics but by adjusting the number of machine-aided cycles. type of ventilation is often combined with pressure support to achieve optimum patient comfort during
Other forms of mechanical ventilation are less commonly used. High-frequency ventilators (jet or osci cycle small pulses of gas rapidly, achieving gas exchange with very small excursions of tidal volume. T usefulness has been limited in adult patients with respiratory failure, in part because establishing adeq exchange is largely an empiric process requiring considerable operator skill. Inverse ratio ventilation p the inspiratory phase to occupy >= 50% of the inspiratory cycle, thereby raising mean alveolar pressur slowing end-inspiratory flow. This type of ventilation is usually used with sedation and paralysis as sup therapy for oxygenation failure. Some of the newest modes regulate the degree of partial ventilatory su satisfy tidal volume and/or minute ventilation criteria with the least required pressure. PEEP (see abov be added to systems that provide high-frequency or inverse ratio ventilation as well as to all conventio modes of ventilation.
Complications: Any mechanical ventilator may decrease venous return to the thorax, cardiac output, systemic BP, especially if the driving pressure into the lung is high. These problems are likely to occur high inspiratory pressure, hypovolemia, and inadequate vasomotor control due to drugs, peripheral neuropathy, or muscle weakness.
Barotrauma--damage to the lung induced by high cycling pressures--may take the form of tissue ruptu pneumomediastinum, pneumothorax, subcutaneous emphysema, systemic gas embolism), parenchym injury (bronchopulmonary dysplasia), or pulmonary edema. Such damage is likely to occur when press distending the alveoli are excessive (> 35 cm H 2 O) or when large tidal volumes (> 12 mL/kg) are used PEEP insufficient to prevent the collapse of unstable lung units.
Section 6. Pulmonary Disorders Chapter 76. Hypersensitivity Diseases Of The Lu Topics

[General] Hypersensitivity Pneumonitis Eosinophilic Pneumonias Allergic Bronchopulmonary Aspergillosis
[General]
Hypersensitivity (allergic) diseases of the lungs include hypersensitivity pneumonitis (extrinsic allergic alveolitis), allergic bronchopulmonary aspergillosis, and many drug reactions. Eosinophilic pneumonia certain noninfectious pulmonary granulomatoses are suspected to be of allergic origin. Bronchial asthm discussed in Ch. 68; occupational asthma, in Ch. 75.
Hypersensitivity reactions (see also Ch. 148) may be classified into four types based on their pathogen mechanisms (see Table 76-1). Although the classification has been criticized as an oversimplification, useful in understanding immune-mediated reactions injurious to host tissue.
Hypersensitivity diseases of the lungs may be caused by more than one type of hypersensitivity reacti example, hypersensitivity pneumonitis may involve types III and IV; allergic bronchopulmonary asperg types I and III.
Section 6. Pulmonary Disorders Chapter 67. Adult Respiratory Distress Syndro Topics
[General]
[General]
Etiology
Adult respiratory distress syndrome: Respiratory failure caused by various acute pulmonary injuries an characterized by noncardiogenic pulmonary edema, respiratory distress, and hypoxemia.
Adult respiratory distress syndrome (ARDS), a common medical emergency, is precipitated by various processes that directly or indirectly injure the lung, eg, sepsis, primary bacterial or viral pneumonias, a of gastric contents, direct chest trauma, prolonged or profound shock, burns, fat embolism, near drown massive blood transfusion, cardiopulmonary bypass, O2 toxicity, acute hemorrhagic pancreatitis, inhal smoke or other toxic gas, and ingestion of certain drugs. The incidence of ARDS is estimated to be > 3 sepsis (see Ch. 156). Although termed "adult," this syndrome also occurs in children.
Pathophysiology
The initial lung injury is poorly understood. Animal studies suggest that activated WBCs and platelets accumulate in capillaries, the interstitium, and airspaces; they may release prostaglandins, toxic O2 ra proteolytic enzymes, and other mediators (such as tumor necrosis factor and interleukins), which injure promote inflammation and fibrosis, and alter bronchomotor tone and vasoreactivity.
When the pulmonary capillary and alveolar epithelia are injured, plasma and blood leak into the interst intra-alveolar spaces. Alveolar flooding and atelectasis result; atelectasis is due in part to reduced surf activity. The injury is not homogeneous and affects mainly the dependent lung zones. Within 2 to 3 da interstitial and bronchoalveolar inflammation develops, and epithelial and interstitial cells proliferate. T collagen may accumulate rapidly, resulting in severe interstitial fibrosis within 2 to 3 wk. These patholo changes lead to low lung compliance, decreased functional residual capacity, ventilation/perfusion imb increased physiologic dead space, severe hypoxemia, and pulmonary hypertension.
interstitial and bronchoalveolar inflammation develops, and epithelial and interstitial cells proliferate. T collagen may accumulate rapidly, resulting in severe interstitial fibrosis within 2 to 3 wk. These patholo changes lead to low lung compliance, decreased functional residual capacity, ventilation/perfusion imb increased physiologic dead space, severe hypoxemia, and pulmonary hypertension.
ARDS usually develops within 24 to 48 h after the initial injury or illness. Dyspnea occurs first, usually accompanied by rapid, shallow respiration. Intercostal and suprasternal retraction may be present on inspiration. The skin may appear cyanotic or mottled and may not improve with O 2 administration. Aus may detect crackles, rhonchi, or wheezes, or findings may be normal.
Early diagnosis requires a high index of suspicion aroused by the onset of dyspnea in settings that pre to ARDS. A presumptive diagnosis can be made with arterial blood gas analysis and chest x-rays. This analysis initially shows acute respiratory alkalosis: a very low PaO2, a normal or low PaCO2, and an ele pH. Chest x-rays usually show diffuse bilateral alveolar infiltrates similar to acute pulmonary edema of origin, but the cardiac silhouette is usually normal. However, changes seen on x-ray often lag many ho behind functional changes, so hypoxemia may seem disproportionately severe compared with the ede observed on chest x-ray. The extremely low PaO2 often persists despite high concentrations of inspire (FI O2), indicating pulmonary right-to-left shunting through atelectatic and consolidated lung units that a ventilated.
After immediate treatment of hypoxemia, further diagnostic steps are indicated. When there is doubt a whether a patient has heart failure, a Swan-Ganz catheter may help. Characteristically, pulmonary arte wedge pressure (PAWP) is low (< 18 mm Hg) in ARDS and high (> 20 mm Hg) in heart failure. If pulm embolism, which may mimic ARDS, is considered likely (see Ch. 72), appropriate diagnostic procedure pulmonary angiography) should be performed after the patient is stabilized. Pneumocystis carinii pneu and occasionally other primary lung infections may mimic ARDS and should be considered, especially immunocompromised hosts; lung biopsy or bronchoscopy-guided bronchoalveolar lavage may be help
The American-European Consensus Conference defines ARDS as PaO2/FIO2< 200 (regardless of pos end-expiratory pressure), bilateral infiltration on frontal chest x-rays, and PAWP <= 18 mm Hg when m or no clinical evidence of left atrial hypertension.
Complications and Prognosis
Secondary bacterial superinfection of the lungs, particularly by aerobic gram-negative bacteria (such a Klebsiella, Pseudomonas, and Proteus spp) and by gram-positive Staphylococcus aureus, especially methicillin-resistant strains; multiple organ system failure, especially renal failure (see Table 67-1); and complications of invasive life support may occur and are associated with high morbidity and mortality. pneumothorax associated with the placement of central venous catheters and with the use of positive ventilation (PPV) and positive end-expiratory pressure (PEEP) may occur suddenly. Prompt recognitio treatment are necessary to prevent death. Tachycardia, hypotension, and a sudden increase in the pe inspiratory pressures required for mechanical ventilation suggest possible pneumothorax. Pneumothor occurring late in ARDS is an ominous sign because it is usually associated with severe lung damage a need for high ventilatory pressures. Without adequate replacement of intravascular volume, PPV and may decrease venous return, resulting in depression of cardiac output and of overall O 2 transport to th tissues, which contributes to secondary multiple organ system failure.
The survival rate for patients with severe ARDS who receive appropriate treatment is about 60%; if the hypoxemia of ARDS is not recognized and treated, cardiopulmonary arrest occurs in 90% of patients. who respond promptly to treatment usually have little or no residual pulmonary dysfunction or disability
may decrease venous return, resulting in depression of cardiac output and of overall O 2 transport to th tissues, which contributes to secondary multiple organ system failure.
The survival rate for patients with severe ARDS who receive appropriate treatment is about 60%; if the hypoxemia of ARDS is not recognized and treated, cardiopulmonary arrest occurs in 90% of patients. who respond promptly to treatment usually have little or no residual pulmonary dysfunction or disability Patients needing prolonged ventilatory support with FIO2 > 50% are more likely to develop lung fibrosis most patients who survive acute illness, lung fibrosis resolves after several months, but the mechanism resolution is unknown.
Treatment
Management principles are similar despite different etiologies. Oxygenation must be maintained, and t underlying cause of acute lung injury corrected. Meticulous attention is necessary to prevent nutritiona depletion, O2 toxicity, superinfection, barotrauma, and renal failure, which may be worsened by intrava volume depletion. While the diagnosis is being considered, life-threatening hypoxemia must be treated high FIO2 and monitored with repeated arterial blood gases or noninvasive oximetry. Prompt endotrach intubation with mechanical ventilation and PEEP may be needed to deliver O2 because hypoxemia is frequently refractory to O2 inhalation by face mask.
Intravascular volume is often depleted with the onset of ARDS, because sepsis is the underlying caus because diuretic therapy was given before ARDS was suspected, or because initiation of PPV decrea venous return. Despite the presence of alveolar edema, IV fluids should be given if needed to restore peripheral perfusion, urine output, and BP. Monitoring vascular volume is crucial because both hypovo and overhydration are deleterious. Physical findings and central venous pressure may be misleading i critically ill patients undergoing mechanical ventilation, and if severe hypoxemia persists, if skin perfus poor, if mentation is impaired, or if urinary output decreases (< 0.5 mL/kg/h), a reliable index of intrava volume is needed immediately. A Swan-Ganz catheter generally is used to guide volume infusions, pa if PEEP is needed. However, the use of Swan-Ganz catheters is not without risk. Close daily monitorin patient's weight and total intake and output of fluids is also essential for fluid management. As a rule, p with ARDS do better if kept on the "dry" side--by restricting fluids and judiciously using diuretics--as lon cardiac output and tissue perfusion are not impaired.
If sepsis is or could be the cause of ARDS, empirical antibiotic therapy should be initiated pending cult results. Surveillance cultures and Gram stains of sputum or tracheal aspirates can help detect lung superinfection early and guide antibiotic therapy. Closed-space infections should be drained. Alimenta should be begun within 48 to 72 h; the enteral route is preferred because it protects the gut mucosal li
Corticosteroids are of no proven benefit in acute ARDS, although anecdotal reports suggest benefit in patients with ARDS in the late fibroproliferative phase, which may develop after 7 to 10 days of mecha ventilation. Concurrent lung infection must be excluded in these patients, who often are febrile and ha leukocytosis, with or without infection.
Many approaches to the prevention and management of ARDS have been unsuccessful or inconclusiv Treatments that have not improved outcome or prevented ARDS include monoclonal antibody to endo monoclonal antibody to tumor necrosis factor, interleukin-1 receptor antagonist, prophylactic (early) PE extracorporeal membrane oxygenation and extracorporeal CO2 removal, IV albumin, volume expansio cardiotonic drugs to increase systemic O 2 delivery, corticosteroids in early ARDS, parenteral ibuprofen inhibit cyclooxygenase, prostaglandin E1 , and pentoxifylline. Several approaches show promise but ne further study.
The prone position can substantially improve oxygenation in some patients, probably because this pos
extracorporeal membrane oxygenation and extracorporeal CO2 removal, IV albumin, volume expansio cardiotonic drugs to increase systemic O 2 delivery, corticosteroids in early ARDS, parenteral ibuprofen inhibit cyclooxygenase, prostaglandin E1 , and pentoxifylline. Several approaches show promise but ne further study.
The prone position can substantially improve oxygenation in some patients, probably because this pos shifts perfusion and gas exchange to more normal, previously nondependent lung zones. Whether this technique improves gas exchange in severe ARDS and whether it can reduce the duration of mechan ventilation and improve overall survival is unclear. Patient positioning is difficult to perform.
Inhaled nitric oxide can significantly improve pulmonary hypertension and arterial oxygenation in patie have severe ARDS without causing systemic hypotension. Whether nitric oxide improves survival and prolonged use promotes further lung injury from toxic nitric oxide by-products, such as the peroxynitrite remains to be shown.
Ketoconazole may help prevent ARDS by suppressing the formation and release of tumor necrosis fac macrophages. Its clinical benefit in small preliminary studies needs to be confirmed in larger well-contr studies. Initial studies of aerosolized synthetic surfactant in adult ARDS patients have been disappoint Improved aerosol delivery devices and natural mammalian surfactant preparations may improve alveo stability, reduce atelectasis and intrapulmonary blood shunting, and enhance the antibacterial and anti-inflammatory properties of the alveolar lining fluid; additional studies using these approaches are progress.
Mechanical ventilation: Most patients require endotracheal intubation and assisted ventilation with a volume-limited mechanical ventilator. Endotracheal intubation and PPV should be considered if the res rate is > 30 breaths/min or if an FI O2 > 60% by face mask is required to maintain arterial PO2 at 70 mm more than a few hours. As an alternative to intubation, a continuous positive airway pressure mask ma effectively deliver PEEP in patients with mild or moderate ARDS. Such masks are not recommended f patients with depressed consciousness because of the risk of aspiration and should be replaced by a if patients progress to severe ARDS or show signs of respiratory muscle fatigue with increasing respira and arterial PCO 2 .
Conventional settings on a volume-limited ventilator in ARDS are a tidal volume of 10 to 15 mL/kg, a P 5 to 10 cm H2O, an FI O2 of <= 60%, and a patient-triggered assist-control mode. Intermittent mandato ventilation with an initial rate of 10 to 12 breaths/min with PEEP may be used instead.
There is concern that high ventilator pressures and volumes in ARDS can worsen lung injury, but this has not been proved. A PEEP that is too low can also damage the lung by allowing unstable terminal l units to open and close repeatedly. This problem may be circumvented with small tidal volumes (6 to 8 and a higher PEEP (between 10 and 18 cm H2O).
The goal of small tidal volumes is to prevent ventilator-generated breaths from exceeding the upper in (deflection) point of the patient's pressure-volume curve and from causing lung overdistention (see Fig Beyond this point, the lung becomes quite stiff, and small increments in tidal volume cause large incre ventilator plateau pressure (the pressure needed to maintain lung and chest wall inflation after inspirat has ended). For technical reasons, the upper inflection point is often not measured directly. Instead, v plateau pressure is measured, which in most patients should not exceed 25 to 30 cm H 2O (or 20 to 25 H2 O according to some investigators). With a reduced tidal volume, the respiratory rate of the ventilato increased to maintain an adequate arterial pH and PCO2 . Some patients still develop hypercapnia and respiratory acidosis, which is usually well tolerated. If arterial pH falls below 7.20, a slow bicarbonate in can be started.
H2 O according to some investigators). With a reduced tidal volume, the respiratory rate of the ventilato increased to maintain an adequate arterial pH and PCO2 . Some patients still develop hypercapnia and respiratory acidosis, which is usually well tolerated. If arterial pH falls below 7.20, a slow bicarbonate in can be started.
Theoretically, the PEEP selected should be several centimeters of water above the lower inflection po the patient's pressure-volume curve (see Fig. 67-1) to promote generous alveolar recruitment and infla the lower inflection point is not directly determined, a PEEP of 10 to 15 cm H2O often suffices. At a sa PEEP setting, the ventilator FI O2 can usually be decreased to a safe level of < 50 to 60%, so that the p has a satisfactory PaO2 of >= 60 mm Hg or arterial O 2 saturation (SaO2) >= 90%. For adequate tissue
transport, the cardiac index should be >= 3 L/min/m 2; occasionally, volume infusion or parenteral card drugs are needed.
Alternatively, pressure-controlled mechanical ventilation may be used, mainly for patients with severe Inspiratory pressure and duration are selected, and tidal volume varies with inspiratory impedance; hig inspiratory ventilator pressures are thus avoided, but permissive hypercapnia often results. This appro often combined with inverse ratio ventilation, in which the duration of inspiration is set to equal or exce of exhalation. This technique may recruit and reexpand more lung units than PEEP can alone (partly b producing intrinsic or auto-PEEP), so that injuriously high FI O2 can be reduced further. This technique uncomfortable and requires patient sedation, often together with a muscle-paralyzing drug.
Weaning readiness is based on continued evidence of improved lung function (ie, a decreasing need f and PEEP), improvement seen on x-rays, and resolution of tachypnea. Patients without previous unde pulmonary disease can usually be weaned smoothly; difficulty in weaning may indicate an untreated o site of infection, overhydration, bronchospasm, anemia, electrolyte disturbance, cardiac dysfunction, o nutritional status causing respiratory muscle weakness. If these conditions are treated, weaning can u accomplished by the use of intermittent mandatory ventilation to decrease the mechanical rate, often w some pressure support ventilation (see Ch. 66), or by trials of spontaneous breathing for progressively periods through a T-piece attached to the endotracheal tube. A low PEEP ( 5 cm H2 O) is usually main throughout the weaning process.

Section 6. Pulmonary Disorders Chapter 77. Goodpasture's Syndrome Topics
[General]
[General]
Pathology
Goodpasture's syndrome: A hypersensitivity disorder (see Ch. 148) of unknown cause, characterized b circulating anti-glomerular basement membrane antibodies in the blood and linear deposition of immunoglobulin and complement in the glomerular basement membrane and causing pulmonary hem with severe and progressive glomerulonephritis.
Changes observed at renal biopsy are like those in any rapidly progressive glomerulonephritis, includin epithelial cell crescents, glomerular adhesions, and interstitial inflammatory exudates. Intra-alveolar hemorrhages, hemosiderin-laden macrophages, and septal fibrosis are present in the lungs. Immunofluorescent staining shows linear deposition of immunoglobulin and complement in the glomer basement membrane and, in some cases, in the alveolar-capillary basement membrane.
In the lungs and kidneys, the primary target of the anti-glomerular basement membrane antibodies is t noncollagenous (NC-1) domain of the 3 chain in type IV (basement membrane) collagen. Infections, c smoking, and inhalation injury are thought to prime capillaries for injury by these antibodies. Heredity m play a role: HLA-DRw2 is associated with anti-glomerular basement membrane disease.
Goodpasture's syndrome is uncommon. The patient, most often a young man, characteristically prese severe hemoptysis, dyspnea, and rapidly progressive renal failure. In some cases, pulmonary hemorrh may antecede the renal disease by weeks to months. Circulating anti-glomerular basement membrane antibodies are present in the blood. Hematuria and proteinuria are common, and the urinary sediment contains cellular and granular casts. Chest x-rays may show progressive, migratory, asymmetric, bilate fluffy densities. Iron-deficiency anemia is usual.
The combination of pulmonary hemorrhage and renal failure can also occur in certain collagen vascula diseases (eg, SLE, RA), idiopathic rapidly progressive glomerulonephritis, microscopic polyarteritis, W
antibodies are present in the blood. Hematuria and proteinuria are common, and the urinary sediment contains cellular and granular casts. Chest x-rays may show progressive, migratory, asymmetric, bilate fluffy densities. Iron-deficiency anemia is usual.
The combination of pulmonary hemorrhage and renal failure can also occur in certain collagen vascula diseases (eg, SLE, RA), idiopathic rapidly progressive glomerulonephritis, microscopic polyarteritis, W granulomatosis, and essential mixed cryoglobulinemia. However, these diseases can usually be distin by laboratory features (eg, the presence of anti-glomerular basement membrane antibodies, antineutro cytoplasmic autoantibodies [ANCA], or cryoglobulins in serum) and by renal biopsy. It has been recent documented that the syndrome of pulmonary hemorrhage and nephritis is most often due to an ANCA-associated condition (microscopic polyarteritis, Wegener's granulomatosis with capillaritis), rath to Goodpasture's syndrome. Linear deposition of immunoglobulin occasionally occurs in lupus nephriti diabetic glomerulosclerosis, but antibodies eluted from the kidneys in these diseases do not have anti-glomerular basement membrane activity.
Goodpasture's syndrome may be rapidly fatal. The cause of death is usually pulmonary hemorrhage a respiratory failure. Intubation, assisted ventilation, and hemodialysis are often required in the acute ph Subsequent management relies on the use of high-dose corticosteroids (methylprednisolone 7 to 15 mg/kg/day IV in divided doses), immunosuppression with cyclophosphamide, and repeated plasmaphe remove anti-glomerular basement membrane antibodies from the circulation. Duration of immunosupp therapy varies considerably and may be necessary for longer than 12 to 18 mo in some patients. Early these measures in combination may preserve renal function. End-stage renal disease can be manage long-term hemodialysis or kidney transplantation.
Section 6. Pulmonary Disorders Chapter 68. Chronic Obstructive Airway Disord Topics
[General] Asthma Chronic Obstructive Pulmonary Disease Giant Bullae
[General]
In these diseases, airflow obstruction may be chronic and persistent or episodic and recurrent.
Chronic obstructive airway disorders: Pulmonary diseases due to physiologically determined chronic a obstruction, regardless of etiology.
Airflow obstruction is usually determined by forced expiratory spirometry--the recording of exhaled volu against time during a maximal expiration (see Ch. 64). Normally, a full forced expiration takes between sec, but when airflow is obstructed, it takes up to 15 or even 20 sec and may be limited by breath-hold The normal forced expiratory volume in the first second of expiration (FEV1) is easily measured and ac predicted on the basis of age, sex, and height. The ratio of FEV1 to forced vital capacity (FEV1/FVC) n exceeds 0.75. Recording airflow against volume during forced expiration and a subsequent forced inspiration--the flow-volume loop--is also useful, mainly for distinguishing upper from lower airway narr
Some of the diseases that cause chronic airflow obstruction are listed in Table 68-1. Emphysema and bronchitis (discussed together under Chronic Obstructive Pulmonary Disease, below) and asthma acc > 95% of the morbidity and mortality from chronic airflow obstruction. Other causes include giant bulla asthmatic bronchitis, bronchiolitis, lymphangiomyomatosis, and diffuse panbronchiolitis.
Section 6. Pulmonary Disorders Chapter 78. Idiopathic Interstitial Lung Diseas Topics
[General] Idiopathic Pulmonary Fibrosis Desquamative Interstitial Pneumonia Acute Interstitial Pneumonia Respiratory Bronchiolitis-Associated Interstitial Lung Disease Idiopathic Bronchiolitis Obliterans With Organizing Pneumonia Lymphocytic Interstitial Pneumonitis Langerhans' Cell Granulomatosis Idiopathic Pulmonary Hemosiderosis
[General]
Idiopathic interstitial lung diseases: A group of diseases of unknown etiology with similar clinical featur producing diffuse pathologic changes primarily in interalveolar interstitial tissue.
Occupational and hypersensitivity diseases of the lungs, which are interstitial lung diseases, are discu Chs. 75 and 76; sarcoidosis is discussed in Ch. 288.
The chest x-ray may be normal in as many as 10% of patients with various interstitial lung diseases, e those with hypersensitivity pneumonitis. High-resolution CT (HRCT) is being increasingly used to evalu diffuse interstitial lung diseases. HRCT enhances pattern recognition in these diseases because it doe superimpose structures and is exposure-independent. HRCT is more accurate than conventional ches distinguishing airspace disease from interstitial lung diseases, and it facilitates earlier detection and confirmation of suspected diffuse lung disease, especially in a symptomatic patient with a normal ches HRCT provides better assessment of the extent and distribution of disease and is more likely to detect coexisting disease (eg, occult mediastinal adenopathy, carcinoma, emphysema).
In selected patients with interstitial lung diseases, analyzing cells obtained via bronchoalveolar lavage help narrow the differential diagnostic possibilities, define the stage of disease, and assess the progre disease or response to therapy. However, the usefulness of this procedure in the clinical assessment management of most patients with these diseases has not been established.

Section 6. Pulmonary Disorders Chapter 69. Acute Bronchitis Topics
[General]
[General]
Etiology
Acute bronchitis: Acute inflammation of the tracheobronchial tree, generally self-limited and with event complete healing and return of function.
Although commonly mild, acute bronchitis may be serious in debilitated patients and in patients with ch lung or heart disease. Airflow obstruction is a common consequence, and pneumonia is a critical comp Chronic bronchitis is discussed under Chronic Obstructive Pulmonary Disease in Ch. 68.
Acute infectious bronchitis, most prevalent in winter, is generally part of an acute URI. It may develo common cold or other viral infection of the nasopharynx, throat, or tracheobronchial tree, often with se bacterial infection. Viruses that cause acute bronchitis include adenovirus, coronavirus, influenza A an viruses, parainfluenza virus, respiratory syncytial virus, coxsackievirus A21, rhinovirus, and the viruses cause rubella and measles. Mycoplasma pneumoniae, Bordetella pertussis, and Chlamydia pneumon cause acute infectious bronchitis, often in young adults. Malnutrition and exposure to air pollutants are predisposing or contributory factors. Bronchitis often recurs in patients with chronic bronchopulmonary diseases that impair bronchial clearance mechanisms and may recur in those with chronic sinusitis, bronchiectasis, bronchopulmonary allergy, or COPD and in children with hypertrophied tonsils and ade
Acute irritative bronchitis may be caused by various mineral and vegetable dusts; fumes from strong ammonia, certain volatile organic solvents, chlorine, hydrogen sulfide, sulfur dioxide, or bromine; the environmental irritants ozone and nitrogen dioxide; and tobacco or other smoke.
Cough-variant asthma, in which the degree of bronchoconstriction is not sufficient to produce overt w may be caused by allergen inhalation in an atopic person or chronic exposure to an irritant in a person relatively mild airway hyperreactivity. Management is similar to that of ordinary asthma.
Pathology and Pathophysiology
Cough-variant asthma, in which the degree of bronchoconstriction is not sufficient to produce overt w may be caused by allergen inhalation in an atopic person or chronic exposure to an irritant in a person relatively mild airway hyperreactivity. Management is similar to that of ordinary asthma.
Hyperemia of the mucous membranes is the earliest change, followed by desquamation, edema, leuko infiltration of the submucosa, and production of sticky or mucopurulent exudate. The protective functio bronchial cilia, phagocytes, and lymphatics are disturbed, and bacteria may invade the normally sterile with consequent accumulation of cellular debris and mucopurulent exudate. Cough is essential to elim bronchial secretions. Airway obstruction may result from edema of the bronchial walls, retained secret and, in some cases, spasm of bronchial muscles.
Symptoms and Signs
Acute infectious bronchitis is often preceded by symptoms of an upper respiratory infection: coryza, m chilliness, slight fever, back and muscle pain, and sore throat. Onset of a distressing cough usually sig onset of bronchitis. The cough is initially dry and nonproductive, but small amounts of viscid sputum ar after a few hours or days; later, sputum may be more abundant and mucoid or mucopurulent. Frankly sputum suggests superimposed bacterial infection. Some patients have burning substernal chest pain is aggravated by coughing. In a severe uncomplicated case, fever of 38.3 to 38.8 C (101 to 102 F) m present for up to 3 to 5 days, after which acute symptoms subside (although cough may continue for s weeks). Persistent fever suggests complicating pneumonia. Dyspnea may occur secondary to airway obstruction.
Pulmonary signs are few in uncomplicated acute bronchitis. Scattered high- or low-pitched rhonchi ma heard as well as occasional crackling or moist rales at the bases. Wheezing, especially after cough, is common. Persistent localized signs noted during chest examination suggest development of bronchopneumonia. Serious complications usually occur only in patients with an underlying chronic respiratory disorder. In patients, acute bronchitis may lead to severe blood gas abnormalities (acute respiratory failure).
Diagnosis
Diagnosis is usually based on the symptoms and signs, but a chest x-ray to rule out other diseases or complications is indicated if symptoms are severe or prolonged. Arterial blood gases should be monito when serious underlying chronic respiratory disease is present. For patients who do not respond to an or who have special clinical circumstances (eg, immunosuppression), Gram stain and sputum culture s be performed to determine the causative organism.
Treatment
The patient should rest until fever subsides. Oral fluids (up to 3 or 4 L/day) are urged during the febrile An antipyretic analgesic (eg, for adults, aspirin 650 mg or acetaminophen 650 mg q 4 to 6 h; for childre acetaminophen 10 to 15 mg/kg q 4 to 6 h) relieves malaise and reduces fever. Symptomatic treatment of cough is discussed in Ch. 63.
Antibiotics are indicated when there is concomitant COPD (see Chronic Obstructive Pulmonary Diseas 68), when purulent sputum is present, or when high fever persists and the patient is more than mildly i
Symptomatic treatment of cough is discussed in Ch. 63.
Antibiotics are indicated when there is concomitant COPD (see Chronic Obstructive Pulmonary Diseas 68), when purulent sputum is present, or when high fever persists and the patient is more than mildly i most adults, oral tetracycline or ampicillin 250 mg q 6 h is a reasonable first choice; alternatively, trimethoprim-sulfamethoxazole 160/800 mg po bid may be given. Tetracycline should not be given to c < 8 yr old; instead, amoxicillin 40 mg/kg/day in divided doses tid can be given. When symptoms persis recur or when disease is unusually severe, smear and sputum cultures are indicated. The antibiotic is chosen according to the predominant organism and its sensitivity. If M. pneumoniae or C. pneumoniae thought to be the causative agent, erythromycin 250 to 500 mg po qid can be given. During an epidemic due to influenza A virus, treatment with rimantadine can be considered.
Section 6. Pulmonary Disorders Chapter 79. Pulmonary Alveolar Proteinosis Topics

[General]
[General]
Pulmonary alveolar proteinosis: A rare disease of unknown etiology characterized pathologically by fill alveolar spaces with granular, periodic acid-Schiff (PAS)-positive material consisting mostly of phosph and proteins.
Pulmonary alveolar proteinosis (PAP) occurs predominantly in previously healthy men and women wh usually 20 to 60 yr old. Occasionally, PAP has developed in patients after exposure to inorganic dusts silica, aluminum, titanium) and in patients with chronic infection due to Pneumocystis carinii, various hematologic malignancies, myeloproliferative diseases, or immunosuppression. The significance of the associations is unclear.
Pathologic findings are limited to the lungs. Typically, the alveolar lining and interstitial cells are norma alveoli are plugged with amorphous PAS-positive granules containing a variety of serum and nonserum proteins. The lipid concentration in the alveolar spaces is high, possibly because of abnormal clearanc alveolar phospholipids. Interstitial fibrosis occurs rarely. The pathologic process may be diffuse or loca affects the basal and posterior lung segments most commonly but occasionally affects only the anterio segments. The pleura and mediastinum are unaffected.
Symptoms and Signs
The natural history of PAP is unknown, and clinical findings vary greatly. The condition may progress, stable, or clear spontaneously. Some patients are asymptomatic; others have severe respiratory insuf Most patients present with gradually progressive exertional dyspnea and cough that is usually unprodu Those who smoke cigarettes usually produce sputum. Sputum characteristics are generally unhelpful. secondary pulmonary infections with nonbacterial organisms (eg, Nocardia, Mycobacteria, Aspergillus Cryptococcus sp) develop. Although the patient may present with or soon after a febrile illness, persist is rare unless secondary infection occurs. Extrapulmonary symptoms are unusual. Physical findings are limited to the lungs but may be absent despite diffuse parenchymal involvement on chest x-ray. Fine inspiratory crackles are usually heard over the affected lung areas.
Cryptococcus sp) develop. Although the patient may present with or soon after a febrile illness, persist is rare unless secondary infection occurs. Extrapulmonary symptoms are unusual. Physical findings are limited to the lungs but may be absent despite diffuse parenchymal involvement on chest x-ray. Fine inspiratory crackles are usually heard over the affected lung areas.
Diagnosis
Specific diagnosis requires a lung biopsy or bronchoscopy with segmental bronchoalveolar lavage. Th requires special staining techniques. Characteristic findings in tissue and lavage fluid are seen by light electron microscopy.
Typical laboratory abnormalities include polycythemia, hypergammaglobulinemia, and increased serum levels. Chest x-ray usually shows a butterfly pattern of opacities resembling that in pulmonary edema; heart appears normal. Hilar lymph nodes are not enlarged. High-resolution CT scanning shows ground opacification and thickened intralobular structures and interlobular septa in typical polygonal shapes, r to as crazy-paving.
Vital capacity, residual volume, functional residual capacity, total lung capacity, and carbon monoxide single-breath diffusing capacity are usually slightly reduced. Obstructive pulmonary disease is not a fe Hypoxemia may be present at rest or, if disease is mild, only with mild to moderate exercise. The Pa O breathing 100% O2 is usually low, indicating an intrapulmonary right-to-left shunt.
Disability from respiratory insufficiency is common, but death rarely occurs if those who need treatmen bronchopulmonary lavage receive it. Secondary infections should be promptly identified and treated.
Patients with minimal or no symptoms do not require treatment but should be observed for exacerbatio may lead to respiratory failure. Treatment is indicated only for patients with significant symptoms and hypoxemia. With the patient under general anesthesia, the lungs are usually lavaged one at a time wit days between lavages. The most effective treatment is whole-lung lavage via a double-lumen endotrac tube, with repeated cycles of filling and emptying of one lung, using 1 to 2 L of warmed 0.9% NaCl sol Some patients require only one lavage because symptoms and infiltrates never recur; others require la 6 to 12 mo for many years.
Many drugs, including potassium iodide and proteolytic enzymes (eg, trypsin and streptokinase-streptodornase), have been tried with varying success. Systemic corticosteroids have be unsuccessful and may increase the possibility of secondary infection. Any therapeutic regimen is diffic evaluate because spontaneous remissions occur and because the number of cases available for stud investigator is limited.

Section 6. Pulmonary Disorders Chapter 70. Bronchiectasis Topics
[General]
[General]
Bronchiectasis: Irreversible focal bronchial dilation, usually accompanied by chronic infection and asso with diverse conditions, some congenital or hereditary.
Bronchiectasis may be focal and limited to a single segment or lobe of the lung, or it may be widespre affect multiple lobes in one or both lungs.
Congenital bronchiectasis is a rare condition in which the lung periphery fails to develop, resulting in dilation of developed bronchi. Acquired bronchiectasis results from (1) direct bronchial wall destructi to infection, inhalation of noxious chemicals, immunologic reactions, or vascular abnormalities that inte with bronchial nutrition--or (2) mechanical alterations--due to atelectasis or loss of parenchymal volum increased traction on the walls of airways, leading to bronchial dilation and secondary infection. Bacte endotoxins and proteases; proteases derived from circulating or pulmonary inflammatory cells; supero radicals; and antigen-antibody complexes may mediate bronchial wall damage. Amounts of functionall neutrophil elastase, cathepsin G, and neutrophil matrix metalloproteinase MMP-8 found in bronchoalv lavage fluid increase with the severity of disease in moderate to severe bronchiectasis. Furthermore, t antiproteases 1-antitrypsin and antichymotrypsin may be proteolytically or oxidatively cleaved into lowe molecular weight forms, which provide less protection against enzymatic destruction of extracellular m Detection of proinflammatory cytokines interleukin-1 (IL-1), IL-8, and tumor necrosis factor-alpha in sp and demonstration of chemokine and cytokine bronchial cell interactions have led to the hypothesis th interactions may result in recruitment and activation of certain inflammatory cells, affect their survival, modulate ongoing inflammation, a cardinal feature of bronchiectasis. Nitric oxide, which affects the im response, cell signaling, and plasma exudation at inflammatory sites, may help perpetuate the inflamm response in bronchiectasis. Exhaled nitric oxide is increased in patients with bronchiectasis compared normal subjects and bronchiectatic patients taking inhaled corticosteroids.
Conditions commonly leading to bronchiectasis are severe pneumonia (especially when complicating m pertussis, or certain adenovirus infections in children); necrotizing pulmonary infections due to Klebsie staphylococci, influenza virus, fungi, mycobacteria, and, rarely, mycoplasmas; and bronchial obstructio
response in bronchiectasis. Exhaled nitric oxide is increased in patients with bronchiectasis compared normal subjects and bronchiectatic patients taking inhaled corticosteroids.
Conditions commonly leading to bronchiectasis are severe pneumonia (especially when complicating m pertussis, or certain adenovirus infections in children); necrotizing pulmonary infections due to Klebsie staphylococci, influenza virus, fungi, mycobacteria, and, rarely, mycoplasmas; and bronchial obstructio any cause (eg, foreign body, enlarged lymph nodes, mucus inspissation, lung cancer, or other lung tum Miscellaneous chronic fibrosing lung diseases (eg, those following aspiration pneumonia or inhalation injurious gases or particles--eg, silica, talc, or bakelite) also predispose to bronchiectasis. Immunologic deficiencies, including AIDS, and various other acquired, congenital, and hereditary abnormalities that host susceptibility to infection or impair respiratory defenses are less common but important predispos factors. Although incidence and mortality have decreased with the widespread use of antibiotics and immunizations in children, bronchiectasis as a manifestation of cystic fibrosis is still common (see Ch.
Bronchiectasis, along with situs inversus and sinusitis, is a feature of Kartagener's syndrome, a subg the primary ciliary dyskinesia (PCD) syndromes. In these syndromes, structural or functional abnorma ciliary organelles result in defective mucociliary clearance that leads to suppurative bronchial infection bronchiectasis as well as chronic rhinitis, serous otitis media, male sterility, corneal abnormalities, sinu headaches, and a poor sense of smell. Bronchiectasis can occur in patients with Young syndrome, w characterized by obstructive azoospermia, chronic sinopulmonary infections, normal spermatogenesis dilated epididymal head filled with spermatozoa, and amorphous material without spermatozoa in the r the corpus. Absent are the ciliary abnormalities seen in the PCD syndromes, the genetic and electroly abnormalities characteristic of cystic fibrosis, and the genetic mutations found in congenital absence o deferens, which accounts for about 6% of obstructive azoospermia.
An unusual pattern of bronchiectasis occurs in allergic bronchopulmonary mycosis (see Allergic Bronchopulmonary Aspergillosis in Ch. 76): The proximal bronchi are dilated rather than the medium-s subsegmental or peripheral bronchi as in idiopathic bronchiectasis. Bronchial wall damage is thought t to an immunologic response to a colonizing protease-producing fungus, most commonly Aspergillus fu permitting the organism to persist and inflammation and destruction to continue. The reported associa bronchiectasis with probable or possible autoimmune diseases, such as rheumatoid arthritis, Sjgren's syndrome, Hashimoto's thyroiditis, and ulcerative colitis, has not been satisfactorily explained.
Pathophysiology
Bronchiectasis may be unilateral or bilateral; it is most common in the lower lobes, although the right m lobe and lingular portion of the left upper lobe are often affected. The traditional classification as cylind varicose, or saccular is based on the pathologic and bronchographic appearance. However, these dist have little clinical value, and current pathologic correlations with high-resolution and helical CT charac are making this classification obsolete.
Pathologically, bronchial walls show extensive inflammatory destruction, chronic inflammation, increas mucus, and loss of cilia. Where adjacent interstitial and alveolar areas are destroyed, tissue reorganiz and fibrosis result in loss of volume. Bronchiectasis is generally associated with chronic bronchitis and emphysema and some fibrosis.
The extent and character of the pathologic changes determine the functional and hemodynamic abnor which often include reduced lung volumes and airflow rates, ventilation/perfusion defects, and hypoxe Extensive anastomoses between the bronchial and pulmonary arteries may occur, with marked enlarg bronchial arteries. Anastomoses between bronchial and pulmonary veins also enlarge. The resultant in blood flow, right-to-left shunts, and hypoxemia lead to pulmonary hypertension and cor pulmonale late disease.
which often include reduced lung volumes and airflow rates, ventilation/perfusion defects, and hypoxe Extensive anastomoses between the bronchial and pulmonary arteries may occur, with marked enlarg bronchial arteries. Anastomoses between bronchial and pulmonary veins also enlarge. The resultant in blood flow, right-to-left shunts, and hypoxemia lead to pulmonary hypertension and cor pulmonale late disease.
Symptoms and Signs
Bronchiectasis, which can develop at any age, begins most often in early childhood, but symptoms ma apparent until much later. Their severity and characteristics vary widely from patient to patient and from time in an individual, depending largely on the extent of the disease and the presence and extent of complicating chronic infection. Most patients have chronic cough and sputum production--the most characteristic and common symptoms--but occasionally, a patient is asymptomatic. These symptoms begin insidiously, usually after a respiratory infection, and tend to worsen gradually over a period of ye Severe pneumonia with incomplete clearing of symptoms and residual persistent cough and sputum production is a common mode of onset. As the condition progresses, the cough tends to become more productive. Typically, it occurs regularly in the morning on arising, late in the afternoon, and on retiring patients are relatively free of cough during the intervening hours. Sputum usually is similar to that of br and is not characteristic. Less commonly, in long-standing cases, sputum is abundant and may separa three layers: frothy at the top, greenish and turbid in the middle, and thick with pus at the bottom. Hem from erosion of capillaries, but sometimes from anastomoses between the bronchial and pulmonary ar systems, is common and may be the first and only complaint. Recurrent fever or pleuritic pain, with or visible pneumonia, is also common; investigation of such symptoms may lead to the diagnosis of bronchiectasis. Wheezing, shortness of breath and other manifestations of respiratory insufficiency, an pulmonale (see Ch. 203) may occur in advanced cases with associated chronic bronchitis and emphys
Physical findings are nonspecific, but persistent crackles over any part of the lungs suggest bronchiec Signs of airflow obstruction (decreased breath sounds, prolonged expiration, or wheezing) tend to be m pronounced in smokers than in nonsmokers. Finger clubbing sometimes occurs with extensive disease persistent chronic infection (see Fig. 63-1).
Diagnosis
Bronchiectasis must be suspected in anyone with the above symptoms and signs. Standard chest x-ra show increased bronchovascular markings from peribronchial fibrosis and intrabronchial secretions, cr from an atelectatic lung, tram lines (parallel lines outlining dilated bronchi due to peribronchial inflamm and fibrosis), areas of honeycombing, or cystic areas with or without fluid levels, but occasionally x-ray normal. High-resolution CT (HRCT) of the chest (1- to 2-mm cuts) has largely replaced bronchography 10-mm collimation, dilation of small bronchi may be missed, but the better resolution of HRCT provide comparable or preferable to bronchography. Its widespread use indicates that bronchiectasis is probab common than can be diagnosed by clinical findings and standard x-rays alone.
Characteristic CT findings are dilated airways, indicated by tram lines, by a signet ring appearance wit luminal diameter > 1.5 times that of the adjacent vessel in cross section, or by grapelike clusters in mo severely affected areas. These dilated medium-sized bronchi may extend almost to the pleura becaus destruction of lung parenchyma. Thickening of the bronchial walls, obstruction of airways (evidenced b opacification--eg, from a mucus plug--or by air trapping), and, sometimes, consolidation are other findi
Helical CT may be considered for surgical candidates because at least one study has shown it to be s to HRCT in identifying the extent of bronchiectasis and distribution within a given segment, but the add radiation exposure has prevented it from supplanting HRCT for general use. HRCT may be performed without contrast; the precise protocol is tailored to the patient's clinical situation. Excessive secretions in the bronchial tree or acute bronchopneumonia can lead to misinterpretation. The reversible dilation
Helical CT may be considered for surgical candidates because at least one study has shown it to be s to HRCT in identifying the extent of bronchiectasis and distribution within a given segment, but the add radiation exposure has prevented it from supplanting HRCT for general use. HRCT may be performed without contrast; the precise protocol is tailored to the patient's clinical situation. Excessive secretions in the bronchial tree or acute bronchopneumonia can lead to misinterpretation. The reversible dilation occurs with airspace consolidation (eg, pneumonia) should not be confused with true bronchiectasis. C bronchitis often accompanies and may mimic bronchiectasis, but recurrent hemoptysis, fever, and pleu pain and the x-ray abnormalities help distinguish bronchiectasis from chronic bronchitis alone. Mycoba and fungal infections should be ruled out, because they are treatable. Sputum cultures, bronchial was serologic studies for fungal antigen or antibodies, and even biopsy of appropriate tissue (but not highly vascular bronchiectatic airways) may be indicated. When CT reveals multiple small nodules with bronchiectasis in a nonimmunocompromised host without cystic fibrosis, Mycobacterium avium-intrace complex (MAIC) cultures are commonly positive, and in some patients, MAIC granulomas suggest dise rather than mere colonization.
When disease is unilateral or of recent onset, fiberoptic bronchoscopy is indicated to rule out tumor, fo body, or other localized endobronchial abnormality. HRCT is often performed first to provide maximum information to the bronchoscopist in advance, but bronchoscopy is usually still necessary for precise p diagnosis.
Associated conditions should be sought, particularly cystic fibrosis, immune deficiencies, and predispo congenital abnormalities. Such a search is most important in symptomatic younger patients and in pat with particularly severe or frequently recurring infections. Cystic fibrosis should be suspected if the abnormalities on x-ray occur predominantly in the apices or upper lobes. Pancreatic insufficiency is a f children but is not common in adults, in whom pulmonary manifestations predominate. Diagnosis of cy fibrosis is based on sweat test results (see Ch. 267). Genetic testing may be informative in fertile patie have unexplained bronchiectasis with normal pancreatic function and sweat electrolytes.
Young syndrome, more common than cystic fibrosis or PCD syndromes, should be suspected in men chronic recurrent sinopulmonary symptoms and infertility. Normal spermatozoa, testicular function, an test results distinguish it from typical cystic fibrosis or PCD syndromes. Some patients with vas defere abnormality have mutations in the cystic fibrosis gene, but such mutations have not yet been demonst those with Young syndrome.
PCD syndromes occur in 11% of children with chronic respiratory disease. Diagnosis is confirmed by examining the ultrastructure and function (motility, beat frequency) of nasal or other respiratory cilia, o via biopsy or brushing, and by measuring nasal ciliary clearance time--the time it takes for a patient to taste saccharin after it is instilled above the inferior turbinate of the nose (normal: 12 to 15 min). Interp ciliary abnormalities involves excluding nonspecific ciliary defects, which can be present in <= 10% of patients with acquired pulmonary disease and in healthy persons; recognizing that infection can cause transient dyskinesia; and being aware that ciliary characteristics of patients and healthy persons can o Ciliary ultrastructure may be normal in patients with PCD syndromes, perhaps because of biochemica molecular abnormalities that affect function but not ultrastructure.
Immunoglobulin (Ig) deficiencies may be identified by serum Ig measurements (see Chs. 146 and 147 serum protein electrophoresis detects low -globulin levels, serum IgG, IgA, and IgM should be measur when total levels of IgG or IgA are normal, some IgG subclass deficiencies have been associated with sinopulmonary infections; IgG subclasses should be measured in patients with unexplained bronchiec 1 -Antitrypsin (1-antiprotease inhibitor) deficiency, which is occasionally associated with bronchiectasis, suspected when 1 -globulin is low and may be confirmed by phenotyping with crossed immunoelectrop (see Chronic Obstructive Pulmonary Disease in Ch. 68). Congenital abnormalities of tracheal or bronchial cartilage and connective tissue are usually detected
1 -Antitrypsin (1-antiprotease
inhibitor) deficiency, which is occasionally associated with bronchiectasis, suspected when 1 -globulin is low and may be confirmed by phenotyping with crossed immunoelectrop (see Chronic Obstructive Pulmonary Disease in Ch. 68).
Congenital abnormalities of tracheal or bronchial cartilage and connective tissue are usually detected In tracheobronchomegaly (Mounier-Kuhn syndrome), the trachea is about twice as wide as normal. In Williams-Campbell syndrome, total or partial absence of cartilage beyond the main segmental bronchi produces wheezing and dyspnea early in infancy; bronchoscopy, CT, or newer imaging techniques ma inspiratory ballooning and expiratory collapse of the affected bronchi.
The yellow nail syndrome, believed to be due to a congenital hypoplasia of the lymphatic system, is re by thickened, curved, yellowish to greenish nails and primary lymphedema. Some patients have exuda pleural effusion and bronchiectasis.
Allergic bronchopulmonary aspergillosis may be suspected when there is a wheal and flare reaction to antigens, serum IgE is high, serum precipitins for Aspergillus fumigatus or another fungus are elevated the clinical picture suggests it. Blood and sputum eosinophilia are often present.
Prophylaxis
Awareness and early identification of conditions frequently associated with bronchiectasis may permit therapy that may prevent its development or reduce its severity. More than half the cases of pediatric bronchiectasis can be accurately diagnosed and promptly managed to lessen morbidity. When there is history of cystic fibrosis, prenatal diagnosis by DNA analysis to identify specific mutations may permit v early treatment and guide counseling.
Childhood immunization against pertussis and measles, widespread use of antibiotics, and improved l conditions and nutrition have helped reduce the prevalence, morbidity, and mortality of bronchiectasis Influenza vaccine yearly and pneumococcal vaccine one time (or repeated after 6 yr for persons at pa risk and likely to respond) may be helpful and are increasing in clinical importance. (See Ch. 152 and Childhood Immunizations in Ch. 256.) Early treatment of respiratory syncytial virus infection with ribavi aerosol and prompt treatment of pneumonia may lessen their damaging potential. Appropriate treatme pneumonia is based on the age of the patient, presence of comorbidities, severity of the infection, prob source, and likely pathogens (see Ch. 73).
Ig replacement in deficiency states, early detection and removal of foreign bodies and localized bronch obstructions, treatment of recurrent sinusitis (see also Ch. 86), and prevention and prompt treatment o conditions predisposing to aspiration of infected or toxic material (see Aspiration Pneumonia in Ch. 73 prevent repeated chest infections or damage that leads to bronchiectasis. Ig replacement, reported to the number and severity of chest infections in Ig deficiency states, may be especially beneficial in patie a documented impairment in antibody production after a specific challenge. Immune globulin is given I doses sufficient to maintain an infection-free state. IV immune globulin (IVIG) is also available. Trough serum IgG > 500 mg/dL are associated with fewer infections and better pulmonary function than are lo levels. IVIG may do more than passively supply antibody. It may neutralize some bacteria-derived toxi otherwise supplement host anti-inflammatory defenses. Dose and frequency must be tailored to the pa (For details of replacement therapy, see Primary and Secondary Immunodeficiencies in Ch. 147.)
Inhalation of noxious gases and particulates, including cigarette smoke, should be avoided or minimize using effective environmental controls or personal protective devices. When acute inhalation injury occ prompt treatment of complicating infection and judicious use of a corticosteroid may reduce inflammat damage. (See Diseases Due to Irritant Gases and Other Chemicals in Ch. 75.)
Treatment
Inhalation of noxious gases and particulates, including cigarette smoke, should be avoided or minimize using effective environmental controls or personal protective devices. When acute inhalation injury occ prompt treatment of complicating infection and judicious use of a corticosteroid may reduce inflammat damage. (See Diseases Due to Irritant Gases and Other Chemicals in Ch. 75.)
Treatment
Treatment is directed against infections, secretions, airway obstruction, and complications (eg, hemop hypoxemia, respiratory failure, cor pulmonale).
Treatment of infection includes antibiotics, bronchodilators, and physical therapy to promote bronchial drainage. Sputum usually contains gram-positive and gram-negative microorganisms (eg, Streptococc pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella [Branhamella] catarrhalis, Pseudomonas sp); anaerobes commonly inhabit bronchiectatic cysts. A broad-spectrum antibiotic (eg ampicillin 250 to 500 mg po q 6 h for adults or 50 to 100 mg/kg/day in divided doses q 6 to 8 h for child with a maximum dose of 2 to 3 g/day for large children; amoxicillin 250 to 500 mg po q 8 h for adults o mg/kg/day in divided doses for children; or, only for adults, tetracycline 250 to 500 mg po q 6 h) is ofte until the sputum is nonpurulent and less voluminous, about 1 to 2 wk. Trimethoprim-sulfamethoxazole (TMP-SMX) 320/1600 mg po q 12 h for 14 days can also reduce sputum volume and eliminate pathog children, TMP-SMX 6/30 to 12/60 mg/kg/day is given in divided doses q 12 h, depending on the size o child and severity of the infection. Tetracycline or trimethoprim can inhibit increased airway absorption sodium in vitro and might have a double benefit in a disease such as cystic fibrosis, in which enhanced absorption in the airways is believed to contribute to inspissated secretions. A newer macrolide, such a clarithromycin or azithromycin, or a 2nd-generation cephalosporin is another possible choice. Antibioti should be repeated at the first sign of recurring infection (eg, increased volume or purulence of sputum infection recurs often, prolonged chemoprophylaxis with ampicillin, amoxicillin, or tetracycline may be t is generally disappointing. In severe cases, high-dose amoxicillin (3 g po bid) is reported to achieve hig serum and sputum concentrations than do equal doses of ampicillin.
Prophylactic or suppressive antimicrobial regimens can reduce the bacterial load (associated with puru and destructive elastase activity in some), but there is no consensus about long-term continuous versu intermittent therapy or about specific regimens. With short-term therapy (1 to 2 wk), purulence and ela activity rapidly return to pretreatment levels. One goal is to prevent development of resistant microorga and conditions favoring Pseudomonas sp, which is particularly difficult to eradicate. Regimens include antibiotic for 7 to 10 days each mo, 7 to 10 days of treatment alternating with equal rest periods, contin long-term treatment with a reduced dose, or high doses of an antibiotic (such as amoxicillin) for 3 to 6 fluoroquinolone, such as ciprofloxacin 500 to 750 mg po bid, may be effective and can be given long-t resistance frequently develops after one or two treatment cycles. In severe cases, aerosol or IV regime be needed, but resistance is always a problem. Alternating drugs may help avoid early resistance and persistence of pneumococci, which tends to occur with ciprofloxacin.
For bronchopneumonia or serious respiratory infection, parenteral antibiotics--chosen on the basis of G stain, cultures, and sensitivity studies--are indicated. Cefuroxime 750 mg IV tid for 48 to 72 h followed cefuroxime axetil 500 mg po bid for 5 days is as effective as amoxicillin 1.2 g IV tid with clavulanic acid followed by amoxicillin 625 mg po tid. Amoxicillin penetrates lung secretions, especially in the presenc active inflammation, but some local inactivation may occur, correlating with -lactamase levels. For broa coverage to include Mycoplasma, Legionella, and Pseudomonas sp, a macrolide plus a 3rd-generation cephalosporin (such as ceftazidime or cefoperazone) plus an aminoglycoside can be used, or piperac azlocillin with an aminoglycoside can be used when Pseudomonas predominates. (See also Ch. 153.) Treatment of cystic fibrosis is discussed in Ch. 267.
When cultures for Mycobacterium tuberculosis are positive, appropriate antituberculosis treatment is r
cephalosporin (such as ceftazidime or cefoperazone) plus an aminoglycoside can be used, or piperac azlocillin with an aminoglycoside can be used when Pseudomonas predominates. (See also Ch. 153.) Treatment of cystic fibrosis is discussed in Ch. 267.
When cultures for Mycobacterium tuberculosis are positive, appropriate antituberculosis treatment is r based on the clinical history and laboratory findings, but MAIC commonly colonizes the lungs of patien bronchiectasis, so treatment is reserved for patients with strongly suspected or proven disease (see C An empirical multidrug regimen for MAIC may include clarithromycin 500 mg po bid, ethambutol 25 mg daily, clofazimine 200 mg po daily, and streptomycin 10 to 12 mg/kg/day IM or amikacin 12 to 15 mg/k three times a week for 1 to 2 mo, followed by clarithromycin 750 mg po daily, ethambutol 15 mg/kg po and clofazimine 50 to 100 mg po daily for 3 to 24 mo, usually given until cultures are negative for 12 m Basing therapy on drug susceptibility testing, however, is important.
Patients with bronchiectasis should avoid cigarette smoke and other irritants and refrain from using se or antitussives. Postural drainage, clapping, and vibration (see Postural Drainage in Ch. 65) performed regularly may facilitate sputum clearance in some patients.
Diffuse chronic bronchitis, often accompanying bronchiectasis, should be treated accordingly (see Chr Obstructive Pulmonary Disease in Ch. 68). 2-Agonists, theophylline, and corticosteroids may decrease obstruction, facilitate ciliary clearance, and reduce inflammation. If asthma or allergic bronchopulmona aspergillosis is also present, corticosteroids may be especially beneficial in reducing inflammation, and young children, who are most susceptible to fungal sensitization, they may enhance fungal elimination Itraconazole 200 to 400 mg/day po reduces the corticosteroid requirements, reduces serum IgE, and i airflow rates in a small number of patients with allergic bronchopulmonary aspergillosis, but antifungal are usually reserved for invasive Aspergillus infection.
Other drugs--such as the mucolytic N-acetylcysteine and recombinant human deoxyribonuclease (rhD which breaks down DNA in purulent sputum--may benefit selected patients but have no proven benefi bronchiectasis. NSAIDs, such as indomethacin, have been tried experimentally. Despite mild reduction sputum volume and changes in peripheral neutrophil function, sputum elastase and myeloperoxidase were not reduced, and viable bacterial load was not altered in bronchial secretions.
Chronic hypoxemia should be treated with O2 , particularly if the PaO2 in a stable patient is < 55 mm H room air or if there is evidence of pulmonary hypertension or secondary polycythemia. Respiratory fail cor pulmonale should be treated as in other patients with chronic obstructive airway disorders (see Ch Obstructive Pulmonary Disease in Ch. 68). Intubation and mechanical ventilation should, if possible, b avoided, because the ability to cough is lost and the risk of inadequately evacuating secretions by suc alone and of promoting further infection is enhanced. Lung transplantation can be performed in patien advanced cystic fibrosis and bronchiectasis. Double lung transplantation is usually the procedure of ch (see Ch. 149). For specific management of acute respiratory decompensation, see Ch. 66.
Surgical resection is rarely necessary but should be considered when conservative management yield recurrent pneumonia, disabling bronchial infections, or frequent hemoptysis and the disease is sufficie localized and stable. For massive pulmonary hemorrhage, emergency resection or embolization of the bleeding vessel (usually a bronchial artery) can be lifesaving.

Section 6. Pulmonary Disorders Chapter 80. Pleural Disorders Topics
[General] Pleurisy Pleural Effusion Pleural Fibrosis And Calcification Pneumothorax
[General]
(For tuberculosis, see Ch. 157.)

Section 6. Pulmonary Disorders Chapter 71. Atelectasis Topics
[General]
[General]
Atelectasis: A shrunken, airless state affecting all or part of a lung.
Atelectasis may be acute or chronic. In chronic atelectasis, the affected area is often composed of a c mixture of airlessness, infection, bronchiectasis, destruction, and fibrosis.
Etiology
In adults, the chief cause of acute or chronic atelectasis is intraluminal bronchial obstruction, often due plugs of tenacious bronchial exudate, endobronchial tumors, granulomas, or foreign bodies. Other cau include bronchial strictures, distortion, or kinking; external bronchial compression by enlarged lymph n tumor, or an aneurysm; external pulmonary compression by pleural fluid or gas (eg, due to pleural effu pneumothorax); and surfactant deficiency. Surfactant, a complex mixture of phospholipids and lipopro covers the surface of the alveoli, reduces surface tension, and contributes to alveolar stability. Damag surfactant-producing pneumonocytes, leakage of inhibitory plasma proteins, the presence of inflamma mediators, and possible incorporation of surfactant components into polymerizing fibrin (during hyaline membrane formation) may interfere with the production or effectiveness of surfactant. These factors m promote atelectasis in such diverse conditions as O2, drug, or chemical toxicity; pulmonary edema; the neonatal respiratory distress syndrome (see Ch. 67 and Respiratory Disorders in Ch. 260); pulmonary embolism (see Ch. 72); general anesthesia; and mechanical ventilation.
Acute massive atelectasis is usually a postoperative complication of upper abdominal procedures, lu resection, or heart operations with heart-lung bypass (endothelial cell damage by hypothermia and the intravascular cardioplegic solution may contribute to atelectasis). Large doses of opiates or sedatives, concentrations during anesthesia, tight dressings, abdominal distention, and immobility of the body als atelectasis because they can limit thoracic movement, elevate the diaphragm, cause viscid bronchial secretions to accumulate, and suppress the cough reflex. Shallow breathing, which interferes with cou effective clearance of secretions, may occur in CNS depressive disorders, thoracic cage abnormalities muscle spasm, and neuromuscular diseases. Blood hyperosmolality in diabetics with ketoacidosis ma contribute to atelectasis, presumably by increasing the viscosity of airway secretions with resultant mu plugging.
concentrations during anesthesia, tight dressings, abdominal distention, and immobility of the body als atelectasis because they can limit thoracic movement, elevate the diaphragm, cause viscid bronchial secretions to accumulate, and suppress the cough reflex. Shallow breathing, which interferes with cou effective clearance of secretions, may occur in CNS depressive disorders, thoracic cage abnormalities muscle spasm, and neuromuscular diseases. Blood hyperosmolality in diabetics with ketoacidosis ma contribute to atelectasis, presumably by increasing the viscosity of airway secretions with resultant mu plugging.
In the middle lobe syndrome (a form of chronic atelectasis), the middle lobe collapses, sometimes du external bronchial compression by surrounding lymph nodes or to endobronchial obstruction. However syndrome may occur without abnormal bronchoscopic findings; a relatively long, narrow bronchus in th middle lobe and ineffective collateral ventilation from neighboring areas may predispose to the atelecta Infection with partial bronchial obstruction may lead to chronic atelectasis and ultimately to chronic pneumonitis because of poor drainage.
Pathophysiology
After sudden bronchial obstruction, circulating alveolar capillary blood absorbs peripheral alveolar gas airlessness and lung retraction within a few hours; in the absence of infection, the lung may shrink or c completely. In the early stages, blood perfuses the airless lung, causing arterial hypoxemia. If capillary tissue hypoxia results in transudation of fluid and pulmonary edema, the alveolar spaces fill with secre and cells, preventing complete collapse of the atelectatic lung. Distention of the unaffected surroundin the lung may partially compensate for the volume loss. However, in cases of extensive collapse, the diaphragm may become elevated, the chest wall may flatten, and the heart and mediastinum may shif affected side.
Dyspnea results from a variety of stimuli affecting the respiratory centers and cerebral cortex. Stimuli m come from the chemoreceptors, when a large atelectatic area causes a considerable decrease in Pa O from lung and respiratory muscle receptors, when the lung loses air, becoming less compliant (stiffer) increasing the work of breathing. PaO2 often improves during and after the first 24 h, presumably as b to the atelectatic area decreases. PaCO2 is usually normal or low due to hyperventilation of the remain normal lung parenchyma.
If the obstruction is relieved, air enters, any complicating infection subsides, and the lung may eventua to normal, depending on the magnitude of the infection. If the obstruction remains and infection is pres lack of air and circulation initiates changes leading to fibrosis and bronchiectasis.
Even without obstruction, changes in alveolar surface tension, reduction in alveolar size, and changes airway-to-pleura pressure relationships can lead to inadequate regional ventilation and small areas of atelectasis or diffuse microatelectasis. Mild to severe disturbances in gas exchange may result. Accele atelectasis, occurring in military pilots, results from absorption of alveolar gas trapped when high acce forces close dependent airways and keep them closed.
Symptoms and Signs
Symptoms and signs depend on how rapidly the bronchus is occluded, how much of the lung is affecte whether infection is present. Rapid occlusion with massive collapse, particularly with infection, causes the affected side, sudden onset of dyspnea and cyanosis, a drop in BP, tachycardia, elevated tempera and sometimes shock. Chest percussion elicits dullness to flatness over the affected area, and auscul detects diminished or absent breath sounds. Chest wall excursion in the area is reduced or absent, an trachea and heart are deviated toward the affected side. Slowly developing atelectasis may be asymp or cause minor pulmonary symptoms.
whether infection is present. Rapid occlusion with massive collapse, particularly with infection, causes the affected side, sudden onset of dyspnea and cyanosis, a drop in BP, tachycardia, elevated tempera and sometimes shock. Chest percussion elicits dullness to flatness over the affected area, and auscul detects diminished or absent breath sounds. Chest wall excursion in the area is reduced or absent, an trachea and heart are deviated toward the affected side. Slowly developing atelectasis may be asymp or cause minor pulmonary symptoms.
The middle lobe syndrome is also often asymptomatic, although a severe, hacking, nonproductive co may result from irritation in the right lower and middle lobe bronchi. Acute pneumonia, usually with del incomplete resolution, may develop. Chest examination may reveal dullness and decreased or absent sounds over the right middle lobe, or it may be normal.
Diffuse microatelectasis, an early manifestation of O 2 toxicity and the adult and neonatal respiratory syndromes, produces dyspnea; rapid, shallow respirations; arterial hypoxemia; decreased lung compli and reduced lung volume. Auscultation of the lungs may be normal, or crackles, rhonchi, or wheezes m heard. Other manifestations depend on the cause of the acute lung injury and the severity of accompa hemodynamic and metabolic derangements and organ system failure.
Diagnosis
Diagnosis is usually made from clinical findings plus x-ray evidence of diminished lung size (indicated retracted ribs; elevated diaphragm; deviated trachea, heart, and mediastinum to the affected side; and overdistention of the unaffected lung) and of a solid, airless area. If only a segment is affected, the sha triangular, with its apex toward the hilum. When small areas are affected, surrounding tissue distention them to appear curiously discoid, particularly in subsegmental lower lobe atelectasis. An entire lobe m affected (lobar atelectasis). As the lobe loses air, the interlobar fissures become displaced, and the lob becomes more densely opacified as the bronchi, blood vessels, and lymphatics are crowded together. x-ray findings depend on which lobe is affected and how other structures compensate for volume loss. Posterior-anterior and lateral views aid in diagnosis.
The middle lobe syndrome is usually recognized by the characterisitic x-ray findings: on posterior-ante subtle obliteration of the right lateral heart border and, on lateral view, the triangular or rectangular sha running from the posterior cardiac border to the anterior chest wall.
The cause of an obstruction should always be sought regardless of the patient's age. With a fiberoptic bronchoscope, lobar as well as segmental and subsegmental divisions can be seen. Chest CT can he the mechanism of collapse; an experienced interpreter can distinguish among the causes of atelectas endobronchial obstruction, compression due to intrapleural fluid or air, and scars resulting from chroni inflammation.
Diffuse microatelectasis is usually not visible initially on x-rays. Subsequently, diffuse microatelectasis progresses to a patchy or diffuse reticular granular pattern, then to a pulmonary edema-like pattern, an to bilateral opacification in severe cases.
An unusual form of peripheral lobar collapse, rounded atelectasis (folded lung syndrome) is often mi for a tumor. Most commonly a complication of asbestos-induced pleural disease, it may also result from pleuropulmonary diseases. Its characteristic appearance on x-rays distinguishes it from a tumor: The l density is round and immediately subpleural, with an acute angle between it and the pleura, and it freq has a "comet tail" extending toward the hilum, thought to represent compressed vessels and bronchi t the atelectatic area. CT scan may improve the reliability of this diagnosis and in most cases obviates t for diagnostic thoracotomy. Needle biopsy is usually not helpful but can be performed when the distinc between rounded atelectasis and a subpleural tumor is less certain.
Massive effusion may also cause dyspnea, cyanosis, weakness, flatness to percussion over the affect
density is round and immediately subpleural, with an acute angle between it and the pleura, and it freq has a "comet tail" extending toward the hilum, thought to represent compressed vessels and bronchi t the atelectatic area. CT scan may improve the reliability of this diagnosis and in most cases obviates t for diagnostic thoracotomy. Needle biopsy is usually not helpful but can be performed when the distinc between rounded atelectasis and a subpleural tumor is less certain.
Massive effusion may also cause dyspnea, cyanosis, weakness, flatness to percussion over the affect and absent breath sounds, but the shifting of the heart and mediastinum away from the affected area absence of chest wall flattening distinguish it from massive atelectasis. Spontaneous pneumothorax p similar symptoms, but the percussion note is tympanitic, the heart and mediastinum are pushed to the side, and x-rays showing air in the pleural space are diagnostic.
Prophylaxis
Acute massive atelectasis may be avoidable. Because preexisting chronic bronchitis and heavy smo increase the risk of postoperative atelectasis, preoperative cessation of smoking and measures to imp bronchial toilet should be encouraged (see Chronic Obstructive Pulmonary Disease in Ch. 68 and Pulm Rehabilitation in Ch. 65). Long-acting anesthetics should be avoided and narcotics used judiciously af surgery because they depress the cough reflex. When anesthesia is ended, the lungs should be left fil an air-O2 mixture because poorly absorbed N2 improves alveolar stability. The patient must be turned and should be encouraged to cough and breathe deeply; early ambulation is important. A combined a is most effective: encouragement of coughing and deep breathing, use of nebulized bronchodilators a aerosols of water or saline to liquefy and facilitate removal of secretions, and tracheal suctioning as ne The value of mucolytics in preventing or treating atelectasis has not been proved. Intermittent positive breathing (IPPB) or incentive spirometry (which uses a simple device to encourage voluntary maximum sustained [3 to 5 sec] inspiratory maneuvers) with physical therapy (percussion, vibration, postural dra and deep breathing) may be useful. For maximal effectiveness, each modality must be used appropria conventional measures. Chest percussion in the postoperative patient may increase the risk of atelect increases pain and muscular splinting. Other preventive measures include positive end-expiratory pres (PEEP)--a system that maintains pressure in a range usually of 5 to 15 cm H2 O--in patients undergoin mechanical ventilation and continuous positive airway pressure (CPAP) administered by an occlusive mask or through the nose continuously or intermittently for 5 to 10 min q 1 to 2 h.
Patients who tend to hypoventilate or to have prolonged shallow breathing because of excessive seda thoracic cage abnormality, neuromuscular weakness or paralysis, or a CNS disorder and those who ar prolonged mechanical ventilation are at special risk for atelectasis.
Treatment
Acute atelectasis: The cause of acute atelectasis (including postoperative acute massive atelectasis) corrected. When mechanical obstruction is suspected, coughing, suctioning, or a 24-h trial of vigorous respiratory and physical therapy, including PEEP or CPAP, may provide relief. If these measures fail o the patient cannot cooperate with them, fiberoptic bronchoscopy should be performed (see Bronchosc Ch. 65). Once bronchial obstruction is confirmed, therapy is directed at the obstruction and at the infec usually present. Often, mucus plugs or inspissated secretions can be removed through the bronchosc the affected lung then reinflates; however, vigorous chest physical therapy and the other measures no above should be continued. If foreign body aspiration is suspected, bronchoscopy should be performe promptly; removal of the foreign body may require use of a rigid bronchoscope.
Patients with established atelectasis should lie with the affected side uppermost to promote drainage ( drainage), have appropriate physical therapy, and be encouraged to cough. Subsequently, they should encouraged to move from side to side and to breathe deeply. Frequent (q 1 to 2 h) supervised use of I an incentive spirometer may help ensure deep breaths.
promptly; removal of the foreign body may require use of a rigid bronchoscope.
Patients with established atelectasis should lie with the affected side uppermost to promote drainage ( drainage), have appropriate physical therapy, and be encouraged to cough. Subsequently, they should encouraged to move from side to side and to breathe deeply. Frequent (q 1 to 2 h) supervised use of I an incentive spirometer may help ensure deep breaths.
If atelectasis occurred outside the hospital and if infection is suspected, a broad-spectrum antibiotic (e ampicillin 500 mg po or 1 g parenterally q 6 h; for children, 50 to 100 mg/kg/day in divided doses q 6 to should be given empirically at the outset. A 2nd-generation cephalosporin, a newer macrolide (such as azithromycin or clarithromycin), or trimethoprim-sulfamethoxazole are also possible choices. Wheneve possible, seriously ill patients in the hospital should receive antimicrobial therapy based on the known institutional pathogens and their drug susceptibility profiles (see Ch. 153). Antibiotic dosage may need adjustment in the elderly and in patients with severe renal or hepatic impairment. If a specific pathogen subsequently isolated from sputum or bronchial secretions, the antibiotic should be modified according
Patients with recurrent atelectasis (eg, due to neuromuscular disease) may benefit from a trial of nas facial mask CPAP at 5 to 15 cm H2O or of PEEP if they are undergoing mechanical ventilation.
The cause of the lung injury should be corrected, oxygenation maintained, and the other pathophysiolo hemodynamic and metabolic derangements corrected, if possible. Depending on the severity of the atelectasis, treatment usually includes supplemental O 2 , CPAP, or mechanical ventilation with PEEP a with fluid and nutritional management and antibiotics. Treatment with pulmonary surfactants is lifesavi some newborns, and assessment of fetal lung maturity by measuring surfactants in amniotic fluid impr management of fetuses and newborns at risk.
Chronic atelectasis: The longer the lung remains unexpanded, the more likely the development of destructive, fibrotic, and bronchiectatic changes. Because infection usually accompanies secondary at regardless of the cause, a broad-spectrum antibiotic (ampicillin, tetracycline, or others based on Gram and culture results) should be given when sputum volume and purulence increase. Surgical resection atelectatic segment or lobe should be considered if the patient has had recurrent disabling respiratory infections or recurrent hemoptysis from the affected area. When a tumor causes the obstruction, its ce and extent and the patient's overall condition and pulmonary function determine whether the obstructio best be relieved by surgery, radiation therapy, or chemotherapy. In selected patients, laser therapy ma effectively reduce obstruction from an endobronchial lesion.

Section 6. Pulmonary Disorders Chapter 81. Tumors Of The Lung Topics
[General] Bronchogenic Carcinoma
[General]
Tumors of the lungs may be benign or malignant primary tumors or metastases from primary cancers other organs and tissues. Primary lung tumors include bronchogenic carcinoma (the most common typ lung cancer), bronchial carcinoid, and a number of rarer types.
Bronchial carcinoid (formerly called bronchial adenoma) may be benign or malignant and occurs equ both sexes. Its course is prolonged. The endobronchial portion of the tumor may obstruct the lumen of bronchi. Brisk bleeding from the overlying mucous membrane often occurs. Recurrent pneumonia with same lung zone and localized overlying pleural pain are common. Metastases are uncommon but may regional lymph nodes.
Less common primary lung tumors include chondromatous hamartoma (benign), solitary lymphoma, a sarcoma (malignant). The lungs are sometimes affected by multifocal lymphomas.
Metastases to the lungs are common from primary cancers of the breast, colon, prostate, kidney, thyr stomach, cervix, rectum, testis, and bone and from melanoma.

Section 6. Pulmonary Disorders Chapter 72. Pulmonary Embolism Topics
[General]
[General]
Pulmonary embolism: Sudden lodgment of a blood clot in a pulmonary artery with subsequent obstruc blood supply to the lung parenchyma.
The most common type of pulmonary embolus is a thrombus that usually has migrated from a leg or p vein. Most of those that cause serious hemodynamic disturbances form in an iliofemoral vein, either de by propagation from calf vein thrombi. Thromboemboli originate infrequently in the arm veins or in the cardiac chambers.
Once released into the venous circulation, thromboemboli are distributed to both lungs in about 65% o to the right lung in 25%, and to the left lung in 10%. Lower lobes are involved four times more often tha lobes. Most thromboemboli lodge in large or intermediate (elastic or muscular) pulmonary arteries; 35% fewer reach the smaller arteries.
Fat emboli, which can form after fractures, and amniotic fluid emboli are rarer causes. They obstruct p the pulmonary microcirculation (arterioles and capillaries rather than pulmonary arteries), which may in the adult respiratory distress syndrome (see Ch. 67). For discussions of air and gas emboli, see Chs. 285.
Acute pulmonary embolism (PE) is a dynamic process. Thrombi begin to lyse immediately after reachi lung. Usually, lysis is complete within several weeks in the absence of preexisting cardiopulmonary dis some instances, even large thrombi may lyse in a few days. The physiologic alterations lessen over ho days as pulmonary circulation improves. However, massive emboli may cause death within minutes or before infarction has time to develop. Infrequently, embolic events recur over a period of months or ye causing progressive pulmonary arterial obstruction with chronic pulmonary hypertension, increasing dy and cor pulmonale.
The pathogenesis of venous thrombosis is discussed in Ch. 212. The risk is increased in persons who certain hematologic disorders, those who are immobilized, and those who undergo hip surgery or knee
days as pulmonary circulation improves. However, massive emboli may cause death within minutes or before infarction has time to develop. Infrequently, embolic events recur over a period of months or ye causing progressive pulmonary arterial obstruction with chronic pulmonary hypertension, increasing dy and cor pulmonale.
The pathogenesis of venous thrombosis is discussed in Ch. 212. The risk is increased in persons who certain hematologic disorders, those who are immobilized, and those who undergo hip surgery or knee replacement. In many patients, no predisposing factor can be found.
Pathophysiology
The pathophysiologic changes that follow PE involve derangements in pulmonary hemodynamics, gas exchange, and mechanics. The change in cardiopulmonary function is proportional to the extent of ob which varies with the size and number of emboli obstructing the pulmonary arteries, and to the patient preembolic cardiopulmonary status. The resulting physiologic changes may include pulmonary hyperte with right ventricular failure and shock, dyspnea with tachypnea and hyperventilation, arterial hypoxem pulmonary infarction.
Pulmonary hypertension results from increased pulmonary vascular resistance. Consequently, the ri ventricle must generate higher pulmonary arterial pressure to maintain normal cardiac output. Althoug degree of pulmonary hypertension can occur after any PE, significant pulmonary hypertension (> 25 m mean pressure) usually occurs in a previously healthy lung only when > 30 to 50% of the pulmonary a tree is occluded. Pulmonary hypertension may be increased by preexisting cardiopulmonary disease ( stenosis or COPD). Pulmonary arterial systolic pressure may rise to 100 mm Hg with acute embolism reach only 70 to 80 mm Hg if significant tricuspid regurgitation develops. Higher pressures more comm occur in patients with preexisting cardiopulmonary disease than in those without.
The primary mechanism of increased resistance is obstruction of pulmonary arteries by thrombi, ie, a d in the total cross-sectional area of the pulmonary vascular bed. Pulmonary vasoconstriction appears to definite but secondary role. Vasoconstriction is partly mediated by hypoxemia, by serotonin release fro platelet aggregates on the thrombi, and possibly by other humoral substances, including prostaglandin
If pulmonary vascular resistance increases acutely to the extent that the right ventricle cannot generat sufficient pressure to maintain cardiac output, hypotension develops and central venous and right atria pressures increase. Cardiogenic shock occurs in persons without preexisting cardiopulmonary disease after massive PE involving at least 50% and usually 75% or more of the pulmonary vascular bed. With hypotension and shock, mean central venous pressure tends to fall.
Tachypnea, often with dyspnea, almost always occurs after a PE. It appears to be due to stimulation o juxtacapillary receptors in the alveolar capillary membrane by swelling of the alveolar interstitial space. stimulation increases reflex vagal afferent activity, which stimulates medullary respiratory neurons. Co alveolar hyperventilation is manifested by a lowered Pa CO2 .
After occlusion of the pulmonary artery, areas of the lung are ventilated but not perfused, resulting in w ventilation--the physiologic hallmark of PE--contributing further to the hyperventilatory state. Depletion of alveolar surfactant within hours after the embolic event results in diminished lung volume compliance. Reduced lung volume secondary to atelectasis or infarction after PE may be manifest on chest x-ray by diaphragmatic elevation.
Diminished lung volume and possibly lowered airway PCO2 may induce bronchoconstriction, leading to expiratory wheezing. Heparin appears to lessen bronchoconstriction, as evidenced by improved maxim expiratory flow rates. Changes in lung mechanics are usually transient, minor, and therefore unlikely to
compliance. Reduced lung volume secondary to atelectasis or infarction after PE may be manifest on chest x-ray by diaphragmatic elevation.
Diminished lung volume and possibly lowered airway PCO2 may induce bronchoconstriction, leading to expiratory wheezing. Heparin appears to lessen bronchoconstriction, as evidenced by improved maxim expiratory flow rates. Changes in lung mechanics are usually transient, minor, and therefore unlikely to important in the genesis of prolonged dyspnea. However, they probably contribute to the development arterial hypoxemia.
Arterial hypoxemia typically occurs with diminished arterial O2 saturation (SaO2 <= 94 to 85%), but S be normal. Hypoxemia is due to right-to-left shunting in areas of partial or complete atelectasis not affe embolization. Characteristically, atelectasis can be partially corrected by deep breathing, either volunta induced by a positive pressure ventilator.
Ventilation/perfusion (/) imbalance probably also contributes to hypoxemia. The mechanisms responsi the / imbalance and atelectasis are not fully defined. In massive PE, severe hypoxemia may result from atrial hypertension that causes right-to-left shunting of blood through a patent foramen ovale. Low ven tension may also contribute to development of arterial hypoxemia.
Pulmonary infarction (PI) is hemorrhagic consolidation (often followed by necrosis) of lung parenchy does not occur with most pulmonary emboli. When bronchial circulation is intact and normal, PI rarely develops (10% of cases). Collateral circulation from the bronchial artery probably keeps the lung tissue despite pulmonary artery blockage. However, patients with previously abnormal pulmonary circulation prone to develop PI. PI is sometimes due to thrombosis of the pulmonary arteries in situ, as may occu congenital heart disease associated with severe pulmonary hypertension or in hematologic disorders ( sickle cell disease). Infarcts may heal by absorption and fibrosis, leaving a linear scar, or may resorb completely, leaving normal lung tissue (incomplete infarction).
Symptoms and Signs
The clinical manifestations of PE are nonspecific and vary in frequency and intensity, depending on th of pulmonary vascular occlusion, preembolic cardiopulmonary function, and the development of PI. Sm thromboemboli may be asymptomatic.
The manifestations of PE usually develop abruptly in minutes; those of PI, over a period of hours. The last several days, depending on the rate of clot lysis and other factors, but usually decrease in intensit In patients with chronic, recurrent small emboli, the symptoms and signs of chronic cor pulmonale tend develop insidiously over weeks, months, or years.
Embolism without infarction causes breathlessness. Tachypnea is a consistent, often striking featur Anxiety and restlessness may be prominent.
Pulmonary hypertension, if severe, may cause dull substernal chest discomfort due to pulmonary ar distention or possibly myocardial ischemia. The pulmonary component of the second heart sound may increase, or the aortic and pulmonary components of the second heart sound may widen but with less widening during inspiration. If PE is massive, acute right ventricular dysfunction may result, with disten cervical veins and right ventricular heave and presystolic (S4) or protodiastolic (S 3 ) gallop, sometimes arterial hypotension and evidence of peripheral vasoconstriction. A significant number of patients may with light-headedness, syncope, seizures, and neurologic deficits, usually reflecting a transient fall in c output with secondary cerebral ischemia. Cyanosis usually occurs only in patients with massive PE. A embolus in the periphery of a lung may cause infarction without pulmonary hypertension.
Results of a lung examination are usually normal in the absence of PI. Wheezing is sometimes heard,
arterial hypotension and evidence of peripheral vasoconstriction. A significant number of patients may with light-headedness, syncope, seizures, and neurologic deficits, usually reflecting a transient fall in c output with secondary cerebral ischemia. Cyanosis usually occurs only in patients with massive PE. A embolus in the periphery of a lung may cause infarction without pulmonary hypertension.
Results of a lung examination are usually normal in the absence of PI. Wheezing is sometimes heard, particularly if underlying bronchopulmonary or cardiac disease is present.
Signs that may indicate PI include cough, hemoptysis, pleuritic chest pain, fever, evidence of pulmona consolidation or pleural fluid, and possibly a pleural friction rub.
Diagnosis and Differential Diagnosis
The diagnosis of PE with or without PI is often difficult to establish unless special procedures are used most important are radioisotope perfusion lung scans and pulmonary arteriography. Differential diagno patients with massive PE includes septic shock, acute MI, and cardiac tamponade. Without infarction, patient's symptoms and signs may be attributed to anxiety with hyperventilation because of the paucity objective pulmonary findings. When PI occurs, the differential diagnosis includes pneumonia, atelecta failure, and pericarditis. A systematic approach to definitive diagnosis is outlined below.
Without infarction, the chest x-ray may be normal, or diminished pulmonary vascular markings in the embolized area may be noted. With infarction, the x-ray frequently shows a peripheral infiltrative lesion involving the costophrenic angle, with elevation of the diaphragm and pleural fluid on the affected side of the pulmonary arteries in the hilar area, the superior vena cava, or the azygos vein signals pulmona hypertension and right ventricular strain. Because ECG changes are typically transient, serial tracings often helpful in diagnosing or excluding acute MI. Changes seen most often with PE include P pulmon bundle branch block, right axis deviation, and supraventricular arrhythmias.
Serum enzyme studies lack sensitivity and specificity and are rarely helpful in diagnosis. The triad of serum LDH and bilirubin and normal AST occurs in < 15% of patients with acute PE and PI. Elevated occur in as many as 85% of patients with PI but is nonspecific, occurring also in heart failure, shock, pregnancy, kidney or liver disease, anemia, pneumonia, and carcinoma and after surgical procedures. levels of fibrin split products, such as D-dimer, may rise after PE, whether PI occurs or not. Howeve specificity is low because false-positive results are common and levels are elevated in other conditions as the postoperative state. Extreme caution has been recommended in the use of D-dimer tests becau are limited. Some authorities suggest that when clinical suspicion is low, a normal D-dimer may increa likelihood that no thromboembolic disease is present.
Lung perfusion scans use IV injection of 20- to 50-m particles of biodegradable albumin labeled wit technetium 99m. These particles ultimately lodge in the small precapillary arterioles of both lungs. Nea 100% of the particles remain in the lungs, except when right-to-left shunting is present, either at the ca pulmonary level. Regional distribution of these particles is relatively homogeneous in healthy persons depends on the patient's position and pulmonary blood flow distribution at the time of injection. Visible is greatest at the base and gradually diminishes up to the apex, reflecting gravitational effects on perfu when the patient is sitting. Perfusion deficit, with reduced or absent radioactivity, may result from vasc obstruction, displacement of a lung by fluid, chest masses, any condition causing pulmonary arterial o hypertension, or loss of lung parenchyma, as in pulmonary emphysema. Basal perfusion deficits, in wh radioactivity is not concentrated at the lung's base, may develop without PE; they may be caused by a process leading to increased pulmonary venous pressure (eg, heart failure, mitral valve disease, or veno-occlusive disease), which can redistribute pulmonary blood flow.
A normal scan excludes life-threatening PE with a high degree of accuracy. Conversely, single or mult wedge-shaped marginal scan defects, especially in a segmental or lobar distribution, are highly sugge
radioactivity is not concentrated at the lung's base, may develop without PE; they may be caused by a process leading to increased pulmonary venous pressure (eg, heart failure, mitral valve disease, or veno-occlusive disease), which can redistribute pulmonary blood flow.
A normal scan excludes life-threatening PE with a high degree of accuracy. Conversely, single or mult wedge-shaped marginal scan defects, especially in a segmental or lobar distribution, are highly sugge vascular obstruction. Acute airway disease, including asthma, or COPD may produce a pattern of foca perfusion deficits, but these deficits are typically accompanied by a corresponding lung ventilation defe usually found with PE.
When differentiation between PE and COPD is difficult, the xenon-133 lung ventilation scan may be Inhaled radioactive gas distributes with the respiratory air. In acute PE with large perfusion defects, thi usually shows relatively normal ventilation of affected areas, but with / mismatches. Areas of parenchy disease (eg, lobar pneumonia) usually have abnormalities of both perfusion and ventilation (a matched with delayed ventilation and trapping of radioactive gas. Matched / defects may also occur with pulmon edema. Sometimes, matched / defects occur with PE as well, particularly if scanning is performed > 24 the event.
Results of scintigraphy are commonly reported as indicating various degrees of probability for PE and interpreted cautiously. If lung scans are entirely normal, the diagnosis of PE is virtually ruled out; if the categorized as highly probable, the positive predictive value approaches 90%. However, although virtu patients with PE have abnormal scans, < 50% are placed in a high probability category. Clinical asses helps determine whether pulmonary arteriography is indicated.
Pulmonary arteriography demonstrates emboli and is the most definitive diagnostic test. It should be performed if the diagnosis is uncertain and the need to make the diagnosis with certainty appears urge two primary diagnostic criteria of PE are intra-arterial filling defects and complete obstruction (abrupt c pulmonary arterial branches. Other frequent but less conclusive findings include partial obstruction of pulmonary arterial branches with increased caliber proximal to and decreased caliber distal to the narr oligemic zones, and persistence of dye in the proximal portion of the artery during the late (venous) ph the arteriogram. In lung segments with obstructed arteries, venous filling with contrast medium is delay absent.
Additional diagnostic studies to establish the presence or absence of iliofemoral venous thrombotic may be useful, particularly when signs of recurrent embolization despite anticoagulant therapy or contraindications to anticoagulant therapy make inferior vena caval interruption (see below) an importa therapeutic consideration. For discussions of duplex ultrasonography, plethysmography, and venograp Diagnosis under Venous Thrombosis in Ch. 212.
Prognosis
Mortality after the initial thromboembolic event varies with the extent of PE and the patient's preexistin cardiopulmonary status. The likelihood that a patient with markedly compromised cardiopulmonary fun die after significant PE is high (probably > 25%). However, a patient with normal cardiopulmonary statu unlikely to die unless the occlusion exceeds 50% of the pulmonary vascular bed. When the initial emb event is fatal, death often occurs within 1 to 2 h.
The likelihood of a recurrent embolus in an untreated patient is about 50%, and as many as half of the recurrences may be fatal. Anticoagulant therapy reduces the rate of recurrence to about 5%; only abo of these will be fatal.
Prophylaxis
The likelihood of a recurrent embolus in an untreated patient is about 50%, and as many as half of the recurrences may be fatal. Anticoagulant therapy reduces the rate of recurrence to about 5%; only abo of these will be fatal.
Prophylaxis
In view of the limitations of treatment, prophylaxis is very important. The choice and intensity of prophy measures are determined by clinical factors that predispose to venous stasis and thromboembolism (s Table 72-1).
Prophylactic regimens for venous thromboembolism include low-dose unfractionated heparin (LDUH), molecular weight heparin (LMWH), dextran infusion, warfarin, intermittent pneumatic compression (IPC graded compression elastic stockings. Aspirin does not help prevent venous thromboembolism in gen surgical patients.
Low-dose heparin (LDUH, LMWH) is effective in reducing the incidence of deep vein (calf) thrombos and PE in patients who undergo a variety of elective major surgical procedures. At a blood level of abo that required to prevent thrombus propagation, heparin activates antithrombin III sufficiently to inhibit f which is required to convert prothrombin to thrombin at an early stage in the coagulation sequence. Th prevents the initiation of clot formation but is ineffective once factor Xa has been activated and the pro has started.
Both LDUH and LMWH are administered sc, and laboratory monitoring is not required. Although placebo-controlled randomized trials demonstrate no significant increase in major bleeding, the inciden wound hematomas is increased with both these drugs. LDUH is usually given 2 h preoperatively (5000 and q 8 or 12 h thereafter for 7 to 10 days or until the patient is fully ambulatory. Of the LMWH prepara dalteparin (anti-Factor Xa IU) may be given 2500 U once daily, and enoxaparin is usually given 30 mg
Adjusted-dose warfarin is effective in preventing DVT. Warfarin may be given as a fixed low dose of 2 or as a dose adjusted to mildly prolong the prothrombin time (INR 1.5 to 2.0).
IPC devices provide rhythmic external compression to the legs or legs and thighs. Their effectiveness approximately equivalent to that of LDUH in reducing the incidence of DVT in general surgery but is inadequate for hip or knee surgery.
Graded elastic stockings reduce the incidence of DVT, but the protective effect on proximal DVT an uncertain. However, combining stockings with other prophylactic measures may give better protection venous thromboembolism than any one approach alone.
Special considerations regarding prophylaxis are relevant for certain conditions with a high incidence o venous thromboembolism, such as hip fracture and lower extremity orthopedic surgery (see Table 72LDUH and aspirin are inadequate for hip fracture surgery or hip replacement; LMWH or adjusted-dose is recommended. For total knee replacement, risk reductions provided by LMWH and IPC are compar the combination should be considered for patients with concomitant clinical risk factors. The regimens orthopedic surgery may be initiated preoperatively and should be continued for at least 7 to 10 days postoperatively. In selected patients at very high risk for both venous thromboembolism and bleeding, vena caval interruption with placement of a filter is a prophylactic option.
A high incidence of venous thromboembolism is also associated with elective neurosurgery, acute spin injury, and multiple trauma. Although physical methods (IPC, elastic stockings) have been used in neurosurgical patients because of concern about intracranial bleeding, LMWH appears to be an accep alternative. The combination of IPC and LMWH may be more effective than either alone in high-risk pa Limited data support the combination of IPC, elastic stockings, and LMWH in spinal cord injury or mult
A high incidence of venous thromboembolism is also associated with elective neurosurgery, acute spin injury, and multiple trauma. Although physical methods (IPC, elastic stockings) have been used in neurosurgical patients because of concern about intracranial bleeding, LMWH appears to be an accep alternative. The combination of IPC and LMWH may be more effective than either alone in high-risk pa Limited data support the combination of IPC, elastic stockings, and LMWH in spinal cord injury or mult trauma. For very high risk patients, inferior vena caval interruption may be necessary.
The most common medical conditions in which prophylaxis is indicated are MI and ischemic stroke. Fo patients, LDUH is effective, and IPC and/or elastic stockings may be used when anticoagulants are contraindicated. LDUH or LMWH can be used in patients with stroke; IPC and/or elastic stockings may beneficial.
Recommendations for some other medical conditions include LDUH for patients with heart failure; adjusted-dose warfarin (INR 1.3 to 1.9) for those with metastatic breast cancer; and warfarin 1 mg/day cancer patients with an indwelling central venous catheter.
Treatment
Initial thromboembolic event: Treatment is supportive. Analgesics are given if pleuritic pain is severe Although anxiety is often prominent, sedatives, especially barbiturates, should be prescribed cautiousl therapy is indicated when appreciable arterial hypoxemia (PaO2 < 60 to 65 mm Hg) is present, particul cardiac output is reduced. Continuous O2 should be given, usually by mask or cannula, in a concentra sufficient to raise PaO2 and Sa O2 to normal levels (85 to 95 mm Hg and 95 to 98%, respectively) or to normal as possible (Pa O2 >= 60 mm Hg, Sa O2 > 90%).
In patients with clinical findings suggestive of pulmonary hypertension and acute cor pulmonale, partic pending diagnostic procedures (eg, lung scanning or arteriography), -adrenergic stimulation may help tissue perfusion because of its effects as a pulmonary vasodilator and cardiotonic. Isoproterenol 2 to 4 5% D/W may be infused at a rate sufficient to maintain systolic BP at 90 to 100 mm Hg under continuo monitoring. Dopamine and norepinephrine have also been used successfully to treat hypotension com PE; norepinephrine is preferred when cardiac output is very low. Appropriate drugs may be useful in a and preventing supraventricular tachyarrhythmias (see Regular Narrow QRS Tachycardias in Ch. 205) Digitalis should be avoided during acute hypoxemia unless absolutely necessary (eg, for serious arrhy heart failure). When digitalis is given IV, a modest initial dose is usually desirable (digoxin 0.25 to 0.5 m Response to therapy in patients suspected of having hemodynamic impairment with acute cor pulmon be monitored by serial measurement of arterial blood gases and hemodynamic parameters. A flow-dir balloon (Swan-Ganz) catheter can be used to determine pulmonary artery and wedge pressures, mixe venous blood O2 saturation and/or content, and cardiac output by the thermodilution technique.
After massive PE: Treatment after massive PE, particularly with hypotension, or after submassive PE hypotension in patients who have preexisting cardiopulmonary disease may involve thrombolytic thera pulmonary embolectomy.
Thrombolytic therapy is now an alternative to embolectomy when massive PE is uncomplicated by hypotension or when systolic BP can be maintained at 90 to 100 mm Hg with moderate dosage of a vasopressor. Streptokinase, urokinase, and tissue plasminogen activator (TPA) enhance the conversio plasminogen to plasmin, the active fibrinolytic enzyme. Contraindications to thrombolytic therapy includ intracranial disease, stroke within 2 mo, active bleeding from any source, preexisting hemorrhagic diat in impairment of hepatic or renal function), pregnancy, severe or accelerated hypertension (diastolic p > 110 mm Hg), and surgery within the preceding 10 days, which is a major limitation to thrombolytic th
hypotension or when systolic BP can be maintained at 90 to 100 mm Hg with moderate dosage of a vasopressor. Streptokinase, urokinase, and tissue plasminogen activator (TPA) enhance the conversio plasminogen to plasmin, the active fibrinolytic enzyme. Contraindications to thrombolytic therapy includ intracranial disease, stroke within 2 mo, active bleeding from any source, preexisting hemorrhagic diat in impairment of hepatic or renal function), pregnancy, severe or accelerated hypertension (diastolic p > 110 mm Hg), and surgery within the preceding 10 days, which is a major limitation to thrombolytic th
If the patient has been receiving heparin, the partial thromboplastin time should be permitted to fall to the control before initiating fibrinolytic therapy. Premedication with hydrocortisone sodium succinate 10 and reinjection q 12 h minimize allergic and pyrogenic reactions to streptokinase. After baseline determ of fibrinogen level or thrombin time, streptokinase 250,000 U is given IV over 30 min, followed by cont infusion of 100,000 U/h for 24 h. After 3 to 4 h, the fibrinogen level should be about the control, and ac partial thromboplastin time (APTT), thrombin time, or euglobulin lysis time should be prolonged, indica fibrinolysis. If no change occurs, the patient is resistant to streptokinase and may be given alternative thrombolytic therapy. A priming dose of urokinase 4400 U/kg is given IV over a 10-min period, followed 4400 U/kg/h for 12 h. Most of the recent experience involves TPA. TPA may be given IV 50 mg/h for 2 repeat pulmonary angiogram shows no evidence of clot lysis and no bleeding complications preclude f therapy, an additional 40 mg may be given over the next 4 h (10 mg/h). After infusion of a thrombolytic the APTT should be allowed to fall to 1.5 to 2.5 times the baseline value before initiation of a sustainin infusion of heparin without a loading dose.
All patients undergoing thrombolytic therapy have an increased risk of bleeding, particularly from recen operative wounds, needle puncture sites, sites of invasive procedures, and the GI tract. Thus, invasive procedures should be avoided. Pressure dressings are usually required to stop oozing; serious or cata bleeding requires stopping the thrombolytic drug and administering cryoprecipitate or fresh frozen plas addition, aminocaproic acid 5 g IV immediately and 1 g/h thereafter for 6 to 8 h or until the bleeding sto reverse the fibrinolytic state.
Pulmonary embolectomy should be considered when systolic BP is <= 90 mm Hg, urine output is <= mL/h, and PaO2 is <= 60 mm Hg for as long as 1 h after massive PE. Angiographic confirmation of PE strongly advised before embolectomy; inferior vena caval interruption and IV heparin therapy generally the embolectomy. In the event of cardiac arrest after massive PE, the usual resuscitative measures ar ineffective because blood flow through the lungs is obstructed. In this setting, emergency partial (femo venoarterial) bypass, pending pulmonary embolectomy, may be lifesaving.
Partial interruption of the inferior vena cava by a filter should be considered in certain situations: w anticoagulation is contraindicated, when emboli recur despite adequate anticoagulation, for septic pelv thrombophlebitis with emboli only when antibiotics and heparin fail, and when pulmonary embolectomy performed. The filter is placed via catheterization of the internal jugular or femoral veins. The optimum for the filter is just below the entry of the renal veins. Patients who have had vena caval filter placemen require anticoagulation for at least 6 mo after the procedure for treatment of underlying DVT.
Preventing further thrombus formation and embolization: After initial treatment, prevention becom focus. Heparin may be given IV q 4 to 6 h or by continuous IV drip with an infusion pump. However, a hemorrhagic disorder or an active bleeding site is an absolute contraindication to heparin therapy; sep embolization is usually a contraindication. Hemorrhagic complications are reduced by continuous infus which obviates the peaks and troughs of blood levels that occur with intermittent injection.
After a rapid IV loading dose of heparin 100 U/kg, heparin is given at a rate to keep the APTT at 1.5 to control. Achieving a therapeutic APTT in the first 24 h is critical, because failure to do so is associated high rate of recurrent venous thromboembolism. APTT may be checked q 4 h after treatment is initiate additional bolus dosing may be used to achieve an adequate APTT, followed by adjustment of the infu (see Table 72-3). The maintenance dose by continuous infusion is usually 10 to 50 U/kg/h; once a the level is established, APTT needs to be measured only 1 or 2 times/day.
After a rapid IV loading dose of heparin 100 U/kg, heparin is given at a rate to keep the APTT at 1.5 to control. Achieving a therapeutic APTT in the first 24 h is critical, because failure to do so is associated high rate of recurrent venous thromboembolism. APTT may be checked q 4 h after treatment is initiate additional bolus dosing may be used to achieve an adequate APTT, followed by adjustment of the infu (see Table 72-3). The maintenance dose by continuous infusion is usually 10 to 50 U/kg/h; once a the level is established, APTT needs to be measured only 1 or 2 times/day.
Oral warfarin sodium may be initiated on the first day of heparin therapy. Warfarin and heparin should for 5 to 7 days, allowing warfarin to take effect, until the INR is in the therapeutic range for two consec days. Warfarin sodium 10 mg may be given the first day, with the daily dosage adjusted thereafter to k INR at 2.0 to 3.0. The elderly tend to be highly sensitive to warfarin.
The duration of anticoagulant therapy is adjusted individually. In patients with a definable, reversible c the postoperative state), anticoagulation may be discontinued after 2 to 3 mo. Otherwise, it may be co empirically for 3 to 6 mo. A patient with a chronic disorder associated with a high incidence of thromboembolism may need long-term or lifelong anticoagulant therapy.
Complications of anticoagulant therapy: Patients treated with anticoagulants are prone to bleeding complications, some of which may be severe. Periodic platelet counts (in patients taking heparin--see Heparin-Induced Thrombocytopenia in Ch. 133), together with hematocrits and tests for occult blood in are recommended. Patients taking anticoagulants should not be given any drug containing aspirin or o NSAIDs, which can further impair hemostatic mechanisms. Many other drugs, by a variety of mechani also cause potentially clinically significant drug-drug interactions with oral anticoagulants, enhancing o decreasing their effects. For example, drugs that decrease intestinal synthesis of vitamin K or interfere other components of normal hemostasis, drugs that interfere with absorption or protein binding, and d increase or decrease hepatic metabolism can modify the pharmacokinetics and pharmacodynamics of warfarin. The direction and extent of effects of these interactions are not completely predictable, but vi and more frequent determinations of prothrombin time are indicated when any drug is added or delete the regimen of a patient stabilized on an oral anticoagulant. Furthermore, patients should be warned n take OTC drugs or drugs prescribed by other physicians without first informing their primary care phys
Other complications of anticoagulant therapy include minor bleeding (ecchymoses at the site of injectio microscopic hematuria, bleeding from gums), which can usually be controlled by withholding the next scheduled dose of heparin and reducing subsequent doses. If major bleeding occurs, protamine sulfat protein that combines with heparin to form an inactive complex, should be used to neutralize the antico effect of heparin. Fifty milligrams (5 mL) diluted with 20 mL of 0.9% sodium chloride solution and injec over a 10-min period (Caution: Rapid injection may cause hypotension, dyspnea, and bradycardia) ne about 5000 U of heparin and usually suffices to counteract overheparinization. Giving > 100 mg of pro over a short time is unwise because of its anticoagulant effect. The therapeutic effect of protamine ma evaluated by the APTT. Transfusion therapy may be required for major blood losses but does not redu anticoagulant effect of overheparinization. Long-term therapy with heparin leads to osteoporosis and hypoaldosteronism, which causes potassium retention. Uncommon side effects include thrombocytope occasionally with severe thromboembolic shock (see Heparin-Induced Thrombocytopenia in Ch. 133); and anaphylactic shock.
As with heparin, the major complication of warfarin therapy is bleeding. Withholding the drug or adjust dosage usually controls minor bleeding. For major hemorrhage, 5 to 25 mg (rarely, up to 50 mg) of pa vitamin K may be given. In emergency situations of severe hemorrhage, clotting factors may be norma giving 200 to 500 mL of fresh whole blood or fresh frozen plasma or by giving factor IX complex paren Purified factor IX preparations should not be used because they do not increase levels of prothrombin VII, or factor X.

Section 18. Gynecology And Obstetrics Chapter 234. Reproductive Endocrinology Topics
[General]
[General]
Normal reproductive function depends on complex hormonal communication between endocrine and t organs. Normal function is essential to sexual development at puberty and to the cyclic processes of o and menstruation.
The hypothalamus secretes a small peptide, gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, which regulates release of the gonadotropins luteinizing horm and follicle-stimulating hormone (FSH) from the anterior pituitary gland (see Fig. 234-1 and Chs. 6 and and FSH promote maturation of ova and stimulate secretion of estrogen and progesterone from the ov
Estrogen and progesterone are polycyclic compounds (with carbon atoms arranged in four rings) deriv cholesterol. They circulate in the bloodstream almost entirely bound to plasma proteins. Only unbound estrogen and progesterone appear to be biologically active. They stimulate the target organs of the reproductive system (ie, breasts, uterus, and vagina) and exert negative and positive feedback effects CNS-hypothalamic-pituitary unit, inhibiting and stimulating gonadotropin secretion.
Virtually all hormones are released in short bursts or pulses at intervals of 1 to 3 h, so descriptions of h patterns are idealized representations. This factor must be considered when interpreting single hormo values.
Hormone Secretion: Infancy Through Pube

LH and FSH are elevated at birth but fall to low levels within a few months and remain low throughout prepubertal years, with FSH generally slightly higher than LH (see Fig. 234-2).
The adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate begin to increase several before puberty. These increases may be important in initiating pubic and axillary hair growth (ie, adren and other pubertal events. Because ACTH and cortisol do not increase at this time, an unidentified pit peptide may initiate adrenal androgen secretion.
The adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate begin to increase several before puberty. These increases may be important in initiating pubic and axillary hair growth (ie, adren and other pubertal events. Because ACTH and cortisol do not increase at this time, an unidentified pit peptide may initiate adrenal androgen secretion.
The mechanisms initiating puberty are unclear. Central influences may inhibit the pulsatile release of G during childhood, then initiate its release to induce puberty early in adolescence.
Early in puberty, a decreased sensitivity of the hypothalamus to sex hormones results in increased sec LH and FSH, which stimulate production of sex hormones (primarily estrogen) and development of sec sexual characteristics. Secretion of LH and FSH increases only during sleep at first, then throughout th period. Patterns of increased basal LH and FSH levels are different for boys and girls, but in both, LH increases more than FSH.
Puberty
The sequence of events by which a child reaches sexual maturity and growth.
Physical changes of puberty occur sequentially during adolescence. Breast budding in girls is usually t noticeable change, followed closely by the appearance of pubic and axillary hair (see Fig. 234-3). Men female's first menstrual period) occurs about 2 yr after breast budding. The pubertal growth spurt typic begins before breast budding but is seldom recognized. Girls reach peak height velocity early in puber before menarche; growth potential is limited after menarche. Habitus changes, and the percentage of increases.
The age at which puberty begins varies, apparently influenced by general health, nutrition, socioecono conditions, and genetic factors. In industrialized nations, the age of onset has decreased consistently; Western Europe, the age at menarche decreased by 4 mo for each decade between 1850 and 1950 b not decreased in the last 4 decades. Moderate obesity is associated with earlier menarche, and mena commonly delayed in severely underweight and malnourished girls. Such observations suggest that a body weight is necessary for menarche. Puberty also occurs early among girls living in urban areas, bl and girls whose mothers matured early.
Ovarian Follicular Development
By the 6th wk of fetal development, primordial germ cells (oogonia) have migrated by ameboid movem their site of origin in the yolk sac to the genital ridges (presumptive ovaries). Oogonia proliferate marke mitosis through the 4th mo, after which most undergo atresia. During the 3rd mo, some cells begin to d meiosis rather than mitosis, and by the 7th mo, all viable cells are arrested in the diplotene stage of m prophase; these cells are primary oocytes. Between 7 and 9 mo, the fetal ovary is organized, and eac becomes a part of a primordial follicle, which consists of a basement membrane, a single layer of squa epithelial granulosa cells, and one oocyte. Primordial follicles constitute the resting follicle pool and are initiated into a growing pool (from which all mature follicles develop) or undergo atresia. The mechanis initiate follicular and oocyte growth are unclear but do not require gonadotropins.
The human female is born with a limited number of ova, 99.9% of which will be eliminated by atresia. B each oocyte remains arrested in meiotic prophase until it is ovulated, it is one of the longest-lived cells body (from embryo to about 50 yr). The long life span may account for the increased incidence of gen abnormal pregnancies among older mothers.
initiate follicular and oocyte growth are unclear but do not require gonadotropins.
The human female is born with a limited number of ova, 99.9% of which will be eliminated by atresia. B each oocyte remains arrested in meiotic prophase until it is ovulated, it is one of the longest-lived cells body (from embryo to about 50 yr). The long life span may account for the increased incidence of gen abnormal pregnancies among older mothers.
During a woman's reproductive years, several follicles in the growing pool are recruited each cycle, an one is usually selected for ovulation (see Fig. 234-4). It develops into a graafian (preovulatory) follicle, can respond to the midcycle LH surge. The mechanism of selection is unknown.
The graafian follicle contains an antrum (fluid-filled cavity), created by proliferating granulosa cells, wh secrete fluid and mucopolysaccharides. The increase in the follicle's size is due primarily to accumulat follicular fluid under the control of FSH, which also induces the development of specific LH receptors o granulosa cells. LH receptors are responsible for the stimulation of progesterone secretion before ovu and for continued production of progesterone in the luteal phase. The granulosa cells in the follicle als develop specific membrane receptors for prolactin, which decrease in number as the follicle matures; physiologic role is unclear.
Menstrual Cycle
Menstruation is the cyclic, approximately monthly vaginal discharging of sloughed endometrium that o throughout a woman's reproductive life; the bloody discharge is called menses or menstrual flow.
The first day of menses is day 1 of a menstrual cycle. The average duration of menses is 5 ( 2) days. median menstrual cycle length is 28 days, but only 10 to 15% of cycles are exactly 28 days long; the n range for an ovulatory cycle is about 25 to 36 days. Generally, variation is maximal and intermenstrual are longest in the years immediately after menarche and before menopause, when anovulatory cycles more common. Blood loss per cycle averages 130 mL (range, 13 to 300 mL) and is usually greatest on day. A saturated pad or tampon absorbs 20 to 30 mL. Menstrual blood does not usually clot (unless bl very heavy), probably because of fibrinolysin and other factors inhibiting clotting.
The menstrual cycle can be divided into three phases on the basis of endocrine events (see Fig. 234-5 follicular (preovulatory) phase extends from the first day of menses to the day before the preovulato surge; its length is the most variable of the phases. During the first half of this phase, FSH secretion is increased slightly, stimulating growth of a cohort of 3 to 30 follicles that have been recruited for accele growth during the last days of the preceding cycle. As FSH levels decline, one of the recruited follicles selected for ovulation; it matures, and the others undergo atresia. Circulating LH levels rise slowly, beg to 2 days after the increase in FSH. Estrogen and progesterone secretion by the ovaries is relatively c and remains low early in this phase.
About 7 to 8 days before the LH surge, ovarian secretion of estrogen, particularly of estradiol, by the s follicle increases slowly at first, then accelerates, generally peaking on the day before the LH surge. Th estrogen is accompanied by a slow but steady increase in LH and a decrease in FSH levels. LH and F levels may diverge because FSH secretion is preferentially inhibited by estrogens (compared with LH secretion) and is specifically inhibited by inhibin. Just before the LH surge, progesterone levels also be increase significantly.
In the ovulatory phase, a series of complex endocrine events culminates in the LH surge--the massiv preovulatory release of LH by the pituitary gland. The LH surge results in part from positive estrogen fe A smaller increase in FSH secretion occurs simultaneously, but its significance is not understood. As L increase, estradiol levels decrease, but progesterone levels continue to increase. The LH surge typica 36 to 48 h and consists of multiple large bursts of LH released in pulses. The LH surge, which results
In the ovulatory phase, a series of complex endocrine events culminates in the LH surge--the massiv preovulatory release of LH by the pituitary gland. The LH surge results in part from positive estrogen fe A smaller increase in FSH secretion occurs simultaneously, but its significance is not understood. As L increase, estradiol levels decrease, but progesterone levels continue to increase. The LH surge typica 36 to 48 h and consists of multiple large bursts of LH released in pulses. The LH surge, which results complete maturation of the follicle, is necessary for ovulation--release of the ovum from the mature gra follicle--which usually occurs 16 to 32 h after onset of the surge. The mechanism of ovulation is unclea
During the LH surge, the follicle swells and bulges above the ovarian epithelium. A stigma, or avascula appears on the follicle's surface. A small vesicle forms on the stigma, then breaks, and the cumulus m oocyte and some surrounding granulosa cells) is extruded. Prostaglandin production by the follicle, pe regulated by LH and/or FSH, appears essential for ovulation. Proteolytic enzymes in granulosa cells a epithelial cells overlying the preovulatory follicle, local growth factors, and cytokines may be important. oocyte remains arrested in meiotic prophase until after the LH surge. Within 36 h of the LH surge, the completes the first meiotic division, when each cell receives 23 chromosomes of the original 46 and th polar body is extruded. The 2nd meiotic division, when each chromosome divides longitudinally with id pairs, is not completed and the 2nd polar body is not extruded unless the egg is penetrated by a spermatozoon.
In the luteal (postovulatory) phase, the granulosa and theca cells, which make up the follicle, reorga form the corpus luteum (yellow body), for which the phase is named. The length of this phase is the m constant, averaging 14 days in nonpregnant women and ending with day 1 of menses. The length corr to the functional life span of the corpus luteum, which secretes progesterone and estradiol for about 1 then degenerates unless pregnancy ensues. The corpus luteum supports the implantation of the fertili ovum by secreting progesterone in increasing quantities, peaking at about 25 mg/day 6 to 8 days after surge. Because progesterone is thermogenic, basal body temperature increases by 0.5 C (0.9 F) du luteal phase and remains elevated until menstruation. Regulation of the life span of the corpus luteum understood, but prostaglandins and insulin-like growth factor II may be involved.
If fertilization occurs, human chorionic gonadotropin (hCG) from the fertilized ovum supports the corpu until the fetoplacental unit can support itself endocrinologically. hCG is structurally and functionally sim LH; however, pregnancy tests typically use antibodies that are specific to the subunit of hCG and that little if any cross-reactivity with LH.
During most of the luteal phase, circulating LH and FSH levels decrease and are low, but they begin to increase with menstruation (next cycle).
Cyclic Changes in Other Reproductive Organs
Endometrium: Cyclic changes in the endometrium culminate in menstrual bleeding. The endometrium consists of glands and stroma, has three layers: the basal layer, the intermediate spongiosa layer, and superficial layer of compact epithelial cells that line the uterine cavity. The basal layer is not sloughed menses and regenerates the other two layers, which are sloughed. Histologic changes during the men cycle are characteristic, and endometrial biopsies may be used to accurately determine the stage of th and assess tissue response to gonadal steroids.
Early in the follicular phase, the endometrium is thin (about 2 mm), with narrow, straight glands lined w columnar epithelium. The stroma is dense. As estradiol levels increase late in the follicular phase, the endometrium grows rapidly and progressively with extensive mitoses (ie, regeneration from the basal l
menses and regenerates the other two layers, which are sloughed. Histologic changes during the men cycle are characteristic, and endometrial biopsies may be used to accurately determine the stage of th and assess tissue response to gonadal steroids.
Early in the follicular phase, the endometrium is thin (about 2 mm), with narrow, straight glands lined w columnar epithelium. The stroma is dense. As estradiol levels increase late in the follicular phase, the endometrium grows rapidly and progressively with extensive mitoses (ie, regeneration from the basal l 11 mm, the mucosa thickens, and the tubular glands lengthen more, becoming coiled. The endometriu be seen using transvaginal ultrasonography; it characteristically has a trilaminar pattern in this phase, ovulation, it is homogeneous.
During the luteal phase, the tubular glands, under the influence of progesterone, dilate, fill with glycoge become secretory, and stromal vascularity increases. As estradiol and progesterone levels decrease l luteal phase, the stroma becomes edematous, necrosis of the endometrium and its blood vessels occ endometrial bleeding ensues.
Cervix: Vascularity, congestion, edema, and mucus secretion increase progressively during the follicu phase. The external os opens to 3 mm at ovulation, then decreases to 1 mm. Increasing levels of estr lead to a 10- to 30-fold increase in the quantity of cervical mucus. The characteristics of cervical mucu clinically useful in evaluating the stage of the cycle and hormonal status of a patient. Mucus elasticity (spinnbarkeit) increases, as does ferning (palm leaf arborization of mucus dried on a glass slide and e microscopically), which becomes prominent just before ovulation. Ferning indicates increased NaCl in mucus, an effect of estrogen. During the luteal phase, progesterone causes the cervical mucus to thic become less watery, and lose its elasticity and ability to fern.
Vagina: Proliferation and maturation of the vaginal epithelium are influenced by estrogen and progest When ovarian estrogen secretion is low early in the follicular phase, the vaginal epithelium is thin and estrogen levels increase during the follicular phase, squamous cells mature and become cornified so t epithelium thickens. During the luteal phase, the number of precornified intermediate cells increases, a number of leukocytes and amount of debris increase as mature squamous cells are shed. Changes in vaginal epithelium can be quantitated histologically and can be used as a qualitative index of estrogen stimulation.
Neuroendocrine Regulation of the Menstru Cycle
The pulsatile secretion of LH and FSH is determined by the pulsatile secretion of GnRH. The frequenc amplitude of the LH and FSH pulses are modulated by ovarian hormones and vary throughout the me cycle. No separate releasing hormone for FSH has been identified. Evidence suggests that the same c sometimes contain LH and FSH, so differential release of LH and FSH must result from interactions of factors (eg, GnRH, estradiol, inhibin). Also, the disparate half-lives of LH (20 to 30 min) and FSH (2 to affect circulating levels.
Of ovarian hormones, estradiol-17 is the most potent inhibitor of gonadotropin secretion, acting on the hypothalamus and the pituitary gland. Inhibin, a peptide hormone produced by ovarian granulosa cells specifically suppresses FSH release. Removal of the ovaries results in a rapid increase in circulating L FSH levels; administration of estradiol to hypoestrogenic women results in a prompt decrease in these However, for ovulation to occur, estradiol must exert a positive effect on gonadotropin secretion. The f effects of estradiol appear to be time- and dose-dependent. Early in the follicular phase, the gonadotro the anterior pituitary have relatively small amounts of LH and FSH available for release from the anter pituitary gland. Levels of estradiol (produced by the selected follicle) increase, stimulating LH and FSH synthesis but inhibiting their secretion. At midcycle, high estradiol levels exert a positive feedback effe
specifically suppresses FSH release. Removal of the ovaries results in a rapid increase in circulating L FSH levels; administration of estradiol to hypoestrogenic women results in a prompt decrease in these However, for ovulation to occur, estradiol must exert a positive effect on gonadotropin secretion. The f effects of estradiol appear to be time- and dose-dependent. Early in the follicular phase, the gonadotro the anterior pituitary have relatively small amounts of LH and FSH available for release from the anter pituitary gland. Levels of estradiol (produced by the selected follicle) increase, stimulating LH and FSH synthesis but inhibiting their secretion. At midcycle, high estradiol levels exert a positive feedback effe with GnRH and low but increasing quantities of circulating progesterone, induce the LH surge. Whethe pulsatile release of GnRH is increased at midcycle is unknown; the midcycle surge could result from a increase in the number of GnRH receptors (stimulated by estrogen) on the pituitary gonadotrophs.
Menopause, when cyclic ovarian function manifested by menstruation ceases, is discussed in Ch. 236

Section 18. Gynecology And Obstetrics Chapter 245. Infertility Topics
[General] Sperm Disorders Ovulatory Dysfunction Tubal Dysfunction Abnormal Cervical Mucus Unexplained Infertility Assisted Reproductive Techniques
[General]
Infertility: Inability of a couple to conceive after 1 yr of unprotected intercourse.
Infertility affects about 1 in 5 couples in the USA; its increasing incidence partly reflects deferment of m and of birth of the first child. Etiologic factors are sperm disorders (35% of couples), ovulatory dysfunc (20%), tubal dysfunction (30%), abnormal cervical mucus (5%), and unidentified factors (10%).
Diagnosis and treatment require thorough assessment of both partners; the extent and course of treat should be individualized (eg, more rapid if the woman is > 35 yr old). Failure to conceive often generat frustration, emotional stress, feelings of inadequacy, anger, guilt, and resentment. The financial burde time commitment for diagnostic and therapeutic infertility procedures can cause marital strife. Consequ counseling and psychologic support are important adjuncts to treatment. Support groups for infertile co (eg, RESOLVE) have been organized at local and national levels. Despite all efforts, some couples do achieve pregnancy. They should be counseled about when to stop treatments and when to consider a
Section 18. Gynecology And Obstetrics Chapter 235. Menstrual Abnormalities And Abnorma Bleeding Topics
Premenstrual Syndrome Primary Dysmenorrhea Secondary Dysmenorrhea Amenorrhea Abnormal Uterine Bleeding
Premenstrual Syndrome
(Premenstrual Tension)
A condition characterized by nervousness, irritability, emotional instability, anxiety, depression, and po headaches, edema, and mastalgia, occurring during the 7 to 10 days before and usually disappearing hours after onset of menses.
Etiology
Premenstrual syndrome (PMS) appears to be related to fluctuations in estrogen and progesterone. Es and progesterone may cause transitory fluid retention, which seems to explain some PMS symptoms. data suggest that women with PMS metabolize progesterone differently, producing less allopregnanolo neurosteroid that enhances GABAA receptor function in the brain and that has anxiolytic effects). Prod pregnenolone, which has an opposite effect in the brain, may be increased.
Symptoms and Signs
The type and intensity of symptoms vary from woman to woman and from cycle to cycle. In many, sym are significant but brief and not disabling; in others, normal functioning is disturbed. Symptoms last a f to >= 10 days, usually ceasing when menses begins; however, in perimenopausal women, symptoms persist through and after menses. When menses begins, some women develop dysmenorrhea. Signif dysmenorrhea is more common among teenagers and tends to diminish with age.
The most common complaints are mood alteration and psychologic effects--irritability, nervousness, la control, agitation, anger, insomnia, difficulty in concentrating, lethargy, depression, and severe fatigue retention causes edema, transient weight gain, oliguria, and breast fullness and pain. Neurologic and v symptoms include headache, vertigo, syncope, paresthesias of the extremities, easy bruising, and car
dysmenorrhea is more common among teenagers and tends to diminish with age.
The most common complaints are mood alteration and psychologic effects--irritability, nervousness, la control, agitation, anger, insomnia, difficulty in concentrating, lethargy, depression, and severe fatigue retention causes edema, transient weight gain, oliguria, and breast fullness and pain. Neurologic and v symptoms include headache, vertigo, syncope, paresthesias of the extremities, easy bruising, and car palpitation. Epilepsy may be aggravated. GI symptoms include constipation, nausea, vomiting, and ch appetite. Pelvic heaviness or pressure and backache may occur. Acne, neurodermatitis, and aggravat other skin disorders may also occur. Respiratory problems (eg, allergies, infection) and eye complaints visual disturbance, conjunctivitis) may worsen.
Treatment
Treatment involves relief of symptoms. Fluid retention may be relieved by reducing sodium intake and diuretic (eg, hydrochlorothiazide 25 to 50 mg/day po), starting just before symptoms are expected. Diu promote sodium and water excretion but do not relieve all symptoms and may have no effect. Counse help the woman and her partner cope with PMS, and the woman's activities can be modified to reduce For some women, hormonal manipulation is effective. Regimens include oral contraceptives; progeste vaginal suppository (200 to 400 mg/day) or by injection (5 to 10 mg IM in oil) for 10 to 12 days premen a long-acting progestin (eg, medroxyprogesterone acetate 200 mg IM q 2 to 3 mo); or a gonadotropin-releasing hormone agonist (eg, leuprolide 3.75 mg IM or goserelin 3.6 mg IM monthly) w low-dose estrogen-progestin "add-back" therapy to eliminate cyclic changes. Tranquilizers (eg, a benzodiazepine) may be used for irritability, nervousness, and lack of control, especially if patients can their stressful environments. Changing the diet (eg, increasing protein, decreasing sugars) and supple with vitamin B complex (especially pyridoxine, sometimes with magnesium) may help. Spironolactone, bromocriptine, and monoamine oxidase inhibitors are not beneficial. Selective serotonin reuptake inhib (eg, fluoxetine 20 mg po daily, sertraline 50 mg po daily) are the most effective drugs in the managem psychologic and physical PMS symptoms.

Section 18. Gynecology And Obstetrics Chapter 246. Family Planning Topics
[General] Contraception Sterilization Induced Abortion
[General]
One or both members of a couple can use contraception to prevent pregnancy temporarily or sterilizat prevent pregnancy permanently. Induced abortion (elective termination of pregnancy) can be used wh contraception fails. The couple's decision to begin, prevent, or interrupt a pregnancy may be influence prenatal diagnosis or genetic counseling (see Chs. 247 and 286). Infertility is discussed in Ch. 245.

Section 18. Gynecology And Obstetrics Chapter 236. Menopause Topics
[General]
[General]
Menopause: Physiologic cessation of menses due to decreasing ovarian function.
Usually, frequency in bleeding decreases (oligomenorrhea), followed by complete amenorrhea; howev many women, bleeding is more frequent, heavier, or prolonged before the onset of oligomenorrhea. M cycles may vary in length. Menopause is established when menses have not occurred for a year. (Any bleeding in a woman who has not bled for >= 6 mo must be investigated.) Menopause may be natural artificial, or premature.
Menopause occurs naturally at an average age of 50 to 51 yr in the USA. As ovaries age, response to gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) decreases, initially res shorter follicular phases (thus, shorter menstrual cycles), fewer ovulations, decreased progesterone production, and more irregularity in cycles. Eventually, the follicle fails to respond and does not produc estrogen. Without estrogen feedback, circulating levels of LH and FSH rise substantially. Circulating le estrogens and progesterone are markedly reduced. The androgen androstenedione is reduced by half testosterone decreases only slightly because the stroma of the postmenopausal ovary continues to se substantial amounts (as does the adrenal gland). Androgens are converted to estrogens in the periphe especially in fat cells and skin, accounting for most of the circulating estrogen in postmenopausal wom transitional phase, during which a woman passes out of the reproductive stage, begins before menopa termed the climacteric or perimenopause, although many persons refer to it as menopause.
Premature menopause refers to ovarian failure of unknown cause that occurs before age 40. It may associated with smoking, living at high altitude, or poor nutritional status. Artificial menopause may r from oophorectomy, chemotherapy, radiation of the pelvis, or any process that impairs ovarian blood s
Symptoms and Signs
Symptoms of the climacteric range from nonexistent to severe. Hot flushes (flashes) and sweating sec to vasomotor instability affect 75% of women. Most have hot flushes for > 1 yr, and 25 to 50% for > 5 y woman feels warm or hot and may perspire, sometimes profusely. The skin, especially of the head an becomes red and warm. The flush, which may last from 30 sec to 5 min, may be followed by chills. Va
Symptoms and Signs
Symptoms of the climacteric range from nonexistent to severe. Hot flushes (flashes) and sweating sec to vasomotor instability affect 75% of women. Most have hot flushes for > 1 yr, and 25 to 50% for > 5 y woman feels warm or hot and may perspire, sometimes profusely. The skin, especially of the head an becomes red and warm. The flush, which may last from 30 sec to 5 min, may be followed by chills. Va symptoms of the hot flush coincide with the onset of LH pulses, but not every increase in LH is associa a hot flush, suggesting that hypothalamic control of LH pulses is independent of that of flushes. This independence is confirmed by the occurrence of hot flushes in women who have had pituitary failure a not secrete LH and FSH.
Psychologic and emotional symptoms--including fatigue, irritability, insomnia, inability to concentrate, depression, memory loss, headache, anxiety, and nervousness--may be related to estrogen deprivatio the stress of aging and changing roles. Sleep disruption by recurrent hot flushes contributes to fatigue irritability. Intermittent dizziness, paresthesias, palpitations, and tachycardia may occur. Nausea, cons diarrhea, arthralgia, myalgia, cold hands and feet, and weight gain are also common.
The large reduction in estrogen leads to profound changes in the lower genital tract; eg, the vaginal m and vulvar skin become thinner, the normal bacterial flora changes, and the labia minora, clitoris, uteru ovaries decrease in size. Inflammation of the vaginal mucosa (atrophic vaginitis) can cause the mucos have a strawberry appearance and can lead to urinary frequency and urgency, vaginal dryness, and dyspareunia. Women tend to lose pelvic muscle tone and to develop urinary incontinence, cystitis, and vaginitis. Complaints of decreased libido are common.
Cardiovascular disease, including stroke, becomes more prevalent after menopause. Estrogen repla therapy should be considered because women who take it have a 50% decrease in risk of heart disea
Osteoporosis is another major health hazard related to menopause (see Ch. 57). At highest risk are s (small-boned), white women; heavy alcohol drinkers; smokers; women taking corticosteroids; those ta levothyroxine; and those who are sedentary. Bone mass losses average 1 to 2%/yr after menopause; rapid loss occurs during the first 2 yr of estrogen deficiency. About 25% of postmenopausal women ha severe osteoporosis, and 50% of women not taking estrogen will fracture bones during their lifetime.
Menopause is usually obvious. In younger patients, the diagnosis is substantiated by elevated serum l FSH. Endocrine disorders, such as thyroid disease and diabetes mellitus, should be ruled out.
Discussing the physiologic causes of menopause and the concerns, fears, and stresses related to this of life with the patient is important. When psychologic symptoms dominate, psychotherapy is indicated antidepressants and mild sedatives may be appropriate.
Estrogen replacement therapy relieves hot flushes and other symptoms and decreases the risk of oste and heart disease. However, in women who have a uterus, unopposed estrogen therapy increases the developing endometrial cancer (which is almost always heralded by vaginal bleeding, thus providing th opportunity for surgical cure in almost all cases--see Ch. 241). Combined therapy with estrogen and p which decreases this risk, is the appropriate treatment for women with a uterus. Women who have had hysterectomy can be given estrogen alone because they have no risk of developing endometrial cance dose of estrogen is increased or decreased, according to the symptoms. There is evidence relating es use to breast cancer, but it is inconclusive. Most evidence suggests that if estrogen increases the risk cancer, it does so in small, undefined groups of women. Low doses are safest. The physician should d the risks and benefits of therapy with the patient, and if therapy is chosen, a complete physical examin mammogram, and Papanicolaou test should be performed before therapy is started. Monitoring with re
which decreases this risk, is the appropriate treatment for women with a uterus. Women who have had hysterectomy can be given estrogen alone because they have no risk of developing endometrial cance dose of estrogen is increased or decreased, according to the symptoms. There is evidence relating es use to breast cancer, but it is inconclusive. Most evidence suggests that if estrogen increases the risk cancer, it does so in small, undefined groups of women. Low doses are safest. The physician should d the risks and benefits of therapy with the patient, and if therapy is chosen, a complete physical examin mammogram, and Papanicolaou test should be performed before therapy is started. Monitoring with re physical examinations and annual mammograms is necessary regardless of whether hormone replace therapy is used.
Use of oral or vaginal estrogen can reverse symptomatic vaginal atrophy, vaginitis, atrophy of the lowe tract (especially of the urethra and trigone of the bladder), urinary frequency, dysuria, and sometimes incontinence.
Estrogen is usually given continuously. Estrogen (conjugated equine estrogen 0.3 to 1.25 mg/day, mic estradiol 0.05 to 2 mg/day, estropipate 0.625 to 2.5 mg/day, or esterified estrogens 0.3 to 2.5 mg/day) orally once a day every day of the month, or transdermal estradiol 0.0375 to 0.1 mg is used. The dose increased as symptoms warrant. If the patient has a uterus, a progestin (eg, medroxyprogesterone ace mg or norethindrone acetate 2.5 to 5 mg po) is given with the estrogen every day. A combination table conjugated equine estrogen and medroxyprogesterone is available for cyclic or continuous therapy.
Irregular bleeding may occur during the first year of continuous therapy, but bleeding eventually ends. endometrial biopsy is indicated during the first year of therapy if irregular heavy bleeding occurs; contin bleeding after 1 yr warrants biopsy, but biopsy has a very low yield in otherwise asymptomatic women narrow or stenotic cervical opening may preclude performing an endometrial biopsy. In such cases, ultrasonography may help; if endometrial thickness is <= 5 mm, the probability of hyperplasia or cance
Alternatively, estrogen may be given every day, with progestin given only on specified days of the cycl (medroxyprogesterone acetate 5 mg for 14 days/mo, 10 mg for 10 to 12 days/mo, or 2.5 mg on days 1 Bleeding should occur only during the withdrawal period. Regular monthly withdrawal bleeding is a disadvantage of cyclic therapy, but if a patient cannot tolerate the irregular bleeding during the adjustm phase of continuous therapy, she may be a candidate for cyclic therapy.
Selective estrogen receptor modulators may someday be used to treat hot flushes, protect bones and the heart, and decrease the risk of breast cancer. Although described as "estrogen-lite," these drugs ( raloxifene) act as estrogen in some women and as anti-estrogens (similar to tamoxifen) in others. Indic the prevention of osteoporosis, they may decrease total cholesterol and inhibit breast tissue growth. B of unknown effects on other tissues (eg, brain), these drugs are most appropriate for women who have history of breast cancer or those who cannot or will not take estrogen. Raloxifene may worsen hot flus
Topical estrogen (eg, conjugated or equine estrogens or estradiol cream) may be used for atrophic va changes and dyspareunia whether or not the patient is taking oral estrogens; 1 applicator/night for 14 then 1/2 applicator/night for 1 mo, followed by 1/2 applicator 2 to 3 times/wk reverses atrophic change maintains a healthy cornified vaginal epithelium. Estrogen is readily absorbed systemically from the va mucosa and may cause bleeding in women who have a uterus. If such women use a topical estrogen long-term, a progestin should be added. Injectable estrogen is rarely indicated; after surgery, a transde patch may be applied before oral drugs are tolerated.
Contraindications to estrogen therapy include a history of estrogen-dependent neoplasia of the endometrium (advanced stage only) or breast, recurrent thrombophlebitis or thromboembolism, uterine bleeding with an undiagnosed cause, and presence or history of severe liver disease. Relative contraindications include a history of thrombophlebitis and intolerance of estrogen therapy.
When estrogens are contraindicated, treatment for reducing discomfort due to hot flushes includes clo 0.1 mg transdermally or progestins (eg, medroxyprogesterone acetate 10 mg/day po or depot 150 mg/
endometrium (advanced stage only) or breast, recurrent thrombophlebitis or thromboembolism, uterine bleeding with an undiagnosed cause, and presence or history of severe liver disease. Relative contraindications include a history of thrombophlebitis and intolerance of estrogen therapy.
When estrogens are contraindicated, treatment for reducing discomfort due to hot flushes includes clo 0.1 mg transdermally or progestins (eg, medroxyprogesterone acetate 10 mg/day po or depot 150 mg/ megestrol acetate 10 to 20 mg/day po). Sedative-hypnotics may be tried, but the patient must be warn their addictive potential.
Section 18. Gynecology And Obstetrics Chapter 247. Prenatal Genetic Evaluation And Cou Topics
[General] Indications For Prenatal Diagnosis Prenatal Screening Prenatal Diagnostic Techniques Principles Of Counseling
[General]
(See also Ch. 286.)
Genetic screening identifies persons at increased risk of developing or of conceiving offspring with gen disorders. Genetic screening is a routine part of prenatal care.
An accurate family history should be obtained and summarized as a pedigree (commonly used symbo described in Fig. 286-1). Minimum information includes three generations: all of the proband's first-deg relatives (parents, siblings, offspring) and second-degree relatives (aunts, uncles, grandparents) and t state of health. Complicated family histories require extended pedigrees. Ethnic background and consanguineous matings should be routinely queried. If genetic disorders are suspected, review of rele medical records is necessary.
Diagnoses of many genetic disorders are based on physical signs (phenotype) rather than symptoms. detailed physical description is therefore vital, particularly of stillborns or newborns dying soon after bir Photographs and full-body x-rays should be taken as part of the permanent record; they can be invalu future counseling. Cryopreservation of fetal tissues (liver, tissue containing fibroblasts) for future DNA enzymatic studies is recommended if cause of death is uncertain.
Carrier screening generally refers to identification of heterozygotes (carriers) of autosomal or X-linked recessive disorders. In obstetrics, screening provides prospective parents with information about whet children could inherit a genetic disorder, so that they can consider reproductive alternatives (eg, prena diagnosis with possible termination or treatment of affected fetuses, artificial insemination if the carrier man, oocyte donation if the carrier is the woman, avoidance of pregnancy). Screening all persons for even the most common disorders is impractical. Broad criteria for screening availability of a simple, accurate, inexpensive carrier test for a suspected disorder; ethnic, racial, and geographic background; increased risk of a specific genetic disorder; and availability of treatment or
diagnosis with possible termination or treatment of affected fetuses, artificial insemination if the carrier man, oocyte donation if the carrier is the woman, avoidance of pregnancy).
Screening all persons for even the most common disorders is impractical. Broad criteria for screening availability of a simple, accurate, inexpensive carrier test for a suspected disorder; ethnic, racial, and geographic background; increased risk of a specific genetic disorder; and availability of treatment or reproductive options for identified carriers. In the USA, three disorders meet these criteria: Tay-Sachs sickle cell anemia, and the thalassemias. For other disorders (eg, hemophilia, cystic fibrosis, Duchenn muscular dystrophy), screening based on family history may be possible. A National Institutes of Healt has recently recommended screening all pregnant women and all persons of reproductive age for cyst fibrosis. Guidelines for carrying out this recommendation are being developed. Molecular techniques ( 286) can often substantially alter theoretic risk, sometimes obviating the need for invasive prenatal dia For example, a pregnant woman whose brother has hemophilia theoretically has a 50% chance of car hemophilia gene; if screening shows she is not a carrier, her risk of having a child with hemophilia is a zero. For the most accurate assessment of risk, several relatives (including those affected) must some participate.
Sickle cell anemia (see also Ch. 127), the most common mendelian disorder in American blacks (abo 400), is an autosomal recessive disorder. Persons with sickle cell anemia are homozygous for the mut gene; those with sickle cell trait are heterozygous (ie, they express both the normal and sickle cell gen single nucleotide substitution (GAG to GTG) in the 6th codon of the -globin gene leads to the transcrip the amino acid valine (rather than glutamic acid), resulting in an abnormal Hb molecule. Several carrie screening tests are available; Hb electrophoresis should be used to confirm screening test results. Pre diagnosis is available by direct analysis of DNA obtained from chorionic villi or amniotic fluid cells. New screening for sickle cell anemia is recommended because prophylactic antibiotics given to those affec decrease the incidence of infection, which often incites sickle cell crisis.
Tay-Sachs disease (GM2 gangliosidosis--see also under Other Lipidoses in Ch. 16) is an autosomal recessive disorder that affects about 1 in 3600 children of Ashkenazic Jews and U.S. Cajuns. Hexosam A, which is involved in the metabolism of gangliosides (a class of nervous system lipids), is absent. Ca can be detected by demonstrating intermediate reduction of hexosaminidase A activity in serum. Howe during pregnancy and during oral contraceptive use, hexosaminidase A activity in serum normally dec relative to total hexosaminidase, producing false-positive results. Leukocyte hexosaminidase assays, w are unaffected in these situations, are recommended instead. Prenatal diagnosis is available by assay hexosaminidase A activity in cultured cells from chorionic villi or amniotic fluid; activity can also be mea directly in chorionic villi tissue. Diagnosis by DNA analysis is sometimes possible.
The thalassemias (see also Thalassemias in Ch. 127) are a heterogeneous group of hereditary anem which Hb synthesis is decreased. In -thalassemias, one to four of the genes (at two different loci) that the two chains in the Hb molecule are deleted; -thalassemias are most common among persons from Southeast Asia. -Thalassemia major (the disorder) falls into two general groups with defective -chain synthesis. In the o group, mRNA for the chain is absent or nonfunctional. In the + group, the gene is incompletely suppressed, reducing the amount of mRNA. -Thalassemia occurs in all populations but is common among persons from Mediterranean countries, the Middle East, and parts of India and Pakist Carrier screening for asymptomatic -thalassemia and -thalassemia minor (the carrier state) can be per by evaluating RBC indices. In persons without iron deficiency, a mean corpuscular Hb value of 20 to 2 MCV values of 50 to 70 fL suggest they are carriers. For -thalassemia, carrier status is confirmed by demonstrating elevated levels of Hb A2 using electrophoresis. Hb A2 levels are normal in -thalassemia carriers. Prenatal diagnosis for - and -thalassemias can be made using molecular techniques. Accurat characterization of the molecular abnormality is essential.

Section 18. Gynecology And Obstetrics Chapter 237. Pelvic Pain Topics
[General]
[General]
Diagnosis
Pelvic pain is a common complaint. It may originate in pelvic or extrapelvic organs, or it may be secon systemic disease. Sometimes no cause is found.
Pelvic pain may be due to a surgical emergency (eg, ovarian cyst torsion, ectopic pregnancy, ruptured tubo-ovarian abscess, appendicitis, bowel perforation). Chronic pelvic pain (lasting >= 6 mo) may requ surgical intervention and can be debilitating.
Categorizing pain as cyclic or noncyclic may help determine the cause. However, disorders causing cy occasionally cause noncyclic pain, and vice versa.
History: A thorough history--including the type, location, radiation, status (stable or increasing or decre severity), and onset (circumstances and suddenness) of the pain--can help identify the cause (see Ta 237-1). The patient should be asked if any factors exacerbate or alleviate the pain and if the pain is re menses, movement, micturition, defecation, sexual activity, sleep, or eating.
The history should include past surgical procedures and episodes of pelvic inflammatory disease. The should be asked about past treatment of the pain and its effectiveness. A detailed menstrual history (in time of menarche, cycle regularity and length, duration of menses, and amount of blood loss) should b obtained. Whether the pain began with menarche or is relatively new should be determined.
Physical examination: General observation may be diagnostically helpful; eg, poor posture and ambu difficulties suggest a musculoskeletal cause.
The abdomen is examined for tenderness or masses. If a painful area is found, the patient should be a whether this pain is the same as the primary complaint.
Pelvic examination: Examination of the introitus includes culture of a specimen obtained with a cotto
difficulties suggest a musculoskeletal cause.
The abdomen is examined for tenderness or masses. If a painful area is found, the patient should be a whether this pain is the same as the primary complaint.
Pelvic examination: Examination of the introitus includes culture of a specimen obtained with a cotto to identify agents (eg, Candida sp) responsible for vulvar pain syndromes, including vulvar vestibulitis, of dyspareunia. A sequential one-finger vaginal examination of the bladder, urethra, cervix, fornices, re and levator muscles can help differentiate pelvic pain from lower abdominal muscular pain. Bladder an urethral pain, associated with such disorders as interstitial cystitis, can be elicited when the anterior va wall is palpated. Levator spasm is present if pain is felt when the levator muscles behind the posterior wall are palpated. Assessment of cervical motion tenderness, vaginal fornix pain, and adnexal tendern help differentiate pelvic inflammatory disease or endometriosis from adhesions.
During bimanual examination, uterine size, tenderness, and mobility are evaluated. A markedly enlarg uterus suggests fibroids; a mildly enlarged, boggy, symmetric uterus suggests adenomyosis. Fixation o uterus may indicate adhesions or endometriosis. Uterosacral nodularity (confirmed by a rectal examina suggests endometriosis. A rectal examination should always be performed, and the stool should be te occult blood.
Special procedures: Laboratory tests are of limited use in evaluating patients with pelvic pain. A seru urine pregnancy test should be performed. For patients with bleeding, measuring Hb or Hct identifies a Measuring ESR or C-reactive protein may help identify an inflammatory or infectious process.
Ultrasonography may help if a physical examination is difficult (eg, if the patient has pain) or if an adn mass is suspected. However, inconclusive ultrasound results may further confuse the diagnosis, resul additional tests and/or unnecessary surgery.
Diagnostic laparoscopy is appropriate if a patient has severe pain and the diagnosis is unclear, if pa is suspected on the basis of the history and physical examination, or if a patient does not respond or r poorly to medical therapy (eg, oral contraceptives, NSAIDs). Laparoscopy can confirm the diagnosis a provide histologic documentation. It can also confirm that there is no anatomic abnormality of the pelvi abdominal organs.
Treatment
Treatment should be directed at the specific cause of the pain, if possible. However, symptomatic trea with NSAIDs is often the only option. Patients who have a poor or partial response to one NSAID may well to another one. Hypnosis helps relieve pelvic pain due to functional causes unamenable to surger
Uterosacral nerve ablation is reserved for patients with central pelvic pain or dysmenorrhea unrespons medical therapy. Long-term complications are unknown. Presacral neurectomy is reserved for patients central pelvic pain, dysmenorrhea, deep-thrust dyspareunia, or sacral backache unresponsive to cons therapy.
Hysterectomy is reserved for patients with chronic pelvic pain unresponsive to medical or conservative therapy. Patients without known organic pelvic disease must be informed that their pain may remain o worsen after hysterectomy.
Nerve block or transection may be helpful when malignancies are inoperable but is of little use if they h metastasized. Nerve blocks can also be performed in some women with severe chronic pain syndrome unknown etiology after workup.
worsen after hysterectomy.
Nerve block or transection may be helpful when malignancies are inoperable but is of little use if they h metastasized. Nerve blocks can also be performed in some women with severe chronic pain syndrome unknown etiology after workup.
Cyclic Pelvic Pain
Cyclic pelvic pain occurs in 30 to 50% of reproductive-aged women; it is severe enough to interfere wi normal activity in 10 to 15%. Cyclic pain may suggest a pelvic cause, but not all pain that occurs durin menstrual cycle has a pelvic cause. It may be due to disorders affecting other abdominal organs or psychosomatic or musculoskeletal disorders.
The premenstrual syndrome (PMS) may produce pelvic heaviness or pressure and backache, occur 10 days before and disappearing after menses begins (see Ch. 235).
Mittelschmerz (severe midcycle pain due to ovulation) frequently occurs. Rupture of the follicle and subsequent irritation of the peritoneum (by the fluid and/or blood from the ruptured follicle) may produc pain. The pain, although sometimes severe, resolves spontaneously. Patients should be monitored an NSAIDs.
Dysmenorrhea (pain related to the menstrual cycle) can be primary or secondary (see Ch. 235). Mos experience primary dysmenorrhea at some time during their life. The pain is cramping or sharp and las first few days of the menstrual period. It may radiate to the back, thighs, or deep pelvis. Occasionally, or vomiting occurs. Secondary dysmenorrhea may be due to endometriosis or cervical stenosis or, if associated with heavy menstrual flow, to fibroids (see Ch. 240), adenomyosis, or large endometrial po Using gonadotropin-releasing hormone agonists to suppress secondary dysmenorrhea associated with may help in diagnosis, but long-term use (> 6 mo) requires caution and coadministration of exogenous estrogen. Adjunctive use of antidepressants relieves pain through peripheral neuroblockade and centr stimulation.
Endometriosis can cause mild to severe pain, probably from irritation of pain fibers on the peritoneal (see Ch. 239). In its early stages, endometriosis causes cyclic pain, which starts several days before m and continues through the first few days. However, as the disorder becomes chronic, pain commonly o variable times unrelated to menses.
Noncyclic Pelvic Pain
Of pelvic origin: Sudden, severe pelvic pain associated with a pelvic mass indicates a serious underl disorder. An incarcerated uterus can cause acute pelvic pain early in pregnancy and is usually associa retroversion and pelvic adhesions. Acute growth or degeneration of a uterine myoma can also cause a pain. Ectopic pregnancy manifests as acute pelvic pain, menstrual irregularity, and an adnexal mass (see
Ovarian cysts and masses are frequently asymptomatic but may cause pressure, aching, or heavine Sudden sharp pain may indicate rupture, adnexal torsion, or hemorrhage. Hemorrhage into a cyst or le into the pelvis is very common and produces severe pain. A ruptured dermoid cyst can cause severe c peritonitis. For ovarian cyst torsion, the pedicle can be untwisted if it appears viable. A thrombosed ova vein with prolonged torsion requires removal of the affected ovary to prevent subsequent thromboemb
Ovarian cysts and masses are frequently asymptomatic but may cause pressure, aching, or heavine Sudden sharp pain may indicate rupture, adnexal torsion, or hemorrhage. Hemorrhage into a cyst or le into the pelvis is very common and produces severe pain. A ruptured dermoid cyst can cause severe c peritonitis. For ovarian cyst torsion, the pedicle can be untwisted if it appears viable. A thrombosed ova vein with prolonged torsion requires removal of the affected ovary to prevent subsequent thromboemb
Acute pelvic inflammatory disease (salpingitis, endometritis) is usually bilateral and is associated wi severe lower abdominal pain and cervical motion tenderness (see Ch. 238). Fever, leukocytosis, and a mucopurulent cervical discharge usually accompany the pain. Nausea and vomiting are uncommon. Tubo-ovarian abscess is a late complication, and rupture may temporarily reduce the pain but is follow sudden severe, unrelenting pain and deterioration requiring surgical intervention.
Pelvic congestion syndrome is pain that occurs 7 to 10 days before menses. It is more severe when woman sits or stands and is relieved by lying down. It is thought to be caused by vascular congestion varicosities of the pelvic veins. It is often accompanied by low back pain, leg ache, and dyspareunia an often, by fatigue, mood lability, headache, and abdominal bloating similar to symptoms of PMS. On examination, the uterus is usually tender, and the pain during the examination is the same as that duri sexual intercourse. The pain usually responds to NSAIDs.
Retroversion of the uterus is an uncommon cause of pelvic pain. Symptoms include pelvic pressure back pain. A successful trial with a pessary predicts a good response to surgery. Vaginal hysterectomy uterine suspension may be performed depending on the patient's desire to have children.
Adhesions resulting from previous surgery or pelvic infection may cause pain. Patients should be war the removal of adhesions (adhesiolysis) may make the pain worse and that even if surgery is beneficia adhesions may recur and cause further pain.
Deep-thrust dyspareunia (see Ch. 243) with no intrinsic abnormality is common. Instructing the partn lessen the depth of thrust during intercourse can provide relief. Pelvic malignancy is an uncommon cause of pelvic pain (see Ch. 241). Vulvodynia (vulvar pain) is pain with no apparent cause. Scarring from an episiotomy may cause it. Vestibulitis must be ruled out, and psychogenic causes must be considered. Of extrapelvic origin: Pain may be referred from extrapelvic organs to the pelvis.
In up to 60% of cases, pelvic pain can be attributed to GI problems. Because the bowel and pelvic org share visceral innervation, lower abdominal pain of GI origin is often confused with that of pelvic origin Peritonitis due to a pelvic infection is difficult to differentiate from that due to appendicitis.
Correlation of pain with eating or defecation suggests GI disease. Alternating constipation and diarrhe lessening of pain after a bowel movement, prompt urge to evacuate after eating, or worsening of pain stress suggests irritable bowel syndrome or spastic colon. Dyspareunia may be linked with irritable bow syndrome. Hard, infrequent stools with pain during or after bowel movements, rectal fullness, or a sen incomplete evacuation suggests chronic constipation. Recurrent left lower quadrant pain with fever, es in a woman > 40 yr, suggests diverticulitis. Inflammatory bowel disease, suggested by tenderness of th rectum, and cancer are uncommon but should be ruled out. Surgical emergencies, such as appendicit usually manifest more acutely but should be considered.
If the pain does not progress, further search for the cause is indicated before initiating treatment. Ultra examinations during the episode may reveal gallbladder or ureteral stones. In selected patients,
incomplete evacuation suggests chronic constipation. Recurrent left lower quadrant pain with fever, es in a woman > 40 yr, suggests diverticulitis. Inflammatory bowel disease, suggested by tenderness of th rectum, and cancer are uncommon but should be ruled out. Surgical emergencies, such as appendicit usually manifest more acutely but should be considered.
If the pain does not progress, further search for the cause is indicated before initiating treatment. Ultra examinations during the episode may reveal gallbladder or ureteral stones. In selected patients, sigmoidoscopy, colonoscopy, or barium enema is appropriate.
Typical symptoms of urinary tract problems include frequency, dysuria, burning, fever, chills, hematu colicky ureteral pain. Occasionally, the only finding is tenderness over the suprapubic or trigone area. Urinalysis, cystourethroscopy, and urodynamic studies help in diagnosis. Postcoital voiding difficulties the urethral syndrome (dysuria and frequency without bacteriuria), with or without chronic urethritis. Th syndrome may require urethral dilation. Once symptoms are alleviated, the woman should regularly vo coitus to reduce the risk of recurrence.
Pain that radiates down the legs or is worsened by motion suggests a musculoskeletal problem. Poo posture, abnormal gait, scoliosis, unilateral standing, marked lumbar lordosis, discrepancy in leg lengt previous surgery with a diagnosis of a normal pelvis, or a history of low back trauma suggests a musculoskeletal cause.
Symptomatic pelvic relaxation (cystocele, rectocele, or uterine prolapse) or pelvic tumors can cause sy of pressure, pelvic heaviness, or a sensation of the "organs falling out of the vagina."
Backache, a common complaint, is more often caused by poor posture, lack of exercise, trauma, or a disease (eg, osteoporosis, ruptured disk of the spine, osteoarthritis, bone tumor) than by a gynecologi disorder.
Separation of the pubic symphysis is a rare cause of pelvic pain, most commonly secondary to pregna history of pubic pain during ambulation and pain on pressure of the pubic bone during the abdominal o examination establish the diagnosis. The patient is treated with pelvic rest and, if not breastfeeding, N The disorder may take up to 6 mo to resolve.
Abdominal wall trigger points can cause pelvic pain and may be identified by an abdominal examinatio lateral borders of the rectus muscle. Trigger points can be injected with a local anesthetic (<= 10 mL bupivacaine 0.25%), resulting in complete pain resolution. If trigger points are not directly injected, the may be less effective but still lessens tenderness, relaxes the muscle spasm, and lessens pain when t rectus muscle is palpated. Physical therapy, NSAIDs, muscle relaxants, and application of heat are us adjuncts.
Laboratory studies are needed to rule out organic causes of pain. Somatization disorder is a commo psychogenic disorder in patients with chronic pelvic pain (see Ch. 186). Emotional problems may man physical complaints. Often the patient has multiple complaints for which no organic cause can be iden Psychiatric consultation is recommended.
Victims of physical or sexual abuse in childhood or in adulthood may present with chronic pelvic pain patients are at high risk of other psychologic or psychiatric disorders. Inquiries must be compassionate patient must be asked if she has ever been touched by anyone against her will as a child or as an adu Referral for counseling and to a support group may help.
Section 18. Gynecology And Obstetrics Chapter 248. Conception And Prenatal Developm Topics
[General]
[General]
Conception (fertilization) occurs about 14 days before a menstrual period, just after ovulation. If period irregular, the time of conception and thus the duration of the pregnancy and the due date may be diffic determine.
At ovulation, the cervical mucus becomes less viscid, facilitating rapid transit of sperm from the vagina endometrial cavity. Sperm may live in the vagina for up to 3 days before ovulation. They can migrate to fimbriated end of the uterine tube in 5 min under experimental conditions.
Conception occurs in the uterine tube, usually near the fimbriated end. The tubal epithelium must func properly for the sperm and ovum to unite and for the resulting zygote to continue dividing and develop during its transit through the tube to the endometrial cavity. The zygote makes this journey in 3 to 5 da moves to the site of implantation in 1 to 2 more days. During this time, the conceptus is dividing; at the implantation, it has formed a blastocyst (a single layer of cells surrounding a central cavity). One area blastocyst's wall is 3 to 4 cells thick. This area is the embryonic pole, which soon becomes recognizab embryo.
Implantation
Implantation, with the embryonic pole penetrating first, usually occurs in the front or back wall of the endometrial cavity near the fundus. Trophoblast cells proliferate from the surface of the blastocyst, inv and penetrating the endometrium so that the blastocyst burrows into the central layer of endometrium. process begins between days 5 and 8 and is completed by day 9 or 10.
By day 10, syncytial (syncytiotrophoblast) and cytotrophoblast cells are identifiable. Beginning about th fluorescent staining shows chorionic gonadotropin in syncytial cells. Presumably, all other trophic horm produced by the placenta appear in syncytial cells shortly thereafter. The blastocyst wall becomes the (the outer layer of membranes surrounding the fetus and amniotic fluid). An inner layer (amnion) deve about day 10 to 12 as a split in the embryonic ectodermal layer and forms the amniotic sac; the sac fil fluid and expands to envelop the embryo, adhering to the inner surface of the chorion (blastocyst wall)
By day 10, syncytial (syncytiotrophoblast) and cytotrophoblast cells are identifiable. Beginning about th fluorescent staining shows chorionic gonadotropin in syncytial cells. Presumably, all other trophic horm produced by the placenta appear in syncytial cells shortly thereafter. The blastocyst wall becomes the (the outer layer of membranes surrounding the fetus and amniotic fluid). An inner layer (amnion) deve about day 10 to 12 as a split in the embryonic ectodermal layer and forms the amniotic sac; the sac fil fluid and expands to envelop the embryo, adhering to the inner surface of the chorion (blastocyst wall) blastocyst cavity disappears.
The embryo continues to grow but is confined within one wall of the endometrial cavity until the 12th w time, the endometrium (decidua) overlying the embryo comes in such close contact with the decidua o opposite wall that they fuse and obliterate the endometrial cavity. The only cavity left in the uterus is th amniotic cavity, containing amniotic fluid and the fetus.
Placentation
The first evidence of placental formation is the development of trophoblast cells at day 10. Invasion of cells into maternal blood vessels causes blood to leak into the space between cells, forming lacunae ( which become the intervillous space. The fetus derives nourishment from the lacunae. Initially, the pla surrounds the blastocyst, transmitting nutrients and discharging wastes directly across cell membrane early as day 11 or 12, villi begin to form on the chorionic surface; they branch and rebranch in a comp treelike arrangement around the chorionic surface. Villous transfer from maternal blood to fetal blood b when fetal vessels appear within the placenta at day 19.
At about 12 wk, apparently influenced by the location of the major source of the maternal blood supply true (discoid) placenta begins to demarcate at the old embryonic pole; the placenta is attached by villi decidua directly overlying maternal spiral arterioles (see Fig. 248-1). The other villi atrophy, disappeari entirely by 16 to 18 wk. The spiral arterioles empty into the intervillous space so that maternal blood ci around and through the latticework of villi, draining out through two or three venous sinuses associated each spiral arteriole. The villi are divided into groups called cotyledons, each supplied by one or two sp arterioles. At term, a placenta contains 10 to 20 cotyledons. Nutrients are transferred from maternal bl the intervillous space, across trophoblast cells, through the fibrous core of the villus, and through the endothelial cells of the fetal capillaries to the fetal blood. Wastes move in the opposite direction. This arrangement is called a hemochorial placenta, because maternal blood is in apposition to fetal chorion trophoblastic tissue.
The discoid placenta reaches its final form at 18 to 20 wk of pregnancy. It continues to grow throughou pregnancy, weighing about 500 g (1 lb) at delivery.
Embryology
The conceptus can be recognized as an embryo about 10 days after fertilization, when the ectoderm s form the amniotic sac. The three germ layers (ectoderm, mesoderm, endoderm) are present and can u be distinguished. Then the primitive streak, which becomes the neural tube, begins to develop. Around or 17, the mesoderm thickens near the cephalic end, forming a central channel that ultimately become heart and great vessels. The heart begins to pump plasma through the vessels on day 20, and on day RBCs appear. These very immature, nucleated RBCs are soon replaced by mature forms. Nucleated reappear only in erythroblastosis fetalis (see Ch. 252) and in ongoing fetal hypoxia. Fetal vessels soon throughout the body. Some arise within the body stalk; the stalk connects the allantoic sac to the fetal abdomen at the umbilicus and contains blood vessels and the extension of the urachus, which drains from the bladder into the allantoic sac. The allantoic sac atrophies rapidly, and the body stalk become umbilical cord, connected to vessels in the placenta. Umbilical vessels carry blood to and from the pla
RBCs appear. These very immature, nucleated RBCs are soon replaced by mature forms. Nucleated reappear only in erythroblastosis fetalis (see Ch. 252) and in ongoing fetal hypoxia. Fetal vessels soon throughout the body. Some arise within the body stalk; the stalk connects the allantoic sac to the fetal abdomen at the umbilicus and contains blood vessels and the extension of the urachus, which drains from the bladder into the allantoic sac. The allantoic sac atrophies rapidly, and the body stalk become umbilical cord, connected to vessels in the placenta. Umbilical vessels carry blood to and from the pla Organ formation is complete by the 12th wk of pregnancy (70 days after fertilization) except in the CNS continues to develop throughout pregnancy.
Most malformations occur during the first 12 wk, when external teratogenic influences, such as the rub virus, are most destructive. All drugs and immunizations should be avoided until after the 12th wk of pregnancy, unless they are essential to protect the mother's health; teratogenic drugs should be avoid completely (see Ch. 249).
Section 18. Gynecology And Obstetrics Chapter 238. Gynecologic Inflammation And Infec Topics
Lower Genital Tract Disorders Upper Genital Tract Infections
Lower Genital Tract Disorders

Age must be considered when attempting to determine the etiology of vaginal or vulvar symptoms.
Infections and other inflammatory disorders affecting the vaginal mucosa and sometimes the vulva, co producing a vaginal discharge.
In newborns, a sterile mucoid vulvovaginal discharge may be secondary to maternal estrogens transf before birth; the discharge subsides about 2 wk after birth. A small amount of bleeding may result from estrogen withdrawal.
In children, vulvitis is most commonly due to infection by Escherichia coli; streptococci, staphylococci, Candida sp are less common causes. Occasionally, pinworms cause infection. If Neisseria gonorrhoea found on culture, sexual abuse is confirmed. Chemicals in bubble baths or soaps may cause irritation. discharge is present, especially with blood, a foreign body must be ruled out. Poor hygiene and fingeri practice common to girls aged 2 to 6 yr, contribute to infection. A normal physiologic discharge may de increase as a child approaches menarche because estrogen production increases.
In women of reproductive age, a normal physiologic discharge may be mistaken for an infection. The discharge is commonly milky white or mucoid, arising from the cervix or vagina as an epithelial transud Lactobacillus and Corynebacterium sp are usually present. Colonization of the vagina by Lactobacillus keeps the pH normal (3.8 to 4.2), preventing the overgrowth of bacteria and yeast. Menstrual blood, ce infections, or semen often makes the vaginal pH alkaline.
Hygiene sprays or perfumes, menstrual pads, laundry soaps, bleaches, fabric softeners, fabric dyes, s fibers, bathwater additives, and toilet tissue may cause vulvar hypersensitivity. Tight, nonporous under or poor hygiene may foster fungal and bacterial growth. Occasionally, sensitivity to spermicides, vagin
keeps the pH normal (3.8 to 4.2), preventing the overgrowth of bacteria and yeast. Menstrual blood, ce infections, or semen often makes the vaginal pH alkaline.
Hygiene sprays or perfumes, menstrual pads, laundry soaps, bleaches, fabric softeners, fabric dyes, s fibers, bathwater additives, and toilet tissue may cause vulvar hypersensitivity. Tight, nonporous under or poor hygiene may foster fungal and bacterial growth. Occasionally, sensitivity to spermicides, vagin lubricants or creams, or latex condoms or diaphragms can cause irritation, which may be confused wit infection. Also, frequent douching with irritants (eg, povidone-iodine) can result in an overgrowth of vag pathogens, leading to infection.
In the reproductive years, vulvitis is usually secondary to vaginal infections, whereas in the premenarc postmenopausal years, vulvitis commonly occurs alone. Differential diagnoses for vulvitis include epith disorders, tumors, and allergic vulvitis or dermatitis.
After menopause (occurring naturally or due to oophorectomy, pelvic radiation, or chemotherapy), es deficiency causes the vaginal mucosa to thin. Consequently, the vaginal mucosa is more vulnerable to and infection. Occasionally, thinning results in irritation without infection (atrophic vaginitis--see Table Discharge is scant and alkaline. Candidal infections rarely occur in postmenopausal nondiabetic wome they are taking hormone replacement therapy. However, infections due to Candida glabrata are comm women taking hormone replacement therapy or tamoxifen. Bacterial vaginosis is less common, except women confined to bed (eg, those in a nursing home). Foreign bodies, such as forgotten pessaries, ca cause a discharge.
Diagnosis
A complete history (including symptoms and color, consistency, odor, and duration of the discharge) s taken, and a complete physical examination should be performed. The patient is asked whether the di occurs in relation to menses; whether it is recurrent; how it responded to previous treatment; whether i burning, pain, or a lesion is present; and what bothers her the most. A sexual history (contraceptive us history of sexually transmitted diseases [STDs]) should be included, as well as questions about urethra discharge, pruritus, postcoital irritation, and vaginal infection and about penile lesions and treatment fo infection in her sexual partner. Which female hygiene products she uses, whether she has recently ch laundry products, and whether anyone else in the household has genital itching are pertinent.
After the general physical examination, a pelvic examination starting with the vulva should be performe Redness, edema, excoriation, and abnormal lesions indicate the need for further evaluation. Suspiciou lesions should be biopsied. Because the toluidine blue test (to help select a biopsy site) has a high rat false-positive and false-negative results, it has largely been replaced by colposcopy of the affected are clinician should palpate for enlarged nodes, culture ulcers for viruses, and note any discharges from th urethra or Bartholin's glands.
Children should be checked for foreign bodies and pinworms. If a discharge is present, a specimen fo can be obtained from the fourchette.
Treatment
Prepubertal girls should be instructed about perineal hygiene (eg, wiping front to back after bowel mov and voiding). For treatment of children with pinworm infestation, see Ch. 265. For children with labial adhesions (which are rare), vaginal estrogen cream applied daily for 7 to 10 days usually opens the la Foreign bodies should be removed, using an anesthetic if needed. Physiologic discharge is annoying because of soiled clothing and the feeling of wetness, but unless
Prepubertal girls should be instructed about perineal hygiene (eg, wiping front to back after bowel mov and voiding). For treatment of children with pinworm infestation, see Ch. 265. For children with labial adhesions (which are rare), vaginal estrogen cream applied daily for 7 to 10 days usually opens the la Foreign bodies should be removed, using an anesthetic if needed.
Physiologic discharge is annoying because of soiled clothing and the feeling of wetness, but unless irritation, or malodor is present, reassurance, not treatment, is indicated. Occasional douching with wa may reduce the secretions and discharge, providing relief. Frequent douching should be discouraged, it may be associated with pelvic inflammatory disease. Propionic acid gel may also relieve symptoms.
For acute vulvitis, the cause should be eliminated; measures to reduce the irritation (eg, wearing loos absorbent cotton clothing that allows air circulation; keeping the vulva clean) should be taken. Soaps s avoided. Intermittent use of ice packs or warm sitz baths with or without baking soda may reduce sore pruritus. Topical corticosteroids reduce itching and are indicated when infection is absent. Oral antihis diminish itching and cause drowsiness, helping the patient sleep. Xylocaine 2% jelly provides anesthe relief from itching.
Postmenopausal patients with atrophic vaginitis are treated with estrogen. Conjugated estrogens 0.6 micronized estradiol 1 mg, or esterified estrogens 0.625 mg, used daily, reverse the atrophy. Women w uterus should be given medroxyprogesterone acetate, megestrol acetate, or micronized progesterone estrogen to prevent endometrial hyperplasia. Patients who do not want to take oral estrogens or who n additional treatment can use a vaginal cream 1 g every day or every other day for 1 mo, then decrease twice weekly.
Poor hygiene can lead to chronic vulvar inflammation. Patients who are incontinent or bedridden im with improved cleanliness. Chronic skin disorders, such as psoriasis and tinea versicolor, can affect th and should be treated appropriately.
VULVOVAGINAL INFECTIONS
Vulvovaginal infections affect primarily the vaginal mucosa and secondarily the vulva. Common vagina infections are discussed below and in Table 238-1. Less common causes of vaginal infections include bacteria as N. gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis, streptococci, E. coli, and staphylococci; foreign bodies; some viruses (eg, herpes simplex); fistulas; radiation; and genital tract neoplasms. A watery discharge, especially if bloody, suggests a malignancy. Other noninfectious caus bleeding include cervical polyps (after coitus) and vaginal atrophy (typical after menopause).
Bacterial Vaginosis
Bacterial vaginosis represents 60% of all vulvovaginal infections. The concentration of anaerobic path (Bacteroides sp, Peptostreptococcus sp, Gardnerella vaginalis, and G. mobiluncus) increases tenfold hundredfold. Risk factors for developing this infection include the presence of STDs, multiple sexual p and use of an intrauterine device (IUD).
The most common complaint is a malodorous discharge; itching and irritation are common. The amine odor often becomes stronger when the discharge is more alkaline--after coitus and menses. Redness edema are uncommon.
The most common complaint is a malodorous discharge; itching and irritation are common. The amine odor often becomes stronger when the discharge is more alkaline--after coitus and menses. Redness edema are uncommon.
Diagnosis is made during pelvic examination. The clinician inspects the vagina, measures the pH, and water-lubricated speculum, obtains a specimen with a cotton-tipped applicator. A gray, homogeneous discharge and a pH of > 4.5 are the initial clues. Saline and potassium wet mounts are prepared: The specimen is divided between two slides and diluted with 0.9% sodium chloride on one slide and with 1 potassium hydroxide on the other; the latter specimen is checked for fishy odor (whiff test). On micros examination, the presence of clue cells (bacteria adherent to epithelial cells obscuring their cell margin suggests bacterial vaginosis. The presence of three of four criteria (gray discharge, pH > 4.5, fishy odo clue cells) is diagnostic. The presence of WBCs on a wet mount suggests a concomitant infection, suc gonorrhea or chlamydial infection, and cultures should be performed. Routine vaginal culture is not recommended because 50 to 60% of women normally carry G. vaginalis and are asymptomatic.
Treatment
Oral metronidazole 250 mg tid or 500 mg bid for 7 days is effective and was the standard therapy for y However, metronidazole vaginal gel 0.75% daily for 5 days or clindamycin 2% vaginal cream daily for 7 has less systemic adverse effects and equal efficacy. Women who use clindamycin cream cannot use products (ie, condoms or diaphragm) for contraception because the drug weakens latex, possibly incre the likelihood of pregnancy. Treatment of sexual partners is not recommended by the Centers for Dise Control and Prevention.
Although bacterial vaginosis used to be considered an inconsequential infection, it is increasingly asso with pelvic inflammatory disease, postabortion endometritis, posthysterectomy vaginal cuff infection, chorioamnionitis, postpartum endometritis, premature rupture of the membranes, preterm labor, and p birth. Preoperative prophylaxis decreases the incidence of postabortion endometritis. Treatment during pregnancy has not been proved to improve pregnancy outcome.
Candidal Vaginitis
Fungal or yeast infections account for 30 to 35% of vaginal infections; most of them are due to Candid albicans. Yeast colonizes 15 to 20% of nonpregnant and 20 to 40% of pregnant women. Candidal infe more common among women who have diabetes, who use IUDs, who have recently used an antibiotic tetracycline for acne), who use corticosteroids regularly, or who are immunodeficient.
Typical symptoms include vaginal pruritus--with or without vulvar itching, burning, or irritation (which m worse with intercourse)--and a thick, white (cottage cheese-like) vaginal discharge that clings to the va walls. Symptoms increase the week before menses. Erythema, edema, and excoriation are common. 4.5 and budding yeast, pseudohyphae, or mycelia are seen on a wet mount, especially the potassium hydroxide preparation. Cultures are not routinely performed. When symptoms persist or worsen during therapy, hypersensitivity to topical antifungals should be considered.
Treatment
hydroxide preparation. Cultures are not routinely performed. When symptoms persist or worsen during therapy, hypersensitivity to topical antifungals should be considered.
Treatment
Topical or oral drugs are highly effective (see Table 238-2). New, one-dose regimens increase complia Miconazole and clotrimazole are available OTC. Frequent episodes of infection require long-term supp with oral drugs (fluconazole or ketoconazole).
Trichomonas Vaginitis
Vaginitis due to Trichomonas vaginalis, an STD, accounts for about 5 to 10% of vaginal infections. Ab of women who harbor the organism are asymptomatic. The most common complaints are a profuse va discharge (which may be frothy, yellowish green, and alkaline), dysuria, and dyspareunia. Vaginal eryt present. Often, symptoms appear after menses. The discharge may have a fishy odor because of coe anaerobic organisms. Acute inflammation may cause the cervix and vagina to have a strawberry appe Motile, flagellated protozoa are seen on wet mount.
Treatment
Metronidazole 500 mg bid for 7 days or a single dose of 2 g po may be used. Adverse effects include and a metallic taste; severe nausea with vomiting is more common with the single dose. The patient's partner should be treated.
Herpes Simplex Genital Ulcers
Herpes simplex virus (HSV) causes genital ulcers and must be differentiated from syphilis and chancro also Ch. 164). Most HSV genital infections are due to type 2. Most often, intimate contact with someon shedding the virus leads to infection. The incubation period is 5 to 7 days, after which small vesicles a During the initial infection, the HSV ascends the peripheral nerves to the sacral plexus, where it reside permanently. The initial infection is usually associated with malaise, regional lymphadenopathy, and fe which resolve in 1 wk. Lesions are extremely tender and heal in about 21 days. Recurrent infections, w tend to be milder and localized, are preceded by a prodrome of numbness or tingling at the site. Viral s from recurrent lesions lasts 4 days, and lesions heal in about 10 days.
Treatment
Antiviral treatments shorten viral shedding by 1 day. For the initial infection, treatment is traditionally a 200 mg po 5 times/day for 10 days. Recurrences can be treated with 200 mg 5 times/day, 400 mg tid, mg bid. New oral antiviral drugs for the treatment of recurrent infections include famciclovir 125 mg bid days and valacyclovir 500 mg bid for 5 days. About 70% of women have a recurrence within 1 yr. Long suppression with acyclovir 400 mg bid for 1 yr (after which it is stopped and recurrences are assessed be considered for women with multiple recurrences.
Human Papillomavirus Genital Warts

(See also Genital Warts in Ch. 164.)
be considered for women with multiple recurrences.
Human Papillomavirus Genital Warts

(See also Genital Warts in Ch. 164.)
Genital warts are the most common viral STD. The reported incidence of human papillomavirus (HPV) infection is 6% in women aged 20 to 34 yr. HPV subtypes primarily infecting vulvar epithelium include and 11. Types 16, 18, 31, 33, 35, 39, 41, 42, 43, 44, 51, 52, and 56 are less common in vulvar disease involved in cervical dysplasia and invasive cervical cancer, in which they play a pathogenic role. Many with HPV also have other sexually transmitted infections.
Treatment
Treatment of the warts is determined by the site and extent of wart growth. Self-administered topical d include imiquimod 5% applied 3 times/wk until resolution for up to 16 wk (for recurrence, treatment can repeated for an additional 16 wk) and podofilox 0.5% applied bid for 3 days followed by 4 days of no th (this sequence can be repeated 3 more times). Trichloroacetic acid 75 to 90% can be applied by a hea practitioner weekly. If no resolution is apparent after six applications, cryotherapy, electrocautery, or la therapy may be used. These options require anesthesia. Biopsy is appropriate if resolution is delayed. Papanicolaou smear should be obtained to rule out cervical dysplasia. Warts recur in 65% of patients.
Section 18. Gynecology And Obstetrics Chapter 249. Normal Pregnancy, Labor, And Del Topics
[General] Physiology Prenatal Care Drugs In Pregnancy Management Of Normal Labor Management Of Normal Delivery
[General]
The first sign of pregnancy and the first reason most pregnant women see a physician is missing a me period. If a patient's periods are usually regular and she is sexually active, missing a period for >= 1 w presumptive evidence of pregnancy. Breast engorgement and nausea with occasional vomiting may a noted. The engorgement is caused by increased levels of estrogen (primarily) and progesterone and is extension of premenstrual breast engorgement. Nausea and vomiting may be caused by human chori gonadotropin (hCG) and estrogen, which the syncytial cells of the placenta begin to produce in increas amounts 10 days after fertilization. The corpus luteum in the ovary is stimulated by hCG to continue se high levels of estrogen and progesterone to maintain the pregnancy. Many women become fatigued a time, and an occasional patient notices abdominal enlargement (bloating) very early in her pregnancy.
Pregnancies are usually dated in weeks, starting from the first day of the last menstrual period. Thus, patient's periods were regular and if ovulation occurred on day 14 of the cycle, obstetric dates are abo longer than embryologic dates. If the patient's periods are irregular, the difference is more or less than Usually, 2 wk after missing a period, the patient is considered to be 6 wk pregnant, and the uterus is correspondingly enlarged.
Pelvic examination detects uterine enlargement compatible with pregnancy. The cervix is softer, and th is irregularly softened and enlarged. The cervix usually becomes bluish to purple, apparently because supply to the uterus is increased.
Blood or urine tests are usually positive. Enzyme-linked immunosorbent assay (ELISA) for hCG can qu and easily detect even small quantities of this hormone in urine. Some of the most sensitive pregnanc using this method (eg, ICON, TestPack) can provide positive results in about 1/2 h with hCG levels as 50 mIU/mL of urine; such levels often occur several days before the missed menstrual period. Radioimmunoassays using specific antibodies to the subunit of hCG (-hCG) can detect even lower hC (a minimum of about 0.05 mIU/mL of serum with most of these tests). Thus, pregnancy can be diagno several days after conception.
Blood or urine tests are usually positive. Enzyme-linked immunosorbent assay (ELISA) for hCG can qu and easily detect even small quantities of this hormone in urine. Some of the most sensitive pregnanc using this method (eg, ICON, TestPack) can provide positive results in about 1/2 h with hCG levels as 50 mIU/mL of urine; such levels often occur several days before the missed menstrual period. Radioimmunoassays using specific antibodies to the subunit of hCG (-hCG) can detect even lower hC (a minimum of about 0.05 mIU/mL of serum with most of these tests). Thus, pregnancy can be diagno several days after conception.
During the first 60 days of a normal single pregnancy, hCG levels double about every 2 to 3 days, risin exponentially. Although hCG levels correlate with gestational age in normal pregnancies, the use of di standards for measuring hCG, interassay variation, and inherent biologic variation preclude using one value to determine if the fetus is growing normally. The best approach is to compare two serum hCG v obtained 48 to 72 h apart and measured by the same laboratory; a doubling of the hCG value strongly suggests that the fetus is growing normally. In abnormal pregnancies (eg, spontaneous abortion, bligh ovum, ectopic pregnancy), hCG levels are off the normal curve and do not double in 2 to 3 days.
At 6 wk of pregnancy, the uterus sometimes can be easily flexed at the markedly softened isthmus. At the uterus is larger than the pelvic cavity and rises out of the true pelvis into the abdomen; it can be pa above the symphysis pubis. At 20 wk, the upper pole of the uterus is at the level of the umbilicus (from of the uterus to the symphysis measures about 20 cm); at 36 wk, the upper pole is near the xiphoid pr
Positive proof of pregnancy is delivery of a fetus. Traditionally, three other signs have been accepted a positive: fetal heart sounds heard by a physician or via a Doppler ultrasound instrument (ordinarily, fet sounds can be detected at 18 to 20 wk with a stethoscope and as early as 8 to 10 wk with a Doppler ultrasound device if the uterus is accessible abdominally); fetal movements felt or heard by the examin physician; and identification of a fetal skeleton on x-ray, usually after 16 wk. Ultrasound detection of an intrauterine sac and fetal cardiac motion also constitutes positive proof. A cavity compatible with pregn can be detected within the uterus at about 5 to 6 wk (4 wk after ovulation) with ultrasonography. Fetal motion may first be observed at about 5 to 6 wk with real-time ultrasound scanning and is observed at wk in > 95% of cases. The pregnant woman usually begins to feel fetal movement between 16 and 20
Pregnancy is considered to last 266 days from the time of conception or 280 days from the first day of menstrual period if periods are regular at 28 days. Ngele's rule calculates the estimated delivery date subtracting 3 mo from the first day of the last menstrual period and adding 7 days. This calculation is o approximate; <= 10% of patients deliver on the calculated day, but 50% deliver within 1 wk and almost within 2 wk. Patients should be told that delivery up to 2 wk earlier or later than the estimated date is n
A pregnant woman is described as a gravida. Each pregnancy (multiple gestation is one pregnancy) i gravidity, so that a patient with two confirmed pregnancies is a gravida 2. Parity describes outcome. P refers to deliveries after 20 wk, which are numbered successively as para 1, 2, 3, and so forth (twins, t or more are 1 para). Abortus refers to losses before 20 wk, which are numbered successively as abort 3, and so forth. The sum of para and abortus equals gravidity. More often, para is recorded in 4 numb first indicates the number of term deliveries (after 37 wk); the 2nd, the number of premature deliveries and < 37 wk); the 3rd, the number of abortions; and the 4th, the number of living children. Thus, a wom is pregnant and has had one term delivery, one set of twins born at 32 wk, and two abortions is gravid 1-1-2-3.

Section 18. Gynecology And Obstetrics Chapter 239. Endometriosis Topics
[General]
[General]
Endometriosis: A nonmalignant disorder in which functioning endometrial tissue is present outside the cavity.
Endometriosis is usually confined to the peritoneal or serosal surfaces of abdominal organs, commonl ovaries, posterior broad ligament, posterior cul-de-sac, and uterosacral ligaments. Less common sites the serosal surfaces of the small and large bowel, ureters, bladder, vagina, surgical scars, pleura, and pericardium.
The most widely accepted hypothesis is that endometrial cells are transported from the uterine cavity, implant at ectopic sites. Retrograde flow of menstrual tissue through the fallopian tubes could cause intra-abdominal endometriosis; the lymphatic or circulatory systems could transport endometrial cells t sites (eg, the pleural cavity). Another hypothesis is that coelomic epithelium is transformed into endometrium-like glands (ie, coelomic metaplasia).
The incidence of endometriosis is higher (by 6%) in first-degree relatives of women with endometriosis the general population, suggesting that heredity may be a factor. The incidence is also higher in wome delay childbearing, who are of Asian descent, or who have mllerian duct anomalies.
The reported incidence varies, but endometriosis is commonly found in 10 to 15% of women between of 25 and 44 yr who are actively menstruating. It also occurs among teenagers. An estimated 25 to 50 infertile women have endometriosis. In patients with severe endometriosis and distorted pelvic anatom incidence of infertility is high because mechanisms of ovum pickup and tubal transport are impaired. H some patients with minimal endometriosis and normal pelvic anatomy are also infertile. In these patien increased incidence of luteal phase dysfunction, luteinized unruptured ovarian follicle syndrome (trapp oocyte), increased peritoneal prostaglandin production, increased peritoneal macrophage activity, or nonreceptive endometrium may account for their decreased fertility.
Symptoms and Signs
incidence of infertility is high because mechanisms of ovum pickup and tubal transport are impaired. H some patients with minimal endometriosis and normal pelvic anatomy are also infertile. In these patien increased incidence of luteal phase dysfunction, luteinized unruptured ovarian follicle syndrome (trapp oocyte), increased peritoneal prostaglandin production, increased peritoneal macrophage activity, or nonreceptive endometrium may account for their decreased fertility.
Symptoms and Signs
The clinical manifestations are pelvic pain, pelvic mass, alteration of menses, and infertility. Some wom extensive endometriosis are asymptomatic, whereas some with minimal disease have incapacitating p Dyspareunia and midline pelvic pain before or during menses, particularly beginning after several year pain-free menses, may occur. Such dysmenorrhea is an important diagnostic clue. Lesions on the larg or bladder may cause pain during defecation, abdominal bloating, rectal bleeding with menses, or sup pain during urination. Endometriotic implants on the ovary or adnexal structures can form an endomet cystic mass > 2 to 3 cm localized to an ovary) or adnexal adhesions, resulting in a pelvic mass. Occas rupture of or leakage from an endometrioma produces acute abdominal pain.
Pelvic examination may be normal or, rarely, may reveal visible lesions on the vulva or cervix or in the umbilicus, or surgical scars. A retroverted and fixed uterus, enlarged ovaries, or uterosacral nodularity found.
Diagnosis
The diagnosis is suspected on the basis of symptoms or physical findings but can be established only visualizing lesions, usually by endoscopy of the pelvis with biopsy. Diagnosis can also be made by bio during laparotomy, sigmoidoscopy, or cystoscopy. Microscopically, endometriotic implants consist of g and stroma identical to intrauterine endometrium (most implants can bleed during menstruation). By d both glands and stroma must be present to diagnose endometriosis. These tissues contain estrogen a progesterone receptors that enable them to grow and differentiate in response to the changes in horm levels during the menstrual cycle. Thus, the macroscopic appearance (eg, clear, red, brown, black) an implants vary. Bleeding from peritoneal implants is thought to initiate inflammation, followed by fibrin deposition, adhesion formation, and eventual scarring, which distorts peritoneal surfaces and normal p anatomy. Other diagnostic procedures (eg, ultrasonography, barium enema, IV urography, CT, MRI) m useful for demonstrating the extent of disease and following its course but are not specific or adequate diagnosis. Investigational serum markers for endometriosis (eg, serum cancer antigen 125 and antien antibody levels) may help the physician monitor the disease, but further refinement of these procedure required. Infertility studies may be indicated (see Ch. 245).
Staging the disease helps the physician formulate a treatment plan and evaluate response to therapy revised staging criteria of the American Society for Reproductive Medicine are based on the location o implants, presence of superficial or deep endometriosis, and presence of filmy or dense adhesions. Endometriosis may be classified as stage I (minimal), II (mild), III (moderate), or IV (severe--see Table Another classification system is based primarily on pelvic pain. However, intraobserver and interobser variability is high in the evaluation of endometriosis, and a more useful method for staging the disorde sought.
Treatment
Treatment must be individualized on the basis of the patient's age, symptoms, desire for pregnancy, a extent of disease. Options include medical suppression of ovarian function to arrest the growth and ac endometrial implants, conservative surgical resection of as much of the endometriotic tissue as possib combination of the two therapies, and total abdominal hysterectomy, usually with bilateral salpingo-oophorectomy.
Treatment must be individualized on the basis of the patient's age, symptoms, desire for pregnancy, a extent of disease. Options include medical suppression of ovarian function to arrest the growth and ac endometrial implants, conservative surgical resection of as much of the endometriotic tissue as possib combination of the two therapies, and total abdominal hysterectomy, usually with bilateral salpingo-oophorectomy.
Drugs that suppress ovarian function and endometrial tissue growth are listed in Table 239-2. Continu contraceptives are commonly used. Other drugs (eg, gonadotropin-releasing hormone [GnRH] agonist produce a state of relative and reversible hypoestrogenemia, have become available. However, treatm GnRH agonists is limited to <= 6 mo because long-term use is associated with bone loss. Danazol, an antigonadotropin, inhibits ovulation but has significant androgenic adverse effects, limiting its usefulne Cyclic or continuous oral contraceptives given after danazol or GnRH agonists may slow disease prog and are warranted in women wishing to delay childbearing. Pregnancy rates with medical therapy rang 40 to 60%. Whether fertility rates are improved by treatment of minimal or mild endometriosis is not cle Medical therapy or conservative surgery does not cure endometriosis, which recurs in most patients on treatment is stopped. Only total ablation of ovarian function prevents recurrence of endometriosis.
Moderate to severe cases are treated most effectively by ablating or excising as many implants as pos while preserving reproductive potential. Indications for surgery include the presence of endometriomas significant pelvic adhesions, fallopian tube obstruction, and intractable and incapacitating pelvic pain unresponsive to medical therapy. Microsurgical techniques must be used to prevent adhesion formatio surgery. During laparoscopy, electrocauterizing peritoneal or ovarian lesions or vaporizing or excising with a CO 2, argon, or neodymium:yttrium-aluminum-garnet (Nd: YAG) laser is sometimes possible. Aft treatment, pregnancy rates are 40 to 70% and are inversely proportional to the severity of the endome resection of disease is incomplete, adjunctive suppressive therapy with oral contraceptives or GnRH a may enhance fertility rates. For patients with midline pelvic pain, laparoscopic resection of the uterosa ligaments with electrocautery or a laser may reduce the pain.
Hysterectomy should be reserved for patients with intractable pelvic pain who have completed childbe After removal of the uterus and both ovaries, replacement estrogen therapy can be started postoperat if a significant amount of endometriotic tissue is left in situ, may be delayed for 4 to 6 mo; adjunctive suppressive medical therapy may be necessary during this interval. Continuous progestin therapy (eg, medroxyprogesterone acetate 2.5 mg po daily) should be given with the estrogen therapy because res tissue may grow and hyperplasia or malignancies may develop if estrogen is given alone. In younger p preserving ovarian function should be considered, although recurrences of endometriosis have been r

Section 18. Gynecology And Obstetrics Chapter 250. High-Risk Pregnancy Topics
[General] Risk Factors
[General]
High-risk pregnancy: Pregnancy in which the mother, fetus, or newborn is or will be at increased risk fo morbidity or mortality before or after delivery.
All pregnancies should be evaluated to determine whether there are or will be risk factors. Many risk fa are involved; weighing each factor as a risk increment requires systematic review and use of a scoring (see Table 250-1). Classifying a pregnancy as high risk helps ensure that it receives extra attention.
A risk assessment enables high-risk patients to be referred to a perinatal center before delivery, thereb significantly decreasing neonatal morbidity and mortality rates, compared with those for newborns of s gestational age and weight who are transported to such centers after delivery. Patients may be identifi high risk during the antepartum period or during labor, when acute events change risk status. The mos common reason for referral is risk of preterm delivery, often associated with premature rupture of the membranes (see Ch. 253).
Maternal mortality occurs in 6 of 100,000 births in the USA. The leading cause is motor vehicle accid followed by thromboembolic disease, anesthesia complications, hemorrhage, infection, and hypertens complications.
Perinatal mortality occurs in 17 of 1000 deliveries in the USA. Slightly > 50% of these deaths are still the remainder occur up to the 28th day of life. Most perinatal deaths that are not directly due to conge anomalies are associated with prematurity, often accompanied by abruptio placentae, multiple pregna preeclampsia and eclampsia, placenta previa, polyhydramnios, or abnormal presentation.

Section 18. Gynecology And Obstetrics Chapter 240. Uterine Fibroids Topics
[General]
[General]
Uterine fibroids (leiomyomas; myomas; fibromyomas): Benign uterine tumors of smooth muscle origin.
Uterine fibroids are the most common pelvic neoplasm, occurring in 1/4 of white and 1/2 of black wom
In the uterus, submucosal, intramural, and subserosal sites are the most common. Occasionally, fibroi in the broad ligaments (intraligamentous) or uterine tubes; 5% occur in the cervix. Fibroids are usually Some are pedunculated. Fibroids are monoclonal, probably arising from a single smooth muscle cell. B they have estrogen receptors, they tend to increase in size during the reproductive years and regress menopause.
Degeneration is initiated by loss of blood supply and is described as hyaline, myxomatous, calcific, cys red (usually only during pregnancy), or necrotic. Although patients are often concerned about cancer in fibroids, sarcomatous change is extremely rare.
Symptoms and Signs
Fibroids are often asymptomatic but can cause menorrhagia, menometrorrhagia, severe pressure or p (from growth, degeneration, hemorrhage, or twisting of a pedunculated fibroid), urinary or bowel comp (eg, urinary frequency or urgency, constipation), recurrent abortions, and infertility. Degeneration or gr fibroid causes acute pain that can become chronic, with continuing degeneration. Fibroids do not usua interfere with becoming pregnant; however, they may complicate pregnancy, causing premature contra or labor or malpresentation, and may even necessitate cesarean section.
Diagnosis is made by pelvic examination and can be confirmed by ultrasonography, CT, or MRI. After diagnosis, a pelvic examination is repeated in 4 to 6 mo to determine if the fibroid is growing rapidly. F fibroids, annual follow-up is sufficient.
Diagnosis is made by pelvic examination and can be confirmed by ultrasonography, CT, or MRI. After diagnosis, a pelvic examination is repeated in 4 to 6 mo to determine if the fibroid is growing rapidly. F fibroids, annual follow-up is sufficient.
For asymptomatic patients, no treatment is required. For patients with symptoms, medical options, inc suppression of estrogen to stop the bleeding, are suboptimal and limited. Preoperative gonadotropinre hormone (GnRH) agonist therapy helps manage anemia before surgery. Menorrhagia or menometrorr should be managed before surgery is considered (see Abnormal Uterine Bleeding in Ch. 235).
Exogenous progestins can partially suppress estrogen stimulation of uterine fibroid growth. Medroxyprogesterone acetate 5 to 10 mg/day po or megestrol acetate 10 to 20 mg/day po given 10 to each menstrual cycle can limit heavy bleeding after one or two cycles. Alternatively, oral therapy may b continuously (every day of the month); it may result in less overall bleeding but often causes irregular b or spotting, which the patient accepts better if she is informed before therapy. Depot medroxyprogeste acetate 150 mg IM q 3 mo controls bleeding similarly to continuous oral therapy and provides contrace Before IM administration, oral progestins should be tried in case the patient cannot tolerate the advers (eg, weight gain, depression, irregular bleeding).
Danazol, an androgenic agonist, can suppress fibroid growth but has a high rate of adverse effects (eg gain, acne, hirsutism, edema, hair loss, deepening of the voice, flushing, sweating, vaginal dryness) an therefore less acceptable to the patient.
GnRH agonists given by IM injection, subdermal pellet, or nasal spray are most helpful when given preoperatively to reduce fibroid and uterine volume. In general, these drugs should not be used for con therapy because rebound growth to pretreatment size within 6 mo is common, often increasing bleedin pain. Long-term GnRH therapy is also associated with rapid bone loss and is therefore not approved. general, women < 35 yr old recoup bone mass after GnRH therapy is discontinued, but women >= 35 cannot. Giving estrogen concurrently is being studied to determine whether its long-term use can prev bone loss.
Surgical options are myomectomy and hysterectomy; both involve major surgery. Surgery is usually re for women with a rapidly enlarging pelvic mass, recurrent uterine bleeding unresponsive to medical the persistent or intolerable pain or pressure, or urinary or bowel complaints. Myomectomy may help wom recurrent abortions or infertility who want to conceive when no other cause of infertility can be found. Indications for hysterectomy are the same as those for myomectomy, but hysterectomy is performed o woman does not want to conceive. Multiple myomectomy can be much more difficult than hysterectom the fibroids are removed, little or no normal myometrium may be left, making restoration of a normal u impossible. Patient choice is important, but it must be based on full information about the anticipated difficulties and sequelae of myomectomy vs. hysterectomy.
Section 18. Gynecology And Obstetrics Chapter 251. Pregnancy Complicated By Disea Topics
[General] Heart Disease Thromboembolic Disease Hypertension Renal Disease Urinary Tract Infection Diabetes Mellitus Thyroid Disease Hepatic Disorders Infectious Disease Anemia Hemoglobinopathies Asthma Autoimmune Diseases Malignancy Disorders Requiring Surgery
[General]
Normal physiologic changes that occur during pregnancy are discussed under Physiology in Ch. 249, of drugs during pregnancy is discussed under Drugs in Pregnancy in Ch. 249.

Section 18. Gynecology And Obstetrics Chapter 241. Gynecologic Neoplasms Topics
Endometrial Cancer Ovarian Cancer Cervical Cancer Vulvar Cancer Vaginal Cancer Fallopian Tube Cancer Gestational Trophoblastic Disease
Endometrial Cancer
In the USA, endometrial cancer is the most common gynecologic malignancy and the fourth most com malignancy in women after breast, colorectal, and lung cancer. About 34,000 new cases of endometria were diagnosed in 1996. It affects mainly postmenopausal women, with incidence peaking between ag and 60; < 5% of cases occur among women < 40 yr.
Endometrial cancer is more common in industrialized countries in which dietary fat intake is high. The significant risk factor is obesity, which increases risk by 3 to 10 times. Endometrial cancer is more com women with conditions that tend to result in unopposed estrogen (high circulating levels of estrogen w low levels of progesterone), such as unopposed estrogen replacement therapy, obesity, polycystic ova syndrome, nulliparity, late menopause, estrogen-producing tumors, anovulation, or oligo-ovulation. Wo with a history of pelvic radiation therapy or with a personal or family history of breast or ovarian cancer increased risk. A small percentage of cases may be hereditary.
Endometrial hyperplasia usually precedes endometrial cancer and is classified by the degree of cytolo atypia. Its treatment consists of progestins or surgery, depending on the complexity of the lesion and t patient's desire to avoid hysterectomy.
Endometrial cancer may spread from the surface of the uterine cavity to the cervical canal; through the myometrium to the serosa and into the peritoneal cavity; via the lumen of the fallopian tube to the ovar ligament, and peritoneal surfaces; via the bloodstream, leading to distant metastases; or via the lymph The higher (more undifferentiated) the grade of the tumor, the greater likelihood of deep myometrial in pelvic or para-aortic lymph node metastases, or extrauterine spread.
Endometrial cancer may spread from the surface of the uterine cavity to the cervical canal; through the myometrium to the serosa and into the peritoneal cavity; via the lumen of the fallopian tube to the ovar ligament, and peritoneal surfaces; via the bloodstream, leading to distant metastases; or via the lymph The higher (more undifferentiated) the grade of the tumor, the greater likelihood of deep myometrial in pelvic or para-aortic lymph node metastases, or extrauterine spread.
Adenocarcinoma accounts for > 80% of cases of endometrial cancer. Sarcomas account for about 5% uterine malignancies and include mixed mesodermal tumors, leiomyosarcomas, and endometrial strom sarcomas. Sarcomas tend to be more aggressive, are more likely to produce local, regional, and dista metastases, and have a worse prognosis.
More than 90% of patients with endometrial cancer have abnormal uterine bleeding (eg, postmenopau bleeding, premenopausal recurrent metrorrhagia). About 1/3 of women with postmenopausal bleeding endometrial carcinoma. In postmenopausal women, a vaginal discharge may precede bleeding by sev weeks or months.
If a Papanicolaou (Pap) smear shows endometrial cells in a postmenopausal woman or atypical endom cells in a woman of any age, further evaluation is indicated. However, a Pap smear does not accurate endometrial malignancies.
Tissue sampling from the endometrium, usually performed in the physician's office, is the definitive dia procedure. This procedure is > 90% accurate, compared with a fractional dilation and curettage with hysteroscopy, performed in the operating room. The latter is used when outpatient sampling is not dia Transvaginal ultrasonography may also be useful.
Once a histologic diagnosis of endometrial cancer is made, pretreatment evaluation includes serum ch studies, liver function tests, a CBC, chest x-ray, and ECG. Additional endoscopic and radiologic studie routinely necessary. Pelvic and abdominal CT may help if extrauterine or metastatic disease is suspec
Staging, Prognosis, and Treatment
Staging is based on histologic differentiation (grade) of the tumor and findings during surgery, includin of invasion, cervical involvement (glandular involvement vs. stromal invasion), and extrauterine metast such as those to the adnexa, lymph nodes, and peritoneal cavity (see Table 241-1). An adequate abdo incision is made, allowing sampling of peritoneal fluid for cytologic evaluation and exploration of the ab and pelvis, with biopsy or excision of suspicious extrauterine lesions. Pelvic and para-aortic lymph nod should be sampled in high-risk situations and, if suspicious, removed. A radical hysterectomy with pelv para-aortic lymph node dissection is indicated if cervical involvement is suspected.
Prognosis is influenced by the tumor's histologic appearance and grading, the patient's age (older wom a poorer prognosis), and metastatic spread. Overall, 63% of patients are cancer-free >= 5 yr after trea For patients with stage I disease, the reported 5-yr survival rate is 70 to 95%; the 5-yr survival rate for with stage III or IV disease is 10 to 60%.
Stage I, grade 1 endometrial cancer without deep myometrial invasion is usually localized; the probabi lymph node metastasis is < 2%. Surgery can usually be limited to a total hysterectomy, bilateral salpingo-oophorectomy, and peritoneal cytologic examination. For grades 2 and 3 and for grade 1 with myometrial invasion, a pelvic and para-aortic lymphadenectomy may be added.
Very few patients with cancer confined to the uterus have recurrences. Accurate surgical staging enab
Stage I, grade 1 endometrial cancer without deep myometrial invasion is usually localized; the probabi lymph node metastasis is < 2%. Surgery can usually be limited to a total hysterectomy, bilateral salpingo-oophorectomy, and peritoneal cytologic examination. For grades 2 and 3 and for grade 1 with myometrial invasion, a pelvic and para-aortic lymphadenectomy may be added.
Very few patients with cancer confined to the uterus have recurrences. Accurate surgical staging enab 75% of patients with stage I disease to forego postoperative radiation therapy. Extrapelvic cancer, dep on the site and extent, is treated with extended-field radiation, systemic chemotherapy, or hormone the Most patients with stage IV disease are best treated with systemic chemotherapy.
Progesterone therapy, used for advanced or recurrent disease, leads to regression in 35 to 40% of pa Progesterone can induce regression of pulmonary, vaginal, and mediastinal metastases. Treatment co indefinitely if the response is favorable. The duration of remission varies but may last 2 to 3 yr.
Several cytotoxic drugs (especially doxorubicin and cisplatin) are active against metastatic and recurre endometrial cancer. Monthly regimens combining doxorubicin 60 mg/m2 and cisplatin 75 mg/m 2 IV ma overall response rates of >= 50%. Paclitaxel shows activity against this cancer.

Section 18. Gynecology And Obstetrics Chapter 252. Abnormalities Of Pregnancy Topics
Spontaneous Abortion Ectopic Pregnancy Hyperemesis Gravidarum Preeclampsia And Eclampsia Abruptio Placentae Placenta Previa Erythroblastosis Fetalis Herpes Gestationis Pruritic Urticarial Papules And Plaques Of Pregnancy
Spontaneous Abortion
(Miscarriage)
Abortion is generally defined as delivery or loss of the products of conception before the 20th wk of pre (which corresponds to a fetal weight of about 500 g [1.1 lb]). Delivery between 20 and 37 wk is conside preterm birth (see Preterm Labor in Ch. 253).
Incidence and Etiology
About 20 to 30% of women bleed or have cramping at some time during the first 20 wk of pregnancy; these women spontaneously abort. In up to 60% of spontaneous abortions, the fetus is absent or gros malformed, and in 25 to 60%, it has chromosomal abnormalities incompatible with life; thus spontaneo abortion in > 90% of cases may be a natural rejection of a maldeveloping fetus.
About 85% of spontaneous abortions occur in the 1st trimester and tend to have fetal causes; those o in the 2nd trimester are more likely to have maternal causes. Suggested maternal causes include an incompetent cervix, congenital or acquired anomalies of the uterine cavity, hypothyroidism, diabetes m chronic nephritis, acute infection, use of cocaine (especially crack), immunologic problems, and severe emotional shock. Many viruses--most notably cytomegalovirus, herpesvirus, and rubella virus--have be implicated as causes. The importance of a retroverted uterus, fibroids, and impaired corpus luteum fun appears to have been overestimated. A relationship between abortion and physical trauma (except for trauma with multiple organ injury or multiple major fractures) has not been substantiated.
Classification
implicated as causes. The importance of a retroverted uterus, fibroids, and impaired corpus luteum fun appears to have been overestimated. A relationship between abortion and physical trauma (except for trauma with multiple organ injury or multiple major fractures) has not been substantiated.
Classification
A distinction is made between early (before 12 wk of pregnancy) and late (between 12 and 20 wk) ab because more difficulties are encountered in late abortions. After 12 wk of pregnancy, the definitive pla with a more organized and larger blood supply has begun to form, so bleeding is more likely. Fetal bon also begun to form, and the long bones of the limbs may perforate the uterus during evacuation. Furth dilating the cervix enough to pass a fetus of > 12 wk is difficult. Abortions may also be classified as spontaneous, induced (see Ch. 246), or therapeutic; threatened or inevitable; incomplete or complete; habitual; missed; or septic (see Table 252-1).
Habitual abortion requires extensive diagnostic investigation, including genetic and chromosomal stu Endocrinopathies and metabolic diseases (eg, hypothyroidism, hyperthyroidism, diabetes mellitus, chr renal disease) must be ruled out. Immunologic causes (eg, lupus anticoagulant) should be investigate Defective corpus luteum function is always suspected. Anatomic abnormalities of the uterus (eg, polyp fibroids, congenital defects) should be evaluated by hysterography, dilation and curettage (D & C), or hysteroscopy. Specific treatment, such as drugs to prolong the luteal phase, unification of a double ute excision of a septum, or myomectomy, may be needed.
Missed abortion should be suspected when the uterus fails to enlarge, when fetal heart sounds are n at the appropriate time with Doppler ultrasonography, or when previously present fetal heart sounds ar absent. In a missed abortion, a serum or urine test for the subunit of human chorionic gonadotropin (-h becomes negative earlier than expected or does not double within 72 h; ultrasonography showing no c activity provides the earliest diagnosis. A missed abortion may lead to the dead fetus syndrome, with disseminated intravascular coagulation, progressive hypofibrinogenemia, and possible massive bleedi delivery finally occurs. The syndrome usually develops only when the loss occurs in the 2nd trimester
With a septic abortion, the patient is acutely ill, with symptoms and signs of infection (chills, fever, se and peritonitis) and of threatened or incomplete abortion. Leukocytosis (WBC count, 16,000 to 22,000 present. Critically ill patients may evidence septic or endotoxic shock with vasomotor collapse, hypothe hypotension, oliguria or anuria, and respiratory distress. Causative organisms include Escherichia coli Enterobacter aerogenes, Proteus vulgaris, hemolytic streptococci, staphylococci, and some anaerobic organisms, such as Clostridium perfringens. If sepsis is due to C. perfringens, intravascular hemolysis anemia, jaundice, hemoglobinemia, hemoglobinuria, and hemosiderinuria) and thrombocytopenia with ecchymoses may result. In the USA, before legalization of abortion, septic abortions were often assoc with induced abortions performed by untrained persons using nonsterile techniques (commonly called abortions). The incidence of septic abortion in the USA has fallen dramatically.
Treatment
Treatment of threatened abortion is conservative; bed rest should be suggested because it seems to the amount of bleeding and cramping, but it rarely changes the outcome. The diagnosis should be con with ultrasonography. If the sac is empty or if cardiac activity has disappeared, evacuation of the uteru indicated. Intercourse should be avoided; although no evidence shows that it is harmful, the risk of gui feelings associated with abortion immediately after intercourse warrants abstention. The patient should encouraged not to work and to stay off her feet at home. There is no evidence that hormones save pregnancies except in a very few instances, but they may cause congenital anomalies, particularly transposition of the great vessels of the heart. Also, vaginal cancer and other genital abnormalities in f offspring have been associated with the use of estrogen for threatened abortions.
feelings associated with abortion immediately after intercourse warrants abstention. The patient should encouraged not to work and to stay off her feet at home. There is no evidence that hormones save pregnancies except in a very few instances, but they may cause congenital anomalies, particularly transposition of the great vessels of the heart. Also, vaginal cancer and other genital abnormalities in f offspring have been associated with the use of estrogen for threatened abortions.
Inevitable and incomplete abortions must be completed, usually by suction curettage or occasionall C. Many physicians consider curettage mandatory to ensure that a spontaneous abortion is complet prefer to watch the patient for a few days and, if no further bleeding occurs, avoid curettage.
In spontaneous abortions due to incompetence of the internal cervical os, the cervix seems unable to progressive pressure of the enlarging components of pregnancy and thus begins to dilate. Weakness cervical connective tissue may be congenital (including due to the effects of diethylstilbestrol [DES] ex in utero) or secondary to deep cervical lacerations or previous excessive operative dilation. Cervical ce may enable the pregnancy to continue to term.
Missed abortion should be completed by physician intervention as soon as the diagnosis is certain; w ultrasonography, the death of a fetus can now be identified much earlier, usually within 1 or 2 wk. Up t gestation, missed abortion is frequently managed by inserting a 20-mg dinoprostone (prostaglandin E 2 suppository into the vagina q 3 or 4 h as necessary to produce contractions. The drug is not approved after 28 wk. Pretreatment of the cervix with laminaria decreases complications. In cases of septic abo vigorous antibiotic management and early emptying of the uterus are mandatory to prevent life-threate sepsis.
Late missed abortion may be completed with a dilute IV infusion of oxytocin, which causes contraction uterus and delivery of the products of conception. After the uterus has contracted following delivery of fetus, curettage may be needed to remove fragments of the placenta. Suction curettage is used for pregnancies of up to 18 wk. After that, dilation and evacuation or oxytocic drugs are used.
Psychologic problems may develop in a woman whose first pregnancy ends in spontaneous abortion o has a second or third consecutive spontaneous abortion. Some psychologic upset probably occurs in patient who has an abortion, whether it is spontaneous, therapeutic, or elective. Usually, sympathetic discussion and counseling can help reassure a couple and diminish their difficulties. Many communitie active support groups.

Section 18. Gynecology And Obstetrics Chapter 242. Breast Disorders Topics
[General] Benign Breast Disorders Breast Cancer Paget's Disease Cystosarcoma Phyllodes
[General]
Breast cancer is the most common cancer among women, and symptoms suggesting it are even more common. In the USA, about 15 million women seek medical care each year because of concern abou cancer, and > 190,000 new cases are diagnosed annually. For every woman diagnosed with the disea another 5 to 10 undergo biopsies that prove benign. Other breast disorders, such as mastalgia (assoc with an underlying cyst or unrelated to any findings within the breast) and nipple discharge, also cause to seek medical care.
Section 18. Gynecology And Obstetrics Chapter 253. Abnormalities And Complications Of La Delivery Topics
Induction Or Stimulation Of Labor Preterm Labor Premature Rupture Of Membranes Prolapse Of The Umbilical Cord Amniotic Fluid Embolism Postdatism And Postmaturity Problems In The First And Second Stages Of Labor Problems In The Third Stage Of Labor
Induction Or Stimulation Of Labor
Elective (not medically necessary) induction of labor is rare and usually reserved for patients who l from the hospital or would have difficulty getting there in time for delivery. Some of these patients shou hospitalized when they are near term. Dating must be accurate (see Ch. 249), and amniocentesis for determining lecithin/sphingomyelin (L/S) ratio may be advisable.
When induction of labor is indicated because of obstetric or medical disease, the disease process s under control; reasons for the induction should be precise and should be recorded. The most success safest method for induction is giving dilute oxytocin IV, using an infusion pump for precise control. Lab usually starts at a flow of 0.5 to 2 mU/min; if contractions are inadequate, the dose is increased by 0.5 at 15- to 30-min intervals. A rate of 40 mU/min should not be exceeded or maintained for > 30 min, be that point, water retention becomes a hazard. Rarely is > 10 to 12 mU/min needed. External fetal mon essential. Internal monitoring should be instituted as soon as the membranes can be safely ruptured.
Stimulation or augmentation of labor with oxytocin is indicated when contractions occur in an unsati pattern; before stimulation is attempted, the diagnosis must be reasonably precise. If the patient is in t phase of labor (ie, has little effacement, minimal dilation, and irregular contractions), resting, walking, o support is preferable to using oxytocin. After true labor has begun (4-cm dilation with nearly complete effacement), the cervix should dilate > 1 cm/h. If true labor does not occur, the patient is considered to hypotonic uterine dysfunction. The best treatment is dilute oxytocin stimulation until the pattern of contractions becomes more normal.
Stimulation or augmentation of labor with oxytocin is indicated when contractions occur in an unsati pattern; before stimulation is attempted, the diagnosis must be reasonably precise. If the patient is in t phase of labor (ie, has little effacement, minimal dilation, and irregular contractions), resting, walking, o support is preferable to using oxytocin. After true labor has begun (4-cm dilation with nearly complete effacement), the cervix should dilate > 1 cm/h. If true labor does not occur, the patient is considered to hypotonic uterine dysfunction. The best treatment is dilute oxytocin stimulation until the pattern of contractions becomes more normal.
An occasional patient has hypertonic dysfunctional labor, in which contractions are too strong, too c together, or both. This contraction pattern is difficult to control. Administration of any oxytocic drug sho discontinued promptly. Repositioning the patient and administering an analgesic may help. A tocolytic such as ritodrine, may be effective.
Section 18. Gynecology And Obstetrics Chapter 243. Sexual Dysfunction In Women Topics
[General] Sexual Arousal Disorder Female Orgasmic Disorder Dyspareunia Vaginismus
[General]
Hypoactive sexual desire disorder, the most common type of sexual dysfunction in women, is discusse 192. Sexual anhedonia (decreased or absent pleasure in sexual activity) is not an official diagnosis. I almost always classified under hypoactive sexual desire disorder, because loss of pleasure almost alw results in loss of desire (although loss of desire may occur first). The cause is likely to be depression o anhedonia is acquired and global (with all partners in all situations); interpersonal factors if anhedonia confined to one partner or one situation; or repressive factors (eg, guilt, shame) due to family dysfunct childhood trauma if anhedonia is lifelong. Sexual aversion is the probable diagnosis in lifelong cases.

Section 18. Gynecology And Obstetrics Chapter 254. Postpartum Care Topics
[General] Puerperal Infection Postpartum Hemorrhage Inverted Uterus
[General]
The clinical manifestations of the puerperium (the 6-wk period after delivery)--which generally reflect re of the physiologic changes that occurred during pregnancy--are mild and temporary and should not be confused with more serious conditions. Within the first 24 h, the mother's pulse rate drops, and her temperature may be slightly elevated. Because WBCs increase during labor, marked leukocytosis (to 20,000/L) occurs in the first 24 h postpartum. Vaginal discharge is grossly bloody (lochia rubra) for 3 days, changing over the next 10 to 12 days to pale brown (lochia serosa) and finally to yellowish white alba). The total volume is about 250 mL; intravaginal tampons (changed frequently) or external pads m used to absorb it. Urine temporarily increases in volume and may contain protein and sugar. Loss of fl elevates the Hct and ESR for a few days. The uterus involutes progressively; after 5 to 7 days, it is firm tender, extending midway between the symphysis and umbilicus. By 2 wk, it is no longer palpable abd Contractions of the involuting uterus are often painful (afterpains) and may require analgesics.
Management in the Hospital
The risk of maternal infection, hemorrhage, and pain must be minimized. The mother is observed for 1 completion of the 3rd stage of labor and given periodic uterine massage to make sure that the uterus c and remains contracted, preventing excess bleeding. If the uterus does not remain contracted with ma alone, oxytocin 10 U IM or dilute oxytocin IV drip (10 or 20 U/1000 mL of IV fluid) at 125 to 200 mL/h f h immediately after delivery of the placenta is given. If general anesthesia was used for operative deliv mother is monitored (preferably in a recovery room or a labor, delivery, recovery, and postpartum room type O-negative blood or blood tested for compatibility, and IV fluids must be available for 2 to 3 h afte delivery.
After the first 24 h, postpartum recovery is rapid. A regular diet should be offered as soon as the patie requests food, sometimes shortly after delivery. Full ambulation is encouraged as soon as possible. E to strengthen abdominal muscles may be started after 1 day. Sit-ups performed in bed with the hips an flexed tighten only the abdominal muscles and usually do not cause a backache. Showers can be enc but vaginal douching is prohibited during the early puerperium. Discomfort from an episiotomy can be
After the first 24 h, postpartum recovery is rapid. A regular diet should be offered as soon as the patie requests food, sometimes shortly after delivery. Full ambulation is encouraged as soon as possible. E to strengthen abdominal muscles may be started after 1 day. Sit-ups performed in bed with the hips an flexed tighten only the abdominal muscles and usually do not cause a backache. Showers can be enc but vaginal douching is prohibited during the early puerperium. Discomfort from an episiotomy can be with hot sitz baths several times a day; codeine 30 mg and aspirin 650 mg q 4 h may be required (acetaminophen 650 mg can be given to breastfeeding mothers).
Bladder care is important. Urine retention, bladder overdistention, and catheterization should be avoid possible. Rapid diuresis may occur, especially when oxytocins are discontinued. The woman must be encouraged to void and monitored to prevent asymptomatic bladder overfilling. The woman should be encouraged to defecate before leaving the hospital, although with early discharge, women often leave bowel movement has occurred. Laxatives may be needed for constipation. If a bowel movement has n occurred within 3 days, a mild cathartic can be given. Hemorrhoids can be minimized by maintaining g bowel function and can be treated with warm sitz baths. Regional anesthesia (spinal or epidural) delay ambulation and may delay spontaneous urination.
A CBC should be performed before discharge to verify that the woman is not anemic. Seronegative wo should be immunized against rubella on the day of discharge. If the woman has Rh-negative blood, is sensitized, and has an infant with Rh-positive blood, she should be given Rh0(D) immune globulin 300 within 72 h of delivery to prevent sensitization; this drug produces a high titer of anti-Rh.
The breasts may become painfully engorged during early lactation, when the amount of milk is beginn increase. Managing engorgement in the breastfeeding mother is discussed under Infant Nutrition in Ch the mother is not going to breastfeed, lactation can be suppressed by firmly supporting the breasts, be gravity stimulates the let-down reflex and encourages milk flow. Many mothers find that tight binding o breasts, restriction of oral fluid intake, and aspirin prn followed by firm support are effective, with symp lasting only 3 to 5 days.
Postpartum depression ("baby blues") can appear within 24 h of delivery, is usually limited in duration h), and is very common. The depression may require treatment if it lasts > 72 h or is associated with la interest in the infant, suicidal or homicidal thoughts, hallucinations, or psychotic behavior. True psycho probably reflects the exacerbation of preexisting mental illness in response to the physical and psycho stress of pregnancy and delivery; psychotherapy is needed.
Management at Home
The mother and child can be discharged within 24 h postpartum; many family-centered obstetric units discharge patients as early as 6 h postpartum if major anesthesia was not used and no complications occurred. Drugs may be offered for pain as necessary but should be limited in breastfeeding mothers, most drugs are secreted in breast milk (see also Drugs in Lactating Mothers in Ch. 256). Normal activi be resumed at will. Major problems are rare, but a home visit or close follow-up regimen is necessary.
Prevention of pregnancy for several months to allow complete recovery is in the woman's best interest immunization mandates a delay of 3 mo before a woman should become pregnant. Therefore, althoug intercourse may be resumed as soon as desired and comfortable, contraception is required because pregnancy is possible. Oral contraceptives can be started at discharge. A diaphragm should be fitted o complete involution of the uterus, at 6 to 8 wk; meanwhile, foams, jellies, and condoms should be use mothers who are not breastfeeding, earliest ovulation usually occurs about 4 wk postpartum, 2 wk befo first menses. However, conception has been reported as early as 2 wk postpartum, so ovulation can o earlier. Breastfeeding mothers tend to ovulate, then menstruate, usually at 10 to 12 wk postpartum. An occasional breastfeeding mother ovulates and menstruates (and becomes pregnant) as quickly as one
pregnancy is possible. Oral contraceptives can be started at discharge. A diaphragm should be fitted o complete involution of the uterus, at 6 to 8 wk; meanwhile, foams, jellies, and condoms should be use mothers who are not breastfeeding, earliest ovulation usually occurs about 4 wk postpartum, 2 wk befo first menses. However, conception has been reported as early as 2 wk postpartum, so ovulation can o earlier. Breastfeeding mothers tend to ovulate, then menstruate, usually at 10 to 12 wk postpartum. An occasional breastfeeding mother ovulates and menstruates (and becomes pregnant) as quickly as one not breastfeeding.
Section 18. Gynecology And Obstetrics Chapter 244. Medical Examination Of The Rape V Topics
[General]
[General]
Rape is the illegal sexual penetration of any body orifice. The definition does not include touching with penetration, but in some jurisdictions, it includes penetration of body orifices by inanimate objects. Exc when a child is seduced by offers of affection or bribes, rape is usually a criminal sexual act using thre force against an unwilling person. Date rape is a variant of sexual assault in which the victim accepts a but the perpetrator (usually male) subsequently forces coitus on the victim without her consent. Statuto is sexual intercourse with a minor; the definition of "minor" varies by state.
In the USA, 75,000 rapes of females are reported each year; estimates of unreported rape range from times that number. About 90% of rapists attack persons of the same race; 50% are known to their vict are often members of the extended family. This finding is important for preteen and teenage victims an implications for follow-up and prevention of child abuse (see also Ch. 264). Most rapes are planned (n impulsive), and more than half the attacks involve a weapon, usually a knife. About 50% of female rap have signs of physical trauma; > 10% require emergency treatment.
Some rape victims are males. Rape of males is not limited to those in prison. The male victim is more than the female to have physical trauma, to have been victimized by several assailants, and to be unw report the crime. A few cases of female rapes of males have been reported.
For both male and female perpetrators, rape is an expression of aggression, anger, or need for power violent more than a sexual act.
Evaluation
Although providing medical and psychologic care for the rape victim is the first concern, rape is a crime forensic medicine has certain requirements for medical evaluation and record keeping. Table 244-1 is for examination procedures and the medical record; it should be adapted to local requirements. Such is sometimes admissible in court and may aid recall if testimony is required later. Unless a subpoena i the record should never be released without written consent of the patient. Whenever possible, the patient should be treated in a rape treatment center that is separate from the
forensic medicine has certain requirements for medical evaluation and record keeping. Table 244-1 is for examination procedures and the medical record; it should be adapted to local requirements. Such is sometimes admissible in court and may aid recall if testimony is required later. Unless a subpoena i the record should never be released without written consent of the patient. Whenever possible, the patient should be treated in a rape treatment center that is separate from the emergency department and staffed by trained, concerned support personnel.
History and physical examination: A brief description of the assault indicates areas for medical inve and treatment; recounting the events is often frightening for the patient, and a complete description ma to be deferred until immediate needs have been met. The reasons for the questions and for the exami procedure are not always clear to patients; eg, the female patient may need to be told that knowing wh last menstrual period was or if she uses a contraceptive helps determine the risk of pregnancy or that information about the time of the previous coitus helps establish the validity of sperm testing.
Because these patients have experienced coercion, enlisting their cooperation and requesting permiss the examination are important. Details of the pelvic examination should be described and explained as proceeds, and the results should be reviewed with the patient. Because being examined by a physicia opposite sex may make the patient feel anxious, a nurse or volunteer of the patient's sex should be pr give support and to corroborate the procedures.
The evidence collected during the examination and all laboratory specimens should be placed in indiv packages and carefully labeled, dated, and sealed. Receipts for them should be obtained when they a delivered to the laboratory or police. Collection of samples for DNA genetic testing to identify the assa not routine; it depends on the jurisdiction. Accurate testing is difficult, and some experts believe that on Federal Bureau of Investigation (FBI) can properly perform it. The FBI's help may be requested, althou FBI cannot investigate all rape cases. Also, the legal use of the results of such testing is controversial, depending on the jurisdiction.
Psychologic assessment: Rape presents psychologic and social problems for the victims, who must their own feelings as well as face the often negative reactions (eg, judgmental, derisive) of friends, fam officials. Patients should be viewed as undergoing posttraumatic stress disorder (see Ch. 187), which has an acute phase lasting a few days to a few weeks, followed by a long-term process of reorganizat recovery.
Common intermediate reactions are fear and anger; patients' outward responses range from talkativen tenseness, crying, and trembling to shock and disbelief, with dispassion, quiescence, and smiling. The responses rarely indicate lack of concern; rather, they may be avoidance reactions or may reflect phys exhaustion or coping styles that require control of emotion. Usually, patients are severely frightened an embarrassed and feel degraded. The anger felt by many victims may be displaced onto hospital staff members, who should be aware of this process and not be troubled by it.
Long-range effects of rape include reexperiencing the assault (flashbacks), aversion to sex, anxiety, p suspiciousness, depression, nightmares, sleep disorders, somatic symptoms, and social withdrawal. S women become promiscuous and act out of character. Guilt and shame occur when patients feel at fa somehow they provoked or should have prevented the attack or that the attack was a punishment for s wrongdoing.
The physician's report may include a brief account of the attack in the patient's words and a statement physician's clinical determination as to injuries and sexual activity. Stating whether rape occurred is no necessary because that is a legal determination, but a diagnosis should be recorded, including all prob possible physical and psychologic problems.
Treatment
The physician's report may include a brief account of the attack in the patient's words and a statement physician's clinical determination as to injuries and sexual activity. Stating whether rape occurred is no necessary because that is a legal determination, but a diagnosis should be recorded, including all prob possible physical and psychologic problems.
Treatment
Physical trauma: Most injuries are minor and can be treated conservatively, but severe injuries can o may require surgical repair. Laceration of the upper vagina may require laparoscopy to determine the the injury, especially in children.
Psychologic trauma: Overall, the psychosocial aspects are the most potentially damaging and requir sophisticated management. Treating patients with respect, ensuring that they are not left alone, assuri that they are safe, demonstrating understanding and empathy, and explaining in detail how the evalua proceed are very important.
An unhurried, nonjudgmental, willing-to-listen attitude in the examiner is therapeutic. Because patients traumatized and may be embarrassed by disclosing details, they often omit important data. Therefore, details of the assailant's aggression, threats, and violent behavior and of the sex acts committed must elicited with careful questioning. Empathy can be shown by acknowledging that the questions may be embarrassing or may exacerbate the patient's fears. Properly done, such a potentially distressing inter may begin the therapeutic process. The full psychologic effect cannot be ascertained at the first exam and follow-up visits must be scheduled. During the first examination, possible psychologic and social s should be explained to the patient, and introduction to a person trained in rape crisis intervention shou arranged. If the patient's acute stress reactions do not subside (noted during follow-up visits) or if long psychologic problems seem likely, psychiatric referral is indicated. Some patients appear to adjust quic unconsciously denying the rape and rapidly returning to normal activities but later manifest the sympto signs of posttraumatic stress disorder.
Support network: The physician often has to deal with the intense reactions of family and friends, wh sources of support or of additional stress. In the immediate situation, the physician should meet with th concerned persons and try to decrease their strong feelings of anxiety, anger, or guilt, because these usually increase the intensity of the patient's emotional reactions. Family and friends must be shown h listen supportively to the patient--they can do this only if they control their feelings when they are with t patient. A support network of health care workers, friends, and family in combination with long-term ca vital.
Prophylaxis for sexually transmitted disease: Because the risk of becoming infected with a sexuall transmitted disease (eg, gonorrhea, chlamydia, syphilis, hepatitis) is almost always a concern, prevent measures should be taken. Hepatitis B and rapid plasma reagin testing is appropriate. In most rape ce the patient is questioned about hypersensitivity to penicillin. Prophylaxis consists of ceftriaxone 250 m single dose, metronidazole 2 g po in a single dose, and doxycycline 100 mg po bid for 7 days. Tests fo gonorrhea, chlamydia, syphilis, and hepatitis should be performed again within 6 wk. Another test for s and hepatitis should be performed at 6 mo.
Transmission of HIV is always a concern, despite the low odds of acquiring it in a single encounter. Af counseling and with informed consent of the patient, the clinician should suggest that blood samples b during the initial examination and 90 and 120 days afterward. If any test is positive, treatment with anti therapy should be instituted immediately (see Ch. 163).
Prophylaxis for pregnancy: Pregnancy after rape is very rare. Factors determining the possibility of a pregnancy include when the patient's last menstrual cycle occurred and whether contraceptives were u With tests for human chorionic gonadotropin, pregnancy can be detected easily and very early (see Ch
during the initial examination and 90 and 120 days afterward. If any test is positive, treatment with anti therapy should be instituted immediately (see Ch. 163).
Prophylaxis for pregnancy: Pregnancy after rape is very rare. Factors determining the possibility of a pregnancy include when the patient's last menstrual cycle occurred and whether contraceptives were u With tests for human chorionic gonadotropin, pregnancy can be detected easily and very early (see Ch test should be performed within 6 wk. However, morning-after contraception should be offered. Two ta an oral contraceptive containing 50 g ethinyl estradiol are given immediately, followed by 2 tablets 12 this treatment is 99% effective if given within 72 h of rape. If 50-g tablets are not available, 4 tablets containing 30 g ethinyl estradiol followed by 4 more tablets 12 h later can be given. Antiemetic drugs oral hydroxyzine, counter the nausea and vomiting due to the contraceptive. If the patient may have be pregnant at the time of the rape, estrogens should not be given until pregnancy is ruled out. If pregnan results from the rape, the patient's attitude toward the pregnancy and abortion should be determined, appropriate, the option of elective termination should be given.
Additional considerations: Privacy for examination and consultation is needed. The patient should b provided with cleansing facilities and toilet (many patients want to wash--some have been urinated on been raped out of doors--and some want to use a mouthwash). Money or transportation to go home m needed. If a rape crisis team operates in the area, referral can provide helpful medical, psychologic, an support for the victim. The police should be notified.
Section 7. Ear, Nose, And Throat Disorders Chapter 82. Approach To The Patient With Ear Pro Topics
[General] Hearing Loss Tinnitus Vertigo Earache
[General]
Hearing loss, tinnitus, vertigo, earache, and otorrhea are the principal symptoms of ear problems. Whe patient has complaints referable to the ears, a thorough history should be taken, and a physical exami performed with emphasis on the ears, nose, nasopharynx, and paranasal sinuses. In addition, the tee tongue, tonsils, hypopharynx, larynx, salivary glands, and temporomandibular joint should be examine because pain and discomfort may be referred from them to the ears. X rays or CT of the temporal bon often indicated for trauma to the ear, possible basal skull fracture, perforation of the tympanic membra hearing loss, vertigo, facial paralysis, and otalgia of obscure origin. Measurements of auditory and ves functions are very important in the diagnosis of complaints referable to the ears.

Section 7. Ear, Nose, And Throat Disorders Chapter 86. Nose And Paranasal Sinuses Topics
[General] Fractures Of The Nose Septal Deviation And Perforation Epistaxis Nasal Vestibulitis Rhinitis Polyps Wegener's Granulomatosis Disorders Of Smell And Taste Sinusitis Neoplasms
[General]
(See also Foreign Bodies in Ch. 272.)
The nose, including the nasal septum that divides the nasal cavity into two passages, is made of bone cartilage. The paranasal sinuses--maxillary, frontal, ethmoid, and sphenoid--open into the nasal cavity

Section 7. Ear, Nose, And Throat Disorders Chapter 83. External Ear Topics
[General] Obstructions External Otitis Perichondritis Aural Eczematoid Dermatitis Malignant External Otitis Trauma Tumors
[General]
Examination of the external ear focuses on the pinna and the ear canal (external auditory canal).

Section 7. Ear, Nose, And Throat Disorders Chapter 87. Pharynx Topics
[General] Tornwaldt's Cyst Pharyngitis Tonsillitis Peritonsillar Cellulitis And Abscess Parapharyngeal Abscess Velopharyngeal Insufficiency Nasopharyngeal Squamous Cell Carcinoma Squamous Cell Carcinoma Of The Tonsil
[General]
The pharynx, which can be divided into the nasopharynx, oropharynx, and hypopharynx, may be affec inflammation, infection, and carcinoma. Disorders of the nasopharynx, located above the soft palate, i adenoid hypertrophy (see under Bacterial Infections in Ch. 265) and juvenile angiofibroma (see Ch. 27 the oropharynx, located behind the mouth, the main structures to be examined are the palatine and lin tonsils, tongue base, and posterior pharyngeal wall. Retropharyngeal abscess is discussed under Bac Infections in Ch. 265, and Zenker's (pharyngoesophageal) diverticulum under Esophageal Diverticula 20.
Section 7. Ear, Nose, And Throat Disorders Chapter 84. Tympanic Membrane And Middle E Topics
[General] Trauma Barotitis Media Infectious Myringitis Acute Otitis Media Secretory Otitis Media Acute Mastoiditis Chronic Otitis Media Otosclerosis Neoplasms
[General]
A patient with a middle ear disorder may present with one or more of the following complaints: a feelin fullness or pressure in the ear; constant or intermittent mild to excruciating pain; otorrhea; diminished h tinnitus; and vertigo. In acute otitis media, systemic symptoms (eg, fever) are also common. Symptom begin with a feeling of fullness and progress serially and additively. Infants and children, especially, ma febrile and present with other prominent systemic manifestations (eg, anorexia, vomiting, diarrhea, leth
Symptoms may result from infection, trauma, or disturbed pressure relationships secondary to eustach obstruction. In determining the cause, a physician should elicit information about antecedent and asso symptoms (eg, rhinorrhea, nasal obstruction, sore throat, URI, allergic manifestations, headache, syst symptoms). The appearance of the ear canal (external auditory canal) and tympanic membrane (see F often yields a diagnosis. The nose, nasopharynx, and oropharynx should be examined for signs of infe and allergy and for evidence of an underlying disorder--eg, a mass in the nasopharynx.
The function of the middle ear should be evaluated with pneumatic otoscopy, Weber's and Rinne's tes tympanometry, and audiologic assessment (see Ch. 82).

Section 7. Ear, Nose, And Throat Disorders Chapter 88. Larynx Topics
[General] Vocal Cord Polyps Vocal Cord Nodules Contact Ulcers Laryngitis Vocal Cord Paralysis Laryngoceles Benign Neoplasms Malignant Neoplasms
[General]
(For acute laryngotracheobronchitis, see Croup under Viral Infections in Ch. 265.)
Examination of the larynx includes inspection of the epiglottis, false cords, true cords, arytenoids, pyrif sinuses (lateral to the larynx), and subglottic region below the cords. The voice should be assessed: If surgical procedures are to be performed, the voice should be recorded. The mobility of the vocal cords be noted.

Section 7. Ear, Nose, And Throat Disorders Chapter 85. Inner Ear Topics
[General] Meniere's Disease Vestibular Neuronitis Benign Paroxysmal Positional Vertigo Herpes Zoster Oticus Purulent Labyrinthitis Sudden Deafness Noise-Induced Hearing Loss Presbycusis Drug-Induced Ototoxicity Temporal Bone Fractures Acoustic Neuroma
[General]
(See also Hearing Loss and Vertigo in Ch. 82 and Hearing Deficits in Children in Ch. 260.)
The inner ear consists of the auditory portion (cochlea, saccule, acoustic nerve) and the vestibular por (semicircular canals, utricle, superior and inferior vestibular nerves).
Section 7. Ear, Nose, And Throat Disorders Chapter 89. Neoplasms Of The Head And Nec Topics
[General] Cervical Metastases
[General]
Epidemiology
Principles of head and neck neoplasms are presented in general terms, and many specific exceptions statements must be acknowledged. Neoplasms of specific organs are discussed elsewhere in The Ma
Excluding the skin and thyroid gland, > 90% of head and neck cancers are squamous cell (epidermoid carcinomas; 5% are melanomas, lymphomas, and sarcomas. The average age of patients with head a cancers is 59 yr; those with sarcomas or carcinomas of the salivary glands, thyroid gland, or paranasa are usually < 59 yr; those with squamous cell carcinoma of the oral cavity, pharynx, or larynx are gene 59 yr.
The most common cancer of the upper respiratory and alimentary tracts is squamous cell carcinoma o larynx, followed by squamous cell carcinoma of the palatine tonsil and hypopharynx. About 85% of pa with cancer of the head and neck have a history of ethanol or tobacco consumption. Oral cavity cance also result from poor oral hygiene, ill-fitting dental appliances, and use of snuff or chewing tobacco; in chewing betel nut is a major cause.
The Epstein-Barr virus plays a role in the pathogenesis of nasopharyngeal cancer. Patients who were with small doses of radiation >= 25 yr ago (for acne, excess facial hair, an enlarged thymus, or hypertr tonsils and adenoids) are predisposed to develop thyroid and salivary gland cancer.
Head and neck cancers usually remain localized to the head and neck for months to years. Local tissu invasion is followed by metastasis to regional lymph nodes. Distant lymphatic metastases tend to occu Hematogenous metastases are usually associated with large or persistent tumors and occur more com in immunocompromised patients.
Head and neck cancers usually remain localized to the head and neck for months to years. Local tissu invasion is followed by metastasis to regional lymph nodes. Distant lymphatic metastases tend to occu Hematogenous metastases are usually associated with large or persistent tumors and occur more com in immunocompromised patients.
Clinical Staging and Prognosis
Head and neck cancers are traditionally classified clinically according to size and site of the primary ne (T), number and size of metastases to the cervical lymph nodes (N), and evidence of distant metastas several stages are described. Stage I: The primary neoplasm is <= 2 cm at greatest dimension or loca one anatomic site without regional or distant metastasis (T1N0M0). Stage II: The primary neoplasm m 2 to 4 cm at greatest dimension or affects two areas within a specific site (eg, larynx) without regional metastasis (T2N0M0). Stage III: The primary neoplasm is > 4 cm at greatest dimension or affects thre adjacent areas in a specific head and neck site and/or has an isolated neck metastasis of <= 3 cm at g dimension (T3N0M0 or T1-3N1M0). Stage IV: The cancer is massive, invades bone and cartilage, and extends outside of its site of origin into another site (eg, oral cavity into oropharynx). The neck metasta measures > 3 cm; it affects multiple ipsilateral, contralateral, or bilateral lymph nodes or is fixed to surr tissue; and/or there is evidence of distant metastases (T1-4N1-3M0-1). Clinical staging is usually supplemented by radiologic staging using CT and/or MRI.
Exophytic or verrucous tumors generally respond to treatment better than do infiltrative, ulcerative, or i lesions. Cervical or distant metastasis is associated with limited survival. The more poorly differentiate cancer, generally the greater the chance of regional and distant metastases. With invasion of muscle, cartilage, cure rates are lower. Perineural spread as evidenced by pain, paralysis, or numbness indica highly aggressive neoplasm likely to persist.
With appropriate treatment, the survival rate generally approaches 90% for stage I, 75% for stage II, 4 for stage III, and < 35% for stage IV. The overall 5-yr survival rate is 65% for all patients with local stag squamous cell carcinoma of the head and neck. The rate drops to <= 30% for patients with metastasis lymph nodes. Patients > 70 yr often have longer disease-free intervals and better survival rates than d younger patients.
Treatment
Many stage I neoplasms, regardless of location in the upper respiratory or alimentary tract, respond si surgery and to radiation therapy; other factors may determine the choice of therapy. If radiation therap chosen for primary therapy, it is delivered to the primary site and, if the probability of regional nonpalpa metastasis is > 20%, also bilaterally to the cervical lymph nodes. The expected 5-yr cure rate is 90%. cases, surgical procedures are needed to achieve the 90% cure rate. Lesions > 2 cm or with bone or c invasion (with or without regional neck metastasis) require surgical resection of the primary site and po resection of regional lymph nodes. If lymph node metastases are found or deemed very likely to occur postoperative radiation to the primary site and bilaterally to any remaining cervical lymph nodes is gen recommended. As an alternative to surgery, radiation therapy--with or without chemotherapy--may be If the cancer recurs, the patient may have recourse to surgery.
In advanced (most stage II and all stages III and IV) squamous cell carcinoma, a combination of surge radiation therapy offers a better chance of cure than does treatment with either alone. Surgery is more effective than radiation therapy and/or chemotherapy in controlling large primary cancers, whereas rad more effective in controlling the periphery of the primary lesion and microscopic or nonpalpable metas Radiation therapy may be given preoperatively or postoperatively, but the latter is usually preferred. The aim of chemotherapy is to kill tumor cells at the local site, in regional lymph nodes, and in distant
radiation therapy offers a better chance of cure than does treatment with either alone. Surgery is more effective than radiation therapy and/or chemotherapy in controlling large primary cancers, whereas rad more effective in controlling the periphery of the primary lesion and microscopic or nonpalpable metas Radiation therapy may be given preoperatively or postoperatively, but the latter is usually preferred.
The aim of chemotherapy is to kill tumor cells at the local site, in regional lymph nodes, and in distant metastases. Whether adjuvant chemotherapy (combined with surgery or radiation therapy) increases t rate is not known; however, combined therapy prolongs the cancer-free interval. Several drugs--cispla fluorouracil, bleomycin, and methotrexate--provide palliation for pain and shrink the neoplasm in patien cannot be treated with surgery or radiation therapy.
If the cancer is excised after chemotherapy or radiation therapy, the surgeon must remove the tissues were affected by the cancer before nonsurgical therapy was started.
Adverse effects of treatment: Surgery requires rehabilitation for swallowing and speaking. Reconstru procedures, including grafts, regional pedicle flaps, and complex free flaps, are used to facilitate the restoration of function. Radiation produces skin changes, fibrosis, ageusia, xerostomia, and, rarely, osteoradionecrosis. Toxic effects of chemotherapy include severe nausea and vomiting, transient hair gastroenteritis, and hematopoietic and immune depression.
Persisting cancer: A palpable mass or ulcerated lesion with edema or pain at the primary site after th strongly suggests a persistent tumor. Such a tumor is more difficult to detect after radiation therapy or chemotherapy than after surgery alone, but it is usually more difficult to eradicate after surgery alone t radiation therapy and/or chemotherapy. Gallium scanning, CT with enhancement, and MRI can somet detect tumors that are persistent or >= 2 cm.
For adequate local control after surgical failure, all scar planes and reconstructive flaps must be excise addition to the cancer. Radiation and/or chemotherapy given after surgical failure is much less effectiv that given before or immediately after surgery.
Terminal care of persons with incurable head and neck cancers is not easy. Pain, difficulty in eating, c on secretions, and other problems make adequate symptomatic treatment essential. Patient directives regarding terminal care should be clarified early (see Ch. 293).

Section 19. Pediatrics Chapter 255. Introduction Topics
[General]
[General]
Since the mid 1900s, pediatrics has widened its scope to include perinatology and adolescent medicin placed increasing emphasis on health promotion and on the prevention and early recognition of diseas through appropriate periodic screening; and has acknowledged the importance and interdependency o organic, functional, behavioral, sociologic, economic, and political aspects of child health care. Most o changes have been prompted by societal changes that have generated disruptions in our homes, scho communities. For many, this has led to poor child rearing, poor individual prospects for success and happiness, and increased stress, self-deprecation, substance abuse, violence, depression, and self-destructive behaviors.
Age groups used in this section are defined as follows: the newborn--birth to 1 mo; the infant--1 mo to early childhood--1 yr through 4 yr; middle childhood--5 yr through 10 yr; adolescence--11 yr through 17 term "child" may be used in a general way from birth on, as in discussions of the number of children in family.
Prenatal diagnosis and genetic counseling are discussed in Ch. 247. Diseases and disorders occurring pediatric age group that are also prevalent in adults are covered more fully elsewhere in The Manual.

Section 19. Pediatrics Chapter 266. Neoplasms Topics
[General] Wilms' Tumor Neuroblastoma Retinoblastoma
[General]
Childhood neoplasms are also discussed elsewhere in The Manual (eg, leukemias are discussed in C and brain tumors in Ch. 177).
Section 19. Pediatrics Chapter 256. Health Management In Normal Newborn And Children Topics
Perinatal Physiology Initial Care Health Supervision Of The Well Child Growth And Physical Development Psychomotor And Intellectual Development Childhood Immunizations Infant Nutrition Common Feeding And Gastrointestinal Problems
Perinatal Physiology
Ventilation and Lung Function
The successful transition of the term fetus, immersed in amniotic fluid and totally dependent on the pla for gas exchange, nutrition, and excretion, to a squalling air-breathing newborn is a source of wonder. Neonatal disorders represent the failure of this transition. Several areas of perinatal physiology are rev below.
The placenta provides exchange of O2 and CO2 for the fetus. Fetal lungs develop throughout gestation fairly well developed alveoli are present by the 25th wk. The fetal lungs continually produce fluid, a tran from pulmonary capillaries plus some pulmonary surfactant secreted by type II pneumocytes.
Fetal breathing movements occur intermittently, usually about 1/3 of the time during rapid eye movem sleep. Lung fluid moves up through the tracheobronchial tree and contributes to amniotic fluid. Fetal b movements appear to be essential for lung development and for the neuromuscular control of breathin the newborn needs to survive.
For normal gas exchange to occur at birth, pulmonary alveolar and interstitial fluid must be cleared pro There are two mechanisms to accomplish this: (1) During vaginal delivery, the fetal thorax is compress expelling some lung fluid. As the thorax is delivered, elastic recoil of the ribs draws some air into the p tree. The first strong inspiratory efforts further fill the alveoli with air. (2) Fetal epinephrine and norepin levels rise during labor and increase the active absorption of sodium and fluid across the respiratory e via epithelial sodium channels. Neonatal wet lung syndrome (transient tachypnea of the newborn--see
For normal gas exchange to occur at birth, pulmonary alveolar and interstitial fluid must be cleared pro There are two mechanisms to accomplish this: (1) During vaginal delivery, the fetal thorax is compress expelling some lung fluid. As the thorax is delivered, elastic recoil of the ribs draws some air into the p tree. The first strong inspiratory efforts further fill the alveoli with air. (2) Fetal epinephrine and norepin levels rise during labor and increase the active absorption of sodium and fluid across the respiratory e via epithelial sodium channels. Neonatal wet lung syndrome (transient tachypnea of the newborn--see Respiratory Disorders in Ch. 260) is probably caused by delay in the active resorption of fetal lung sod fluid via epithelial sodium channels.
Because fetal lung alveoli are filled with fluid, surface tension is not an issue in fetal breathing moveme Following the first breath after birth, the alveoli contain air, and because a layer of fluid lines the alveol surface, air-fluid interfaces then exist. At the first breath, pulmonary surfactant is normally secreted int layer of fluid; otherwise, excessively high surface tension would cause alveolar collapse (atelectasis) a greatly increase the work of breathing. Pulmonary surfactant (a complex mixture of phospholipids, incl phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, neutral lipids, and three surface active proteins) is largely stored in lamellar inclusions in the type II pneumocytes and is released in large am with the first breath.
By 34 to 35 wk gestation, enough surfactant usually is produced to prevent diffuse atelectasis, the prim defect in respiratory distress syndrome (see in Ch. 260).
Circulation
In fetal circulation, pulmonary arteriolar resistance is very high, so that there is little blood flow to the lu (only 5 to 10% of cardiac output). By contrast, there is low resistance to blood flow in the systemic circ largely because of low resistance to blood flow through the placenta. Low fetal systemic Pa O2 (about 2 Hg) along with locally produced prostaglandins keeps the fetal ductus arteriosus open. Because of the pulmonary resistance, blood ejected by the right ventricle flows from right to left, from the pulmonary a through the ductus arteriosus into the aorta. Another right-to-left shunt occurs through the patent foram ovale. Left atrial pressure is low in the fetus because little blood is returned from the lungs, while right pressure is relatively high, because large volumes of blood return from the placenta. The difference in pressures keeps the flap of the foramen ovale open and permits blood to shunt from the right to the le
A profound change in the circulation occurs after the first few breaths, resulting in increased pulmonar flow and closure of the foramen ovale. Pulmonary arteriolar resistance drops acutely as a result of vas caused by expansion of the lungs, by increased PaO2, and by reduced PaCO2 . Air breathing also crea alveolar air-fluid interfaces that exert force toward alveolar collapse (see above); these forces are opp the elastic forces of the ribs and chest wall. As a result, pulmonary interstitial pressure drops, further enhancing blood flow through the pulmonary capillaries.
As pulmonary blood flow is established, venous return from the lungs increases and left atrial pressure raised. Air breathing increases the PaO2, which causes the umbilical arteries to constrict. Placental blo is reduced or stops, and blood return to the right atrium is reduced. Thus, right atrial pressure decreas left atrial pressure increases; as a result, the foramen ovale closes.
Soon after birth, systemic resistance becomes higher than pulmonary resistance, a reversal from the f state. Therefore, the direction of blood flow through the patent ductus arteriosus reverses, creating lef shunting of blood (called transitional circulation). This state lasts from moments after birth (when the pulmonary blood flow increases and functional closure of the foramen ovale occurs) until about 24 h o when the ductus arteriosus closes. Blood entering the ductus and its vasa vasorum from the aorta has Po2 , which, along with alterations in prostaglandin metabolism, leads to constriction and closure of the arteriosus. Once the ductus arteriosus closes, an adult-type circulation exists. The two ventricles now
state. Therefore, the direction of blood flow through the patent ductus arteriosus reverses, creating lef shunting of blood (called transitional circulation). This state lasts from moments after birth (when the pulmonary blood flow increases and functional closure of the foramen ovale occurs) until about 24 h o when the ductus arteriosus closes. Blood entering the ductus and its vasa vasorum from the aorta has Po2 , which, along with alterations in prostaglandin metabolism, leads to constriction and closure of the arteriosus. Once the ductus arteriosus closes, an adult-type circulation exists. The two ventricles now series, and there are no major shunts between the pulmonary and systemic circulations.
During the first days after birth, a stressed newborn may revert to a fetal-type circulation. Asphyxia wit hypoxia and hypercarbia causes the pulmonary arterioles to constrict and the ductus arteriosus to dila reversing the processes described above and resulting in right-to-left shunting through the now patent arteriosus and/or the reopened foramen ovale. Consequently, the newborn becomes severely hypoxem condition called persistent pulmonary hypertension or persistent fetal circulation (of course, there is no umbilical circulation). The goal of treatment is to reverse the conditions that produced pulmonary vasoconstriction.
Bilirubin Excretion
This process begins during fetal life. Aged or damaged RBCs are removed from the circulation by reticuloendothelial cells, which then convert the heme to bilirubin (1 g of Hb yields 34 mg of bilirubin). T unconjugated bilirubin, which is bound to serum albumin, is then transported in the circulation to the liv hepatocytes, which contain binding proteins, take up free bilirubin from blood in the hepatic sinusoids. Glucuronyl transferase then conjugates the bilirubin with uridine diphosphoglucuronic acid (UDPGA) to bilirubin diglucuronide (conjugated bilirubin), which is secreted actively into the bile ducts. The bilirubin diglucuronide makes its way into meconium in the GI tract but cannot be eliminated from the body, bec the fetus does not normally pass stools. The enzyme -glucuronidase, present in the fetus' small intesti luminal brush border, is released into the intestinal lumen, where it deconjugates the bilirubin glucuron (unconjugated) bilirubin is then reabsorbed from the intestinal tract and reenters the fetal circulation. T bilirubin is cleared from the circulation by placental transfer into the mother's plasma following the concentration gradient. The maternal liver then conjugates and excretes the fetal bilirubin.
At birth, the placenta is "lost" and the newborn's liver must then effectively take up, conjugate, and exc bilirubin into bile so it can be eliminated when the newborn passes stools. However, the newborn lacks intestinal bacteria for oxidizing bilirubin to urobilinogen in the gut; consequently, unaltered bilirubin exc the stools imparts a typical bright-yellow color. The newborn's GI tract (like that of the fetus) contains -glucuronidase, which deconjugates some of the bilirubin so that unconjugated bilirubin can be reabso returned to the circulation from the intestinal lumen (enterohepatic circulation of bilirubin), contributing physiologic hyperbilirubinemia and physiologic jaundice (see also Ch. 260). Feedings produce the gas reflex, and bilirubin is then excreted in the stools before most of it can be deconjugated and reabsorbe
Fetal Hemoglobin
Because of the high O2 affinity of fetal Hb, a high O2 concentration gradient is maintained across the p resulting in abundant O 2 transfer from the maternal to the fetal circulation. This increased O2 affinity is useful after birth, because fetal Hb gives up O 2 to tissues less readily; this may be deleterious if sever pulmonary or cardiac disease with hypoxemia exists. The transition from fetal to adult Hb begins befor
The abrupt increase in PaO2 from about 25 to 30 mm Hg in the fetus to 90 to 95 mm Hg in the normal causes serum erythropoietin to fall, which explains the shutdown of RBC production that normally occu birth and persists for 6 to 8 wk. This bone marrow shutdown results in physiologic anemia, particularly
useful after birth, because fetal Hb gives up O 2 to tissues less readily; this may be deleterious if sever pulmonary or cardiac disease with hypoxemia exists. The transition from fetal to adult Hb begins befor
The abrupt increase in PaO2 from about 25 to 30 mm Hg in the fetus to 90 to 95 mm Hg in the normal causes serum erythropoietin to fall, which explains the shutdown of RBC production that normally occu birth and persists for 6 to 8 wk. This bone marrow shutdown results in physiologic anemia, particularly premature newborns whose body mass and blood volume are now increasing rapidly. However, the fa eventually results in reduced tissue O2 tension and an appropriate increase in erythropoietin release, w stimulates the bone marrow to produce new RBCs. Erythropoietin may prove to be effective in treating of prematurity (not to be confused with iron-deficiency anemia, which does not usually occur until age mo).
Immunologic Status of the Fetus and Newborn
At birth, most immune mechanisms function relative to gestational age, but, even in term infants, funct lower than in adults. Thus, the newborn and young infant (especially between ages 3 and 12 mo) have significant transient immunodeficiency involving all limbs of the immune system, putting the newborn a overwhelming infection. This risk can be enhanced by prematurity, traumatic delivery, maternal illness neonatal stress, and drugs (eg, immunosuppressive and antiseizure drugs). The newborn's decreased inflammatory response contributes to increased susceptibility to infections and may help explain the ab of localized clinical signs (eg, fever or meningismus), unlike in older children with infections. (Immuniza are discussed below under Childhood Immunizations.)
PHAGOCYTIC SYSTEM
In the fetus, phagocytic cells, first present at the yolk sac stage of development, are critical for the inflammatory response that combats bacterial and fungal infection. Granulocytes and monocytes can identified in the 2nd and 4th mo of gestation, respectively. Their level of function increases with gestat but is still low at term.
The circulating monocyte is the precursor of the fixed tissue macrophage, which is capable of phagocy utero and has low-to-normal microbicidal activity at term. Pulmonary alveolar macrophages migrate int position at or near birth and help clear the alveoli of amniotic fluid debris and microorganisms. These a tissue macrophages, including those in the spleen, have diminished phagocytic capacity.
At birth, the ultrastructure of neutrophils is normal, but membrane deformability and adherence are de possibly influencing cell functions such as chemotaxis and phagocytosis. Neutrophil and monocyte phagocytosis and microbial killing usually are normal in healthy infants after 12 h of age but are decrea low-birth-weight or stressed term newborns.
In most newborns, chemotaxis of neutrophils and monocytes is decreased because of an intrinsic abn of cellular locomotion and adherence to surfaces. The latter can be attributed to failure to up-regulate surface expression of adhesion glycoproteins and to decreased fibronectin. Neonatal serum also has a decreased ability to generate chemotactic factors (substances that attract phagocytes to sites of micro invasion). Decreased chemotaxis of neonatal monocytes may contribute to their cutaneous anergy. Chemotaxis does not reach adult levels until the child is several years old. Opsonization is necessary for efficient phagocytosis of many microorganisms. Serum opsonic factors IgG and IgM antibody (heat-stable) and complement (heat-labile). Unlike IgG, IgM and complement
decreased ability to generate chemotactic factors (substances that attract phagocytes to sites of micro invasion). Decreased chemotaxis of neonatal monocytes may contribute to their cutaneous anergy. Chemotaxis does not reach adult levels until the child is several years old.
Opsonization is necessary for efficient phagocytosis of many microorganisms. Serum opsonic factors IgG and IgM antibody (heat-stable) and complement (heat-labile). Unlike IgG, IgM and complement components do not cross the placenta. IgM opsonizes gram-negative bacteria more efficiently than do but complement is needed for optimal serum opsonic activity. Synthesis of complement components b early as 5 wk gestation, but levels of most classical and alternative pathway components reach only 50 of adult levels by term. WBCs in newborns have normal Fc and C3 receptors for both groups of opson the C3 receptors are slow to undergo increased expression on the cell surface after stimulation. Serum opsonic activity varies with gestational age, being decreased in low-birth-weight infants for all organism and in term infants usually for some organisms, particularly gram-negative bacteria. Decreased serum activity is at least partly responsible for the decreased efficiency of the reticuloendothelial system at bi
CELLULAR (T-CELL) IMMUNITY
At about the 6th wk of gestation, the thymus begins to form from the epithelium of the 3rd and 4th pha pouches. At 8 wk, the thymus develops rapidly; by 12 wk, it has developed cortex and medullary areas wk, the major thymocytic subsets (triple negative thymocytes: CD3-, CD4-, CD8-; double positive thym CD4+, CD8+; and single positive thymocytes: CD4+ or CD8+) are present in the thymus. Also by 14 wk and CD8 + T cells are present in the fetal liver and spleen, indicating that mature T cells are establishe peripheral lymphoid organs by this age.
The thymus is most active during fetal development and in early postnatal life. It grows rapidly in utero readily noted on chest x-ray in the normal newborn, reaching a peak size at age 10 yr, then involuting over many years. The thymus is considered the mediator of tolerance to "self" antigens during the feta perinatal periods and is essential for the development and maturation of peripheral lymphoid tissue. T epithelial elements in the thymus produce humoral substances, eg, cytokines that are important in T-c differentiation and maturation.
The number of T cells in the fetal circulation gradually increases during the 2nd trimester and reaches normal levels by 30 to 32 wk gestation. At birth, the newborn has a relative lymphocytosis compared to adult, with an increased CD4+/CD8+ ratio that reflects a relatively low percentage of CD8+ T cells. Afte changes in lymphocytic subsets occur in the peripheral T-cell compartment. However, in contrast to ad newborn T-cell compartment contains mostly naive CD4+ T cells expressing CD45RA and little CD29. contrast, adult peripheral blood lymphocytes are mostly CD4+ memory T cells that express CD45RO a relatively high levels of CD29. The significance of this difference in T-cell membrane markers may rela differences in the ability of T-cell subpopulations to respond to antigen and produce cytokines. For exa neonatal T cells provide poor help for B-cell immunoglobulin synthesis. While the secretion of interleuk by neonatal T cells seems to be adequate, the production of many other cytokines, ie, interferon-, IL-4 and IL-3, are deficient compared with adult T cells in response to various stimuli.
At birth, cytotoxic activity, including natural killer, antibody-dependent, and cytotoxic T-cell killer, is considerably lower than in adult lymphocytes. Also, T-cell suppressor activity is considerably increased depending on the stimulus, which may relate to the naive phenotype of CD4+ T cells in the newborn. T effect is a partial T-cell immunodeficiency, which may cause increased susceptibility to infection and, u rare circumstances, engraftment of transfused or maternal lymphocytes. Many factors, such as viral in hyperbilirubinemia, and drugs taken by the mother late in pregnancy, may depress T-cell function in th newborn.
Delayed hypersensitivity skin test responses are diminished until about 1 yr of age. Persistence of mat lymphocytes and graft-vs.-host disease are rare in term infants, which suggests that T-cell function is a
effect is a partial T-cell immunodeficiency, which may cause increased susceptibility to infection and, u rare circumstances, engraftment of transfused or maternal lymphocytes. Many factors, such as viral in hyperbilirubinemia, and drugs taken by the mother late in pregnancy, may depress T-cell function in th newborn.
Delayed hypersensitivity skin test responses are diminished until about 1 yr of age. Persistence of mat lymphocytes and graft-vs.-host disease are rare in term infants, which suggests that T-cell function is a in term infants.
ANTIBODY (B-CELL) IMMUNITY
B cells are present in fetal bone marrow, blood, liver, and spleen by the 12th wk of gestation. Trace am IgM and IgG synthesis occur by the 20th wk and IgA synthesis by the 30th wk. However, because the normally in an antigen-free environment, only small amounts of immunoglobulin (predominantly IgM) a produced in utero. Elevated levels of cord serum IgM (> 20 mg/dL) indicate in utero antigen challenge, from congenital infection. Almost all IgG is acquired maternally from the placenta. After 22 wk gestatio placental transfer of IgG increases to reach maternal levels or greater at term. IgG2 is transported acr placenta less well than the other IgG subclasses (IgG1 > IgG3 > IgG4 > IgG2). IgG levels at birth in pr infants are decreased relative to gestational age.
After birth, catabolism of the transplacental IgG with a half-life of about 25 days results in a physiologic hypogammaglobulinemia by age 2 to 6 mo, which begins to resolve after 6 mo as the infant's rate of Ig synthesis begins to exceed catabolism of maternal antibody. Premature infants, in particular, may bec profoundly hypogammaglobulinemic during the first 6 mo of life. By 1 yr, the IgG level is about 70% of adult levels. IgA, IgM, IgD, and IgE do not cross the placenta. Their levels increase slowly from very lo about 30% of adult levels by 1 yr of age. Adult immunoglobulin levels are reached approximately as fo IgM by 1 yr, IgG by 8 yr, and IgA by 11 yr. Secretory IgA is low or absent in the salivary and GI secretio the newborn until about 1 mo after birth in term infants.
The newborn has deficient antibody responses to many antigens, including those in vaccines. Antibod responses to polysaccharide antigens such as Haemophilus and pneumococcal polysaccharides are p the first 2 yr of life, unless conjugated to diphtheria toxoid. When a response occurs to these bacteria an infection, it is usually accompanied by a prolonged IgM response and a diminished IgG response. T newborns are protected against most potential pathogens by passively acquired maternal antibodies. V birth weight infants are not as protected because the smaller amounts of maternal antibodies disappea 4 mo of age. Nevertheless, premature infants can respond to vaccines, eg, diphtheria-pertussis-tetanu polio, although not as well as term infants.
Passive transfer of maternal immunity as transplacental IgG antibody and immune factors in breast mi compensate for the newborn's immature immune system and gives immunity to many serious bacteria pneumococcus, Haemophilus, meningococcus) and viruses (eg, rubeola, varicella). However, occasio passively acquired IgG can also inhibit the newborn's response to immunization against viruses such a rubeola or rubella. Breast milk contains many antimicrobial factors (eg, IgG, secretory IgA, WBCs, com proteins, lysozyme, and lactoferrin) that coat the GI and upper respiratory tracts and help prevent inva mucous membranes by respiratory and enteric pathogens. Breastfeeding is particularly important whe water supply may be contaminated.
Even with use of antibiotics and attempts to augment the newborn's immature immune system, the mo and mortality due to neonatal infections remain significant. Recent studies suggest a possible role for or hyperimmune globulin in some neonatal infections (eg, group B streptococcal disease and respirato syncytial virus). Although data on their efficacy are conflicting, leukocyte transfusions of adequate dos useful for treating neonatal sepsis. However, more research is needed to assess the situations for whi transfusions can be used.
and mortality due to neonatal infections remain significant. Recent studies suggest a possible role for or hyperimmune globulin in some neonatal infections (eg, group B streptococcal disease and respirato syncytial virus). Although data on their efficacy are conflicting, leukocyte transfusions of adequate dos useful for treating neonatal sepsis. However, more research is needed to assess the situations for whi transfusions can be used.

Section 19. Pediatrics Chapter 267. Cystic Fibrosis Topics
[General]
[General]
Incidence and Etiology
Cystic fibrosis (mucoviscidosis; fibrocystic disease of the pancreas; pancreatic cystic fibrosis): An inhe disease of the exocrine glands, primarily affecting the GI and respiratory systems, and usually charact COPD, exocrine pancreatic insufficiency, and abnormally high sweat electrolytes.
Cystic fibrosis (CF), the most common life-shortening genetic disease in the white population, occurs i USA in about 1/3,300 white births, 1/15,300 black births, and 1/32,000 Asian-American births; 30% of are adults.
CF is carried as an autosomal recessive trait by about 3% of the white population. The gene responsib been localized to 250,000 base pairs of genomic DNA on chromosome 7q (the long arm). It encodes a membrane-associated protein called the cystic fibrosis transmembrane regulator (CFTR). The most co gene mutation, F508 , leads to absence of a phenylalanine residue at position 508 on the CFTR protein found on about 70% of CF alleles; > 600 less common mutations account for the remaining 30%. Alth exact function of CFTR is unknown, it appears to be part of a cAMP-regulated Cl channel and appears regulate Cl and Na transport across epithelial membranes. Heterozygotes may show subtle abnormali epithelial transport but are clinically unaffected.
Persons with congenital bilateral absence of the vas deferens and other causes of obstructive azoosp have an increased frequency of mutations in one or both CFTR genes or an incompletely penetrant m (5T) in a noncoding region of CFTR. Such persons usually have no evidence of respiratory tract or pan disease and may have normal, borderline, or elevated sweat Cl concentrations.
Nearly all exocrine glands are affected in varying distribution and degree of severity. Involved glands a types: those that become obstructed by viscid or solid eosinophilic material in the lumen (pancreas, in glands, intrahepatic bile ducts, gallbladder, submaxillary glands); those that are histologically abnorma
Nearly all exocrine glands are affected in varying distribution and degree of severity. Involved glands a types: those that become obstructed by viscid or solid eosinophilic material in the lumen (pancreas, in glands, intrahepatic bile ducts, gallbladder, submaxillary glands); those that are histologically abnorma produce an excess of secretions (tracheobronchial and Brunner's glands); and those that are histologi normal but secrete excessive Na and Cl (sweat, parotid, and small salivary glands). Duodenal secretio viscid and contain an abnormal mucopolysaccharide. Infertility occurs in 98% of adult men secondary maldevelopment of the vas deferens or to other forms of obstructive azoospermia. In women, fertility is decreased secondary to viscid cervical secretions, but many women with CF have carried pregnancies However, the incidence of maternal complications increases.
Evidence suggests that the lungs are histologically normal at birth. Pulmonary damage is probably init diffuse obstruction in the small airways by abnormally thick mucus secretions. Bronchiolitis and mucop plugging of the airways occur secondary to obstruction and infection. Bronchial changes are more com than parenchymal changes. Emphysema is not prominent. As the pulmonary process progresses, bro walls thicken; the airways fill with purulent, viscid secretions; areas of atelectasis develop; and hilar lym nodes enlarge. Chronic hypoxemia results in muscular hypertrophy of the pulmonary arteries, pulmona hypertension, and right ventricular hypertrophy. Much of the pulmonary damage may be caused by immune-mediated inflammation secondary to the release of proteases by neutrophils in the airways. Bronchoalveolar lavage fluid, even early in life, contains large numbers of neutrophils and increased concentrations of free neutrophil elastase, DNA, and interleukin-8.
Early in the course, Staphylococcus aureus is the pathogen most often isolated from the respiratory tra as the disease progresses, Pseudomonas aeruginosa is most frequently isolated. A mucoid variant of Pseudomonas is uniquely associated with CF. Colonization with Burkholderia cepacia occurs in up to adult patients and may be associated with rapid pulmonary deterioration.
Meconium ileus due to obstruction of the ileum by viscid meconium is the earliest sign (see under Gastrointestinal Defects in Ch. 261) and is present in 15 to 20% of affected newborns. It is often assoc with volvulus, perforation, or atresia and, with rare exceptions, is always followed by other CF signs. C may be associated with delayed neonatal passage of meconium and with the meconium plug syndrom transient form of distal intestinal obstruction secondary to one or more plugs of inspissated meconium anus or colon).
In infants without meconium ileus, disease onset is frequently heralded by a delay in regaining birth we inadequate weight gain at 4 to 6 wk of age.
Infants with CF who have been on soy protein formula or breast milk may develop hypoproteinemia wi edema and anemia secondary to protein malabsorption.
Fifty percent of patients present with pulmonary manifestations, usually chronic cough and wheezing associated with recurrent or chronic pulmonary infections. Cough is the most troublesome complaint, o accompanied by sputum, gagging, vomiting, and disturbed sleep. Intercostal retractions, use of access muscles of respiration, a barrel-chest deformity, digital clubbing, and cyanosis occur with disease prog Upper respiratory tract involvement includes nasal polyposis and chronic or recurrent sinusitis. Adoles may have retarded growth, delayed onset of puberty, and a declining tolerance for exercise. Pulmonar complications in adolescents and adults include pneumothorax, hemoptysis, and right heart failure sec to pulmonary hypertension.
muscles of respiration, a barrel-chest deformity, digital clubbing, and cyanosis occur with disease prog Upper respiratory tract involvement includes nasal polyposis and chronic or recurrent sinusitis. Adoles may have retarded growth, delayed onset of puberty, and a declining tolerance for exercise. Pulmonar complications in adolescents and adults include pneumothorax, hemoptysis, and right heart failure sec to pulmonary hypertension.
Pancreatic insufficiency is clinically apparent in 85 to 90% of patients, usually presents early in life, an be progressive. Manifestations include the frequent passage of bulky, foul-smelling, oily stools; abdom protuberance; and poor growth pattern with decreased subcutaneous tissue and muscle mass despite normal or voracious appetite. Rectal prolapse occurs in 20% of untreated infants and toddlers. Clinica manifestations may be related to deficiency of fat-soluble vitamins.
Excessive sweating in hot weather or with fever may lead to episodes of hypotonic dehydration and cir failure. In arid climates, infants may present with chronic metabolic alkalosis. Salt crystal formation and taste on the skin are highly suggestive of CF.
Insulin-dependent diabetes develops in 10% of adult patients, and multilobular biliary cirrhosis with va portal hypertension develops in 4 to 5% of adolescents and adults. Chronic and/or recurrent abdomina may be related to intussusception, peptic ulcer disease, periappendiceal abscess, pancreatitis, gastroesophageal reflux, esophagitis, gallbladder disease, or episodes of partial intestinal obstruction secondary to abnormally viscid fecal contents. Inflammatory complications may include vasculitis and arthritis.
Diagnosis and Laboratory Findings
The diagnosis of CF is suggested by its characteristic clinical and laboratory features and confirmed b sweat test (see below). In a patient who exhibits one or more phenotypic features consistent with CF o history of CF in a sibling, the diagnosis also can be confirmed by the identification of two known CF m Mutation analysis (testing for CF mutations) can be used for prenatal diagnosis and carrier testing in with a previously affected child. Mutation analysis also can be used for carrier detection in the general population, but it is not yet recommended for population-based screening. The diagnosis is usually con in infancy or early childhood, but 10% of patients escape detection until adolescence or early adulthoo
Pancreatic insufficiency manifests as abnormally viscid duodenal fluid, absence or diminution of enzym activity, and decreased HCO3 - concentration; stool trypsin and chymotrypsin are absent or diminished of fat absorption, including 72-h fecal fat excretion, provide an indirect assessment of pancreatic exoc function. Patients with normal exocrine pancreatic function fail to produce HCO3 - after IV secretin stim About 40% of older patients show a diabetic oral glucose tolerance curve secondary to a reduced and insulin response, but only 10% develop CF-related diabetes mellitus. Fasting blood levels of carotenoi vitamins A and E, essential fatty acids, and cholesterol are reduced in patients with steatorrhea. Total protein is initially normal, but with advanced disease, the 1-, 2-, and -globulin fractions are elevated an albumin is decreased.
The serum concentration of immunoreactive trypsin is elevated in newborns with CF. Measurement of enzyme in conjunction with sweat testing and mutation analysis is the basis of CF newborn screening programs performed in many parts of the world.
Chest x-ray findings may aid in diagnosis. Hyperinflation and bronchial wall thickening are the earlies findings. Subsequent changes include areas of infiltrate, atelectasis, and hilar adenopathy. With advan disease, segmental or lobar atelectasis, cyst formation, bronchiectasis, and pulmonary artery and righ ventricular enlargement occur. Branching, fingerlike opacifications that represent mucoid impaction of
programs performed in many parts of the world.
Chest x-ray findings may aid in diagnosis. Hyperinflation and bronchial wall thickening are the earlies findings. Subsequent changes include areas of infiltrate, atelectasis, and hilar adenopathy. With advan disease, segmental or lobar atelectasis, cyst formation, bronchiectasis, and pulmonary artery and righ ventricular enlargement occur. Branching, fingerlike opacifications that represent mucoid impaction of bronchi are characteristic. In almost all cases, sinus x-rays and CT studies show persistent opacificatio paranasal sinuses.
Pulmonary function tests reveal hypoxemia and reduction in forced vital capacity (FVC), forced expi volume in 1 sec (FEV1 ), and FEV 1/FVC ratio and an increase in residual volume and the ratio of residu volume to total lung capacity. Fifty percent of patients have evidence of airway hyperreactivity.
Sweat test: The diagnosis is confirmed by an elevation of Cl concentration in sweat. The only reliable test is the quantitative pilocarpine iontophoresis test: Localized sweating is stimulated pharmacologica amount of sweat is measured, and its Cl concentration is determined. In patients with a suggestive clin picture or a positive family history, a Cl concentration > 60 mEq/L confirms the diagnosis; probably < 1 patients with CF have a sweat Cl < 50 mEq/L. False-negative results are rare but may occur in the pre edema and hypoproteinemia or with collection of inadequate quantities of sweat. False-positive results usually related to technical errors or inappropriate equipment. Transient elevation of sweat Cl concent can occur in association with environmental deprivation (child abuse, neglect) and in patients with ano nervosa. Although results are valid after the first 24 h of life, it may be difficult to obtain an adequate s sample (> 75 mg on filter paper or > 15 L in microbore tubing) before 3 to 4 wk of age. Although the s concentration normally increases slightly with age, the test is still valid in adults.
A small subset of patients, labeled as having atypical CF, have chronic Pseudomonas bronchitis, norm pancreatic function, and normal or intermediate sweat Cl concentrations.
Patients with CF have increased nasal transepithelial potential differences secondary to increased Na reabsorption across epithelium, which is relatively impermeable to Cl. This observation may be diagno useful when sweat Cl values are borderline or normal and two CF mutations are not identified.
Prognosis
The course, largely determined by the degree of pulmonary involvement, varies greatly. However, dete is inevitable, leading to debilitation and eventual death, usually from a combination of respiratory failur cor pulmonale. The prognosis has improved steadily over the past 5 decades, mainly because of aggr treatment before the onset of irreversible pulmonary changes. Median survival is to age 31 yr. Long-te survival is significantly better in patients without pancreatic insufficiency. Early colonization with mucoi Pseudomonas, female sex, presentation with respiratory symptoms, and airway hyperreactivity are ass with a somewhat worse prognosis. The FEV 1, adjusted for age and sex, is the best predictor of mortal
Treatment
Comprehensive and intensive therapy should be directed by an experienced physician in conjunction w other physicians, nurses, nutritionists, physical and respiratory therapists, counselors, and social work goals of therapy are maintenance of adequate nutritional status, prevention or aggressive therapy of pulmonary and other complications, encouragement of physical activity, and provision of adequate psychosocial support. With appropriate support, most patients can make an age-appropriate adjustme home and school. Despite myriad problems, the occupational and marital successes of patients are impressive.
goals of therapy are maintenance of adequate nutritional status, prevention or aggressive therapy of pulmonary and other complications, encouragement of physical activity, and provision of adequate psychosocial support. With appropriate support, most patients can make an age-appropriate adjustme home and school. Despite myriad problems, the occupational and marital successes of patients are impressive.
For pancreatic insufficiency: Pancreatic enzyme replacement as powder (in infants) or capsules sho given with all meals and snacks. The most effective enzyme preparations contain pancrelipase in pH-s enteric-coated microspheres or microtablets. Infants are usually started at a dose of 2,000 to 4,000 lip U/120 mL of formula or per breastfeeding session. After infancy, weight-based dosing is used starting lipase U/kg/meal for children < 4 yr and at 500 lipase U/kg/meal for those > 4 yr. Usually, half the stan dose is given with snacks. Doses > 2,500 lipase U/kg/meal or 10,000 lipase U/kg/day should be avoide because high enzyme dosages have been associated with fibrosing colonopathy. In patients with high requirements, use of an H2 blocker or proton pump inhibitor may improve enzyme effectiveness.
Diet therapy includes sufficient calories and protein to promote normal growth--30 to 50% more than t recommended dietary allowances may be required (see Table 1-3); a normal-to-high total fat intake to the caloric density of the diet; multivitamins in double the recommended daily allowance; supplementa E in water-miscible form; and salt supplementation during periods of thermal stress and increased swe Infants receiving broad-spectrum antibiotics and patients with liver disease and hemoptysis should be vitamin K supplements. Formulas containing protein hydrolysates and medium chain triglycerides may instead of modified whole milk formulas for infants with severe pancreatic insufficiency. Glucose polym medium chain triglyceride supplements can be used to increase caloric intake. In patients who fail to m adequate nutritional status, enteral supplementation via a nasogastric tube, gastrostomy, or jejunostom restore normal growth and stabilize pulmonary function (see Enteral Nutrition under Nutritional Suppor 1).
For intestinal obstruction in uncomplicated meconium ileus: Obstruction can sometimes be reliev enemas containing a hyperosmolar or iso-osmolar radiopaque contrast material; otherwise, surgical enterostomy to flush out the viscid meconium in the intestinal lumen may be necessary. After the newb period, episodes of partial intestinal obstruction (distal intestinal obstruction syndrome) can be treated enemas containing a hyperosmolar or iso-osmolar radiopaque contrast material or acetylcysteine or by administration of a balanced intestinal lavage solution. A stool softener such as dioctyl sodium sulfosu or lactulose or a prokinetic agent such as metoclopramide may help prevent such episodes.
For pulmonary manifestations: Treatment includes prevention of airway obstruction and prophylaxis and control of pulmonary infection. Prophylaxis against pulmonary infections consists of maintenance pertussis, Haemophilus influenzae, varicella, and measles immunity and annual influenza vaccination. unvaccinated patients, amantadine can be used for prophylaxis against influenza A. There has been n demonstrated increase in susceptibility to or morbidity from pneumococcal infections, and routine use pneumococcal vaccine is not advocated.
Chest physical therapy consisting of postural drainage, percussion, vibration, and assisted coughing is recommended at the first indication of pulmonary involvement (see Ch. 65). In older patients, alternativ clearance techniques such as active cycle of breathing, autogenic drainage, flutter valve device, positi expiratory pressure mask, and mechanical vest therapy may be effective. For reversible airway obstru bronchodilators may be given orally and/or by aerosol and corticosteroids by aerosol. O 2 therapy is ind for patients with severe pulmonary insufficiency and hypoxemia. In general, mechanical ventilation is n indicated for patients with chronic respiratory failure. Its use should be restricted to patients with good status in whom acute respiratory failure develops, in association with pulmonary surgery, or in patients awaiting lung transplantation who develop hypercapnic respiratory failure. Noninvasive positive pressu ventilation by nasal or face mask also can be beneficial. IPPB devices should not be used because th cause a pneumothorax.
indicated for patients with chronic respiratory failure. Its use should be restricted to patients with good status in whom acute respiratory failure develops, in association with pulmonary surgery, or in patients awaiting lung transplantation who develop hypercapnic respiratory failure. Noninvasive positive pressu ventilation by nasal or face mask also can be beneficial. IPPB devices should not be used because th cause a pneumothorax.
Oral expectorants are widely used, but few data support their efficacy. Cough suppressants should be discouraged. Long-term daily aerosol administration of dornase alfa (recombinant human deoxyribonu has been shown to slow the rate of decline in pulmonary function and to decrease the frequency of se respiratory tract exacerbations.
Pneumothorax can be treated by closed chest tube thoracostomy drainage. Open thoracotomy or thoracoscopy with resection of pleural blebs and sponge abrasion of the pleural surfaces is effective in recurrent pneumothoraces. Massive or recurrent hemoptysis is treated by embolizing involved bronchial arteries.
Drug therapy: Oral corticosteroids are indicated in infants with prolonged bronchiolitis and in those p with refractory bronchospasm, allergic bronchopulmonary aspergillosis, and inflammatory complication arthritis and vasculitis). Long-term use of alternate-day corticosteroid therapy can slow the decline in pulmonary function, but because of steroid-related complications it is not recommended for routine us Patients receiving corticosteroids must be closely monitored for evidence of carbohydrate abnormalitie linear growth retardation.
Ibuprofen, when given at a dose sufficient to achieve a peak plasma concentration between 50 and 1 g/mL over several years, has been shown to slow the rate of decline in pulmonary function, especiall children 5 to 13 yr. The appropriate dose must be individualized based on pharmacokinetic studies.
Antibiotics should be used in symptomatic patients to treat bacterial pathogens in the respiratory trac according to culture and sensitivity testing. A penicillinase-resistant penicillin (eg, cloxacillin or dicloxac cephalosporin (eg, cephalexin) is the drug of choice for staphylococci. Erythromycin, amoxicillin-clavul ampicillin, tetracycline, trimethoprim-sulfamethoxazole, or occasionally chloramphenicol may be used individually or in combination for protracted ambulatory therapy of pulmonary infection due to a variety organisms. Ciprofloxacin is effective against sensitive strains of Pseudomonas. For severe pulmonary exacerbations, especially in patients colonized with Pseudomonas, parenteral antibiotic therapy is adv often requiring hospital admission but safely conducted at home in carefully selected patients. Combin an aminoglycoside (tobramycin, gentamicin) with an anti-Pseudomonas penicillin are given IV. Intrave administration of cephalosporins and monobactams with anti-Pseudomonas activity also may be usefu aminoglycoside concentrations should be monitored and dosage adjusted to achieve a peak level of 8 g/mL (11 to 17 mol/L) and a trough value of < 2 g/mL (< 4 mol/L). The usual starting dose of tobr or gentamicin is 7.5 to 10 mg/kg/day in 3 divided doses, but high doses (10 to 12 mg/kg/day) may be r to achieve acceptable serum concentrations. Because of enhanced renal clearance, large doses of so penicillins may be required to achieve adequate serum levels. The goal of treating pulmonary infection be to improve the clinical status sufficiently so that continuous use of antibiotics is unnecessary. Howe some ambulatory patients with frequent pulmonary exacerbations, long-term use of antibiotics may be indicated. In selected patients, long-term tobramycin therapy by aerosol may be effective. Aerosol therapy with ribavirin should be considered in infants with respiratory syncytial viral infection. Patients with symptomatic right heart failure should be treated with diuretics, salt restriction, and O 2.
Surgery: Surgery may be indicated for localized bronchiectasis or atelectasis that cannot be effectivel medically; nasal polyps; chronic sinusitis; bleeding from esophageal varices secondary to portal hyper
Patients with symptomatic right heart failure should be treated with diuretics, salt restriction, and O 2.
Surgery: Surgery may be indicated for localized bronchiectasis or atelectasis that cannot be effectivel medically; nasal polyps; chronic sinusitis; bleeding from esophageal varices secondary to portal hyper gallbladder disease; and intestinal obstruction due to a volvulus or an intussusception that cannot be m reduced. Liver transplants have been performed successfully in patients with end-stage liver disease. Heart-lung and bilateral lung transplants have been performed successfully in patients with advanced cardiopulmonary disease.
Section 19. Pediatrics Chapter 257. Caring For Sick Children And Their F Topics
Parent-Infant Bonding: The Sick Newborn The Chronically Disabled Child
Parent-Infant Bonding: The Sick Newborn
Bonding refers to the strong psychologic attachments between parents and their newborn that begin b birth and are bolstered in the first hours and days after birth. Bonding is influenced by the parents' own childhood experiences, by their cultural and social attitudes toward child rearing, by their personalities, desire to have a child, and by prior psychologic planning for their newborn's arrival. Bonding helps ens parental support in the development of the child's personality (see also Initial Care in Ch. 256).
When a newborn is sick or premature, explanations and realistic encouragement should be given to th parents. Parents should be encouraged to visit their newborn early and frequently and to participate fu care. Supportive attention to the parents helps minimize their anxiety and promotes bonding.
Difficulties can arise when a critically ill newborn must be transferred to an intensive care nursery at a hospital. The parents may be separated from their infant for days or weeks, and the progression of no attachments may not be possible because of distance and anxiety. Parents and close relatives are encouraged to visit the newborn frequently and as soon after birth as possible. After appropriate hand washing, they should be helped to touch or hold the newborn as his condition allows. No newborn, eve respirator, can be considered too ill for the parents to see and touch. Bonding is strengthened if the pa can feed, bathe, apply lotion, and change their newborn and if the mother can provide breast milk for h baby, even if he must initially be fed by tube. (See also The Chronically Disabled Child, below.)
When a newborn has a birth defect, the parents should see him as soon after birth as possible, regard his condition. Otherwise, they may imagine his appearance and condition to be much worse than the r Intensive parental support is essential, with as many counseling sessions as are needed for parents to understand their newborn's condition and needed treatment and to accept him psychologically. The ph should emphasize what is normal about the child and what potential he has and not dwell on his abno
When a newborn has a birth defect, the parents should see him as soon after birth as possible, regard his condition. Otherwise, they may imagine his appearance and condition to be much worse than the r Intensive parental support is essential, with as many counseling sessions as are needed for parents to understand their newborn's condition and needed treatment and to accept him psychologically. The ph should emphasize what is normal about the child and what potential he has and not dwell on his abno
When an infant dies and the parents have never seen or touched him, they may later feel as though th never really had a baby. Such parents have reported exaggerated feelings of emptiness; prolonged pa depression may result because the parents could not grieve for the loss of a "real infant." The process mourning will then be incomplete. Parents who have not been able to see or hold their infant during life usually be helped in the long term if allowed to do so after the infant has died. In all cases, follow-up v the physician and a social worker are helpful to review the circumstances of the infant's illness and de answer questions that often arise later, and to assess and alleviate inappropriate guilt feelings. The ph can also evaluate the parents' grieving process and, if it is pathologic, provide appropriate guidance or referral for more extensive support. If an increased risk of complications exists for future pregnancies, counseling with a geneticist and/or a perinatologist is advisable.

Section 19. Pediatrics Chapter 268. Gastrointestinal Disorders Topics
Recurrent Abdominal Pain Peptic Ulcer Disease Gastroesophageal Reflux Disease Meckel's Diverticulum
Recurrent Abdominal Pain

Three or more episodes of abdominal pain over >= 3 mo. (See also Abdominal Pain in Ch. 25.)
The three types of recurrent abdominal pain (RAP)--psychogenic, organic, and functional--are differen the underlying cause.
Incidence
The incidence in the general pediatric population is slightly > 10%; the girl:boy ratio is 4:3. RAP is rare ages 4 to 5 yr and most common between ages 8 and 10 yr, with a second peak in girls during early adolescence.
RAP is psychogenic in 80 to 90% of patients. Organic and functional RAP occur about equally (each 5 10%), although the precise incidences are unknown.
Psychogenic RAP is thought to arise from stress, anxiety, or depression. Its pathophysiology is unkno What constitutes a stressful situation is relative; patients susceptible to RAP appear to be stressed ea possibly due to events at home (eg, recent illness, financial problems, separation or loss) or at school concern about performance, interpersonal relationships with teachers or peers). RAP itself may cause
Psychogenic RAP is thought to arise from stress, anxiety, or depression. Its pathophysiology is unkno What constitutes a stressful situation is relative; patients susceptible to RAP appear to be stressed ea possibly due to events at home (eg, recent illness, financial problems, separation or loss) or at school concern about performance, interpersonal relationships with teachers or peers). RAP itself may cause by creating new problems (eg, significant school absenteeism, isolation from peers) or by compoundin preexisting problems (eg, sibling rivalry).
Organic RAP is due to an organic disorder, most commonly inflammatory bowel disease, chronic app peptic ulcer disease, Helicobacter pylori infection, parasitism (especially in endemic areas), urinary tra disease, and sickle cell disease. In adolescent girls, pelvic inflammatory disease and ovarian cyst are causes. Other common causes are listed in Table 268-1.
Functional RAP arises from abnormal or changed functioning of a nondiseased organ as a result of interaction between constitutional and environmental factors. Why some persons develop abdominal p others do not is unknown. Perhaps anxiety alters autonomic and GI function, causing pain in susceptib persons.
Symptoms and Signs
Psychogenic RAP may occur daily or several times per week or month. Occasionally, the patient is symptom-free for weeks or months. The pain is generally vague and ill-defined but sometimes is cram colicky or, rarely, sharp. Some patients wake early because of discomfort; unusually, a patient wakes the night because of pain. Pain is most often periumbilical. However, the suggestion that the farther th from the umbilicus, the greater the likelihood of an organic disorder is not diagnostically useful, and psychogenic RAP can mimic any symptom complex. A significant finding is that symptoms progress lit at all. Any change in the location or pattern of pain deserves immediate evaluation because an acute o condition may have intervened.
Organic RAP is commonly described as constant or cyclic (associated with certain activities or related and eating); is well localized, especially to areas other than the periumbilical region; and may penetrat back. It frequently wakes the patient. Associated findings, depending on the underlying disease, includ recurrent or persistent fever; jaundice; changes in bowel consistency, color, or elimination pattern; bloo stools; vomiting; hematemesis; abdominal distention; joint symptoms; change in appetite; and weight l
Functional RAP depends on the underlying cause: Cramping and bloating are common in lactase def cramping pain in a lower quadrant is common with mittelschmerz; and rebound tenderness is sometim present for 1 or 2 h in rupture of a benign ovarian cyst.
Diagnosis
The persistence, recurrence, and chronicity of RAP differentiate it from the pain of an acute abdomen. However, determining whether RAP is psychogenic, organic, or functional can be difficult.
The history should begin with initial onset of pain and its frequency, nature, and location; the relationsh meals, defecation, and voiding; and the results of any treatment (eg, change in position, home remedi and prescription drugs). It is helpful to gather data from parents (or other persons caring for the child). Differences in perception about what precipitates the pain and how the pain is used provide insight int dynamics, which can be useful in developing a management plan that is consistent yet comfortable for parents. Inclusion of the parents underlines the potential role of each in precipitating, perpetuating, an overcoming the pain.
meals, defecation, and voiding; and the results of any treatment (eg, change in position, home remedi and prescription drugs). It is helpful to gather data from parents (or other persons caring for the child). Differences in perception about what precipitates the pain and how the pain is used provide insight int dynamics, which can be useful in developing a management plan that is consistent yet comfortable for parents. Inclusion of the parents underlines the potential role of each in precipitating, perpetuating, an overcoming the pain.
Psychogenic RAP is suggested by a lack of consistent bowel symptoms, fever, weight loss, or growth however, these findings are not pathognomonic. Common associated symptoms include headache, di (not vertigo), facial pallor, and diaphoresis. Fatigue, anorexia, nausea, vomiting, diarrhea, constipation limb pain are less common than in organic or functional RAP.
Psychosocial characteristics consistent with psychogenic RAP include immaturity, unusual dependenc parents, anxiety or depression, apprehension, tension, and perfectionism. Often, parents perceive the special because of the position in the family (only child, youngest child, only male or female in a large or because of a medical problem (colic, eating difficulty). Parents are often anxious, overprotective, authoritarian, and preoccupied with the child. Any possible precipitating factor should be noted (eg, illn family discord, separation and loss, school-related stress), evidence of primary gain (what the child av because of pain) or secondary gain (what psychosocial benefits may be derived from being sick), and child's personality. School records may reveal the effect of the pain on daily functioning in the classroo
A family history of chronic somatic complaints or pain, peptic ulcer disease, headaches, "nerves," or depression is common. The history should include questions about similar or related illnesses in other members, especially in the parents at a similar age.
Most children present when symptom-free. Before a diagnosis of psychogenic RAP is confirmed, the c should be evaluated during a pain episode to look for bowel distention and to ensure that no signs of a organic disorder are overlooked. Except for periumbilical discomfort on palpation of the abdomen, find typically negative. In younger children, a complete physical examination generally should be performe the parents present to impress on them its care and thoroughness. If comfortable for a preadolescent child, the parent of the same sex should stay for the examination.
Between the initial evaluation and the follow-up visit, the child and family should record any pain, inclu nature, intensity, duration, and precipitating factors; diet; defecation pattern; and any remedies tried an results obtained. This record often reveals inappropriate behavior patterns and exaggerated response which support the diagnosis. Once the diagnosis is confirmed, frequent examinations should be avoide because they may focus on or magnify the physical complaints or imply that the physician lacks confid the diagnosis.
Organic RAP, if suspected, requires appropriate testing (see Table 268-1). Peptic ulcer disease is ofte missed because the typical relationship of food intake to epigastric pain in adults is infrequent in childr Peptic Ulcer Disease, below). UTI, which may be experienced as abdominal or pelvic pain with no refe the flank or the urethra, will be missed unless tested for specifically.
Functional RAP is best diagnosed by a thorough history defining associated symptoms or precipitatin (eg, food intake over the preceding 24 h to investigate for allergy or dietary indiscretion; menstrual hist Causes of functional RAP that should be differentiated include inappropriate diet, ineffective toilet train use of a regular toilet seat (which may be too large, causing the child to fear falling in) that lead to con or fecal retention and incontinence; dysmenorrhea; mittelschmerz; and lactose intolerance secondary normal physiologic decline in lactase activity occurring in many patients between ages 10 and 20 yr. B pain may not occur for up to 2 h after ingestion of milk or a milk product, lactose intolerance may not b suspected initially.
Laboratory Findings
or fecal retention and incontinence; dysmenorrhea; mittelschmerz; and lactose intolerance secondary normal physiologic decline in lactase activity occurring in many patients between ages 10 and 20 yr. B pain may not occur for up to 2 h after ingestion of milk or a milk product, lactose intolerance may not b suspected initially.
Laboratory Findings
Laboratory studies should be ordered promptly to allay patient and parent anxiety. However, investiga should be limited to the most likely organic or functional causes of RAP. Initial tests should be directed clinical suspicion and may include Hb, Hct, blood smear, WBC count, and ESR; urinalysis and urine cu examinations of the stool for ova, parasites, H. pylori, blood, pH, and reducing substances; a tuberculi liver function tests; serum amylase levels; and plain x-ray of the abdomen. Further evaluation, includin contrast studies of the GI or urinary tract, EEG, or endoscopy, should be not be done without supportiv clinical evidence (see Table 268-1).
Psychogenic RAP has a guarded long-term prognosis, and no treatment regimen is universally succes Some children later develop other somatic complaints or emotional difficulties. In organic or functional the prognosis depends on the underlying condition.
Psychogenic RAP requires a trusting relationship between the physician and family. The laboratory s and the reason for each should be explained to the patient and family; findings should be shared in de
Even if the physician is fairly certain during the initial visit that the RAP is psychogenic, it is premature suggest specific treatment. Most parents are concerned about an organic cause, and, unless reassure diagnostic work-up and interpretation of the findings, are unlikely to react favorably or consistently to a behavioral management plan. As soon as possible after laboratory findings are available, a follow-up appointment should be scheduled. The family should be reassured that the child is not in physical dan the parents' and child's specific concerns should be addressed. The physician should explain the labo findings and the nature of the problem, describing how the pain is generated and how the child perceiv that the child has a constitutional tendency to feel pain at times of stress (as with back pain or tension headache). Almost invariably, another family member is identified as having a similar problem.
The first step in treating psychogenic RAP is to avoid perpetuating the negative psychosocial consequ chronic pain (eg, prolonged absences from school, withdrawal from peer activities) and to promote age-appropriate activities and increased independence and self-reliance. Such strategies help the chil or tolerate the symptoms while participating fully in everyday activities. However, as parents stop treat child as special or ill, the symptoms may worsen before they abate.
The next step is to work with the family to eliminate or reduce unnecessary stress and help the child c more effectively with unavoidable stress. Involvement of school personnel is critical for children whose interferes with attendance or functioning. The child can rest in the nurse's office during the school day expectation that he will return to class after 15 to 30 min. The nurse can be authorized to dispense a m analgesic (eg, acetaminophen) as necessary. The nurse can sometimes allow the child to call a paren should encourage the child to stay in school. Typically, a child will rest in the nurse's office >= 1 time/d during the first week or two of treatment, then gradually less frequently. Except for occasional use of simple non-aspirin-containing analgesics, drugs are ineffective and not recommended for psychogenic RAP; they may reinforce hypochondriasis or lead to dependency.
Regular follow-up visits should be scheduled (weekly, monthly, or bimonthly, depending on the family's
during the first week or two of treatment, then gradually less frequently. Except for occasional use of simple non-aspirin-containing analgesics, drugs are ineffective and not recommended for psychogenic RAP; they may reinforce hypochondriasis or lead to dependency.
Regular follow-up visits should be scheduled (weekly, monthly, or bimonthly, depending on the family's until a few months after the problem has resolved. Psychiatric referral may be required (up to 50% of f in some reports) when symptoms persist, especially if the child is depressed or the parents have chron marital conflict or serious psychologic difficulties. Hospitalization is usually reserved for patients whose have difficulty accepting a nonorganic diagnosis or in whom further studies (eg, psychologic evaluation interaction observation) are necessary. Hospitalization should be brief and goal-directed to avoid reinfo symptoms or unduly magnifying any aspect of the problem. Organic RAP is managed by treating the underlying cause.
Functional RAP therapy, once the underlying dysfunctional state has been identified, is directed towa (eg, defecating regularly at the same time each day) or diet change, administration of analgesics, and education of the patient or family.
Section 19. Pediatrics Chapter 258. Drug Treatment In Newborns, Infants Children Topics
[General] Drug Dosages Adverse Drug Reactions And Toxicity Compliance
[General]
(See also 22 and Drugs in Lactating Mothers in Ch. 256.)
Effective and safe drug therapy in newborns, infants, and children requires an understanding of matur changes that affect drug action, metabolism, and disposition. Virtually all pharmacokinetic parameters with age. Pediatric drug dosage (in mg/kg) must be adjusted for the kinetic characteristics of individual age (the major determinant), disease states, sex (in the postpubertal child), and individual needs. Othe ineffective treatment or toxicity may result.
Drug absorption: GI drug absorption may be slower than in adults, especially in the newborn with pro gastric emptying time and in children with celiac disease. Absorption of some drugs given intramuscula digoxin, phenytoin) may be erratic in newborns. Dermal and subcutaneous absorption of drugs is rema enhanced in newborns and young infants; eg, topically administered epinephrine may cause systemic hypertension, and dermal absorption of dyes and antibacterials (eg, hexachlorophene) may result in p Theophylline administered subcutaneously to premature newborns with apnea is well absorbed and m therapeutic plasma concentrations.
Drug distribution: Changes in drug distribution during growth parallel changes in body composition (s 258-1). Total body water is greater in newborns (ranging from at least 80% of body weight in prematur newborns to about 70% at full term) than in adults (55 to 60%). Therefore, to maintain equivalent drug concentrations, water-soluble drugs are given in decreasing doses (per kilogram of body weight) with advancing postnatal age. Interestingly, this decline in total body water continues into old age.
Plasma protein binding: Plasma protein binding of drugs is less in newborns than in adults but appro adult capacity a few months after birth. This decreased protein binding could be due to qualitative and quantitative differences in neonatal plasma protein and also to exogenous and endogenous substrates plasma. Decreased protein binding may alter pharmacologic responses and drug clearance but is seld considered in older children. The increased sensitivity of newborns to certain drugs, eg, theophylline, h
Plasma protein binding: Plasma protein binding of drugs is less in newborns than in adults but appro adult capacity a few months after birth. This decreased protein binding could be due to qualitative and quantitative differences in neonatal plasma protein and also to exogenous and endogenous substrates plasma. Decreased protein binding may alter pharmacologic responses and drug clearance but is seld considered in older children. The increased sensitivity of newborns to certain drugs, eg, theophylline, h attributed in part to decreased protein binding, resulting in more available drug at the receptor site and to a more intense pharmacologic effect. Thus, adverse reactions may occur at much lower plasma dru concentrations, considered safe in adults.
Drug metabolism and elimination: The maintenance dose of a drug is largely a function of body clea which depends mainly on rates of metabolism and elimination. These processes tend to be very slow newborn, increase progressively during the first few months of life, and exceed adult rates by the first years of life. Drug elimination slows during adolescence and probably attains adult rates by late puber
Changes in drug metabolism and disposition as a function of age are extremely variable and depend a the substrate or drug. Most drugs, including phenytoin, barbiturates, analgesics, and cardiac glycoside plasma half-lives two to three times longer in newborns than in adults. Other drugs are eliminated very in newborns and young infants; eg, the mean plasma half-life of theophylline is 30 h in the newborn an the adult. Whereas adult rates of elimination for some drugs (eg, barbiturates, phenytoin) may be achi to 4 wk postnatally, others (eg, theophylline) require months.
Metabolism and drug elimination show marked interpatient variability and vulnerability to pathophysiolo states. Moreover, activation of alternative biotransformation pathways occurs in the newborn (eg, conv theophylline to caffeine). These observations have resulted in modified dosages for infants and childre principles are illustrated in Fig. 258-2 by theophylline, a bronchodilator and CNS stimulant commonly u pediatrics. Theophylline is eliminated very slowly in the newborn, reaches adult rates within months, a exceeds them by age 1 to 2 yr. Thus, to maintain drug plasma concentrations within therapeutic range dose/body wt is extremely low during the neonatal period but increases and exceeds adult dosages by 4 yr of age.
Renal elimination is the primary route for antimicrobials, which are the most commonly used drugs in n and young children. Renal elimination depends on GFR and tubular secretion. Both functions are defic the newborn and mature functionally during the first 2 yr of life. Neonatal GFR is about 30% of the adu and is greatly influenced by gestational age at birth. Effective renal blood flow (RBF) affects the rate a drugs are eliminated by the kidneys. The effective RBF is low during the first 2 days of life (34 to 99 mL/min/1.73 m2), increases to 54 to 166 mL/min/1.73 m 2 by 14 to 21 days, and further increases to ad levels of about 600 mL/min/1.73 m 2 by age 1 to 2 yr. Plasma clearance of drugs is significantly increas early childhood after age 1; this is partly due to increased renal and hepatic elimination of drugs in you children relative to adults, especially the elderly. Dosages of aminoglycosides and other antimicrobials adjusted accordingly.
Section 19. Pediatrics Chapter 269. Endocrine And Metabolic Disord Topics
Congenital Goiters Hypothyroidism Hyperthyroidism Short Stature Due To Hypopituitarism Short Stature Due To Miscellaneous Causes Congenital Adrenal Hyperplasia Male Hypogonadism Genetic Abnormalities Of Carbohydrate Metabolism Anomalies In Amino Acid Metabolism
Congenital Goiters
An enlarged thyroid gland present at birth, with or without hypothyroidism.
Type 1 involves a defect in iodide transport, probably secondary to an alteration in synthesis of cell su proteins necessary for transport.
Type 2 is caused by several defects in iodination mechanisms within the thyroid. One involves the abs the enzyme peroxidase, necessary for the organification of iodine, which can result in goitrous cretinis Another defect, which is inherited as an autosomal recessive trait, appears to involve hydrogen peroxi generation and is associated with deaf-mutism (Pendred's syndrome). These patients are usually euth therefore, the deafness is not secondary to hypothyroidism. A third defect, associated with abnormal peroxidase, allows sufficient compensation for maintenance of a euthyroid state.
Type 3 congenital goiters are found in patients with dehalogenase defects. Although the precise bioch abnormality is unclear, patients have complete or partial deiodination defects of monoiodotyrosine and diiodotyrosine within thyroglobulin. Type 4 congenital goiters are associated with defects in the synthesis of thyroglobulin.
A congenital goiter may cause deviation or compression of the trachea and thereby compromise breat Although treatments vary with the type and subtype, goiters associated with hypothyroidism are usuall with thyroid hormone. Tracheal compression and hyperthyroidism can be treated surgically.
Section 19. Pediatrics Chapter 259. Fluid And Electrolyte Disorders In Infa Children Topics
[General] Deficit Excess Maintenance Fluid Requirements Practical Example
[General]
Dehydration, usually due to diarrhea, remains a major cause of morbidity and mortality in infants and c worldwide. However, overhydration may be as devastating as dehydration in seriously ill pediatric patie have cerebral edema, impairment of renal or circulatory function, or immature organ systems (eg, prem infants).
The young infant cannot communicate thirst or seek fluid and has a relatively large obligatory evapora loss, which is partly due to the high ratio of body surface area (BSA) to volume. The infant's metabolic two to three times that of the adult when expressed per unit of body weight. Heat generated by metabo activity must be dissipated (largely through evaporation), and solutes must be excreted (largely in the The net result is a more rapid turnover of body fluids in the infant than in the adult.
In managing infants and children with fluid and electrolyte disorders, less margin for error exists for ca fluid and electrolyte needs than exists for adults. In general, the younger the child, the more careful the calculations must be. Cases that demand attention to detail are those in which organ function (especia heart, brain, or kidney) is critically compromised. Absolute precision is impossible; nevertheless, suffic accuracy can usually be attained to restore and maintain normal balance and avoid serious complicati
The guidelines discussed below are approximations; close monitoring is essential. Frequency of monit must be individualized, depending on the severity of the disorder and the potential rate of change. Onc is rarely sufficient. Unfortunately, there is no single, simple sign or test that infallibly reflects fluid and electrolyte balance; Table 259-1 lists 10 signs and tests in rough order of practical value, considering d ease, availability, invasiveness, time to perform, and cost.
Fluid and electrolyte disorders are most simply approached by considering separately the deficit, ongo losses, and maintenance requirements (see Table 259-2) and by calculating first the volume of fluid re then its composition (eg, electrolytes), and, finally, the rate of replacement. In this way, even complex
electrolyte balance; Table 259-1 lists 10 signs and tests in rough order of practical value, considering d ease, availability, invasiveness, time to perform, and cost.
Fluid and electrolyte disorders are most simply approached by considering separately the deficit, ongo losses, and maintenance requirements (see Table 259-2) and by calculating first the volume of fluid re then its composition (eg, electrolytes), and, finally, the rate of replacement. In this way, even complex problems can be simplified. The examples below focus on the IV administration of fluid and electrolyte the same principles apply equally to oral rehydration therapy (see under Acute Infectious Gastroenteri 265).
Section 19. Pediatrics Chapter 270. Musculoskeletal And Connective Ti Disorders Topics
Rheumatic Fever Juvenile Rheumatoid Arthritis Common Hip, Knee, And Foot Disorders Inherited Connective Tissue Disorders The Osteochondrodysplasias The Osteopetroses The Osteochondroses
Rheumatic Fever
(See also Sydenham's Chorea in Ch. 271.)
A nonsuppurative acute inflammatory complication of group A streptococcal infection, characterized m arthritis, chorea, or carditis (sometimes followed by residual heart disease), alone or in combination; th (subcutaneous nodules and erythema marginatum) may also be involved.
Group A streptococcus is the etiologic precursor, but the role of constitutional and environmental facto unknown. Familial susceptibility is significant. Malnutrition, overcrowding, and lower socioeconomic sta seem to predispose to streptococcal infections and subsequent rheumatic attacks.
Rheumatic fever (RF) occurs mostly during school age; a first attack is rare before age 4 and uncomm 18. Exact incidence of acute RF is difficult to determine because most patients in developing countries seek medical care, particularly those with only mild asymptomatic carditis. In the USA, incidence is pro 1/100,000. However, the incidence of RF in untreated persons ranges from 0.1 to 3% of those with streptococcal infections. The incidence approaches 50% in untreated persons with a history of RF who develop streptococcal pharyngitis. The prevalence of rheumatic heart disease is also difficult to determ because clinical diagnostic criteria are not standardized, and autopsy is not performed routinely.
Although RF flourishes in developing countries, incidence rates have declined recently in most develop countries. However, real reduction in incidence due to antibiotics is difficult to separate from apparent reduction due to the use of more specific diagnostic criteria.
because clinical diagnostic criteria are not standardized, and autopsy is not performed routinely.
Although RF flourishes in developing countries, incidence rates have declined recently in most develop countries. However, real reduction in incidence due to antibiotics is difficult to separate from apparent reduction due to the use of more specific diagnostic criteria.
In the USA, for unknown reasons, RF is relatively rare, even when streptococcal pharyngitis is not trea however, reports indicate a resurgence. Outbreaks were reported in the 1980s in Utah and Ohio and i 1990s in Pennsylvania. Surprisingly, cases tended to occur in white middle class children living in subu rural areas. A mucoid M type 18 group A streptococcus was prevalent in these cases; this type had be associated previously with RF but had been uncommon in the USA for several decades. An outbreak reported from a military camp in 1989; 3 of 10 adult men with the disease developed carditis. More viru strains of streptococci appear to be returning to the USA, and the incidence may increase in the next f years.
Pathology
The histopathology of acute RF is difficult to assess because few patients die during the acute attack.
Joint involvement: Biopsy of inflamed synovial membrane shows nonspecific edema and hyperemia.
Brain involvement: Only hyperemia has been found in the brains of patients who died during an acut of chorea or years later.
Cardiac involvement: Valve involvement is the most characteristic and potentially dangerous patholo effect. An acute interstitial valvulitis may cause valvular edema. Left untreated, valve thickening, fusion retraction or other destruction of leaflets and cusps may occur, leading to stenotic or regurgitant functi changes. Similar involvement can shorten, thicken, or fuse chordae tendineae, adding to the regurgita damaged valves or producing regurgitation of an otherwise unaffected valve. Dilation of valve rings ma third mechanism causing regurgitation. Regurgitation and stenosis are the usual effects on the leaflets and tricuspid valves; the aortic valve generally becomes regurgitant initially and stenotic only later. The valve is involved most commonly; the aortic valve, often; the tricuspid valve, rarely; and the pulmonic v rarely.
Aschoff bodies are often found in the myocardium and other parts of the heart of patients with carditis Fibrinous nonspecific pericarditis, sometimes with effusion, occurs only in patients with endocardial inflammation and almost always subsides without permanent damage.
Skin involvement: Biopsy of subcutaneous nodules shows certain features resembling Aschoff bodie characteristics distinguish the nodules from those of RA. Erythema marginatum has no specific histop lesions.
Symptoms and Signs
The five major manifestations of RF are migratory polyarthritis, chorea, carditis, subcutaneous nodules erythema marginatum. These can appear alone or in combination and produce many clinical patterns. Cutaneous and subcutaneous features are uncommon and almost never occur alone, usually develop patient who already has arthritis, chorea, or carditis. Fever is prominent but is not specific.
Migratory polyarthritis is the most common clinical manifestation, although monarthritis may occur. J
The five major manifestations of RF are migratory polyarthritis, chorea, carditis, subcutaneous nodules erythema marginatum. These can appear alone or in combination and produce many clinical patterns. Cutaneous and subcutaneous features are uncommon and almost never occur alone, usually develop patient who already has arthritis, chorea, or carditis. Fever is prominent but is not specific.
Migratory polyarthritis is the most common clinical manifestation, although monarthritis may occur. J become extremely painful and tender and may also be red, hot, and swollen, sometimes with effusion knees, elbows, or wrists are most commonly involved. The shoulders, hips, and small joints of the han feet also may be involved, but almost never alone. If vertebral joints are affected, other disease should suspected.
Joint pain and fever usually subside within 2 wk, often more rapidly, and seldom last > 1 mo. In the ab carditis, the ESR (see Laboratory Findings, below) usually returns to normal within 3 mo.
Arthralgia-like symptoms may be due to nonspecific myalgia or tenodynia in the para-articular zone; tenosynovitis may develop at the site of muscle insertions. These symptoms can be distinguished from arthralgia of RA by the absence of tenderness during passive movement of the allegedly involved joint Isometric contraction of the neighboring muscles or tendons often reproduces the pain.
Chorea can occur alone or with other rheumatic manifestations (see Sydenham's Chorea in Ch. 271).
Carditis can occur alone or in combination with pericardial rub, murmurs, cardiac enlargement, or hea failure. In first attacks of RF, carditis occurs in about 50% of patients with arthritis. In the absence of a (or chorea), a patient with carditis will seek medical attention only if sufficiently febrile, if pericarditis is and painful, or if heart failure produces respiratory, peripheral, or abdominal manifestations. Otherwise about 50% of affected adults, the cardiac damage may not be discovered until much later.
Murmurs are the most frequent manifestation of carditis and are usually evident when the patient is firs The soft diastolic blow of aortic regurgitation (heard best along the lower left sternal border) and the pr murmur of mitral stenosis (heard focally above or medial to the apex) may be difficult to detect.
If no worsening occurs during the next 2 to 3 wk, new manifestations of carditis seldom occur thereafte murmurs often do not disappear and new cardiac phenomena are uncommon, inflammatory rather tha cardiac manifestations are the best indexes of therapeutic response. Evidence of acute inflammation, ESR, usually subsides within 5 mo in uncomplicated carditis. RF does not seem to produce chronic sm carditis. Scars left by acute valvular damage may contract and change, and secondary hemodynamic difficulties may develop in the myocardium without the persistence of acute inflammation.
Heart failure in acutely ill children may be undiagnosed because symptoms may be different from tho adults. Children's symptoms may be dyspnea without rales, nausea and vomiting (due to gastric hyper right upper quadrant or epigastric ache (due to distention of the hepatic capsule), and a hacking nonpr cough (due to pulmonary congestion).
Subcutaneous nodules, which occur most frequently on the extensor surfaces of large joints, usually with carditis. Ordinarily, the nodules are painless, transitory, and responsive to the treatment for assoc joint or heart inflammation.
Erythema marginatum is a serpiginous, flat, nonscarring, painless rash. It is transient, sometimes las day. Its appearance is often delayed after the inciting streptococcal infection; if it appears as (or even other aspects of rheumatic inflammation subside, it should not be mistaken for a new attack.
Other manifestations may include abdominal pain and anorexia, either via the hepatic mechanism de above for heart failure or via a concomitant mesenteric adenitis. Because of the elevated WBC count a
Erythema marginatum is a serpiginous, flat, nonscarring, painless rash. It is transient, sometimes las day. Its appearance is often delayed after the inciting streptococcal infection; if it appears as (or even other aspects of rheumatic inflammation subside, it should not be mistaken for a new attack.
Other manifestations may include abdominal pain and anorexia, either via the hepatic mechanism de above for heart failure or via a concomitant mesenteric adenitis. Because of the elevated WBC count a abdominal guarding, the situation may resemble acute appendicitis, particularly when other rheumatic manifestations are absent.
The lethargy, malaise, or fatigue often ascribed to RF may be caused by heart failure. Rheumatic pneu or pleurisy is no longer regarded as specific to RF.
Prolonged attacks of RF (>= 8 mo) occur in about 5% of patients, with spontaneously recurrent episo inflammation (clinical and laboratory manifestations) unrelated to intervening streptococcal infection or cessation of anti-inflammatory therapy. Such recurrent episodes within a prolonged attack are more lik associated with carditis.
Laboratory Findings
Systemic inflammatory indexes include ESR and C-reactive protein. Using the Westergren method, is elevated often to levels > 120 mm/h. The WBC count reaches 12,000 to 20,000/L and may go high corticosteroid therapy. Serum C-reactive protein is abnormally high; because it rises and falls faster th a negative result is useful to confirm the absence of inflammation in a patient with prolonged ESR elev after an acute attack has subsided.
Local inflammatory indexes are found in synovial fluid, although aspiration is seldom necessary for d or to guide therapy. The fluid is usually clear and yellow, with an elevated WBC count composed prima PMNs; culture is negative.
ECG abnormalities include PR prolongation, which is the most common abnormality but does not cor well with prognosis or with other evidence of carditis. PR prolongation reflects delayed atrioventricular conductivity in about 30% of RF patients. Other ECG abnormalities may be due to pericarditis, enlarge ventricles or atria, or cardiac arrhythmias.
Diagnosis
No single test or other evidence is pathognomonic. Diagnosis usually is based on the modified Jones which requires evidence of recent group A streptococcal infection (scarlet fever, positive throat culture elevated antistreptolysin O or other streptococcal antibody titers) together with two of the five major manifestations cited above under Symptoms and Signs, or one major and two minor manifestations (w include fever, arthralgia, prior history of RF, elevated ESR or C-reactive protein, elevated WBC count, prolonged PR interval).
Differential diagnosis includes gout, sickle cell anemia, leukemia, SLE, embolic bacterial endocarditis, sickness, Kawasaki disease, drug reactions, traumatic arthritis, and gonococcal arthritis, all of which c usually be distinguished by history or specific laboratory tests. Systemic juvenile RA (see below) some begins with a relatively abrupt onset, occasionally with rheumatoid cardiac involvement, and can be co with RF. Patients with systemic juvenile RA do not develop rheumatoid factor or antinuclear antibodies serologic tests are not helpful. The absence of an antecedent streptococcal infection and the prolonge course of an arthropathic episode usually distinguishes RA from rheumatic arthritis.
Rheumatic carditis must be distinguished from congenital heart disease, which has characteristic murm frequent cyanosis; echocardiography, cardiac catheterization, or angiography can be used to verify dif
begins with a relatively abrupt onset, occasionally with rheumatoid cardiac involvement, and can be co with RF. Patients with systemic juvenile RA do not develop rheumatoid factor or antinuclear antibodies serologic tests are not helpful. The absence of an antecedent streptococcal infection and the prolonge course of an arthropathic episode usually distinguishes RA from rheumatic arthritis.
Rheumatic carditis must be distinguished from congenital heart disease, which has characteristic murm frequent cyanosis; echocardiography, cardiac catheterization, or angiography can be used to verify dif diagnoses. Subendocardial fibroelastosis has been increasingly recognized as an uncommon mimic o rheumatic cardiac abnormalities; it can be suspected when there is no convincing evidence of rheuma congenital lesions.
Prognosis
Prognosis depends on the severity of the initial carditis. Patients with severe carditis during the acute e may be left with residual heart disease that is often worsened by the rheumatic recurrences to which th particularly susceptible. Murmurs eventually disappear in about 1/2 of patients whose acute episodes manifested by mild carditis without major cardiac enlargement or decompensation. Risk of recurrences intermediate, between the low risk of those without carditis and the high risk of those with a history of s carditis, but the recurrences may cause or worsen permanent cardiac damage. Patients who did not h carditis are less likely to have rheumatic recurrences and are unlikely to develop carditis if RF does rec other manifestations of RF subside without residual effects.
Treatment
Patients should generally limit their activities appropriately if symptomatic with arthritis, chorea, or hea In the absence of carditis, no physical restrictions are needed after the acute episode subsides. In asymptomatic patients with carditis, strict bed rest has no proven value, and it may create undesirable psychologic reactions. Physical restrictions to reduce or eliminate symptoms seem advisable only in p with symptomatic heart failure.
In patients with arthritis only, therapy aims to relieve pain. In mild cases, codeine or another analgesi as an NSAID in relatively small doses, is adequate. In more severe cases, aggressive use of anti-infla drugs may be required.
Aspirin is titrated upward until clinical effectiveness has been attained or toxicity supervenes. Measure blood or urine levels of salicylate are needed only to help manage toxicity. The starting dose for childre adolescents is 60 mg/kg (about 30 mg/lb), divided into 4 daily oral doses. If not effective overnight, the is increased to 90 mg/kg the next day and 120 mg/kg on the next. High doses can be divided into 5 or doses/day. Enteric-coated, buffered, or complex salicylate molecules appear to have no advantage ov ordinary aspirin. Local gastric reactions can be avoided (or treated) by taking with meals and/or consu milk or antacids 1/2 h after ingestion. Salicylate toxicity is manifested by tinnitus, headache, or tachypn may not appear until after 1 wk or more on fixed dosage. Management involves reducing the dosage i drug appears effective, or by abandoning the drug.
Other NSAIDs can also be used in children. Dosing intervals are longer, and toxicity, including tinnitus hepatic irritation, may be less. Naproxen and indomethacin are available in liquid and tablet form. Nap given bid up to 20 mg/kg/day. Indomethacin is given tid up to 3 mg/kg/day. While not yet subjected to comparison with aspirin, these drugs appear to achieve similar results. If a therapeutic effect has not o after the 4th day, aspirin or other NSAIDs should be abandoned in favor of a corticosteroid.
In patients with carditis, the goal is to suppress inflammation while avoiding a rebound. Aspirin or ano NSAID is the first choice; after an 8-wk course, rebounds seldom occur and adverse effects are less s than those of high-dose corticosteroid therapy. However, with severe carditis, particularly with heart fa
comparison with aspirin, these drugs appear to achieve similar results. If a therapeutic effect has not o after the 4th day, aspirin or other NSAIDs should be abandoned in favor of a corticosteroid.
In patients with carditis, the goal is to suppress inflammation while avoiding a rebound. Aspirin or ano NSAID is the first choice; after an 8-wk course, rebounds seldom occur and adverse effects are less s than those of high-dose corticosteroid therapy. However, with severe carditis, particularly with heart fa aspirin may be ineffective; corticosteroids should then be started promptly. Prednisone 0.5 to 2 mg/kg/ up to 60 mg/day given q 6 or 12 h can be used. If inflammation is not suppressed after 2 days, methylprednisolone succinate 30 mg/kg/day IV on 3 successive days may be substituted. The fully suppressive oral dose of corticosteroid should then be resumed until the ESR has remained normal fo more and is then tapered at the rate of 5 mg q 2 days. To prevent rebound, NSAIDs are begun simulta and continued until 2 wk after the corticosteroid has been stopped. A rebound manifested only by feve pain often subsides spontaneously, but anti-inflammatory therapy should be resumed for heart failure uncontrolled by cardiotonic drugs such as digoxin. In patients with prolonged, spontaneously recurrent of carditis, treatment with immunosuppressive drugs may be effective.
Although poststreptococcal inflammation is well developed by the time RF is detected, antibiotics a to remove any lingering organisms. Appropriate regimens are described under Streptococcal Infection 157.
Antistreptococcal prophylaxis should be maintained continuously after an attack of acute RF (or cho prevent recurrences. Benzathine penicillin G in a monthly IM injection of 1.2 million U is most effective injections are painful and require monthly medical attention. Sulfadiazine, in a single oral dose of 1 g/d mg/day in patients <= 27 kg [<= 60 lb]), is as effective as other oral regimens, including penicillin G 40 divided bid or penicillin V 250 mg divided bid.
The optimum duration of antistreptococcal prophylaxis is uncertain. Some authorities believe prophyla should be lifelong in all RF or chorea patients, or as long as they have close contact with children, who higher rates of carriage of group A streptococci. Others recommend prophylaxis only for the first few y after an acute attack in all patients < 18 yr, and for life only in patients with severe cardiac damage.
In patients with mild cardiac damage (ie, murmurs but no cardiomegaly or decompensation), prophyla be maintained; if it is discontinued, early treatment of streptococcal infections is required. In patients w known or suspected rheumatic valvular disease, prophylaxis against bacterial endocarditis should be i for dental or oral surgical procedures likely to cause gingival bleeding, for upper respiratory tract surge for surgery or instrumentation of the GU and lower GI tracts. Recommendations of the American Hear Association appear in Tables 270-1 and 270-2.
Section 19. Pediatrics Chapter 260. Disturbances In Newborns And Inf Topics
[General] Premature Infant Postmature Infant Small-For-Gestational-Age Infant Large-For-Gestational-Age Infant Birth Trauma Respiratory Disorders Hematologic Disorders Metabolic Problems In The Newborn Neonatal Seizure Disorders Hearing Deficits In Children Retinopathy Of Prematurity Neonatal Infections Necrotizing Enterocolitis Sudden Infant Death Syndrome Hemorrhagic Shock And Encephalopathy Syndrome
[General]
Each newborn is classified as premature, term, or postmature. Gestational age, which is the primary determinant of organ maturity, can be rapidly and accurately determined in the first days after birth usi Ballard score (see Fig. 256-1).
Through plotting of weight vs. gestational age (see Fig. 260-1), each infant is then classified as small, appropriate, or large for gestational age. Head circumference and length are also plotted against gesta age (see Fig. 260-2). These parameters may be influenced by genetic factors and by abnormal intraut states, which can predispose the infant to perinatal problems. They also help to predict subsequent gr development.

Section 19. Pediatrics Chapter 271. Neurologic Disorders Topics
Sydenham's Chorea Cerebral Palsy Syndromes
Sydenham's Chorea
(Chorea Minor; Rheumatic Chorea; St. Vitus' Dance)
A CNS disease, often of insidious onset but of finite duration, characterized by involuntary, purposeles nonrepetitive movements and subsiding without neurologic residua.
Etiology, Epidemiology, and Incidence
Sydenham's chorea is generally regarded as an inflammatory complication of group A -hemolytic strep infection, which causes rheumatic fever (see also Rheumatic Fever in Ch. 270). Chorea occurs in up t cases of rheumatic fever. The illness is probably immune-mediated: streptococcal antigens resemble n tissue antigens, and cross-reactive antibodies bind to nerve tissue, which provokes an inflammatory ca and tissue injury.
The disease is more common in females than in males and in childhood. The incidence ratio is even m pronounced in adolescence, as affected populations are composed almost entirely of females. Chorea occurs (in temperate climates) in the summer and early fall, after the spring and early summer peak in of rheumatic fever.
Symptoms and Signs
After streptococcal infection, the interval before symptom onset (sometimes up to 12 mo) is longer tha other manifestations of rheumatic fever, and chorea may begin when (or after) other clinical and labora features return to normal. It does not typically occur simultaneously with arthritis but occurs frequently carditis.
The patient develops rapid, purposeless, nonrepetitive, involuntary movements that disappear with sle may involve all except the ocular muscles. Voluntary movements are abrupt, with impaired coordinatio grimacing is common. In mild cases, the patient may appear clumsy and may have slight difficulties in and feeding. The neurologic examination shows no defect in muscle strength or sensory perception ex
carditis.
The patient develops rapid, purposeless, nonrepetitive, involuntary movements that disappear with sle may involve all except the ocular muscles. Voluntary movements are abrupt, with impaired coordinatio grimacing is common. In mild cases, the patient may appear clumsy and may have slight difficulties in and feeding. The neurologic examination shows no defect in muscle strength or sensory perception ex an occasional pendulous knee jerk.
The course is variable and difficult to delineate precisely because of its insidious onset and gradual ce A month or more may elapse before the movements become intense enough to make the patient or p seek medical attention. The condition may end within another 3 mo but occasionally lasts 6 to 12 mo.
Laboratory Findings and Diagnosis
Aside from occasional lingering evidence of previous streptococcal infection, chorea has no characteri laboratory features. The CSF is usually unremarkable, and the EEG shows no more than nonspecific dysrhythmias.
The diagnosis frequently is entirely clinical. The irregular, involuntary movements of this disorder are pathognomonic. They resemble those of cerebral palsy but can be distinguished by a history of recent Other conditions that must be differentiated are habit spasms, which are repetitive, and the movement hyperkinetic children, which are purposeful. Huntington's chorea is usually associated with a family his appears in adulthood. The Parkinson-like side effects of tranquilizers, given to control a hyperactive ch confuse the diagnosis of chorea until the drugs are discontinued and the unaltered choreic movement noted. Chorea can also occur in SLE.
Delayed-onset chorea is the only instance in which Jones criteria (see Ch. 270) do not have to be fulfil make the diagnosis of rheumatic fever. This is possible because chorea can occur many months after streptococcal exposure, at a time when arthritis, carditis, and evidence of prior streptococcal infection absent.
Treatment
In extreme cases, the patient may need vigorous sedation and protection to avoid self-injury from flaili or legs. No drug is consistently effective. When movements are severe, a benzodiazepine or an antips drug such as haloperidol or risperidone should be titrated to the lowest effective dose that moderates t movements. Dosing for benzodiazepines is as follows: diazepam 0.04 to 0.1 mg/kg/dose po q 6 h for c and 2 to 10 mg/dose po q 6 h for adults; lorazepam 0.05 mg/kg/dose po q 8 h for children and 1 to 2 m h for adults. Haloperidol may help with severe choreiform movements at a dosage of 0.01 to 0.03 mg/k po given bid to tid but may cause tardive dyskinesia. Risperidone may have a lower risk of tardive dysk but use is approved by the FDA only for adults. Dosing is 0.5 mg bid, then titrated in 0.5-mg increment control is achieved. If these fail, a corticosteroid may be given in the dosage described for rheumatic fe in Ch. 270). Although supportive studies are scarce, anecdotal reports as well as theory suggest that corticosteroids may help accelerate improvement.
Chorea is best regarded and treated as a transitory event. Patients, parents, and others (eg, friends, n teachers, classmates) should be reassured that the ailment will ultimately subside without residual dam and that the temporary impairment of motor functions will not affect intellectual capacity. Patients shou school only if movements are uncontrollably severe and should return to school as soon as they can m the necessary locomotion and residual dysfunction is minimal. Many of the so-called psychologic effec previously ascribed to chorea were due not to the disease itself, but to the associated scholastic depri and to the patients' anxiety and dismay at the bizarre movements and at the reactions they invoke in p who do not understand.
and that the temporary impairment of motor functions will not affect intellectual capacity. Patients shou school only if movements are uncontrollably severe and should return to school as soon as they can m the necessary locomotion and residual dysfunction is minimal. Many of the so-called psychologic effec previously ascribed to chorea were due not to the disease itself, but to the associated scholastic depri and to the patients' anxiety and dismay at the bizarre movements and at the reactions they invoke in p who do not understand.
Severe cardiac involvement seldom occurs in patients with active chorea but can be managed as desc rheumatic fever (see in Ch. 270). After an attack resolves, antistreptococcal prophylaxis against recurr chorea should be maintained as described for rheumatic fever.

Section 19. Pediatrics Chapter 261. Congenital Anomalies Topics
[General] Congenital Heart Disease Pulmonary Vascular Disease Heart Failure Gastrointestinal Defects Biliary Atresia And Neonatal Hepatitis Musculoskeletal Abnormalities Neurologic Abnormalities Congenital Eye Defects Renal And Genitourinary Defects Anomalies In Kidney Transport Chromosomal Abnormalities
[General]
Congenital anomalies: Structural defects present at birth.
Congenital anomalies may be inherited or sporadic, isolated or multiple, apparent or hidden, gross or microscopic. They cause nearly half of all deaths in term newborns. A major anomaly is apparent at bi to 4% of newborns; up to 7.5% of children manifest a congenital defect by age 5 yr.
Incidence varies with the type of defect; the geographic area, presumably due to genetic and/or enviro factors (spina bifida occurs in 3 to 4/1000 births in areas of Ireland but in 1/1000 in the USA); and cultu practices (consanguineous marriages increase the risk of genetic abnormalities). Increasing age of the (and, to a lesser extent, of the father) may increase the risk of chromosomal defects, especially Down syndrome (see Table 247-1).
Etiology may involve genetic and/or teratogenic factors. Different factors operating at the same period organogenesis may produce identical defects. Genetic factors may cause many single anomalies and syndromes. They may operate via simple mendelian or multifactorial inheritance. Some syndromes, su Down syndrome, result from chromosomal abnormalities (see below under Chromosomal Abnormalitie Teratogenic factors include environmental toxins, radiation, diet, drugs, infection, and metabolic disord
Diagnosis
Prenatal diagnosis may be possible by ultrasonography, amniocentesis, or chorionic villus sampling (s
Down syndrome, result from chromosomal abnormalities (see below under Chromosomal Abnormalitie Teratogenic factors include environmental toxins, radiation, diet, drugs, infection, and metabolic disord
Diagnosis
Prenatal diagnosis may be possible by ultrasonography, amniocentesis, or chorionic villus sampling (s 247). Obstetric factors that may suggest an anomaly include breech presentation; polyhydramnios, wh result from difficulty in swallowing (eg, due to severe CNS disorders such as anencephaly) or blockage GI tract (eg, due to esophageal atresia); and oligohydramnios, which may be caused by low urine outp to GU anomalies.
Treatment
If a defect is identified prenatally and is serious, parents can decide whether to terminate the pregnanc Prenatal therapy is theoretically possible for obstructive disorders (uropathy and hydrocephalus) but is experimental.
When an anomaly is identified at or after birth, parents should be informed promptly, although extensiv discussion may be deferred until specialists are consulted. The family should be given a realistic appra the severity of the condition, its prognosis, and the medical care available, and they should actively pa in decisions (see also Ch. 257). If genetic factors are suspected, the parents should receive genetic counseling (see Ch. 247).

Section 19. Pediatrics Chapter 272. Nose And Throat Disorders Topics
[General] Foreign Bodies Juvenile Angiofibroma Juvenile Papillomas
[General]
(See also 7; nasal septal problems are discussed in Ch. 86, tonsillitis in Ch. 87, and stomatitis and ot problems in Ch. 105.)

Section 19. Pediatrics Chapter 262. Developmental Problems Topics
Failure To Thrive Behavioral Problems Learning Disorders Attention Deficit Disorder Mental Retardation
Failure To Thrive
Weight consistently below the 3rd percentile for age; progressive decrease in weight to below the 3rd percentile; weight < 80% of ideal weight for height-age; or a decrease in expected rate of growth base child's previously defined growth curve, irrespective of whether below the 3rd percentile.
Two points should be considered in using the above definitions: (1) by the law of normal distribution, th of 3% of "normal" children will fall consistently below the 3rd percentile (conversely, however, most ch whose weight is below the 3rd percentile will have true growth failure); and (2) ideal weight for height-a be adjusted for expected height (as defined by the child's previously established height growth curve) than current height, if there is evidence that linear growth has been impaired.
About 3 to 5% of all children admitted to tertiary care centers and 1% of all children admitted to any ho have failure to thrive (FTT).

The physiologic basis for FTT of any etiology is inadequate nutrition for weight gain to occur.
Organic FTT refers to growth failure due to an acute or chronic disorder known to interfere with norma nutrient intake, absorption, metabolism, or excretion or to result in increased energy requirements to s promote growth (see Table 262-1).
Nonorganic FTT most commonly refers to growth failure due to environmental neglect (eg, lack of foo stimulus deprivation in the absence of a physiologic disorder that accounts for the growth failure. Up to children with growth failure who do not have a readily apparent growth-inhibiting disorder have nonorg FTT. Lack of food may be due to impoverishment, poor understanding of feeding techniques, imprope prepared formula (eg, overdiluting formula to "stretch" it because of financial difficulties), or an inadequ
Nonorganic FTT most commonly refers to growth failure due to environmental neglect (eg, lack of foo stimulus deprivation in the absence of a physiologic disorder that accounts for the growth failure. Up to children with growth failure who do not have a readily apparent growth-inhibiting disorder have nonorg FTT. Lack of food may be due to impoverishment, poor understanding of feeding techniques, imprope prepared formula (eg, overdiluting formula to "stretch" it because of financial difficulties), or an inadequ supply of breast milk (eg, because the mother is under stress, exhausted, or poorly nourished).
In most cases, the psychologic basis of nonorganic FTT appears similar to that of hospitalism, a synd observed in infants who have depression secondary to stimulus deprivation; the unstimulated child be depressed, apathetic, and ultimately anorexic. In nonorganic FTT, stimulation may be lacking because caregiver (usually, the mother) is depressed or apathetic, has poor parenting skills, is anxious about o unfulfilled by the caregiving role, feels hostile toward the child, or is responding to real or perceived ex stresses (eg, demands of other children in large or chaotic families, marital dysfunction, a significant lo financial difficulties).
However, poor caregiving by the mother does not fully account for nonorganic FTT. The child's temper capacities, and responses help shape maternal nurturance patterns; ie, nonorganic FTT may be consi the result of a disordered interaction between mother and child. Thus, nonorganic FTT may result from situations, ranging from a severely disturbed or ill child, whose care poses a major challenge to even t competent parent, to a potentially undemanding and compliant child being cared for by a mentally ill p lacking adequate social, emotional, financial, cognitive, or physical resources. Within these extremes a mother-child mismatches, in which the child's demands, although not pathologic, cannot be adequatel the mother, who might, however, do well with a child who has different needs or even with the same ch under different circumstances.
In mixed FTT, organic and nonorganic FTT overlap. The physician must ascertain the relative contribu each to the child's abnormal growth. Mixed FTT is diagnosed in children who were born prematurely a have evidence of disproportionate growth failure later in infancy; in those who have or have had a defe does not explain the current growth failure (eg, repaired cleft palate); and in those who are frustrating because of neurologically impaired sucking) or repugnant (eg, because of a deformity) to the caregive
Diagnosis
Children with organic FTT may present at any age depending on the underlying disorder; most childre nonorganic FTT manifest growth failure before age 1 yr, and many by age 6 mo.
Weight is the most sensitive indicator of nutritional status. Reduced linear growth usually indicates mo severe, prolonged malnutrition. The brain is preferentially spared in protein-energy malnutrition (see C reduced growth in head circumference occurs late and indicates very severe or long-standing malnutri
Usually, when growth failure is noted, a history (including diet history--see Table 262-2) is obtained, di counseling is provided, and the child's weight is monitored frequently. If the child does not gain weight satisfactorily, he is usually admitted to the hospital so that all necessary observations can be made an diagnostic tests performed quickly. Without historic or physical evidence of a specific underlying etiolo growth failure, no single clinical feature or test can reliably distinguish organic from nonorganic FTT. B establishing a diagnosis of nonorganic FTT, the physician should simultaneously search for an underly medical problem and for personal or family characteristics that support a psychosocial etiology for FTT Optimally, evaluation is multidisciplinary, involving a physician, a nurse, a nutritionist, an expert in child development, a social worker, and a psychiatrist or psychologist. The child's feeding behaviors with he practitioners and with the parents must be observed, whether the setting is inpatient or outpatient.
Engaging the parents as co-investigators is essential. It helps foster their self-esteem and avoids blam
medical problem and for personal or family characteristics that support a psychosocial etiology for FTT Optimally, evaluation is multidisciplinary, involving a physician, a nurse, a nutritionist, an expert in child development, a social worker, and a psychiatrist or psychologist. The child's feeding behaviors with he practitioners and with the parents must be observed, whether the setting is inpatient or outpatient.
Engaging the parents as co-investigators is essential. It helps foster their self-esteem and avoids blam parents, who may already feel frustrated or guilty because of a perceived inability to nurture their child family should be encouraged to visit as often and as long as possible. Staff members should make the welcome, support their attempts to feed the child, and provide toys and ideas that promote parent-chil and other interactions. Staff members should avoid any comments implying parental inadequacy, irresponsibility, or other fault as the cause of FTT; however, parental adequacy and sense of responsi should be evaluated. Suspected neglect or abuse must be reported to social services; however, in ma instances, referral for preventive services that are targeted to meet the family's needs for support and education (eg, additional food stamps, more accessible child care, parenting classes) is more appropr
During hospitalization, the child's interaction with persons in the environment is carefully observed, and evidence of self-stimulatory behaviors (eg, rocking, head banging) is noted. Children with nonorganic F have been described as hypervigilant and wary of close contact with persons, preferring interactions w inanimate objects if they interact at all. Although nonorganic FTT is more consistent with neglectful tha abusive parenting, the child should be examined closely for evidence of abuse (see Ch. 264). A scree of developmental level should be performed and, if indicated, followed with more sophisticated assess
Extensive laboratory tests are nonproductive. If the history or physical examination does not indicate a particular test, most experts recommend limiting screening tests to a CBC, an ESR, urinalysis (includin to concentrate and acidify), BUN or serum creatinine level, urine culture, and examination of the stool reducing substances, odor, color, consistency, and fat content. Depending on prevalence of specific d in the community, a blood lead level, an enzyme-linked immunosorbent assay (ELISA) for antibodies t proteins, or a Mantoux tuberculin test may be warranted. Other tests may be appropriate--eg, electroly concentrations if the child has a history of significant vomiting or diarrhea; a thyroxine level if growth in is more severely affected than growth in weight; and a sweat test if the child has a history of recurrent lower respiratory tract disease, a salty taste when kissed, a ravenous appetite, foul-smelling bulky stoo hepatomegaly, or a family history of cystic fibrosis. Investigation for infectious diseases should be rese children with evidence of infection (eg, fever, vomiting, diarrhea). Radiologic investigation should be re for children with evidence of anatomic or functional pathology (eg, pyloric stenosis, gastroesophageal
Prognosis
With nonorganic FTT, 50 to 75% of children > 1 yr achieve a stable weight above the 3rd percentile. C function, especially verbal skills, is below the normal range in about 50%; children who develop FTT b yr of age are at particular risk, and those < 6 mo of age--when the rate of postnatal brain growth is maximal--are at highest risk. General behavioral problems, identified by teachers or mental health professionals, occur in about 50% of children; problems specifically related to eating (eg, pickiness, slo or elimination tend to occur in a similar proportion of children, usually those with other behavioral or pe disturbances.
Treatment
The goal of treatment is to provide sufficient health and environmental resources to promote satisfacto growth. A nutritious diet containing adequate calories for catch-up growth (about 150% of normal kcal requirement/kg ideal wt/24 h) and individualized medical and social supports are usually required. Abil gain weight in the hospital does not differentiate infants with nonorganic FTT from those with organic F children grow when given sufficient nutrition. However, some children with nonorganic FTT lose weigh hospital, suggesting that care even by "inadequate" parents is often better than being separated from
The goal of treatment is to provide sufficient health and environmental resources to promote satisfacto growth. A nutritious diet containing adequate calories for catch-up growth (about 150% of normal kcal requirement/kg ideal wt/24 h) and individualized medical and social supports are usually required. Abil gain weight in the hospital does not differentiate infants with nonorganic FTT from those with organic F children grow when given sufficient nutrition. However, some children with nonorganic FTT lose weigh hospital, suggesting that care even by "inadequate" parents is often better than being separated from
For children with organic or mixed FTT, the underlying disorder should be treated as quickly as possib children with apparent nonorganic FTT or mixed FTT, management consists of providing education an emotional support to correct problems interfering with the parent-child relationship. Because long-term support or psychiatric treatment is often required, the evaluation team may be able only to define the f needs, provide initial instruction and support, and institute appropriate referrals to community agencies parents should understand why the referrals are being made and, if options exist, should participate in decisions concerning which agencies will be involved (eg, some families accept and profit from commu nurse intervention but refuse assistance from a social worker). If the child is hospitalized in a tertiary c center, the referring physician should be consulted regarding local agencies and the level of expertise available in the community.
A predischarge planning conference involving hospital-based personnel, representatives from the com agencies who will provide follow-up services, and the child's primary physician should be routine. Area responsibility and lines of accountability must be clearly defined, preferably in writing, and distributed t everyone involved. The parents should be invited to a summary session after the conference so that th meet the community workers, ask questions, and perhaps arrange appointments.
In some cases, the child must be placed in foster care. If the child is expected to eventually return to th biologic parents, parenting skill training and psychologic counseling must be provided for them, and th progress must be monitored scrupulously. Return to the biologic parents should be based on the pare demonstrated ability and resources to adequately care for the child, not only on the passage of time.

Section 19. Pediatrics Chapter 273. Strabismus Topics
[General]
[General]
Strabismus (squint; cross-eyes; heterotropia): Deviation of one eye from parallelism with the other.
(Disorders of the eye are also discussed in 8; in Ch. 178; and under Congenital Eye Defects in Ch. 2
Etiology and Symptoms
Paralytic (nonconcomitant) strabismus results from paralysis of one or more ocular muscles; it may caused by a specific oculomotor nerve lesion. Eye motion is limited and diplopia increases in the fields action of the paralyzed muscles (see also Ch. 178). Diplopia is not present if the paralysis is congenita vision in the deviated eye is suppressed.
Nonparalytic (concomitant) strabismus usually results from unequal ocular muscle tone caused by supranuclear abnormality within the CNS. It may be convergent (esotropia), divergent (exotropia), or v (hypertropia or hypotropia). The deviation from parallelism does not vary with ocular movements and t function of individual muscles is usually intact, unless secondary contraction occurs.
Phoria (latent strabismus) is nonparalytic; the muscle imbalance is overcome by the CNS tendency to images from each eye. It may occur as esophoria, exophoria, or hypophoria or hyperphoria. Unless lar phoria rarely causes symptoms and is apparent only when the CNS is unable to constantly maintain fu
Disuse of an eye, as in cases of severe refractive error or impaired vision due to disease, may also res strabismus.
Amblyopia (reduced visual acuity due to an abnormal visual experience early in life) may occur in stra usually due to cortical suppression of the image in the deviating eye to avoid confusion and diplopia.
Diagnosis
Amblyopia (reduced visual acuity due to an abnormal visual experience early in life) may occur in stra usually due to cortical suppression of the image in the deviating eye to avoid confusion and diplopia.
Diagnosis
Since strabismus may result from serious ocular or neurologic disease, the eyes (including corneas, le retinas, and optic nerves) and neurologic status of the patient, regardless of age, should be evaluated deviation, if constant, should be investigated shortly after birth; if intermittent, by age 6 mo. Because s disease may be overlooked, strabismus should not be ignored on the assumption that it will be outgrow
The patient is asked to fix on a pencil or flashlight held in front of the examiner. By alternately covering uncovering one eye, the examiner can detect a shift in the eye's position when it is uncovered and pro fix on the object. In exotropia, the eye that was covered turns in to fixate; in esotropia, it turns out to fix Tropia can be quantified by using prisms positioned such that the deviating eye need not move to fixat power of the prism (in diopters) used to prevent deviation quantifies the tropia.
Permanent loss of vision can occur if strabismus and its attendant amblyopia are not treated before ag yr. If possible, underlying causes of strabismus should be treated. If muscle imbalance alone is respon strabismus should be treated early with corrective glasses or contact lenses, miotics (eg, echothiophat 0.03% bid), orthoptic training (eg, eye exercises), botulinum toxin, or surgical restoration of muscle bal
Early treatment of amblyopia by patching the normal eye is the mainstay of treatment for all causes an result in improved vision, leading to a better prognosis for development of binocular vision and more s surgery is performed. Some variation (eg, glasses, contact lenses) in addition to patching may be used conditions such as congenital cataract (see Ch. 261).
Section 19. Pediatrics Chapter 263. Injuries, Poisoning, And Cardiopulm Resuscitation Topics
Injuries Poisoning Cardiopulmonary Resuscitation
Injuries
Epidemiology
Injury is the most common cause of death in children, killing more children than cancer, congenital abnormalities, pneumonia, meningitis, and heart disease combined. The cause of injury varies by age location (eg, home, urban vs. rural, cold vs. hot climate). In children < 1 yr, almost 1000 deaths/yr occu falls, burns, drowning, and suffocation. In 18 U.S. states, drowning is the leading cause of injury death children aged 1 to 4 yr, and for all of the USA, burns and fires are the most common cause of death in group. In adolescence, the leading cause of death is from motor vehicle accidents and the second mo common is from homicide--a reflection of the increased violence in our society (see also Ch. 275). Inju also the leading cause of disability in children. For every death from an injury, 1000 children are nonfa injured.
Predisposing Causes
Injuries are the result of a sequence of events, most of them preventable, and, especially in the young often triggered by the child's curiosity. Certain factors predispose the young child to injury. Injuries are common when the child is hungry or tired (eg, before meals or naps), is being cared for by a parent su is in new surroundings (eg, a recent family move or vacation), or is highly active. Injuries are likely whe parents are rushed and busy or when parents do not anticipate the risks associated with new stages o development. Finally, children are often the innocent victims of unsafe environments and/or adult beha The frequent injuries occurring from gunshots, from motor vehicle accidents caused by drunk drivers, house fires that could have been prevented by using smoke or heat detectors, and from swimming bec a lack of fences around pools attest to this.
Prevention
house fires that could have been prevented by using smoke or heat detectors, and from swimming bec a lack of fences around pools attest to this.
Prevention
Safety education for parents and children is a key preventive measure: Passive protection is not enou child must be protected from potential hazards and taught an appropriate response to unavoidable ha Because children mimic their parents' actions, parents must set good safety examples (eg, wearing se and should learn to avoid situations conducive to injuries. Several measures to prevent injury appear i 263-1.
Physicians can help prevent injuries by educating parents, distributing safety information, setting good examples themselves, and anticipating potentially high-risk situations (eg, suggesting that a mother wh occupied with the care of a sick child obtain appropriate help for her other children).
INJURY IN MOTOR VEHICLE ACCIDENTS

Epidemiology
Injury in motor vehicle accidents is a major cause of death among all age groups in the USA, claiming 4/100,000 infants < 1 yr of age, 7/100,000 children aged 1 to 14 yr, and increasing up to 40/100,000 b to 24 yr. An unrestrained child may be the only casualty of a sudden stop that results in neither proper damage nor other personal injury.
Prevention of Injury
To reduce the incidence and severity of injuries in motor vehicle accidents, all occupants should be re State laws vary, but most states have child restraint laws. It is extremely unsafe for a restrained adult t an unrestrained child; the adult will be unable to maintain hold of the child, who will be thrown with trem force even at minimal speed (eg, restraining a 10-lb [4.5-kg] child, traveling 30 miles/h [48 km/h], would the strength to lift 300 lb [136 kg] 1 ft [30 cm] off the ground). If the adult is unrestrained, he may also thrown forward and crush the child against the interior of the car with a force equal to the adult weight (speed)2/2. The effectiveness of restraints in reducing trauma is undeniable; their use reduces fatalitie to 50% and serious injuries by 45 to 55%.
In a car, the back seat is the safest place for all children (< 12 yr), particularly when the car is equippe front-seat airbags. (The release/activation of airbags has resulted in the death of infants and children.)
Child restraints must be used properly to be effective. The child must be strapped into a restraint that designed for his size and stage of development. The entire restraint must be secured to the car accord the manufacturer's instructions, or it may worsen the trajectory path of the child in a crash. An infant ca (restraint) should be placed in the back seat facing the rear of the vehicle and is appropriate up to a w 20 lb (9 kg). Car seats for children from 21 to 40 lb (9.5 to 18.2 kg) should face forward, should be equ with shoulder restraints and lap guards, and should also provide stability for the head. Children weighi lb (> 18.6 kg) should be secured by seat belts at all times; shoulder belts should be used with lap belts the shoulder belt crosses the face or neck (usually when children are < 55 inches tall). If this problem o children should ride in a booster seat until the shoulder belt fits properly.
Many seats have been approved by the National Highway Traffic Safety Administration; a list of appro models is available from the American Academy of Pediatrics and the National Highway and Traffic Sa
lb (> 18.6 kg) should be secured by seat belts at all times; shoulder belts should be used with lap belts the shoulder belt crosses the face or neck (usually when children are < 55 inches tall). If this problem o children should ride in a booster seat until the shoulder belt fits properly.
Many seats have been approved by the National Highway Traffic Safety Administration; a list of appro models is available from the American Academy of Pediatrics and the National Highway and Traffic Sa Council. Those that meet federal crash standards are appropriately marked.
HEAD INJURY
Epidemiology
A high percentage of deaths from trauma in childhood are due to craniocerebral trauma and its compli Serious injury to the developing CNS often results in residual impairment of physical, cognitive, and em functions.
Head injury is the second most common form of trauma for which children are admitted to hospitals. T greatest incidence of head injuries occurs in children < 1 yr and in those > 15 yr of age. Boys exceed g victims. Injuries in young children are predominantly due to falls in and around the home. Falls from he are a major cause of preventable death in urban children. A campaign to prevent falls from windows in York City during 1 year produced a 96% decrease in these injuries.
Classification
Most head injuries are due to minor trauma without loss of consciousness, concussion, contusion, or f Far more serious but less frequent are injuries associated with a significant brain injury, resulting in dif axonal injury and varying types of hematomas (epidural, subdural, intraparenchymal, intraventricular). fractures also occur often, with or without brain injury.
A concussion is a transient and rapidly reversible state of neuronal dysfunction associated with a loss consciousness immediately after the head injury.
A contusion is the focal bruising or tearing of cerebral tissue accompanied by parenchymatous hemo and/or local edema. The ventral surface of the frontal lobes and inferolateral aspects of the temporal l the most common areas injured.
Diffuse axonal injury results from acceleration-deceleration forces with shearing and tearing of axons matter) and disruption of myelin sheaths. Diffuse cerebral edema results, often without obvious eviden bleeding. It is one of the most common severe brain injuries in childhood, occurring much more often t intracranial hematomas.
An epidural hematoma is a collection of blood between the dura mater and the skull resulting from ar venous injury.
A subdural hematoma is a collection of blood beneath the dura mater, usually associated with a sign contusion of the brain.
Intraventricular, intraparenchymal, and subarachnoid hemorrhages are collections of blood in the ventricular system, the brain tissue, or the subarachnoid space, respectively.
A subdural hematoma is a collection of blood beneath the dura mater, usually associated with a sign contusion of the brain.
Intraventricular, intraparenchymal, and subarachnoid hemorrhages are collections of blood in the ventricular system, the brain tissue, or the subarachnoid space, respectively.
Skull fractures occur when the bony integrity of the skull is disrupted. Fractures may be linear, depre comminuted and can occur anywhere in the skull, including occipital, temporoparietal, frontal, and bas areas. Impacts to the face may result in facial fractures of the nasal bones, sinuses, or orbital areas.
In infants, the meninges may become trapped in a linear skull fracture and result in a growing fracture actually a leptomeningeal cyst, which develops over 3 to 6 wk and may be the first evidence that a line fracture occurred at the time of injury.
History, Symptoms, and Signs
Because the history of the event and the course of symptoms that follow are extremely important, the should be meticulously gathered from family and witnesses. The mechanism of injury, location of injur specific symptoms and signs resulting, including the effect on the patient's level of consciousness, are especially critical to management.
Minor head trauma without loss of consciousness or abnormal neurologic signs may be associated w vomiting, pallor, irritability, or lethargy. Persistence of symptoms for > 6 h or worsening of symptoms m indicate a more severe injury, and a more in-depth evaluation should be performed as quickly as poss
Patients with a concussion often have no neurologic signs but have amnesia for both the event and t just before (antegrade amnesia).
In patients with contusions, neurologic signs and symptoms depend on the precise location of the co There may be disturbances of strength and sensation, altered sensorium, and an associated increase intracranial pressure, particularly if the contused area is large.
Diffuse axonal injury results in diffuse cerebral edema, and the child presents with a globally depress of consciousness. Long-term sequelae often result. Increase in intracranial pressure from edema may pupillary abnormalities, bradycardia, hypertension, and respiratory and hemodynamic abnormalities.
In epidural hematomas, associated neurologic symptoms are usually due to compression of the brain than direct injury. The classic symptoms in the adult (loss of consciousness, a lucid interval, and then neurologic deterioration) often do not occur in the child.
In subdural hematomas, hyperemia and cerebral edema are commonly associated, resulting in an al state of consciousness and signs of increased intracranial pressure. Focal deficits are also common a be permanent. The incidence of seizures secondary to the contusion is high. Although most subdural hematomas occur acutely, occasionally blood accumulates in the subdural space more gradually from tears in the frontal and parietal cortical veins as they pass into the sagittal sinus. Such chronic subdura hematomas may also result in symptoms of increased intracranial pressure.
Intraventricular, intraparenchymal, and subarachnoid hemorrhages are usually associated with a significant depression of mental status because of associated neuronal injury and increased intracrani pressure. Seizures commonly occur, as do abnormal motor movements.
Skull fractures may or may not be associated with neurologic or other symptoms. Palpation of the sk
Intraventricular, intraparenchymal, and subarachnoid hemorrhages are usually associated with a significant depression of mental status because of associated neuronal injury and increased intracrani pressure. Seizures commonly occur, as do abnormal motor movements.
Skull fractures may or may not be associated with neurologic or other symptoms. Palpation of the sk reveal a depression or generalized swelling that has already been noted by a parent. Seizures (focal) result from a contusion underlying the fracture location, particularly if the fracture has resulted in a dep fragment of bone.
Assessment
After elucidating the mechanism of injury and history of subsequent events, performing a physical exa is key to assessing the severity of the brain injury. Attention to mental status using the Glasgow Coma (see Table 175-1) or, for infants < 1 yr, using the Modified Glasgow Coma Scale for Infants and Childr Table 263-2) is imperative, as is attention to pupillary responses, vital signs, and evidence of any asso injuries. A Glasgow Coma score <= 12 suggests a severe head injury. A score < 8 suggests the need intubation and ventilation because airway protective reflexes are usually lost, and it is highly likely that increased intracranial pressure exists (mild hyperventilation reduces increased intracranial pressure). <= 6 clearly suggests the need for intracranial pressure monitoring, and many would place a monitor fo score <= 7. Because examination of the ocular fundi can provide strong evidence of child abuse (ie, shaken-baby-impact syndrome), they should be examined carefully for retinal hemorrhages.
Skull fractures are generally unreliable predictors of the severity of the CNS injury; a thorough neurolo examination is more helpful. Nevertheless, the presence of a fracture is not usually consistent with a h a minor head injury, and patients with certain types of fractures may be at higher risk for intracranial pr Fractures across the middle meningeal artery (temporal bone) may be associated with an epidural hem Because the occipital bone and the base of the skull (basilar bones) are thick and much force is requir fracture them, fractures in these areas indicate a high-intensity impact. Basilar skull fractures are often visible on skull x-rays or CT; however, associated signs include the drainage of CSF from nose or ears behind the tympanic membrane (or in the ear canal if the tympanic membrane has been ruptured), ecc behind the ear (Battle's sign) or in the periorbital area (raccoon eyes), or fluid in the frontal/maxillary si (noted on CT). Depressed skull fractures require immediate evaluation because they are more likely to associated with a contusion of the underlying brain. Neurosurgical consultation is needed to determine fragment should be surgically elevated.
Simple linear skull fractures are usually visible on plain skull x-rays. They are not usually of concern un associated with abnormal neurologic findings or if present in an infant. In such cases, the risk of leptomeningeal cyst should be evaluated and child abuse considered.
Treatment
Most children with mild head trauma can be observed at home by competent parents. Children with al consciousness at the time of examination, a history of unconsciousness for even a brief period of time selected skull fractures (occipital, depressed, across the middle meningeal artery), and focal or diffuse neurologic findings should be observed in the hospital. If circumstances suggest possible child abuse, children should also be observed (see Ch. 264). Children with head injuries must be monitored careful any changes in neurologic status, including mental status, vital signs, pupillary findings, localization or lateralization of signs, and seizures. Head CT should be performed in children with alteration of consc (Glasgow Coma score <= 14), persistent vomiting, focal neurologic findings, clinical evidence of a bas fracture, and seizures.
Although nothing can be done to alter the primary injury, avoidance of secondary brain dysfunction by
any changes in neurologic status, including mental status, vital signs, pupillary findings, localization or lateralization of signs, and seizures. Head CT should be performed in children with alteration of consc (Glasgow Coma score <= 14), persistent vomiting, focal neurologic findings, clinical evidence of a bas fracture, and seizures.
Although nothing can be done to alter the primary injury, avoidance of secondary brain dysfunction by preventing hypoxia, hypercarbia, hypotension, and elevated intracranial pressure may be accomplishe aggressive and meticulous management. Brain swelling resulting in elevated intracranial pressure requ immediate appropriate management to prevent further interference with O2 delivery and cellular metab
Management of a child with a serious head injury should be performed in a stepwise fashion. Of great importance initially is adequacy of the airway, since both hypoxia and hypercarbia increase intracrania pressure by worsening cerebral hyperemia. If the Glasgow coma score is < 8, the child should be intub with appropriate medication in a controlled and efficient fashion to minimize the acute elevation in intra pressure occurring with the intubation procedure. This is accomplished by using a sedative (thiopental hemodynamically stable or etomidate if not), lidocaine IV (1 to 2 mg/kg), and a paralytic agent. Blind nasotracheal intubation should not be performed. Mechanical ventilation should be instituted, and arte blood gases, pulse oximetry, and end-tidal PCO2 monitoring should be used to assess adequacy of oxygenation and ventilation.
IV fluids consisting of 5% dextrose in 0.9% sodium chloride should be given at 3/4 to 4/5 maintenance provided there is no systemic hypotension or hypovolemic shock. (The child should always have an ad intravascular volume and be euvolemic.) Because infants and children often secrete an increased amo ADH after head injury and so are at risk of becoming overloaded with free water with subsequent wors cerebral edema, mild fluid restriction is appropriate. Hypotonic fluids (especially dextrose 5% in water) contraindicated because of the excess free water they contain. Monitoring should include maintaining sodium levels at >= 140 mEq/L.
Children with a Glasgow coma score < 8, with or without evidence of cerebral swelling or bleeding on a CT scan, should be mildly hyperventilated initially to keep PCO2 between 34 and 36 mm Hg. A lower P may result in decreased cerebral perfusion with an increased risk of ischemia. Subsequently, placeme intracranial pressure monitor should be strongly considered to determine whether interventions are ne decrease excessively high intracranial pressure and maintain cerebral perfusion pressures at > 50 mm preferably at > 70 mm Hg (mean arterial BP minus intracranial pressure). Intracranial pressure should at <= 15 mm Hg by preventing an elevation of the arterial PCO2 above normal (elevated PCO2 results cerebral vasodilation), controlling pain, maintaining normothermia (or slightly lower at 36 C [96.8 F]), using muscle relaxant drugs if necessary. Similarly, arterial BP should be maintained to keep the cereb perfusion pressure > 50 to 70 mm Hg. The head of the bed should be elevated to 30 with the head ke midline position to enhance cerebral venous drainage. Judicious, small doses of 20% mannitol at 0.25 g/kg can be used to lower increases in intracranial pressure or to increase the serum osmolality to 295 mOsm/kg. Furosemide 1 mg/kg IV is also helpful in decreasing total body water, particularly when the hypervolemia associated with mannitol is to be avoided. In the first 24 h after a head injury, furosemide even be preferred as a method to increase serum osmolality. Dexamethasone has not been shown to effective in head trauma and is not recommended. Induced pentobarbital coma and induced hypother also not been shown to be of consistent benefit and have significant risks. The use of the latter modali should be individualized to specific patients.
Frequent evaluation of the child who has sustained a head injury is imperative. If the child's condition deteriorates, another CT should be performed to detect surgically treatable lesions and/or the cause o deterioration.
Fixed and dilated pupils, loss of oculovestibular reflexes, and decerebrate posturing are not necessari irreversible with proper treatment. Aggressive early management directed toward maintaining adequat pulmonary gas exchange and brain perfusion can reduce the risks of increased intracranial pressure a
deteriorates, another CT should be performed to detect surgically treatable lesions and/or the cause o deterioration.
Fixed and dilated pupils, loss of oculovestibular reflexes, and decerebrate posturing are not necessari irreversible with proper treatment. Aggressive early management directed toward maintaining adequat pulmonary gas exchange and brain perfusion can reduce the risks of increased intracranial pressure a secondary complications.
Seizures increase intracranial pressure and should be treated promptly, initially with lorazepam, then w phenytoin. If a contusion or hemorrhage is present, prophylactic phenytoin should be strongly conside prevent cardiovascular adverse effects (eg, hypotension, bradycardia), a loading IV dose of 20 mg/kg separate 10 mg/kg boluses should be given at a maximum rate of 2 mg/kg/min (up to 50 mg/min). The maintenance IV dose is 3 to 6 mg/kg/day divided bid. However, brain-injured children appear to require doses of phenytoin. Measurement of levels is, therefore, imperative so that dosage can be titrated. So children require 7 to 8 mg/kg/day. Duration of treatment is variable and depends on the type of injury a results of the EEG. Seizures occur in about 5% of children > 5 yr and in 10% of those < 5 yr during the week posttrauma.
Surgery: In epidural hematomas, emergency evacuation must be performed quickly to prevent neurol deterioration. If rapid evacuation is performed, these children do well. In subdural hematomas, early neurosurgical consultation is mandatory to determine whether evacuation of the hematoma is indicate assist in the management of increased intracranial pressure. Chronic subdural hematomas may requir repeated subdural taps, surgical drainage, or shunting.
Prognosis and Rehabilitation
The degree of brain recovery depends on the patient's age, duration of coma, presence of intracranial bleeding, and site of maximal trauma. Of the nearly 5 million children who sustain head injuries each y 4,000 die and 15,000 require prolonged hospitalization. Of those with severe injury whose coma excee 50% suffer major neurologic sequelae. Between 2 and 5% remain severely handicapped. The mortalit head-injured children with Glasgow coma scores of 5, 6, or 7 is <= 10%, with children < 5 yr (especiall having higher mortality rates than older children. For children who survive, functional recovery is usual good, but a prolonged period of rehabilitation, particularly in cognitive and emotional areas, is often req and rehabilitation services should be planned early, even at the time of admission. Common problems recovery include retrograde amnesia, behavioral changes, emotional lability, sleep disturbances, decre intellectual ability, and residual seizures. (See also Ch. 175.)
Brain injury support groups can significantly assist families with brain-injured children and can be instru in the coordination of necessary medical, surgical, educational, and rehabilitation services.
SPINAL CORD INJURY
Although children < 10 yr have the lowest rate of spinal cord injuries of all age groups, such injuries ar rare.
In children < 8 yr, cervical spine injuries occur most commonly above C-4; in those > 8 yr, injuries at C are more common. Of increasing importance is the recognition of Spinal Cord Injury Without evidence Radiologic Abnormality (SCIWORA). This type of injury occurs almost exclusively in children and is re direct spinal cord traction, spinal cord concussion, and vascular injury to the spinal cord. Complete neu injury by anatomic or functional transection (more common in children < 8 yr) has a potentially poor pr
In children < 8 yr, cervical spine injuries occur most commonly above C-4; in those > 8 yr, injuries at C are more common. Of increasing importance is the recognition of Spinal Cord Injury Without evidence Radiologic Abnormality (SCIWORA). This type of injury occurs almost exclusively in children and is re direct spinal cord traction, spinal cord concussion, and vascular injury to the spinal cord. Complete neu injury by anatomic or functional transection (more common in children < 8 yr) has a potentially poor pr
Symptoms and signs of spinal cord injury are described in Ch. 182. Hypotension is common and usua associated with bradycardia.
Any patient who has been in a motor vehicle accident, has fallen over 10 ft, or has had a submersion i should be considered to have had a spinal cord injury. Thorough radiologic assessment, including thin CT, MRI, or myelography, is indicated.
Treatment
Cervical spine injury requires early stabilization. A well-fitting pediatric collar that prevents flexion/exten should be applied and left on until clear evidence of injury can be ruled out. If the patient cannot indica or obey commands, the collar should remain in place until it can be clearly determined that neither bon ligamentous, nor spinal cord injury has occurred. To prevent undue neck flexion and allow the neck to neutral position, an indentation in the pediatric spine board for the occiput should be the norm for child yr. Traction on the cervical spine as part of the stabilization maneuver during intubation is contraindica
If a spinal cord injury is suspected, attention to the adequacy of oxygenation/ventilation and circulation critical. Because hypotension can result in spinal cord ischemia, a bolus (20 mL/kg) of crystalloid fluid saline or Ringer's lactate) should be infused rapidly in the hypotensive patient. Additional fluid boluses given to attain a normal BP, and the addition of an -adrenergic drug should be considered. A continuo infusion of phenylephrine or epinephrine can be initiated at a starting dose of 0.1 g/kg/min. In addition use of Solu-Medrol (30 mg/kg) followed by an IV dose of 5.4 mg/kg/h for 23 h may be beneficial as lon given in the first 8 h after injury (based on data from adults with spinal cord injury).
Children with significant spinal cord trauma, as with other forms of major trauma, should be transferred soon as possible to a pediatric trauma center.
OTHER SERIOUS INJURIES
Blunt trauma is the most common form of pediatric trauma. In addition to head and spine injury, occult abdominal and chest trauma is common. Attention should be paid to the possibility of splenic lacerations/rupture, liver lacerations, renal contusions, pulmonary contusions, pneumothorax/hemotho in the younger child, duodenal hematomas. These injuries may not be obvious at the time of the initial examination but may have devastating consequences. Chest and abdominal CT scans are, therefore, indicated whenever the mechanism of injury suggests that a significant force has been applied to the c Any evidence of circulatory instability (increased heart rate, decrease in pulses, capillary refill > 2 sec w without hypotension) suggests external or internal loss of blood volume from the intravascular space a should be treated rapidly by infusing 1 to 2 boluses (20 mL/kg) of crystalloid fluids (normal saline or Ri lactate), then 10 mL/kg of blood (packed cells) if circulatory compromise is present. Because surgical exploration (abdominal or chest) may be required to determine the cause, a surgical consultation is im
Section 19. Pediatrics Chapter 274. Psychiatric Conditions In Childhood Adolescence Topics
[General] Childhood Psychosis Childhood Depression Adolescent Psychiatric Conditions Suicide In Children And Adolescents
[General]
(See also Gender Identity Disorders in Ch. 192 and Attention Deficit Disorder in Ch. 262.)

Section 19. Pediatrics Chapter 264. Child Abuse And Neglect Topics
[General]
[General]
Child abuse and neglect: The physical or mental injury, sexual abuse, negligent treatment, or maltreat a child < 18 yr.
Physical abuse involves the physical battery of a child. Emotional abuse involves the emotional or m battery of a child, which often damages the child's emotional growth and self-esteem. Sexual abuse o molestation includes exposure, genital manipulation, sodomy, fellatio, and coitus. Vaginal penetration unrelated person constitutes rape. Often, the adult is a close family friend. If the adult is biologically re the offense is termed incest. When young children are involved, the offense most often is nonviolent a repetitive and may be concealed within the family. Neglect includes failure to meet a child's basic phys medical needs, emotional deprivation, and desertion.
All social classes and races contribute to incidents of abuse and neglect, but poor children suffer such incidents 12 times more frequently than others. About 25% of abused or neglected children are < 2 yr. sexes are affected equally. In 1994 in the USA, 2 million cases were reported, of which 1 million were confirmed. Of confirmed cases, 53% involved neglect; 26%, physical abuse; 14%, sexual abuse; and 5 emotional abuse. About 20% of physically abused children are permanently injured, and 1000 to 1200 die each year in the USA.
Physicians are required by law to report incidents of suspected abuse or neglect in any child whom the examine or treat and are granted immunity from suit or liability for so reporting. The reports usually are to a designated child protection agency.
Etiology
Abuse and neglect are complicated problems of adult-child interactions that often coexist and may not easily differentiated.
Abuse: Generally, abuse is caused by the breakdown of impulse control in the parent or guardian. Fo contributing factors are recognized:
Abuse and neglect are complicated problems of adult-child interactions that often coexist and may not easily differentiated.
Abuse: Generally, abuse is caused by the breakdown of impulse control in the parent or guardian. Fo contributing factors are recognized:
1. Parental personality features: The childhood experience of the parent may have lacked affecti warmth, often included abuse, and was not conducive to the development of adequate self-estee emotional maturity. Lacking an early loving environment, abusive parents may look toward their c as a source of the affection and support they never received. As a result, they may have unrealis expectations of what their child can supply for them; they are frustrated easily and lose control, u give what they never experienced. Drug or alcohol use may provoke impulsive and uncontrolled behaviors toward the child. Less commonly, a parent may be frankly psychotic. 2. A "difficult" child: Irritable, demanding, or hyperactive children may provoke parents' tempers, handicapped child, who often is more dependent for care. Premature or sick infants separated fr parents early in infancy and biologically unrelated children (eg, stepchildren) may not form strong emotional ties with their parents or guardians. Even in the absence of these conditions, parents m have unrealistic expectations of what a child's performance should be and may punish him sever little justification. 3. Inadequate support: Parents may feel isolated, unprotected, and vulnerable without the physica psychologic support of relatives, friends, neighbors, or peers, particularly in times of stress. 4. A crisis: Situational stress may precipitate abuse, particularly when support is unavailable.
Neglect: Often, neglect is seen among families with physical, psychologic, or substance abuse proble Acute or chronic depression, especially maternal, is often present; chronic medical problems of a pare also contribute. Drug or alcohol abuse by one or both parents frequently results in chronic impoverishm a distortion of priorities in family life. Desertion by the father, himself inadequate, unable or unwilling to controlling influence in the family, may precipitate neglect. Children of cocaine-using mothers are parti risk for desertion.
Manifestations of Abuse
History: Features suggestive of abuse are (1) parental reluctance to give a history of injury; (2) a histo may be inconsistent with the apparent stage of resolution of the injury and may vary depending on the information source; (3) a history of injury that is incompatible with the child's developmental capability; inappropriate response by the parents to the severity of the injury; and (5) delay in reporting the injury.
Physical: Common signs are skin lesions, such as ecchymoses, hematomas, burns, welts, and abras various stages of development (eg, cigarette burns, arcuate bruises from extension cord whipping, sym scald burns of upper or lower extremities); serious traumatic injury to the mouth, eye, abdominal organ CNS, which may produce permanent damage; and fractures. Fractures may be single or multiple, and skeletal survey may show bony injuries in various stages of resolution. Metaphyseal fractures and subperiosteal elevations in long bones occur in infants. Major diagnostic considerations in the examina (1) multiple injuries at different stages of resolution or development; (2) cutaneous lesions specific for particular sources of injury; and (3) repeated injury, which is suggestive of abuse or inadequate superv
Physical signs of sexual abuse may include difficulty in walking or sitting, genital trauma, vaginal disch pruritus, recurrent UTIs, or a sexually transmitted infection. However, there may be no physical indicat injury. Sexually transmitted disease of any sort in any child < 12 or 13 yr must be viewed as the result molestation until ruled out.
Emotional: Emotional manifestations of abuse are less easily defined than are physical signs. In infan
Physical signs of sexual abuse may include difficulty in walking or sitting, genital trauma, vaginal disch pruritus, recurrent UTIs, or a sexually transmitted infection. However, there may be no physical indicat injury. Sexually transmitted disease of any sort in any child < 12 or 13 yr must be viewed as the result molestation until ruled out.
Emotional: Emotional manifestations of abuse are less easily defined than are physical signs. In infan failure to thrive (see also Failure to Thrive in Ch. 262) is a common early observation. Delayed develo social and language skills often results from inadequate parental stimulation and interaction. Small chi may be distrustful, superficial in interpersonal relationships, passive, and overly concerned with pleasi adults. The emotional impact on children usually becomes obvious at school age, when difficulties dev forming relationships with teachers and peers. Often, emotional effects can be documented only after has been placed in another environment, at which time aberrant behaviors abate.
When a child has been sexually abused, his behavior (eg, irritability, fearfulness, insomnia) may be the clue for diagnosis. Careful interviewing of the child by a trained professional may be the only means o necessary details. Older children may be threatened with physical injury by the offender if they tell and may conceal repeated assaults.
Manifestations of Neglect
Malnutrition, fatigue, and lack of hygiene or appropriate clothing are common due to inadequate provis food, clothing, or shelter, despite available supportive community resources. Desertion or death by sta is seen in extreme cases. As many as 1/2 of infantile failure-to-thrive cases may be due to neglect.
In early infancy, retardation of emotional growth may occur with blunting of affect and lack of interest in environment. This commonly accompanies failure to thrive and is often misdiagnosed as mental retard physical illness. Signs of emotional deprivation in older children include poor attendance and performa school and bad relationships with peers and adults.
Failure to seek preventive medical or dental attention, such as immunizations and routine health supe and delay in seeking care for illness may be clues to inadequate family functioning.
Prevention
Knowing which settings are conducive to abuse and neglect helps identify at-risk families. Parents who been victims of abuse or neglect are especially apt to interact in like fashion with their children. Such p often verbalize anxiety about their abusive background and are amenable to assistance. First-time par teenage mothers rebelling against their parents are also at risk. Medical problems during pregnancy, d or early infancy that may affect the baby's health can weaken parent-infant bonding (see also Parent-I Bonding: The Sick Newborn in Ch. 257). During such times it is important to elicit the parents' feelings their own inadequacies and the baby's well-being. How well can they tolerate a small or sickly baby in house? Does the father give moral and physical support to the mother? Are there relatives or friends t times of need? The care provider who is alert to clues and able to provide support in such settings goe way toward preventing tragic events.
Treatment
Treatment must involve a long-range perspective, because the disturbed patterns of personal interacti usually long-standing. In both abuse and neglect settings, families should be approached in a helping than a punitive manner.
A careful review of the family setting and of the parents' deficiencies and needs is essential diagnostic
Treatment must involve a long-range perspective, because the disturbed patterns of personal interacti usually long-standing. In both abuse and neglect settings, families should be approached in a helping than a punitive manner.
A careful review of the family setting and of the parents' deficiencies and needs is essential diagnostic is the first step in treatment. Hospitalization of the child (emergency temporary removal from the home is not required and depends on the rapport established with the parents. When hospitalization is nece parents should be told that they will be interviewed and that their child will undergo diagnostic tests.
Social work consultation: Adequate understanding of the parents' backgrounds usually requires considerable review of medical records and of prior contacts with various community service agencies worker can help conduct such reviews and may help with interviews and family counseling.
Reporting to a social service or welfare department: When abuse or neglect cases are reported, a face-to-face conference should be held if possible with a child protective services representative to en clear understanding and to help in treatment planning. The parents should be told beforehand by the p that a report is being made pursuant to the law.
Care planning: Many communities have a multidisciplinary team consisting of a social worker, psychia pediatrician, and primary care person to provide diagnostic assistance and guidance in designing a tre program. A source of primary medical care is fundamental and should be acceptable to both the family reporting physician. Periodic or ongoing social work contact usually is needed. Psychiatric assistance understanding personality disorders and in dealing with specific conditions, such as depression, often indicated.
Managing the effects of sexual molestation: Sex offenses may have lasting psychologic effects on child's development and sexual adaptation, particularly among older children and teenagers. Counseli psychotherapy for the child and the adults concerned may lessen these effects.
Community care programs: Day care centers for small children and homemaker services can relieve mother under stress, allowing her a few hours each day for herself. Parent-aide programs, which emp trained nonprofessionals to relate closely to abusive and negligent parents, are being developed in so communities. Parents Anonymous groups also have been successful.
Temporary removal from the home: If the home setting carries a high risk to the child's health, if the child is < 1 yr of age, or if work with the family has not progressed, temporary removal may be indicate particularly if the child has identified his abuser and will be returning to the care of that person and oth caregivers do not support the child's allegations. Removal requires a court petition, presented by the le counsel of the appropriate welfare department. The procedure varies from state to state but usually en family court testimony by a physician. When the court decides in favor of removing the child from the h disposition is arranged. The family's physician should participate in this disposition planning; if not, his agreement and consent to the disposition should be sought. While the child is in temporary placement physician should, if possible, maintain contact with the parents and ensure that adequate efforts are b made to help them. He should also participate when the decision is made to reunite child and parents. dynamics of the family setting improve, the child may be able to return to the parents' care. However, recurrences of abuse are common. Permanent removal may be indicated.
Follow-up: The families of abused and neglected children frequently relocate, making continuity of ca difficult. Broken appointments are common; outreach and home visits by social workers or a public he nurse may be needed to relay the patient's progress to all concerned.
Section 19. Pediatrics Chapter 275. Physical Conditions In Adolescen Topics

[General] Growth And Development Adolescent Pregnancy Accidents And Violence Obesity
[General]
The most common health problems of adolescents relate to growth and development, childhood illnes continuing into adolescence, and experimentation (resulting in such problems as adolescent pregnanc accidents, and violence, including suicide--see Suicide in Children and Adolescents in Ch. 274).

Section 19. Pediatrics Chapter 265. Childhood Infections Topics
Bacterial Infections Viral Infections Miscellaneous Infections
Bacterial Infections
(See also Infectious Myringitis, Acute Otitis Media, and Acute Mastoiditis in Ch. 84.)
DIPHTHERIA
An acute, contagious disease caused by Corynebacterium diphtheriae, characterized by the formation fibrinous pseudomembrane, usually on the respiratory mucosa, and by myocardial and neural tissue d secondary to an exotoxin.
Three biotypes of C. diphtheriae exist (mitis, intermedius, and gravis). Only toxinogenic isolates produ exotoxin; this ability is mediated by bacteriophage infection of the bacterium. Nontoxinogenic isolates produce symptomatic diphtheria, but the clinical course is usually milder. Spread is chiefly by the secre infected persons, directly or via contaminated fomites. Humans are the only known reservoir for C. dip Sporadic cases generally result from exposure to carriers who may never have had apparent disease Infection can occur in immunized persons and is most common and severe in those partially immunize Communicability in untreated persons usually lasts for <= 2 wk. In patients treated with appropriate antimicrobials, communicability usually lasts 4 days. Occasionally, chronic carriage occurs even after antimicrobial treatment.
Cutaneous diphtheria (infection of the skin) can occur when any disruption of the integument is colon C. diphtheriae. Lacerations, abrasions, ulcers, burns, and other wounds are potential reservoirs of the organism. Skin carriage of C. diphtheriae is also a silent reservoir of infection. Poor personal and com hygiene contribute to the spread of cutaneous diphtheria. Warm climate appears to favor the infection however, the disease is not restricted to tropical zones; large outbreaks have occurred in temperate cl In the USA, indigent adults and impoverished groups such as Native Americans living in endemic area
Cutaneous diphtheria (infection of the skin) can occur when any disruption of the integument is colon C. diphtheriae. Lacerations, abrasions, ulcers, burns, and other wounds are potential reservoirs of the organism. Skin carriage of C. diphtheriae is also a silent reservoir of infection. Poor personal and com hygiene contribute to the spread of cutaneous diphtheria. Warm climate appears to favor the infection however, the disease is not restricted to tropical zones; large outbreaks have occurred in temperate cl In the USA, indigent adults and impoverished groups such as Native Americans living in endemic area particularly at risk.
Pathology
Ordinarily, the organisms lodge in the tonsil or nasopharynx, and as they multiply, toxinogenic C. dipht may produce exotoxins lethal to the adjacent host cells. Occasionally, the primary site is the skin or mu elsewhere. The exotoxin, carried by the blood, also damages cells in distant organs, creating patholog lesions in the respiratory passages, oropharynx, myocardium, nervous system, and kidneys.
The myocardium may show fatty degeneration or fibrosis. Degenerative changes in cranial or peripher nerves occur chiefly in the motor fibers. In severe cases, anterior horn cells and anterior and posterior roots may show damage proportional to the duration of infection before antitoxin is given. The kidneys show a reversible interstitial nephritis with extensive cellular infiltration.
The diphtheria bacillus first destroys a layer of superficial epithelium, usually in patches, and the result exudate coagulates to form a grayish pseudomembrane containing bacteria, fibrin, leukocytes, and ne epithelial cells. However, the areas of bacterial multiplication and toxin absorption are wider and deepe indicated by the size of the membrane formed in the wake of the spreading infection.
Symptoms and Signs
The incubation period ranges between 1 and 4 days, followed by a prodromal period of between 12 an Initially, the patient with tonsillar or faucial diphtheria has only a mild sore throat, dysphagia, a low-grad increased heart rate, and rising polymorphonuclear leukocytosis. Nausea, emesis, chills, headache, a are more common in children.
The characteristic membrane, usually found in the tonsillar area but sometimes in other areas (eg, t nasopharynx), is dirty gray, tough, and fibrinous and may adhere firmly so that removal causes bleedin Depending on the duration of infection, the membrane may be punctate or extensive and yellow-gray o creamy. In young children, who may show no signs of illness until the disease is well established, a me is often present at the first examination. In older children and adults, complaints of sore throat and fati precede appearance of the membrane, and some patients never develop a membrane.
The disease may remain mild. When it progresses, dysphagia, toxemia, and prostration are prominen Pharyngeal and laryngeal edema obstruct breathing. If the larynx or the trachea and bronchi are involv membrane may partially obstruct the airway or suddenly detach, causing complete obstruction. The ce lymph glands are enlarged. In severe cases, exotoxin may diffuse into the neck tissue, producing seve edema (bull neck). Nasopharyngeal involvement may produce a serosanguineous nasal discharge, oft unilaterally.
The lesions of cutaneous diphtheria are not morphologically specific; they generally occur on the extre and, if untreated, may become anesthetized by exotoxin infiltration, although pain, tenderness, erythem exudate are typical. They also usually harbor group A -hemolytic streptococci, Staphylococcus aureus A pseudomembrane is uncommon. Concomitant nasopharyngeal infection with the same biotype occu to 40% of patients with cutaneous diphtheria.
The lesions of cutaneous diphtheria are not morphologically specific; they generally occur on the extre and, if untreated, may become anesthetized by exotoxin infiltration, although pain, tenderness, erythem exudate are typical. They also usually harbor group A -hemolytic streptococci, Staphylococcus aureus A pseudomembrane is uncommon. Concomitant nasopharyngeal infection with the same biotype occu to 40% of patients with cutaneous diphtheria.
Rarely, C. diphtheriae causes ocular infection, with or without cutaneous lesions. It can also cause infe other mucocutaneous sites, such as the ear (otitis externa) and genital tract (purulent and ulcerative vulvovaginitis).
Complications and Diagnosis
Severe complications are likely if antitoxin (see below) is not given promptly on the basis of clinical dia even before culture results are available. Insignificant ECG changes occur in 20 to 30% of patients; atrioventricular dissociation, complete heart block, and ventricular arrhythmias are associated with a h mortality rate. Myocarditis is usually evident by the 10th to 14th day but can appear any time during th 6th wk. Heart failure may follow; sudden death may occur. Dysphagia and nasal regurgitation, from bu paralysis, may occur in the 1st wk of illness; peripheral nerve palsies appear from the 3rd to 6th wk. Spontaneous reversal occurs slowly over many weeks. Myocarditis and palsies do not abate with corticosteroids or delayed administration of antitoxin.
The clinical appearance of the membrane suggests the diagnosis, pending confirmation by culture. Gr of the membrane may reveal gram-positive bacilli with metachromatic (beaded) staining in typical Chinese-character configuration. Material for culture should be obtained from below the membrane, or portion of membrane itself should be submitted. Loeffler's medium or tellurite agar is preferred for prim isolation of the organism. The laboratory should be notified that C. diphtheriae is suspected. Cutaneou diphtheria should be considered when a patient develops skin lesions during an outbreak of respirator diphtheria. In geographically remote areas, swab or biopsy specimens can be placed in silica gel pack sent to a distant reference laboratory for culture.
Active immunization with diphtheria-tetanus-pertussis (DTP) vaccine should be routinely given to all ch and all susceptible contacts (see Childhood Immunizations in Ch. 256). For previously immunized con booster dose of adult-type tetanus and diphtheria toxoids, adsorbed (Td), is sufficient.
Symptomatic patients should be hospitalized in ICUs. Diphtheria antitoxin must be given early, since th antitoxin neutralizes only toxin not yet bound to cells. Antitoxin must be given immediately upon clinica diagnosis, without waiting for culture confirmation. Caution: Diphtheria antitoxin is derived from horses a skin (or conjunctival) test to rule out sensitivity should always precede administration (see discussion serum sickness under Hypersensitivity to Drugs in Ch. 148). If after 30 min no erythema or a flat erythe area < 0.5 cm in diameter appears around the site of the skin-test injection, antitoxin should be admini The dose, ranging from 20,000 to 100,000 U, is determined empirically. Patients with moderately symp diphtheritic pharyngitis require 20,000 to 40,000 U, whereas those with more severe symptoms or with complications require larger doses. Antitoxin may be given IM or IV. Doses > 20,000 U may be added to 200 mL of 0.9% sodium chloride and given slowly IV over 30 to 45 min to facilitate delivery of the large volume. For mild cases, 40,000 be given; moderate cases, 80,000 U; and severe cases, 120,000 U.
An urticarial wheal in response to the skin test indicates sensitivity and mandates extreme caution in g antitoxin. The patient must first be desensitized with dilute antitoxin, given in graduated doses, as desc desensitization to foreign serum under Hypersensitivity to Drugs in Ch. 148. If untoward symptoms app
and given slowly IV over 30 to 45 min to facilitate delivery of the large volume. For mild cases, 40,000 be given; moderate cases, 80,000 U; and severe cases, 120,000 U.
An urticarial wheal in response to the skin test indicates sensitivity and mandates extreme caution in g antitoxin. The patient must first be desensitized with dilute antitoxin, given in graduated doses, as desc desensitization to foreign serum under Hypersensitivity to Drugs in Ch. 148. If untoward symptoms app to 1 mL epinephrine 1:1000 (0.01 mL/kg) should immediately be injected sc, IM, or slowly IV. In the hig sensitive patient, IV administration of antitoxin is contraindicated.
Bed rest is necessary, as is intensive nursing care with emphasis on nutrition, fluid intake, oxygenation constant observation for signs that endotracheal intubation or a tracheostomy is needed, continuous monitoring for cardiac problems, and frequent examination for CNS complications. Since the membran easily be dislodged, tracheostomy is the preferred emergency airway treatment.
Antimicrobial treatment is required to eradicate the organism and prevent spread; it is not a substitu antitoxin. Adults may be given either procaine penicillin G 600,000 U IM q 12 h for 10 days or enteric-c erythromycin 250 to 500 mg or erythromycin ethylsuccinate 400 mg po q 6 h for 14 days. Children wei 20 lb should receive procaine penicillin G 25,000 to 50,000 U/kg/day IM in 2 divided doses or erythrom to 50 mg/kg/day (maximum, 2 g/day) po or IV in 4 divided doses. Oral cephalosporins are not recomm Elimination of organism should be documented by two consecutive negative throat cultures after comp antimicrobial treatment.
Recovery from severe diphtheria is slow, and patients must be advised against resuming activities too Even normal physical exertion may harm the patient recovering from myocarditis.
For cutaneous diphtheria, thorough cleansing of the lesion with soap and water and administration of s antimicrobials for 10 days is recommended.
Management of an Outbreak
All symptomatic patients should be isolated. In addition to standard procedures, droplet precautions (ie room and use of mask if within 3 ft of patient) are recommended for patients with pharyngeal diphtheri Contact precautions (ie, private room, use of gloves at all times, hand washing with an antibacterial ag gowns worn at all times) are also recommended. Patients should be treated as described above until t throat (or skin, if appropriate) cultures, taken 24 and 48 h after antibiotics are discontinued, are negati diphtheriae. If positive cultures persist after clinical recovery, treatment should be resumed for 10 days erythromycin (2 g/day po in 4 divided doses for adults, 50 mg/kg/day for children). The enteric-coated ethylsuccinate form should be used to avoid impaired absorption from food. With current antibiotic reg tonsillectomy is no longer indicated for eradication of persistent foci.
All C. diphtheriae isolates should be submitted to the local health department for biotyping and toxigen determination. Toxinogenic and nontoxinogenic biotypes may coexist in a community. Analysis of DNA restriction enzyme patterns and hybridization patterns with DNA probes of the isolates can help charac an outbreak epidemiologically.
Nasopharyngeal and throat cultures for C. diphtheriae should be obtained for all close contacts of kno diphtheria patients regardless of their immunization status. The throat and integument should be exam and symptomatic patients hospitalized and treated as described above, pending culture results. Asym contacts with positive throat cultures for C. diphtheriae ("carriers") should be confined to their homes, visitors, for the duration of therapy, and given erythromycin 250 to 500 mg q 6 h po for adults (50 mg/k 4 divided doses for children). Carriers should not receive antitoxin. After 3 days of treatment, heads of households may resume work while continuing antibiotics. Cultures should be rechecked at a minimum after completion of antimicrobials. Erythromycin treatment failures are usually due to noncompliance in
and symptomatic patients hospitalized and treated as described above, pending culture results. Asym contacts with positive throat cultures for C. diphtheriae ("carriers") should be confined to their homes, visitors, for the duration of therapy, and given erythromycin 250 to 500 mg q 6 h po for adults (50 mg/k 4 divided doses for children). Carriers should not receive antitoxin. After 3 days of treatment, heads of households may resume work while continuing antibiotics. Cultures should be rechecked at a minimum after completion of antimicrobials. Erythromycin treatment failures are usually due to noncompliance in the drug rather than to drug-resistant organisms. Occasional resistance of C. diphtheriae to erythromy been recognized within the USA. Antimicrobial sensitivity tests should be performed on isolates from p who fail treatment. Contacts who cannot be kept under surveillance should receive benzathine penicill erythromycin, for reasons of compliance, and a dose of DTP, acellular pertussis vaccine (DTaP), or diphtheria-tetanus (DT), depending on their age and immunization status.
Diphtheria immunization should be updated in all contacts, including hospital personnel; adult-type teta diphtheria toxoids, adsorbed (Td), should be used. Protective immunity levels cannot be relied upon > after a booster dose. If immunization status is unknown, active immunization should be undertaken wi or DT, depending on age.
From both personal and public health standpoints, persons with negative cultures and full immunizatio safe.
PERTUSSIS
(Whooping Cough)
An acute, highly communicable bacterial disease caused by Bordetella pertussis and characterized by paroxysmal or spasmodic cough that usually ends in a prolonged, high-pitched, crowing inspiration (th whoop).
Epidemiology
Transmission is by aspiration of B. pertussis (a small, nonmotile, gram-negative coccobacillus) spraye the air by a patient, particularly in the catarrhal and early paroxysmal stages. Transmission by contact contaminated articles is rare. Patients usually are not infectious after the 3rd wk of the paroxysmal pha
Pertussis is endemic throughout the world; its incidence in the USA increased in the late 1980s. In a g locality, it becomes epidemic every 2 to 4 yr. It occurs at all ages, but 38% of the cases occur in infant mo, and 71% occur in children < 5 yr. Adolescents and adults have recently been recognized as a ma source of pertussis. One attack does not confer natural immunity for life, but second attacks, if they oc usually mild and often unrecognized.
Parapertussis is caused by B. parapertussis, which closely resembles B. pertussis; parapertussis ma clinically indistinguishable from pertussis but is usually milder and less often fatal.
Symptoms and Signs
The incubation period averages 7 to 14 days (maximum, 3 wk). B. pertussis invades the mucosa of the nasopharynx, trachea, bronchi, and bronchioles, increasing the secretion of mucus, which is initially th later viscid and tenacious. The uncomplicated disease lasts about 6 to 10 wk and consists of three sta catarrhal, paroxysmal, and convalescent. The catarrhal stage begins insidiously, generally with sneezing, lacrimation, or other signs of coryza;
The incubation period averages 7 to 14 days (maximum, 3 wk). B. pertussis invades the mucosa of the nasopharynx, trachea, bronchi, and bronchioles, increasing the secretion of mucus, which is initially th later viscid and tenacious. The uncomplicated disease lasts about 6 to 10 wk and consists of three sta catarrhal, paroxysmal, and convalescent.
The catarrhal stage begins insidiously, generally with sneezing, lacrimation, or other signs of coryza; anorexia; listlessness; and a troublesome, hacking nocturnal cough that gradually becomes diurnal. Fe rare.
The paroxysmal stage occurs after 10 to 14 days when the cough increases in severity and number. 15 or more rapidly consecutive forceful coughs occur during a single expiration and are followed by the a hurried, deep inspiration. After a few normal breaths, another paroxysm may begin. Copious amoun viscid mucus may be expelled (usually swallowed by infants and children but also producing large bub the nares) during or after the paroxysms. Vomiting subsequent to paroxysms or due to gagging on the tenacious mucus is characteristic. In infants, choking spells (with or without cyanosis) may be more co than whoops.
The convalescent stage usually begins within 4 wk; paroxysms are not so frequent or severe, vomitin decreases, and the patient looks and feels better. Average duration of illness is about 7 wk (range, 3 w mo). Paroxysmal coughing may recur for months, usually induced by irritation from a URI.
The WBC count is usually between 15,000 and 20,000/L but may be normal or as high as 60,000/L with 60 to 80% small lymphocytes.
Complications and Diagnosis
Respiratory complications are most common, including asphyxia in infants. Bronchopneumonia (also c in the elderly) may be fatal at any age. Interstitial and subcutaneous emphysema and pneumothorax a uncommon complications of the increased intrathoracic pressure during paroxysms. Bronchiectasis, particularly in debilitated children, and residual emphysema can result. Atelectasis may occur when a plug occludes a bronchiole. A primary tuberculous lesion may be extended by simultaneous occurrenc pertussis. Convulsions are common in infants but rare in older children. Hemorrhage into the brain, ey and mucous membranes can result from severe paroxysms and consequent anoxia. Cerebral hemorrh edema or toxic encephalitis may result in spastic paralysis, mental retardation, or other neurologic diso An ulcer may develop on the frenulum of the tongue from lower incisor trauma during paroxysms. Umb hernia and rectal prolapse occasionally occur. Otitis media occurs frequently.
Cultures of nasopharyngeal specimens are positive for B. pertussis in 80 to 90% of cases in the catarr early paroxysmal stages. Best results are obtained with small sterile cotton swabs on 28-gauge, zinc-c wire passed through the nostril to the nasopharynx. Freshly prepared Bordet-Gengou or charcoal agar medium, containing penicillin or cephalexin to inhibit overgrowth by other flora, should be used. Specif fluorescent antibody testing of nasopharyngeal smears accurately diagnoses pertussis but is not as se as culture. Bordetella pertussis polymerase chain reaction can also be used.
The catarrhal stage is often difficult to distinguish from bronchitis or influenza. Adenovirus infections a should also be considered in the differential diagnosis, since either can mimic pertussis. Lymphocytos 70% in an afebrile or slightly febrile child > 3 yr with a suspicious cough often suggests pertussis but d distinguish it from an adenoviral pertussis-like syndrome. Parapertussis is differentiated by culture or the fluorescent antibody technique.
Prognosis and Prophylaxis
distinguish it from an adenoviral pertussis-like syndrome. Parapertussis is differentiated by culture or the fluorescent antibody technique.
Prognosis and Prophylaxis
Pertussis is serious in children aged < 2 yr; mortality is about 1 to 2% in children aged < 1 yr (highest i first month of life). Most deaths are caused by bronchopneumonia and cerebral complications (see ab Pertussis is troublesome but rarely serious in older children and adults, except in the elderly.
Active immunization is described in Childhood Immunizations in Ch. 256. Passive immunization is unr and is not recommended.
Patients should be quarantined, particularly from susceptible infants, for at least 4 wk from disease on until symptoms have subsided. If quarantine is uncertain or difficult, oral erythromycin (preferably the e preparation) 12.5 mg/kg po q 6 h (maximum, 2 g/day) starting during the incubation period and continu 10 to 14 days usually eradicates nasopharyngeal carriage of the organism, thus diminishing infectivity and possibly aborting the infection in contacts. However, efficacy is not yet fully established, and there recognized therapeutic benefit after the paroxysms have begun.
Treatment
Hospitalization is recommended for seriously ill infants to assess progression of disease and prevent a complications. Small frequent meals are advisable. Parenteral fluid therapy may be required to replace and water losses if vomiting is severe. In infants, suction to remove excess mucus from the throat may lifesaving, and tracheostomy or nasotracheal intubation is occasionally needed. O2 should be given if persists after removal of mucus. Because any disturbance can precipitate serious paroxysmal spells w anoxia, seriously ill infants should be kept in a darkened, quiet room and disturbed as little as possible attention should be paid to the nutritional needs of the infant, since preexisting or developing malnutrit adversely affect outcome.
Expectorant cough mixtures, cough suppressants, and mild sedation are of questionable value and sh used cautiously or not at all. Drugs such as theophylline or albuterol and corticosteroids have also bee suggested for the treatment of severely ill patients; however, further controlled studies are needed to a their effectiveness and potential hazards. Antibiotics given in the catarrhal stage may ameliorate the d After paroxysms are established, antibiotics usually have no discernible effect but are recommended t spread. The drug of choice is erythromycin 40 to 50 mg/kg po q 6 h for 14 days. Antibiotics should also used for any bacterial complications such as bronchopneumonia and otitis media. Bed rest is unneces older children with mild disease.
OCCULT BACTEREMIA
Presence of viable pathogenic bacteria in the bloodstream of young febrile children who have no appa of infection and look well enough to be managed as outpatients.
Occult bacteremia is caused by Streptococcus pneumoniae in 65 to 75% of cases, and the remainder bacteria, including Neisseria meningitidis, Salmonella sp, and Staphylococcus aureus. The incidence o bacteremia due to Haemophilus influenzae type b (Hib) has decreased remarkably in countries where
Occult bacteremia is caused by Streptococcus pneumoniae in 65 to 75% of cases, and the remainder bacteria, including Neisseria meningitidis, Salmonella sp, and Staphylococcus aureus. The incidence o bacteremia due to Haemophilus influenzae type b (Hib) has decreased remarkably in countries where conjugate vaccine is part of routine childhood immunization.
Occult bacteremia is detected in about 4 to 17% of febrile infants between 1 and 24 mo of age; most c occur in infants between 6 and 24 mo of age. Children who look well enough to be managed as outpa who later are found to be bacteremic usually are < 24 mo of age. Incidence does not vary with sex or r
Occult bacteremia is most often associated with URIs, pharyngitis, or isolated fever; however, the perc of infants with one of these conditions who are actually bacteremic is very small.
Since diagnosis depends on isolating bacteria from the blood, an immediate diagnosis cannot be mad the child is first seen. Cultures usually take 24 to 48 h to become positive, and specimens can often be contaminated with microorganisms from the skin. Available rapid diagnostic techniques (eg, erythrocyt sedimentation rate, C-reactive protein) are not sensitive enough for clinical use.
Nonspecific tests may help determine the likelihood of bacteremia. In most bacteremic children, the W count is elevated and thus is a sensitive test; however, only about 10% of children with WBC counts o 15,000/L are bacteremic (so specificity is low). Acute phase reactants such as ESR and C-reactive p add little information. Urinalysis with < 5 WBC/high-power field and absence of nitrite and leukocyte es help to rule out UTI. A combination of risk factors--eg, 1 to 24 mo of age, temperature > 38.5 C (> 101 high WBC count (> 15,000/L and > 5000/L of band forms), and abnormal urinalysis--increases the c that bacteremia is present but only to between 10 and 25%. Various clinical scoring scales have been developed, such as the Rochester criteria for low risk of serious bacterial infection in infancy (see Tabl
Occult bacteremia should be distinguished from sepsis, neonatal sepsis, and septic shock. (For discus these infections, see Ch. 156, and Neonatal Sepsis and Neonatal Meningitis under Neonatal Infection 260.)
Regardless of whether children receive antibiotics before confirmation of bacteremia, about 10 to 15% develop meningitis. Of children who receive antibiotics before bacteremia is confirmed, a majority will i clinically and a small percentage will have persistent bacteremia. In contrast, of the children who do no receive antibiotics before confirmation of bacteremia, a minority will improve clinically, and about the s number as those receiving antibiotics before confirmation of bacteremia will develop localized bacteria infection, continued fever, and persistent bacteremia.
Some authorities advocate initiating treatment with IM ceftriaxone or oral amoxicillin while awaiting the of outpatient blood cultures for infants between the ages of 3 and 24 mo who have temperatures > 40 104 F) and WBC counts > 15,000/L. Others believe treatment is not necessary if meticulous observ be guaranteed. In both cases, close observation and follow-up are essential, especially for the first 72
About 50% of outpatients in whom bacteremia is suspected have a treatable infection--usually otitis m pneumonia--and will almost certainly be receiving oral antibiotics by the time bacteremia is confirmed.
104 F) and WBC counts > 15,000/L. Others believe treatment is not necessary if meticulous observ be guaranteed. In both cases, close observation and follow-up are essential, especially for the first 72
About 50% of outpatients in whom bacteremia is suspected have a treatable infection--usually otitis m pneumonia--and will almost certainly be receiving oral antibiotics by the time bacteremia is confirmed.
URINARY TRACT INFECTION
Significant bacteriuria (eg, > 103 colonies/mL in a catheterized specimen), either asymptomatic or with manifestations of cystitis, pyelonephritis, or septicemia.
The urinary tract from the kidneys to the bladder is normally sterile, despite probable frequent contami with colonic bacteria via the distal urethra. Mechanisms that maintain the tract's sterility include urine a and free flow, a normal emptying mechanism, intact ureterovesical and urethral sphincters, and immun and mucosal barriers. Abnormality of any of these mechanisms and urinary stasis are major predispos factors to UTI.
In abnormal urinary tracts, many organisms can cause infection. In relatively normal tracts, the causes are strains of Escherichia coli with specific attachment factors for transitional epithelium of the bladder ureters. E. coli causes > 75% of UTIs in all pediatric age groups. The remaining causes are other gram-negative enterobacteria, especially Klebsiella, Proteus mirabilis, and Pseudomonas aeruginosa. Enterococci (group D streptococci) and coagulase-negative staphylococci (eg, Staphylococcus saprop are the most frequently implicated gram-positive organisms. Fungi and mycobacteria are unusual caus Adenoviruses are implicated in hemorrhagic cystitis.
In newborns, 1 to 2% develop UTI, and the male:female ratio is 5:1. Infections in males often are bac Predisposing factors include malformations and obstructions of the urinary tract, prematurity, indwellin catheters, and lack of circumcision; major renal abnormalities are present in 20 to 40% of newborns w
After the newborn period, UTIs occur in 2 to 5% of young children and in 5% of school-aged children female:male ratio rises with age and is > 10:1 after age 4 yr. Female infections usually are ascending associated with bacteremia. The marked female preponderance is attributed to the shorter female ure Other predisposing factors in this age group include indwelling catheters, constipation, Hirschsprung's and anatomic abnormalities of the urinary tract (eg, obstructions, neurogenic bladder, and ureteral duplications). Other risk factors include IgA deficiency, diabetes, trauma, and, in adolescents, sexual intercourse. Five to 15% of school-aged children with UTI have urinary tract abnormalities that will req surgery; 30 to 40% have vesicoureteral reflux that will require antibiotic prophylaxis. The incidence of r varies inversely with age at the first episode of UTI.
Symptoms and Signs
In newborns, symptoms and signs are nonspecific and often mimic those of neonatal sepsis. Poor fee diarrhea, failure to thrive, vomiting, mild jaundice, lethargy, fever, and hypothermia can suggest UTI.
Infants and toddlers also present with poorly localizing signs. Some children are asymptomatic and diagnosed on routine screening; others have symptoms referable to the GI tract (eg, vomiting, diarrhea abdominal pain).
diarrhea, failure to thrive, vomiting, mild jaundice, lethargy, fever, and hypothermia can suggest UTI.
Infants and toddlers also present with poorly localizing signs. Some children are asymptomatic and diagnosed on routine screening; others have symptoms referable to the GI tract (eg, vomiting, diarrhea abdominal pain).
In children > 2 yr, the more classic picture of cystitis or pyelonephritis can occur, although as many a UTIs are asymptomatic. Symptoms of cystitis include dysuria, frequency, hematuria, urinary retention, suprapubic pain, urgency, pruritus, incontinence, foul-smelling urine, and enuresis. Symptoms of pyelo may include those of cystitis plus high fever, chills, and costovertebral pain and tenderness.
Diagnosis
Diagnosis requires demonstration by culture of significant bacteriuria in properly collected urine. If urin obtained by suprapubic aspiration of the bladder, the presence of any gram-negative bacteria is signifi are > 1000 coagulase-negative staphylococci/mL of urine. In a catheterized specimen, > 103 colonies/ usually are significant. Clean-catch, midstream-voided specimens from males are significant when col counts are > 104; from females, when colony counts are > 105. Bagged specimens are unreliable and not be used for diagnosing UTIs.
All children with suspected UTI also should be examined for abdominal masses, enlarged kidneys, ure abnormalities, costovertebral angle tenderness, and signs of lower spinal malformations. Diminished f the urinary stream may be the only clue to obstruction or neurogenic bladder. BP, height, and weight s recorded. Hct, BUN, and creatinine should be checked.
Urine microscopy: Microscopic examination of urine is useful but not definitive. Pyuria (> 5 WBCs/hig field in the spun urine sediment) usually indicates UTI but is absent in 60% of culture-proven UTIs. Gra of urine can be a sensitive procedure for identifying UTI. The presence of 1 bacterium/10 oil immersio (1000) fields in unspun urine or > 10 WBC/L in a spun urine (by hemocytometer) correlates with the presence of > 105 bacteria/mL of urine by culture.
Chemical detection methods: Chemical tests to detect bacteria (eg, the nitrite test and the leukocyte esterase test) are useful for screening purposes only, but a positive nitrite test result on a freshly voide specimen is highly indicative of UTI.
Urine culture: Urine should be cultured as soon as possible or stored at 4 C (40 F) if a delay of > 10 min is expected. Urine is best cultured on blood agar plates and incubated 24 to 48 h at 37 C (98.6 F urine is streaked on the plates using quantitative bacteriologic loops. When urine is from suprapubic a or catheterization, 0.001 mL and 0.1 mL should be cultured. Clean-catch, midstream-voided specimen sufficiently cultured at only 0.001 mL. For office bacteriology, culturing on blood agar plates is the proc choice, although kit methods (eg, the dipslide or filter paper) are sensitive. Occasionally, UTI may be p despite low colony counts, possibly because of prior antibiotic therapy, very dilute urine (sp gr < 1.003 obstruction to the flow of grossly infected urine. Repeating the culture improves the diagnostic accurac positive result.
Tests to differentiate upper from lower tract infection: Differentiating upper from lower tract infecti be difficult. When the child has high fever, costovertebral angle tenderness, and gross pyuria with cas is little doubt that the child has pyelonephritis. However, when sensitive distinguishing techniques (eg, washout, concentrating ability, detection of antibody-coated bacteria) have been applied in research s many children with asymptomatic UTIs or with only symptoms of cystitis were found to have upper trac disease. These tests are not indicated in the usual clinical settings.
be difficult. When the child has high fever, costovertebral angle tenderness, and gross pyuria with cas is little doubt that the child has pyelonephritis. However, when sensitive distinguishing techniques (eg, washout, concentrating ability, detection of antibody-coated bacteria) have been applied in research s many children with asymptomatic UTIs or with only symptoms of cystitis were found to have upper trac disease. These tests are not indicated in the usual clinical settings.
Urinary tract imaging: The urinary tracts of all children with diagnosed UTI should be evaluated with ultrasound, radionuclide scan, or IVU to detect major abnormalities and with a voiding cystourethrogra (VCUG) to detect significant reflux, which is found in 20 to 50% of children with UTI. Reflux of infected into the renal pelvis or infected urine behind an obstruction can lead to chronic pyelonephritis, renal sc poor kidney growth, and renal failure. IVU or ultrasound can be performed at any time but is recomme within the 1st wk of diagnosing UTI in younger infants. VCUG is best postponed 3 to 6 wk to allow the reflux usually associated with cystitis to resolve, thereby allowing a more accurate evaluation of the competence of the ureterovesical valves. Some physicians postpone x-ray evaluation in females > 3 y after the second UTI.
For vesicoureteral reflux, the VCUG is the best anatomic test. However, a radionuclide VCUG with tec 99m pertechnetate delivers a gonadal radiation dose 1% that of the radiographic VCUG; it is quite sen detecting reflux and can be recommended as the initial test. When the radiographic or radionuclide VC shows no reflux, renal ultrasound can be performed to rule out anatomic abnormalities; when reflux is the upper tract is best evaluated with an IVU or with a radionuclide scan with a cortical agent (eg, tech 99m glucoheptonate), which delivers a lower radiation dose than the IVU and can be quite sensitive in detecting renal scarring. Ultrasound is now the procedure of choice for following renal growth in childre documented reflux.
Vesicoureteral reflux can be classified by grade as defined by the International Reflux Study Committe
Grade I: Only the ureters are involved Grade II: The reflux reaches the calices Grade III: The ureter and renal pelvis are dilated Grade IV: The dilation is increased and the sharp angle of the fornices is obliterated Grade V: The ureter, pelvis, and calices are grossly dilated, and papillary impressions frequently absent
The overall prognosis for UTI is good. Properly managed patients rarely progress to renal failure unles have uncorrectable urinary tract abnormalities. Recurrences occur in about 50% of patients with symp or asymptomatic UTIs but are more common in those with urologic abnormalities.
Treatment aims to preserve renal parenchymal function and to minimize acute morbidity. In the newb after blood and urine cultures have been collected, treatment should be started parenterally with ampi an aminoglycoside in dosages appropriate for neonatal sepsis (see Table 260-6). If blood cultures are negative, clinical response is good, and repeat urine culture 48 to 72 h into therapy is negative, an app oral antibiotic (eg, ampicillin, amoxicillin, or a cephalosporin chosen on the basis of sensitivities) can b to complete a 10-day course. Urine should be cultured again 7 to 10 days after therapy ends. A poor r suggests a resistant organism or an obstructive lesion and warrants urgent evaluation.
After the newborn period, children can be treated with oral antibiotics unless they have high fever, h prominent signs of toxicity, or are vomiting, in which case parenteral treatment is indicated. The initial of choice is ampicillin, amoxicillin, sulfisoxazole, trimethoprim-sulfamethoxazole (TMP-SMX), or a cephalosporin (see Table 265-2). These provide adequate coverage for E. coli. Changes in therapy sh guided by the results of cultures and sensitivities. Children hospitalized with acute pyelonephritis and s sepsis should receive parenteral ampicillin and an aminoglycoside or a 3rd-generation cephalosporin s
After the newborn period, children can be treated with oral antibiotics unless they have high fever, h prominent signs of toxicity, or are vomiting, in which case parenteral treatment is indicated. The initial of choice is ampicillin, amoxicillin, sulfisoxazole, trimethoprim-sulfamethoxazole (TMP-SMX), or a cephalosporin (see Table 265-2). These provide adequate coverage for E. coli. Changes in therapy sh guided by the results of cultures and sensitivities. Children hospitalized with acute pyelonephritis and s sepsis should receive parenteral ampicillin and an aminoglycoside or a 3rd-generation cephalosporin s cefotaxime or ceftriaxone. Length of treatment for UTI is 7 to 10 days, although many older children w uncomplicated UTI can be successfully treated with a shorter course of antibiotics.
Urine should be recultured 2 to 3 days after therapy starts if efficacy is not apparent and in all children days after stopping antibiotics to document efficacy of treatment. Failure to sterilize the urine after 48 h antibiotics may be due to a resistant organism, an obstructive lesion, or poor compliance.
Because of the risk of recurrences, repeat urine cultures should be performed 3 to 4 times during the f after diagnosis and at least twice a year during the next 2 or 3 yr (or any time the child develops UTI symptoms). Prophylactic antibiotics are indicated for children with grade II or higher reflux to reduce recurrences and prevent kidney damage. Nitrofurantoin 2 mg/kg/day or TMP-SMX (2 mg/kg/day TMP) orally once daily, usually at night.
Vesicoureteral reflux should be managed based on the grade (see Diagnosis, above). Children with no x-rays or grade I reflux can be followed with periodic urine cultures. Infants with grade II or III reflux are candidates for antibiotic prophylaxis. If grade IV or V reflux or a major renal abnormality is detected, ur referral is indicated, because surgery may be needed (see Ch. 216).
ACUTE INFECTIOUS GASTROENTERITIS

(See also Ch. 28 and Acute Infectious Neonatal Diarrhea under Neonatal Infections in Ch. 260.)
A syndrome of vomiting and diarrhea caused by pathogenic microorganisms that may lead to dehydra electrolyte imbalance.
About 1 billion episodes/yr are estimated to occur worldwide, most commonly in developing countries children < 5 yr. Death due to dehydration occurs in about 5 million cases. Most deaths can be prevent prompt rehydration. In many developing countries, if infants < 2 yr having 6 to 10 episodes/yr of diarrh vomiting are not treated, severe malnutrition is likely to occur.
Many bacterial, viral, and parasitic organisms can cause acute gastroenteritis (see Table 265-3). Appr laboratory tests identify a causative agent in 60 to 80% of cases.
The epidemiology, duration, character, and frequency of vomiting and diarrhea in relation to the child's may indicate the cause and severity of the illness. Usually, at least one family member or close contac recently had symptoms of gastroenteritis or a respiratory infection. Infants < 6 mo may develop dehydr and electrolyte imbalance as early as 24 h after onset. However, in patients of any age, severe dehydr and metabolic acidosis may develop within 24 h of onset if vomiting is intractable, diarrhea is explosive intake is drastically reduced. Physical examination should exclude any extraintestinal cause and deter state of hydration. Lethargy, oliguria, and substantiated weight loss are signs of dehydration (see Tabl
In older infants, overweight young children, and patients with hypernatremia, some signs may not appe dehydration is severe. In patients with hypernatremic dehydration, irritability and fever may be present
and metabolic acidosis may develop within 24 h of onset if vomiting is intractable, diarrhea is explosive intake is drastically reduced. Physical examination should exclude any extraintestinal cause and deter state of hydration. Lethargy, oliguria, and substantiated weight loss are signs of dehydration (see Tabl
In older infants, overweight young children, and patients with hypernatremia, some signs may not appe dehydration is severe. In patients with hypernatremic dehydration, irritability and fever may be present may feel doughy, which is a distinctive feature. Dry skin with poor tissue turgor usually associated with common isotonic dehydration may not be present. Common signs of dehydration include a sunken an fontanelle, sunken eyes with absent tearing, dry oral mucous membranes, weak or absent sucking, an lethargy (see Table 265-4).
The Hct and serum electrolyte levels may reflect the state of hydration and electrolyte balance. Urinary also helps assess the state of hydration, and microscopic examination of urine for bacteria helps deter whether a UTI (a common cause of symptoms similar to those of gastroenteritis) may be present.
Stool cultures may be useful for differentiating bacterial from viral gastroenteritis, and sensitivity studie specific antibiotic therapy. A Wright's, Gram, or methylene blue staining of a watery stool specimen us shows abundant PMNs when bacterial infection is present.
Treatment
The mainstay of treatment for diarrhea and vomiting of any cause is to give appropriate fluids and elec Before therapy is begun, the degree of dehydration should be clinically assessed. The degree of dehy indicates the need for rehydration, maintenance, and replacement of ongoing stool losses (see Table
Rehydration: Infants with no signs of dehydration do not need rehydration. However, they should rece same fluids recommended for patients with dehydration for the maintenance phase and for ongoing st losses. They should also be encouraged to drink fluids (eg, soup, rice water, cereal-Oral rehydration solution, recommended by the WHO, has been used worldwide for > 20 yr. This solution contains (in Na 90, K 20, Cl 80, bicarbonate 30, and glucose 111; it is made by adding 1 L of water to 3.5 g sodium chloride, 2.5 g sodium bicarbonate, 1.5 g potassium chloride, and 20 g glucose. This solution is effecti patients with acute diarrhea regardless of age, cause, or type of electrolyte imbalance (hyponatremia, hypernatremia, or isonatremia). After rehydration, oral rehydration solution must be supplemented by o free water or a low-Na fluid.
If oral rehydration solution is unavailable, a sugar/salt solution of similar composition can be used du rehydration and maintenance. It is prepared by adding 1 L of water to 15 mL (1 tbsp) of sugar and 2 m tsp) of salt. Although sugar/salt solution is less effective than oral rehydration solution, it is usually ade for treating diarrhea.
IV fluids (lactated Ringer's or similar solution) may be needed for children who cannot tolerate oral flu
At the end of the rehydration period (about 4 h), the patient should be reassessed. If signs of dehydrat persist, rehydration therapy should be repeated until dehydration is corrected.
Maintenance: Ongoing stool losses should be replaced on a 1:1 basis with oral rehydration solution. I stool output is unknown, about 10 mL/kg or 0.5 to 1 cup (120 to 240 mL or 4 to 8 oz) of oral rehydratio solution should be given for each diarrheal stool.
Children with diarrhea who are not dehydrated should continue to eat an age-appropriate diet. Childre are dehydrated should eat an age-appropriate diet as soon as they have been rehydrated. Breastfed i with diarrhea should continue breastfeeding. For nonbreastfed infants, full-strength animal milk or anim
stool output is unknown, about 10 mL/kg or 0.5 to 1 cup (120 to 240 mL or 4 to 8 oz) of oral rehydratio solution should be given for each diarrheal stool.
Children with diarrhea who are not dehydrated should continue to eat an age-appropriate diet. Childre are dehydrated should eat an age-appropriate diet as soon as they have been rehydrated. Breastfed i with diarrhea should continue breastfeeding. For nonbreastfed infants, full-strength animal milk or anim formula is usually well tolerated if diarrhea is mild and self-limited. Children who develop signs or symp malabsorption should be given lactose-free formula. If lactose-free formula is not available or affordab milk normally consumed by the infant can be diluted 1:1. Older children and adults can take normally consumed fluids as desired.
Antibiotics: Antibiotics should only be used for specific indications, as shown in Table 265-5. Antibiot not affect the course of Salmonella gastroenteritis; when they are used, fecal excretion of the organism prolonged, and emergence of resistant strains is enhanced. However, when Salmonella organisms inv bloodstream or localize in extra-intestinal sites, ampicillin, ceftriaxone, cefotaxime, or chloramphenicol IV depending on in vitro susceptibility tests, especially in infants < 6 mo and immunosuppressed childr including those with sickle cell disease. Yersinia gastroenteritis usually subsides without antibiotic ther Vibrio cholerae gastroenteritis should be treated with tetracycline or trimethoprim-sulfamethoxazole. Campylobacter jejuni enterocolitis severe enough to require hospitalization should be treated with erythromycin. Trimethoprim-sulfamethoxazole can be used in ampicillin-resistant shigellosis.
PERIORBITAL AND ORBITAL CELLULITIS
Primarily childhood infections that cause acute swelling and redness of the eyelid and surrounding ski (periorbital cellulitis) or of the periorbital skin and orbital contents (orbital cellulitis).
Periorbital cellulitis is more common (occurring in 85 to 90% of affected patients) than orbital cellulitis occurs more frequently in children < 5 yr of age, whereas orbital cellulitis is more frequent in children >
Periorbital and orbital cellulitis may be caused by an external focus of infection (eg, a wound, an insec an internal source of infection (eg, sinusitis), or seeding from bacteremia. Before widespread immuniz Haemophilus influenzae type b was the most common cause secondary to bacteremia (about 80% of and remains so in nonimmunized populations. Streptococcus pneumoniae accounted for most of the remaining 20%. S. pneumoniae is the most likely agent in Haemophilus influenzae type b-vaccinated p The most common pathogens associated with external foci are Staphylococcus aureus and Streptoco pyogenes, but these are seldom isolated from the blood. In general, a bacterial pathogen is isolated fr blood in <= 33% of patients with periorbital cellulitis.
Infection usually spreads by direct extension from infected ethmoid sinuses or by local cutaneous infec Infection can spread in either direction via the inferior and superior ophthalmic veins, which drain the e and pass through the ethmoid sinuses. Local inflammation can result in venous or lymphatic obstructio leading to swelling in areas distant from the site of infection.
Symptoms and Signs
Swelling and redness of the eyelid (unilateral in > 90% of cases) are usually the first signs. About 33% patients have a history of trauma or signs of local infection, regardless of whether any pathogen is isol About 75% of children have fever, which is most elevated with bacteremic disease; about 20% have n
Symptoms and Signs
Swelling and redness of the eyelid (unilateral in > 90% of cases) are usually the first signs. About 33% patients have a history of trauma or signs of local infection, regardless of whether any pathogen is isol About 75% of children have fever, which is most elevated with bacteremic disease; about 20% have n discharge; and about 20% have conjunctivitis. Chemosis can occur in periorbital cellulitis, whereas ophthalmoplegia, proptosis, eye pain, or decreased visual acuity indicates orbital disease.
The most common complications are central retinal artery or retinal vein thrombosis and retinal damag secondary to ischemia caused by increased intraocular pressure. Intracranial complications, which occ the infection is not contained in the orbit, include epidural, subdural, or cerebral abscesses; cavernous cortical vein thrombosis; and bacterial meningitis.
Diagnosis
The position of the globe, eye movement, and visual acuity must be evaluated. Because lid swelling fr requires the use of lid retractors for evaluation of the globe, an ophthalmologist should be consulted w possible. Table 265-6 summarizes the findings in patients with periorbital cellulitis and varying degrees orbital involvement. The direction of proptosis may be a clue to the site of the infection; eg, extension frontal sinus pushes the globe down and out, and extension from the ethmoid sinus pushes the globe and out. If eye examination fails to demonstrate proptosis, ophthalmoplegia (usually painful), or decrea visual acuity, a local nidus of infection should be sought on the skin. If local injury or infection is not ev sinus infection should be sought.
Blood cultures yield pathogens in up to 33% of patients; other laboratory tests are not particularly help X-rays of the sinuses are useful for diagnosing sinusitis in children > 1 yr, but they generally do not differentiate preseptal from postseptal involvement. When orbital involvement is suspected, CT can be assess sinus involvement, subperiosteal elevation, and intraorbital cellulitis or abscess formation and be done as soon as specimens have been taken for culture and antibiotic therapy has begun.
Differential diagnosis of swelling and erythema of the eyelid includes trauma, insect bites, allergy, and Other inflammatory diseases (eg, hordeolum, dacryocystitis, dacryoadenitis, conjunctivitis) can usually diagnosed by location and appearance.
Treatment
Children require hospitalization and prompt treatment. An ophthalmologist and otolaryngologist should consulted early in case surgical drainage of the orbit or a sinus is necessary. If the focus of infection is obviously external, Gram stain and cultures of exudate should be obtained and antibiotic therapy for S and S. pyogenes given. With no obvious external focus of infection, blood cultures should be obtained therapy for H. influenzae type b and S. pneumoniae begun. In an infant < 1 yr with no external focus o infection, a lumbar puncture should be performed. Because the absence of an external focus of infect usually difficult to ascertain, it is best to obtain CSF and blood specimens for culture and begin admini antibiotics (cefuroxime or ceftriaxone with either nafcillin or clindamycin or, alternatively, chlorampheni nafcillin) for H. influenzae type b and gram-positive aerobes. When CNS involvement is suspected, ce alone or chloramphenicol with nafcillin provides adequate antibacterial coverage until culture results ar known.
ACUTE EPIGLOTTITIS
(Supraglottitis)
known.
ACUTE EPIGLOTTITIS
(Supraglottitis)
Rapidly progressive infection and inflammation of the epiglottis and surrounding tissues that may lead sudden respiratory obstruction and death.
The incidence has declined dramatically in the past decade. The infection is usually caused by encaps bacteria. Before widespread vaccination, H. influenzae type b was the most common cause. Currently organisms include S. pneumoniae, S. aureus, nontypable H. influenzae, H. parainfluenzae, and -hemo streptococci.
Pathophysiology
Infection, acquired through the respiratory tract, may produce initial nasopharyngitis. Subsequent dow extension produces supraglottic cellulitis with marked inflammation of the epiglottis, the vallecula, the aryepiglottic folds, the arytenoids, and the ventricular bands; bacteremia is common with H. influenzae infection.
The inflamed epiglottis mechanically obstructs the airway; the work of breathing increases, and CO2 re and hypoxia may result. Clearance of inflammatory secretions is also impaired. These factors may res fatal asphyxia within a few hours.
Symptoms and Signs
Onset is usually acute and fulminant. Sore throat, hoarseness, and, frequently, high fever develop abr previously well child. Dysphagia and respiratory distress characterized by drooling, dyspnea, tachypne inspiratory stridor develop rapidly, often causing the child to lean forward and hyperextend the neck to enhance air exchange. On physical examination, the child may appear moribund or restless and in sev respiratory distress. Deep suprasternal, supraclavicular, intercostal, and subcostal inspiratory retractio noted. Breath sounds may be diminished bilaterally, and rhonchi may be heard. The pharynx is usually inflamed.
H. influenzae type b pneumonia, occasionally with empyema, may occur concurrently with epiglottitis. Infrequently, metastatic infection to the joints, meninges, pericardium, or subcutaneous tissues results abscess or cellulitis.
Diagnosis
The patient should be hospitalized immediately whenever the diagnosis is suspected clinically. Direct visualization of the epiglottis is diagnostic, but manipulation may initiate sudden, fatal airway obstructio Visualization should be attempted only by designated trained personnel using equipment to establish a airway if necessary. If direct laryngoscopy confirms the diagnosis by revealing a beefy red, stiff, and edematous epiglottis, an artificial airway should be placed immediately (see Treatment, below). The ca organism may then be cultured from the upper respiratory tract and, usually, from the blood.
The differential diagnosis includes croup (see Table 265-7 and under Viral Infections, below) and bact tracheitis (see below). Diphtheria (see above) should be considered in a nonimmunized patient.
airway if necessary. If direct laryngoscopy confirms the diagnosis by revealing a beefy red, stiff, and edematous epiglottis, an artificial airway should be placed immediately (see Treatment, below). The ca organism may then be cultured from the upper respiratory tract and, usually, from the blood.
The differential diagnosis includes croup (see Table 265-7 and under Viral Infections, below) and bact tracheitis (see below). Diphtheria (see above) should be considered in a nonimmunized patient.
Epiglottitis caused by H. influenzae type b can be prevented with highly effective Haemophilus influenz b (Hib) conjugate vaccines in infants >= 2 mo.
Because sudden complete airway obstruction occurs so unpredictably, a continually adequate airway secured immediately, preferably by nasotracheal intubation, and specific parenteral antibiotics given. S vital. The nasotracheal tube is usually required until the patient has been stable for 24 to 48 h (usual to intubation time < 60 h). Alternatively, tracheotomy may be performed. For emergency care of children epiglottitis, each institution should have a predetermined protocol that involves a pediatrician, otolaryn and anesthesiologist. Skilled nursing care is required because secretions can cause obstruction even intubation or tracheostomy.
Inflammation is effectively controlled with parenteral antibiotics. A -lactamase-resistant antibiotic shoul used initially because ampicillin-resistant H. influenzae type b organisms are common. A third-generat cephalosporin or chloramphenicol 75 to 100 mg/kg/day IV may be used. Rarely, H. influenzae type b s resistant to chloramphenicol are isolated, and a 3rd-generation cephalosporin should be used. If the o proves to be ampicillin-sensitive, ampicillin 200 mg/kg/day IV in 4 divided doses can be given. Sedativ should be avoided, although initial muscular paralysis achieved with neuromuscular blockers may be n to protect the nasotracheal tube; this should be performed by a physician skilled in tracheal intubation.
BACTERIAL TRACHEITIS
(Pseudomembranous Croup)
Infection of the trachea caused by several bacteria.
This infection is uncommon and affects children of any age. S. aureus, group A -hemolytic streptococc influenzae type b are most frequently involved. Onset is acute and is characterized by respiratory strid fever, and often copious purulent secretions. The child may appear to have epiglottitis with marked tox respiratory distress that may progress rapidly and may require intubation. Bacterial tracheitis is diagno direct laryngoscopy revealing purulent secretions and inflammation in the subglottic area or by lateral n x-ray revealing subglottic narrowing with a shaggy, purulent membrane.
Antimicrobial therapy with drugs effective against S. aureus, streptococci, and H. influenzae type b is r Cefuroxime IV is appropriate for empiric therapy. Once definitive microbial diagnosis is made, specific antimicrobial therapy should be given, usually for >= 10 to 14 days.
Severe bacterial tracheitis should be managed in the same way as epiglottitis. Complications include bronchopneumonia, sepsis, and retropharyngeal cellulitis or abscess. Subglottic stenosis secondary to prolonged intubation is uncommon. Most children treated appropriately recover without sequelae.
ADENOID HYPERTROPHY
bronchopneumonia, sepsis, and retropharyngeal cellulitis or abscess. Subglottic stenosis secondary to prolonged intubation is uncommon. Most children treated appropriately recover without sequelae.
ADENOID HYPERTROPHY
Enlargement of adenoidal tissue due to lymphoid hyperplasia.
Adenoid hypertrophy occurs in children and may be physiologic or secondary to infection or allergy. It results in obstruction of the eustachian tubes and/or choanae. Obstruction of the eustachian tubes ma in recurrent acute, chronic, or secretory (serous) otitis media (middle ear effusion). Obstruction of the c may cause mouth breathing, obstructive sleep apnea, a hyponasal voice, and purulent rhinorrhea, and obstruction contributes to chronic sinusitis. Chronic adenoiditis is common.
In persistent serous and chronic otitis media, adenoidectomy is often indicated to reduce exacerbation improve the results of tympanoplasty. In recurrent acute otitis media, the indication for adenoidectomy depends on the duration of the earache after antibiotic therapy is initiated, whether the eardrum is per the frequency with which myringotomy is required, and the severity of systemic symptoms. In obstructi choanae, the need for adenoidectomy depends on the severity of the obstruction and the patient's age because lymphoid hyperplasia reaches its maximum at puberty. In purulent rhinorrhea (or recurrent or persistent sinusitis despite adequate antibiotic treatment), adenoidectomy may be appropriate in caref selected, otherwise healthy children.
RETROPHARYNGEAL ABSCESS
A collection of pus from suppurative lymph node inflammation in the posterior and/or lateral pharyngea
Retropharyngeal abscesses generally occur in infants or young children as complications of suppurativ retropharyngeal lymph nodes. Infection (usually caused by a -hemolytic streptococcus) reaches the lym nodes from the pharynx, sinuses, adenoids, nose, or middle ear. Such abscesses are unusual in adult because the retropharyngeal lymph nodes diminish or disappear after childhood. Occasional causes in or children are TB or perforation of the posterior pharyngeal wall by foreign bodies or instrumentation.
Symptoms include pain on swallowing, fever, cervical lymphadenopathy, and, if airway obstruction occ stridor, dyspnea, and hyperextension of the neck. The cervical vertebrae cannot be palpated through t posterior pharyngeal wall, which is boggy and fluctuant, with a definite, usually unilateral, bulging. Diag made by finding widening of the prevertebral space on lateral x-rays of the neck; abscess formation ca demonstrated on CT.
Complications include hemorrhage; rupture of the abscess into the airway, causing asphyxia or pulmo aspiration; laryngeal spasm; mediastinitis; and suppurative thrombophlebitis of the internal jugular vein
Treatment includes draining the abscess through an incision in the posterior pharyngeal wall and givin parenteral antibiotics. If -lactamase-producing strains of Staphylococcus aureus and Bacteroides sp a cultured, a -lactamase-resistant antibiotic may be needed (eg, ampicillin-sulbactam, oxacillin, nafcillin, ceftizoxime, ticarcillin-clavulanic acid). Clindamycin is particularly useful if B. fragilis is cultured.
IMPETIGO AND ECTHYMA
Impetigo (impetigo contagiosa) is a superficial vesiculopustular skin infection. Ecthyma is an ulcerativ
IMPETIGO AND ECTHYMA

Etiology
Impetigo (impetigo contagiosa) is a superficial vesiculopustular skin infection. Ecthyma is an ulcerativ of impetigo.
Staphylococcus aureus is the most frequent cause of superficial skin infections; it is a much more com initial cause than group A -hemolytic streptococcus. S. aureus is the primary pathogen in bullous impe occurring anywhere on the body and in crusted facial impetigo; its role in ecthyma varies worldwide. A increase in furuncles and in several more serious staphylococcal infections has occurred. Purulent infe of the ears or nostrils may be the source of staphylococci, but the nose and throat seldom yield cutane staphylococci. Spread of untreated infection to others is often suspected, but deliberate experimental infections are difficult to induce.
The arms, legs, and face are more susceptible to impetigo and ecthyma than are unexposed areas. B impetigo and ecthyma may follow superficial trauma with a break in the skin or may be secondary to pediculosis, scabies, herpes simplex or zoster, fungal infections, other causes of dermatitis, or insect b
Impetigo may occur on normal skin, especially on the legs in children. Lesions vary from a pea-sized vesicopustule to large, bizarre, circinate ringworm-like lesions. Lesions caused by S. aureus progress from maculopapules to vesicopustules or from bullae to exudative and then honey-colored, crusted, ci lesions.
Ecthyma is characterized by small, purulent, shallow, punched-out ulcers with thick, brown-black crust surrounding erythema. Itching is common, and scratching may cause spread. Diagnosis is usually based on clinical findings.
Prognosis
Untreated infection in adults can result in cellulitis, lymphangitis, or furunculosis. In children, untreated erythematous lesions may persist for months. Pigmentary changes with or without scarring may result Ecthyma penetrates more deeply than impetigo, resulting in ulceration with subsequent scarring.
Prompt recovery usually follows treatment. Acute glomerulonephritis in children, but not acute rheuma may follow cutaneous infection with a group A -hemolytic streptococcus; however, because nephrogen strains of streptococci are less prevalent, nephritis is less common.
Treatment
Application of mupirocin ointment 3 times daily has been effective in treating impetigo caused by S. au and group A -hemolytic streptococcus, although some resistant strains have developed. Patients show response to mupirocin in 3 to 5 days should be treated systemically. Because most cases are caused penicillinase-producing staphylococci, cloxacillin or a 1st-generation cephalosporin is the drug of choic
Treatment
Application of mupirocin ointment 3 times daily has been effective in treating impetigo caused by S. au and group A -hemolytic streptococcus, although some resistant strains have developed. Patients show response to mupirocin in 3 to 5 days should be treated systemically. Because most cases are caused penicillinase-producing staphylococci, cloxacillin or a 1st-generation cephalosporin is the drug of choic Penicillin-allergic patients should receive cefadroxil 30 mg/kg/day po divided in 2 daily doses or cepha 10 days (50 mg/kg/day po divided q 6 h for children, 250 mg qid for adults) rather than erythromycin; th increased frequency of erythromycin-resistant staphylococci (10 to 40%) has decreased the drug's effectiveness. Most streptococci are sensitive to erythromycin but rarely to tetracycline. In pure staphy pyoderma, a penicillinase-resistant penicillin (eg, cloxacillin 50 mg/kg/day po divided q 6 h for children mg qid for adults) should be given for 10 days. In secondary impetigo or ecthyma, the underlying condition must also be treated. Back to top of page
Section 8. Ophthalmologic Disorders Chapter 90. Approach To The Patient With Eye Di Topics
[General] Ocular Symptoms And Signs
[General]
When ocular complaints are nonspecific, a complete history and examination of all parts of the eye an adnexa (see Fig. 90-1) are necessary to identify the source of the complaint. The patient should be as about the location and duration of symptoms; the presence and nature of pain, discharge, or redness; changes in visual acuity.
Visual Acuity and Visual Field Examination
Unless chemicals requiring immediate irrigation have splashed into the eye, the first step in ocular eva to record the visual acuity. Vision is tested by having the patient look at an eye chart 20 ft (6 m) away; who normally wears glasses should have them on. As each eye is covered alternately, the acuity in the opposite eye is determined. A Snellen notation of 20/40 (6/12) indicates that the smallest letter that ca read by someone with normal vision at 40 ft (12 m) has to be brought to 20 ft (6 m) before it is recogni the patient. Gross inspection of the glasses provides an approximation of the degree of ametropia (eg hyperopia, myopia, astigmatism). Visual fields and ocular motility may also be determined at this time. fields can be checked by confrontation examination, as described in assessment of visual fields in Ch.
Eyelid Examination
Under a focal light and magnification (eg, provided by loupe or slit lamp), systematic examination of th should proceed. The eyelids are examined for lesions of the margins and subcutaneous tissues. The a the lacrimal sacs is palpated and an attempt made to express any contents up through the canaliculi a puncta. The lids are then everted, and the palpebral and bulbar conjunctivae and the fornices are insp foreign bodies, signs of inflammation (eg, follicular hypertrophy, exudate, hyperemia, or edema), or oth abnormalities.
Corneal Examination
the lacrimal sacs is palpated and an attempt made to express any contents up through the canaliculi a puncta. The lids are then everted, and the palpebral and bulbar conjunctivae and the fornices are insp foreign bodies, signs of inflammation (eg, follicular hypertrophy, exudate, hyperemia, or edema), or oth abnormalities.
Corneal Examination
The cornea should be inspected closely. If pain and photophobia make it difficult for the patient to ope eye, topical anesthesia can be added before examination by instilling 1 drop of proparacaine 0.5% or tetracaine 0.5%. Fluorescein staining with sterile, individually packaged fluorescein strips makes corne abrasions or ulcers more apparent. The strip is moistened with 1 drop of sterile saline and, with the pa eye turned upward, is touched momentarily to the inside of the lower lid. The patient is asked to blink s times to spread the dye into the tear film and then the eye is examined under good magnification and blue illumination. Areas where the corneal or conjunctival epithelium is absent will stain green.
Pupil Examination
The size and shape of the pupils and their reaction to light and accommodation should be noted. Intra pressure and anterior chamber depth should be estimated before dilation, because mydriasis can prec an attack of acute angle-closure glaucoma if the anterior chamber is shallow.
Tonometry
The measurement of intraocular pressure can be performed using one of several available instrument eye should be anesthetized (eg, proparacaine 0.5%) before using a tonometer. The Schitz tonomete to learn to use, portable, but requires thorough cleaning between uses. The patient's eye must be vert the eyelids spread off the globe. The use of Goldmann's applanation tonometry requires more training the preferred testing method.
Ophthalmoscopy and Related Tests
Ophthalmoscopy is aided by dilating the pupil with 1 drop of tropicamide 1% and/or phenylephrine 2.5 (repeated in 5 to 10 min if necessary); for longer action or wider dilation, cyclopentolate 1% and/or phenylephrine 10% may be used. However, the pupils should not be dilated if the patient has had hea or is suspected of having acute disease of the CNS, and phenylephrine should not be used if the patie hypertension or is receiving an oral -blocker. Atropine and scopolamine are not recommended becaus prolonged action. Ophthalmoscopy will disclose opacities of the cornea, lens, and vitreous as well as l the retina and optic nerve. The strength of the ophthalmoscope lens required to bring the retina into fo gives an approximate measure of refractive error. The fundus may show changes due to systemic dise diabetes mellitus, hypertension).
Other instruments (eg, gonioscope, tangent screen, perimeter) may be needed for precise diagnosis; t requires special training. Slit-lamp examination is especially helpful in distinguishing corneal lesions. A other physicians can care for many diseases of the eye, an ophthalmologist should be consulted when there is doubt about diagnosis or treatment, especially when the cause of pain or diminished vision is apparent or when symptoms persist.
Ultrasonography
requires special training. Slit-lamp examination is especially helpful in distinguishing corneal lesions. A other physicians can care for many diseases of the eye, an ophthalmologist should be consulted when there is doubt about diagnosis or treatment, especially when the cause of pain or diminished vision is apparent or when symptoms persist.
Ultrasonography
B-mode ultrasonography delineates retinal tumors, detachments, and vitreous hemorrhages even in th presence of opacities of the cornea and lens. A handheld B-scanner has simplified ultrasonic examina the eye and has made it possible to perform such studies in the ophthalmologist's office. Orbital defini improved by using higher frequencies (7 to 10 MHz). B-mode ultrasonography has also been useful in metallic and nonmetallic foreign bodies. A-mode ultrasonography can be used to determine the axial le the eye (a measurement needed to calculate the power of an intraocular lens before it is implanted). T successful application of ultrasonic tissue characterization has been in differentiating between maligna melanoma of the choroid and choroidal nevus, metastatic carcinoma, and subretinal hemorrhage.

Section 8. Ophthalmologic Disorders Chapter 97. Cataract Topics
[General]
[General]
Cataract: Developmental or degenerative opacity of the lens. (For congenital cataracts, see Congenital Eye Defects in Ch. 261.)
Juvenile or adult cataract may be caused by aging, exposure to x-rays, heat from infrared exposure, s disease (eg, diabetes mellitus), uveitis, or systemic medications (eg, corticosteroids), or possibly chron ultraviolet (UV) exposure.
Symptoms and Signs
The cardinal symptom of juvenile or adult cataract is a progressive, painless loss of vision. The degree depends on the location and extent of the opacity. When the opacity is in the central lens nucleus (nuc cataract), myopia develops in the early stages, so that a presbyopic patient may discover that he can r without his glasses (second sight). Rarely, the cataract swells, producing secondary glaucoma and pa
Opacity beneath the posterior lens capsule (posterior subcapsular cataract) disproportionately affects because the opacity is located at the crossing point of the light rays from the viewed object. Such cata particularly troublesome in bright light.
Diagnosis
Gradual loss of vision beginning in middle age or later is characteristic of glaucoma as well as catarac the pupils are dilated for an ophthalmoscopic examination, increased intraocular pressure and a shallo anterior chamber must be ruled out.
Well-developed cataracts appear as gray or yellow-brown opacities in the lens. Examination of the dila (see Pupil Examination in Ch. 90) with the ophthalmoscope held about 30 cm (1 ft) away usually disclo subtle opacities. Small cataracts stand out as dark defects in the red reflex. A large cataract may oblite red reflex. Slit-lamp examination provides more details about the character, location, and extent of the
anterior chamber must be ruled out.
Well-developed cataracts appear as gray or yellow-brown opacities in the lens. Examination of the dila (see Pupil Examination in Ch. 90) with the ophthalmoscope held about 30 cm (1 ft) away usually disclo subtle opacities. Small cataracts stand out as dark defects in the red reflex. A large cataract may oblite red reflex. Slit-lamp examination provides more details about the character, location, and extent of the
Treatment
Frequent refractions and eyeglass prescription changes help maintain useful vision during cataract development. Occasionally, chronic pupillary dilation (with phenylephrine 2.5%) is helpful for small len opacities. Many ophthalmologists recommend that UV-coated glasses or sunglasses be worn while in sunlight.
Surgery: Usual indications for cataract surgery include maximally corrected vision of <= 20/50 (6/15) a subjective visual impairment that prevents needed or desired activities (eg, driving, reading, and other occupational activities). Disabling glare can also be an indication for surgery and is most common with posterior subcapsular cataracts. Less common indications include lens-induced diseases (eg, phacoly glaucoma, phacoantigenic uveitis) or the need to visualize the fundus for the management of diseases diabetic retinopathy or glaucoma.
Cataract extraction is usually performed using local anesthesia and IV sedation. There are three extra techniques: intracapsular cataract extraction, which consists of removing the cataract in one piece (no performed); extracapsular cataract extraction, which consists of removing the hard central nucleus in o piece, then removing the soft cortex in multiple small pieces; and phacoemulsification, which consists dissolving the hard central nucleus within the eye by ultrasound, then removing the soft cortex in multi pieces. The smallest incision is used with phacoemulsification, thus enabling the fastest healing.
A plastic or silicone lens is almost always implanted intraocularly to replace the optical focusing power removal of the crystalline lens. The lens implant can be placed in front of the iris (anterior chamber intr lens), attached to the iris and within the pupil (iris plane intraocular lens), or placed behind the iris (pos chamber intraocular lens). Iris plane intraocular lenses are now rarely used in the USA because many were associated with a high frequency of postoperative complications. The posterior chamber lens is b most common placement.
In most cases, patients are on a tapering schedule of topical antibiotics and topical corticosteroids for wk after surgery. Patients often are asked to wear a shield while sleeping and to avoid the Valsalva ma heavy lifting, bending forward too far, and eye rubbing. Complications of cataract surgery include retin detachment, cystoid macular degeneration, bullous keratopathy, choroidal hemorrhage (intraoperative bleeding beneath the retina causing the intraocular contents to be expulsed through the incision), endophthalmitis (infection within the eye), posterior capsular opacification (treatable with laser), and gl
When preexisting disorders such as amblyopia, macular degeneration, or glaucoma are excluded, 95% eyes achieve vision of 20/40 (6/12) or better. If an intraocular lens is not implanted, contact lenses or t glasses are needed to correct the refractive error (hyperopia and presbyopia).

Section 8. Ophthalmologic Disorders Chapter 91. Eye Injuries Topics
[General] Foreign Bodies Contusions And Lacerations Burns
[General]
Trauma to the eye or adjacent structures requires meticulous examination to determine the extent of in Vision, range of extraocular motion, depth of anterior chamber, location of lid and conjunctival laceratio of foreign bodies, and presence of anterior chamber or vitreous hemorrhage or cataract should be det and recorded in detail for protection of the patient, physician, and, in industrial cases, employer.

Section 8. Ophthalmologic Disorders Chapter 98. Uveitis Topics
[General] Common Uveitic Syndromes Masquerade Syndromes
[General]
Uveitis: Inflammation of any component of the uveal tract (iris, ciliary body, or choroid).
The uveal tract of the eye consists of the iris, ciliary body, and choroid. Inflammation of the overlying re called retinitis, or of the optic nerve, called optic neuritis, may occur with or without accompanying uve
Uveitis is most commonly classified anatomically as anterior, intermediate, posterior, or diffuse. Anteri is localized primarily to the anterior segment of the eye and includes iritis and iridocyclitis. Intermediate also called peripheral uveitis, is centered in the area immediately behind the iris and lens in the region ciliary body and pars plana, hence the alternate terms "cyclitis" and "pars planitis." Posterior uveitis sig any of a number of forms of retinitis, choroiditis, or optic neuritis. Diffuse uveitis implies inflammation in all parts of the eye, including anterior, intermediate, and posterior structures.
Symptoms and Signs
The symptoms and signs of uveitis may be subtle, and vary considerably depending on the site and se the inflammation.
Anterior uveitis tends to be the most symptomatic, typically presenting with pain, redness, photophob decreased vision. Signs of anterior uveitis include pupillary miosis and injections of the conjunctiva adj the cornea, so-called perilimbal flush. Biomicroscopic, or slit-lamp, findings include cells and flare in th aqueous humor as well as keratic precipitates, which are clumps of cells and proteinaceous material a to the corneal endothelium.
Intermediate uveitis is classically painless and presents with floaters and decreased vision. Signs of intermediate uveitis include cells in the vitreous humor and cellular aggregates and condensations ove pars plana, most frequently inferior. Intermediate uveitis is best appreciated with indirect ophthalmosco Idiopathic intermediate uveitis, called pars planitis, is most common and is discussed below.
Intermediate uveitis is classically painless and presents with floaters and decreased vision. Signs of intermediate uveitis include cells in the vitreous humor and cellular aggregates and condensations ove pars plana, most frequently inferior. Intermediate uveitis is best appreciated with indirect ophthalmosco Idiopathic intermediate uveitis, called pars planitis, is most common and is discussed below.
Posterior uveitis may give rise to diverse symptoms but most commonly causes floaters and decreas vision similar to intermediate uveitis. Signs include cells in the vitreous humor, white or yellow-white le the retina and/or underlying choroid, exudative retinal detachments, retinal vasculitis, and optic nerve e Diffuse uveitis may produce any or all of the above-mentioned symptoms and signs.
Complications
Ocular complications of uveitis may produce profound and irreversible loss of vision, especially when unrecognized or treated improperly. The most frequent complications include cataract; glaucoma; retin detachment; neovascularization of the retina, optic nerve, or iris; and cystoid macular edema, the mos common cause of decreased vision from uveitis. Patients suspected of having uveitis should, therefore referred immediately for complete ophthalmologic evaluation.

Section 8. Ophthalmologic Disorders Chapter 92. Disorders Of The Orbit Topics
Orbital Cellulitis Cavernous Sinus Thrombosis Exophthalmos
Orbital Cellulitis
Etiology, Symptoms, and Signs
Inflammation of the orbital tissues caused by infection that extends from the nasal sinuses or teeth, by metastatic spread from infections elsewhere, or by bacteria introduced via orbital trauma.
(For orbital cellulitis in children, see Periorbital and Orbital Cellulitis under Bacterial Infections in Ch. 26
The most common causes of orbital cellulitis are paranasal sinusitis leading to secondary orbital inflam and trauma to the eyelid, which becomes infected. Symptoms include extreme orbital pain, eyelid redn swelling, conjunctival hyperemia and edema, exophthalmos, impaired mobility of the eye, fever, and m Possible complications are loss of vision from optic neuritis, thrombophlebitis of the orbital veins result cavernous sinus thrombosis, panophthalmitis, and spread of the infection to the meninges and brain.
The primary locus of infection should be sought. Thorough examination of the skin, nasopharynx, teet oral cavity is helpful, as are x-rays or CT of the sinuses. The conjunctiva, skin, blood, and oral or nasa discharge should be cultured, as indicated. Treatment with antibiotics (eg, cephalexin 500 mg po q 6 h days for mild cases or cefazolin 1 g IV q 6 h for 7 days for severe cases) should be started, pending cu results. Incision and drainage are indicated if suppuration is suspected or if the infection does not resp antibiotics.

Section 8. Ophthalmologic Disorders Chapter 99. Retinal Disorders Topics
Vascular Retinopathies Age-Related Macular Degeneration Retinal Detachment Retinitis Pigmentosa
Vascular Retinopathies
HYPERTENSIVE RETINOPATHY
Retinopathy resulting from high blood pressure.
Retinal hemorrhage, exudates, edema, ischemia, or infarction due to ocular or systemic vascular disor
Vascular retinopathies include hypertensive retinopathy, diabetic retinopathy, central retinal artery occ and central retinal vein occlusion. For retinopathy of prematurity, see Retinopathy of Prematurity in Ch
Hypertensive retinopathy occurs in chronic essential hypertension, malignant hypertension, and toxem pregnancy. It develops from hypertensive arteriolosclerosis, which refers to thickening of the arterioles response to chronic hypertension. These sclerotic changes cause the arteriole light reflex to become b and dull. In the early stages of hypertensive retinopathy, the fundus shows generalized or focal retinal arteriolar constriction. As the disease progresses, superficial flame-shaped hemorrhages and small wh superficial foci of retinal ischemia (cotton-wool spots) develop. Yellow hard exudates, due to lipid depo deep in the retina and arising from leaking retinal vessels, are seen later. These exudates can form a star-shaped figure in the macula (see also Ch. 199). The optic disk becomes congested and edemato severe hypertension (papilledema--see in Ch. 101).
Treatment
Hypertensive retinopathy and hypertensive arteriosclerosis are primarily managed by medical control o hypertension.
DIABETIC RETINOPATHY
Hypertensive retinopathy and hypertensive arteriosclerosis are primarily managed by medical control o hypertension.
DIABETIC RETINOPATHY
A variety of pathologic retinal changes characteristic of chronic diabetes mellitus.
This major cause of blindness can be particularly severe in persons who have insulin-dependent diabe mellitus (IDDM; type I diabetes mellitus); it also occurs frequently in persons with chronic non-insulin-dependent diabetes mellitus (NIDDM; type II diabetes mellitus). The degree of retinopathy correlated with the duration of the diabetes.
Nonproliferative retinopathy (formerly known as background retinopathy) is characterized by increas capillary permeability, microaneurysms, hemorrhages, exudates, and edema. Visual symptoms genera not occur in the early stages of nonproliferative retinopathy. However, significant early visual changes occur in a small number of patients, especially in those with NIDDM. Therefore, examination guideline immediate yearly examinations for those with NIDDM and yearly examinations starting 5 years after di for those with IDDM. Examinations of female diabetics should be performed every trimester during pre
The first signs of diabetic retinopathy are often venous dilation and small red dots seen ophthalmosco the posterior retinal pole. The dots are capillary microaneurysms that can be demonstrated by fluoresc angiography. Dot and blot retinal hemorrhages and deep-lying edema and lipid exudates may impair m function. Late symptoms relate to generalized diminution of vision as a result of diminished capillary pe and macular edema. Macular edema is a common cause of visual impairment in diabetics and may be detected or confirmed by fluorescein angiography. Cotton-wool spots (soft exudates) appear, which ar microinfarcts caused by decreased retinal perfusion. They are white and obscure underlying vessels. H exudates are caused by chronic edema. They are yellow and generally deep to retinal vessels.
Proliferative retinopathy is characterized by abnormal new vessel formation (neovascularization), wh grows on the vitreous surface or extends into the vitreous cavity. In advanced disease, neovascular membranes can occur, resulting in a traction retinal detachment. Vitreous hemorrhages may result fro neovascularization. Visual symptoms vary, depending on pathologic events. For example, a sudden se loss of vision can occur when there is intravitreal hemorrhage. Visual prognosis with proliferative retino more guarded if associated with severe retinal ischemia, extensive neovascularization, or extensive fib tissue formation.
Treatment
Control of the diabetes and BP is important. The Diabetes Control and Complications Trial demonstra intensive insulin therapy can delay the onset and slow the progression of diabetic retinopathy, nephrop and neuropathy in diabetic patients with IDDM. Visual symptoms, including blurred vision, sudden loss vision in one or both eyes, and black spots or flashing lights in the field of vision, are indications for ophthalmologic referral at any time.
Panretinal photocoagulation may diminish or eliminate proliferative retinopathy and neovascularization iris. Early photocoagulation decreases the risk of neovascular glaucoma development. Vitrectomy may useful in cases of vitreous hemorrhage.
vision in one or both eyes, and black spots or flashing lights in the field of vision, are indications for ophthalmologic referral at any time.
Panretinal photocoagulation may diminish or eliminate proliferative retinopathy and neovascularization iris. Early photocoagulation decreases the risk of neovascular glaucoma development. Vitrectomy may useful in cases of vitreous hemorrhage.
CENTRAL RETINAL ARTERY OCCLUSION

Blockage of the central retinal artery, producing painless, sudden, unilateral blindness.
The occlusion may be due to embolism (disseminated atherosclerotic plaques, endocarditis, fat embo myxoma) or to thrombosis in a sclerotic central artery. Another important cause is cranial arteritis (tem arteritis--see Ch. 50). Branch retinal artery occlusion is often caused by an embolus.
The pupil may respond poorly to direct light but may constrict briskly when the other eye is illuminated cases, ophthalmoscopy discloses a pale, opaque fundus with a red fovea (cherry-red spot). Typically, arteries are attenuated and may even appear bloodless. An embolic obstruction is sometimes visible; relieved quickly, retinal infarction occurs and blindness is permanent. If a major branch is occluded rat the entire artery, fundus abnormalities are limited to that sector of the retina, and a permanent subtota field loss follows unless the occlusion is relieved.
Treatment
Immediate treatment is imperative. Reduction of intraocular tension by intermittent digital massage ove closed eyelids or anterior chamber paracentesis may dislodge an embolus and allow it to enter a smal branch of the artery, thus reducing the area of retinal ischemia.
CENTRAL RETINAL VEIN OCCLUSION

Blockage of the central retinal vein, usually occurring in elderly patients.
Glaucoma, diabetes mellitus, hypertension, increased blood viscosity, and an elevated Hct are predisp factors. Occlusion in a young person is uncommon; it may be idiopathic and resemble retinal phlebitis.
Painless visual loss occurs less abruptly than in arterial obstruction. The retinal veins appear distende tortuous; the fundus is congested and edematous; and numerous retinal hemorrhages appear. These are limited to one quadrant if the obstruction involves only a branch of the vein. Neovascularization of retina or iris (rubeosis iridis) with secondary (neovascular) glaucoma can occur weeks to months after occlusion. Fluorescein angiography is helpful in determining the state of circulation.

Patients with normal retinal vessel perfusion usually do well; those with poor perfusion are more likely develop complications.

Patients with normal retinal vessel perfusion usually do well; those with poor perfusion are more likely develop complications.
There is no generally accepted medical therapy. Involution of secondary retinal neovascular overgrow panretinal photocoagulation may decrease vitreous hemorrhages and prevent secondary neovascular glaucoma.
Section 8. Ophthalmologic Disorders Chapter 93. Disorders Of The Lacrimal Appara Topics
Dacryostenosis Dacryocystitis
Dacryostenosis
Stricture of the nasolacrimal duct, often resulting from a congenital abnormality or an infection.
Congenital dacryostenosis usually appears between ages 3 and 12 wk as epiphora of one eye or, ra both (epiphora is persistent tearing due to chronic overflow of tears over the lid margin onto the cheek later onset and lack of purulent exudate in congenital dacryostenosis differentiate it from neonatal con due to either silver nitrate instillation or bacterial infection.
Acquired dacryostenosis with epiphora may result from inflammatory obstruction of the duct due to c lacrimal sac infection or severe or chronic conjunctivitis. Other causes of obstruction include deviated hypertrophic rhinitis, mucosal polyps, hypertrophied inferior turbinate, or residual congenital dacryoste Fracture of the nose and facial bones may also cause mechanical obstruction. Prolonged blockage us leads to infection of the lacrimal sac (dacryocystitis--see below). Pressure on the lacrimal sac frequent causes a copious reflux of mucus or pus from the punctum.
Treatment
Congenital dacryostenosis usually resolves spontaneously by age 6 mo. Milking the lacrimal sac thr nasolacrimal duct with fingertip massage twice daily may speed resolution; antibiotic drops may be req intermittently for recurrent infections. If resolution is not spontaneous, the punctum should be dilated a lacrimal drainage system probed. Brief general anesthesia usually is necessary in infants.
For acquired dacryostenosis, a local anesthetic such as proparacaine 0.5% is instilled and the punc dilated. Isotonic saline is irrigated gently through the nasolacrimal system with a fine blunt canaliculus (a drop of fluorescein in the saline makes obstruction in the nose easily detectable). If this technique fa lacrimal probing may establish patency. The use of probes of increasing size followed by irrigation with isotonic saline may be successful in incomplete obstruction. However, complete obstruction requires a
For acquired dacryostenosis, a local anesthetic such as proparacaine 0.5% is instilled and the punc dilated. Isotonic saline is irrigated gently through the nasolacrimal system with a fine blunt canaliculus (a drop of fluorescein in the saline makes obstruction in the nose easily detectable). If this technique fa lacrimal probing may establish patency. The use of probes of increasing size followed by irrigation with isotonic saline may be successful in incomplete obstruction. However, complete obstruction requires a opening from the lacrimal sac into the nasal cavity.

Section 8. Ophthalmologic Disorders Chapter 100. Glaucoma Topics
[General] Primary Open-Angle Glaucoma Angle-Closure Glaucoma
[General]
Glaucoma: A group of disorders characterized by progressive damage to the eye at least partly due to intraocular pressure.
Normal intraocular pressure (IOP) ranges between 11 and 21 mm Hg; however, this level may not nec be healthy for all people. Some people with normal pressure develop optic nerve injury (normal- or low-pressure glaucoma). In contrast, many patients have pressure > 21 mm Hg without any optic nerv (ocular hypertension).
Incidence
Glaucoma is the second most common cause of blindness in the USA. About 2 million Americans hav glaucoma, but roughly half are unaware of it. Although glaucoma is generally considered a disorder of elderly, it can occur in any age group. Of those with ocular hypertension, only about 1% per year will d glaucoma.
Pathogenesis
Glaucoma can be described according to the mechanism of outflow obstruction as either open-angle o closed-angle (angle-closure) glaucoma. Alternatively, classification can be based on etiology as prima secondary (see Table 100-1).
The primary (conventional) outflow system of the eye is located in the anterior chamber angle and acc 83 to 96% of aqueous outflow in human eyes under normal circumstances. It refers to aqueous outflow through the trabecular meshwork, canal of Schlemm, intrascleral channels, and episcleral and conjunc veins. In open-angle glaucoma with elevated IOP, the pressure elevation occurs because outflow is inadequate despite an angle that appears open and relatively normal on gonioscopic examination. In closed-angle glaucoma, elevated IOP occurs when normal drainage of aqueous fluid from the eye is
The primary (conventional) outflow system of the eye is located in the anterior chamber angle and acc 83 to 96% of aqueous outflow in human eyes under normal circumstances. It refers to aqueous outflow through the trabecular meshwork, canal of Schlemm, intrascleral channels, and episcleral and conjunc veins. In open-angle glaucoma with elevated IOP, the pressure elevation occurs because outflow is inadequate despite an angle that appears open and relatively normal on gonioscopic examination. In closed-angle glaucoma, elevated IOP occurs when normal drainage of aqueous fluid from the eye is sufficiently prevented by a physical obstruction of the peripheral iris. The secondary (alternative) aque outflow pathways (known as the unconventional or uveoscleral aqueous outflow system) account for 5 of the total aqueous outflow. It refers to aqueous exiting the eye through the anterior face of the ciliary and percolating through the ciliary muscles to the suprachoroidal space (ie, between the choroid and s where it eventually exits the eye via scleral channels.
Diagnosis
A comprehensive ophthalmic examination is essential for diagnosis and prompt treatment. Examinatio includes visualization of the angle by a special prism or contact lens (gonioscopy), IOP measurement, field examination and, most importantly, examination of the optic disks. A screening test for glaucoma only on IOP has low sensitivity, specificity, and positive predictive value. Patients who are at risk for gl should be referred to an ophthalmologist for a comprehensive ophthalmic examination.
Visualization of the anterior chamber angle allows differentiation of angle-closure from open-angle gla However, because the overlying sclera and limbus are opaque, the anterior chamber angle can only b visualized using gonioscopy.
If the decision to treat glaucoma is based solely on elevated IOP, then some patients with normal-pres glaucoma will incorrectly be excluded from treatment, whereas others with ocular hypertension will unnecessarily receive treatment that may cause lifelong side effects. About 90% of people with elevate (> 21 mm Hg) never develop glaucoma. Although many people with ocular hypertension can tolerate e IOP once the IOP routinely reaches 27 to 30 mm Hg, therapy should probably be initiated, especially f persons with additional risk factors for glaucoma.

Section 8. Ophthalmologic Disorders Chapter 94. Eyelid Disorders Topics
Lid Edema Blepharitis Hordeolum Chalazion Entropion And Ectropion Tumors
Lid Edema
Etiology
Allergies usually produce marked crinkly lid edema with hyphemia and scaling of one or both eyes. Th type, seasonal allergic lid edema, is caused by a hypersensitivity to airborne pollens or direct hand-toapplication of pollens (eg, after working in the garden). Chronic allergic reactions occur from contact se due to topical drugs (eg, atropine, neomycin) or cosmetics or metals (nickel) and perennial allergic lid which is believed to be due to a hypersensitivity to molds or to animal or dust mite dander (see Other A Eye Diseases in Ch. 148).
Trichinosis produces chronic lid edema that is usually bilateral and resembles the allergic type; the ass fever and other systemic symptoms may not be present initially. An eosinophilia > 10% is characteristi
Hereditary angioedema due to C1 esterase inhibitor deficiency (see Hereditary Angioedema in Ch. 14 also cause acute lid edema.
Treatment
In allergic lid edema, removal of the offending cause is often the only treatment needed. Cold compres over the closed lids may speed resolution; topical corticosteroid ointments (eg, fluorometholone 0.1% not more than 7 days) may be needed if swelling persists > 24 h. Treatments for hereditary angioedem trichinosis are discussed in Chs. 148 and 161, respectively.
Section 8. Ophthalmologic Disorders Chapter 101. Optic Nerve And Optic Pathway Diso Topics
Papilledema Papillitis Retrobulbar Neuritis Toxic Amblyopia Optic Atrophy Higher Optic Pathway Lesions
Papilledema
(Choked Disk)
Swelling of the optic nerve head due to increased intracranial pressure.
Papilledema is almost always bilateral and occurs with brain tumor or abscess, cerebral trauma or hemorrhage, meningitis, arachnoidal adhesions, cavernous or dural sinus thrombosis, encephalitis, space-occupying brain lesions, severe hypertensive disease, and pulmonary emphysema. Papilledem occurs with pseudotumor cerebri, which is usually far less serious than other causes. Because papilled a sign of elevated intracranial pressure, finding it requires immediate further evaluation or intervention
Vision is not affected initially, and there is no scotoma, but the blind spot is enlarged. The degree of di elevation is determined by comparing the highest plus lens needed to bring the most elevated portion disk into sharp focus with the lens needed to clearly see an unaffected portion of the retina. Engorged tortuous retinal veins, a hyperemic disk, and retinal hemorrhages around the disk but not into the retin periphery are usually observed. The absence of changes in the arterioles and a normal BP help differe the papilledema of brain tumor from that of hypertension. If the intracranial pressure is not reduced, se optic atrophy and loss of vision eventually occur.

Section 8. Ophthalmologic Disorders Chapter 95. Conjunctival Disorders Topics
[General] Acute Conjunctivitis Chronic Conjunctivitis Episcleritis Scleritis Cicatricial Pemphigoid
[General]
Pathophysiology
The conjunctiva lines the back of the lid (palpebral or tarsal conjunctiva), extends into the space betwe lid and the globe (forniceal conjunctiva), and spreads up over the sclera to the cornea (bulbar conjunc The appearance of the conjunctiva changes in response to various stimuli.
Conjunctival blood vessels can dilate (hyperemia) or can bleed (extravasation of blood beneath the conjunctiva, called a subconjunctival hemorrhage). The extent and location of conjunctival hyperemia useful in determining etiology. Diffuse hyperemia of both the bulbar and tarsal conjunctivae is typical o conjunctivitis. Circumcorneal conjunctival hyperemia produced by dilated, fine, straight, deep vessels t radiate 1 to 3 mm out from the limbus, otherwise without significant hyperemia of the bulbar and tarsal conjunctiva, is seen with iritis and acute glaucoma. A large patch of deep hyperemia involving 20 to 10 the bulbar conjunctiva without hyperemia of the tarsal conjunctiva is typical of episcleritis and scleritis.
Features that distinguish "red eye" disorders, including acute conjunctivitis, acute iritis, acute glaucom episcleritis and scleritis, are shown in Table 95-1.
Edema of the bulbar conjunctiva results in a translucent, bluish, thickened conjunctiva. Gross edema w ballooning of the conjunctiva often leading to prolapse of conjunctiva is known as chemosis. Edema of tarsal conjunctiva results in fine, minute projections (papillae), giving the conjunctiva a velvety appeara
The conjunctiva contains lymphoid follicles, most commonly in the inferior tarsal conjunctiva. Hyperpla these follicles appears as small bumps with pale centers. Two benign neoplasms of the conjunctiva commonly occur:
tarsal conjunctiva results in fine, minute projections (papillae), giving the conjunctiva a velvety appeara
The conjunctiva contains lymphoid follicles, most commonly in the inferior tarsal conjunctiva. Hyperpla these follicles appears as small bumps with pale centers. Two benign neoplasms of the conjunctiva commonly occur:
A pinguecula is a raised yellowish white mass on the bulbar conjunctiva, adjacent to the cornea and/or 9-o'clock position. It may be unsightly but does not tend to grow onto the cornea and need removed. A pterygium is a fleshy triangular growth of bulbar conjunctiva onto the cornea at the 3- and/or 9 position and is found more often in hot, dry climates. This growth may spread across and distort cornea, induce astigmatism, and change the refractive power of the eye. In some cases, remova indicated to reduce irritation and to prevent changes in vision.

Section 8. Ophthalmologic Disorders Chapter 102. Refractive Error Topics
[General] Contact Lenses Refractive Surgery
[General]
In the emmetropic (normal) eye, parallel rays of light that enter the eye come to focus on the retina, an sharp image is perceived by the brain. In myopia, or nearsightedness, rays of light fall in front of the re because the cornea is too steep or the axial length of the eye is too long. Without glasses, distant ima blurry, but near objects can be seen clearly. In hyperopia, or farsightedness, the theoretic focal point the retina, because either the cornea is too flat or the axial length is too short. Both distant and close o appear blurry. In astigmatism, there is unequal curvature of the cornea or the lens, and the light rays focus at different points in the eye. Anisometropia is a significant difference between the refractive er the two eyes (usually > 2 diopters). Errors of refraction are shown in Fig. 102-1.

Section 8. Ophthalmologic Disorders Chapter 96. Corneal Disorders Topics
Superficial Punctate Keratitis Corneal Ulcer Herpes Simplex Keratitis Herpes Zoster Ophthalmicus Keratoconjunctivitis Sicca Phlyctenular Keratoconjunctivitis Interstitial Keratitis Peripheral Ulcerative Keratitis Keratomalacia Keratoconus Bullous Keratopathy Corneal Transplantation
Superficial Punctate Keratitis

Scattered, fine, punctate loss or damage of epithelium from the corneal surface of one or both eyes.
Superficial punctate keratitis is a nonspecific finding. It is often caused by viral conjunctivitis; blephariti keratitis sicca; trachoma; ultraviolet light exposure (eg, welding arcs, sunlamps); contact lens overwea systemic drugs (eg, adenine arabinoside); and topical drug or preservative toxicity. Symptoms include photophobia, foreign-body sensation, lacrimation, conjunctival hyperemia, and decreased vision. An e preauricular node may be present in viral conjunctivitis. Keratitis due to ultraviolet light exposure does appear until several hours after the exposure; it lasts 24 to 48 h. Permanent vision loss is rare, regardl the cause.
Treatment
Superficial punctate keratitis of adenovirus viral conjunctivitis (the most common type of viral conjuncti resolves spontaneously in about 3 wk. Blepharitis (see Ch. 94), trachoma (see Ch. 95), and keratitis si
the cause.
Treatment
Superficial punctate keratitis of adenovirus viral conjunctivitis (the most common type of viral conjuncti resolves spontaneously in about 3 wk. Blepharitis (see Ch. 94), trachoma (see Ch. 95), and keratitis si below) require specific therapy. Ultraviolet light exposure is treated with short-acting cycloplegic drugs, antibiotic ointment, and patching for 24 h. When caused by overwearing contact lenses, it is treated w antibiotic ointment (eg, tobramycin 0.3% tid), but the eye is not patched because of the high incidence serious infection. These patients should be seen the next day. If superficial punctate keratitis results fr topical drug or preservative, that agent should be discontinued.
Section 20. Disorders Due To Physical Agents Chapter 276. Burns Topics
[General]
[General]
Burns: Tissue injury caused by thermal, radiation, chemical, or electrical contact resulting in protein denaturation, burn wound edema, and loss of intravascular fluid volume due to increased vascular permeability.
Thermal burns may be due to any external heat source capable of raising the temperature of skin an tissues to a level that causes cell death and protein coagulation or charring. The most common cause flame, scalding liquids, and hot objects or gases contacting the skin. The extent and depth of the dam depends on the amount of energy transferred from the source.
Radiation burns are most commonly due to prolonged exposure to the sun's ultraviolet radiation (sun may be due to prolonged or intense exposure to other sources of ultraviolet radiation (eg, from tanning or to sources of x-ray or other radiation.
Chemical burns may be due to strong acids or alkalis, phenols, cresols, mustard gas, or phosphorus. these agents produce necrosis, which may extend slowly for several hours.
Electrical burns result from the generation of heat, which may reach 5000 C (9032 F). Because mo resistance to electric current occurs where the conductor contacts the skin, electrical burns usually aff skin and subjacent tissues; they may be of almost any size and depth (see Ch. 277). Progressive necr sloughing are usually greater and affect deeper tissues than the original lesion indicates. Electrical inju particularly from alternating current, may cause immediate respiratory paralysis, ventricular fibrillation, (see Ch. 206).
Symptoms and Signs
Burn depth is classified as first, second, or third degree. First-degree burns are red and very sensitive touch. The surface markedly and widely blanches to light pressure; no blisters develop.
Second-degree burns may or may not produce blisters. The bases of the blisters may be erythematou
Symptoms and Signs
Burn depth is classified as first, second, or third degree. First-degree burns are red and very sensitive touch. The surface markedly and widely blanches to light pressure; no blisters develop.
Second-degree burns may or may not produce blisters. The bases of the blisters may be erythematou whitish with a fibrinous exudate; they are sensitive to touch and may blanch to pressure.
Third-degree burns usually do not produce blisters. The burn's surface may be white and pliable; blac charred, and leathery; or bright red because of fixed Hb in the subdermal region. Pale third-degree bu be mistaken for normal skin, but the subdermal vessels do not blanch to pressure. Third-degree burns generally anesthetic or hypoesthetic. Hairs may be pulled easily from their follicles. Often, deep secon third-degree burns can be distinguished only after 3 to 5 days of observation.
Complications
Systemic sequelae (eg, hypovolemic shock, infection) and respiratory tract ventilation injury are more threatening than local effects. Infection, even in small burns, is a major source of mortality and the mo important cause of loss of function and cosmetic appearance, particularly of the hands and face. Vasoconstriction leading to peripheral hypoperfusion, particularly in the burned areas, creates a major in local host defense, enhancing bacterial invasion. Dead tissue, warmth, peripheral hypoperfusion, an moisture are ideal for bacterial growth. Streptococci and staphylococci usually predominate shortly afte burn, and gram-negative bacteria after 5 to 7 days; mixed flora are always present. The exact course o events, including materials used to put out the fire, provides important clues about the extent of bacter contamination of the burn and the probability of infection.
Thermal damage to the lower respiratory tract is commonly caused only by steam inhalation in alert pe but, if alertness is impaired, may be caused by inhalation of hot gases, which produces immediate upp airway obstruction. Airway edema can produce upper airway obstruction that develops more slowly; ch injury to small airway alveolar capillaries can cause delayed progressive respiratory failure. Inhaling to products (eg, cyanide, toxic aldehydes, carbon monoxide) generated by burning material (eg, wood, p may result in thermal injuries to the pharynx and upper airway as well as in ventilation injuries. In addit inhaled carbon monoxide binds to Hb, greatly reducing O2 transport.
Most cardiac arrhythmias in burn patients are caused by hypovolemia, hypoxia, acidosis, or hyperka These metabolic disorders should be corrected before cardiac drugs are used. Ventricular tachycardia fibrillation are exceptions that require immediate treatment while underlying metabolic abnormalities ar evaluated. Pulse, BP, temperature, ECG, arterial blood gases, and Hct should be monitored to detect metabolic abnormalities, particularly in the elderly.
Hypokalemia is common during the early resuscitation period because K is not generally included in e replacement, because K stores in patients taking diuretics may be depleted, and because some K is le into hypotonic 0.5% silver nitrate dressings. Serum K should be maintained at > 4 mEq/L. Silver nitrate leaches Na and Cl into the dressing, sometimes resulting in severe hyponatremia, hypochloremia, and hypochloremic alkalosis.
Hypoalbuminemia results from the combination of dilutional effects of sodium-containing replacemen and loss of protein into the subeschar edema fluid. Colloid solution is continued throughout the resusc period at rates that maintain albumin levels at about 2.5 g/dL and total protein at > 5 g/dL. Because m serum Ca is reversibly bound to albumin, hypocalcemia may result from hypoalbuminemia. The ionize fraction of serum Ca is usually normal but should be measured periodically. Replacement Ca, phosph Mg may be given daily.
and loss of protein into the subeschar edema fluid. Colloid solution is continued throughout the resusc period at rates that maintain albumin levels at about 2.5 g/dL and total protein at > 5 g/dL. Because m serum Ca is reversibly bound to albumin, hypocalcemia may result from hypoalbuminemia. The ionize fraction of serum Ca is usually normal but should be measured periodically. Replacement Ca, phosph Mg may be given daily.
Metabolic acidosis may result from poor tissue perfusion due to hypovolemia or to heart failure. Bloo 7.2 should be treated with sodium bicarbonate IV (see Metabolic Acidosis in Ch. 12).
Peripheral vasoconstriction causing local hypoperfusion is due to inadequate fluid replacement durin resuscitation. Poor focal tissue perfusion can result from a constricting eschar or fascia, which should treated with escharotomy or fasciotomy (see below).
Myoglobinuria can result from ischemic constrictions of muscle, crush injuries, or deep thermal or ele burns of muscle. Initially, urinary output should be maintained at 100 mL/h in adults and at > 1 mL/kg/h children; osmotic diuresis is needed--adults may be given mannitol 12.5 g IV q 4 to 8 h or more freque necessary until the myoglobinuria clears. For adults with severe myoglobinuria, urine should be alkalin sodium bicarbonate 50 mEq IV q 4 to 8 h as necessary, with frequent monitoring of serum and urine p goal is a urinary pH > 8. Management of hemoglobinuria, which may result from erythrocyte destruct burns, is identical to that of myoglobinuria. Without prompt, accurate management, myoglobinuria or hemoglobinuria may result in renal tubular necrosis.
Hypothermia (see Ch. 280) is common among extensively burned patients. Those with a rectal tempe 36 C (< 97 F) are treated by warming replacement fluids. If the temperature is < 33 C (< 91 F), rew may result in fatal arrhythmias. Such patients should be warmed slowly, and their ECG, core temperat electrolytes, vital signs, and mental status should be monitored continuously.
Assessment
History: Information about the burn episode may come from the patient or such sources as the ambu driver, accompanying family member, coworker, police officer, or firefighter. The history should include prescription drug use; the presence of physical disorders (eg, allergies; heart, pulmonary, or renal dise diabetes) or psychiatric disorders (the injury may represent physical abuse or a suicide attempt); and s drinking, and drug habits. All of these factors affect the patient's ability to respond to the injury.
Physical examination: A complete examination must be performed before burns mature (when physi findings may be more difficult to discern). BSA must be calculated for all patients. Often, the height ca measured immediately, and preburn weight estimated by a family member.
Involved areas are outlined on a burn diagram. For adults, the extent of the burn (% BSA) is estimated comparing the patient's diagram with the rule of nines (see Fig. 276-1, A). For children, the % BSA can more accurately estimated with the Lund-Browder chart (see Fig. 276-1, B). The estimated burn depth second-, or third-degree) is also recorded on the diagram.
Prognosis
Without intervention, the epidermis in superficial burns regenerates rapidly from uninjured epidermal e hair follicles, and sweat glands; little scarring results unless infection develops. With deep burns in wh epidermis and much of the dermis are destroyed, reepithelialization starts from the edges of the woun the scattered remains of integument, or from remaining dermal appendages. The process is slow, and excessive granulation tissue forms before epithelium covers the area. Such wounds generally contract disfiguring or disabling scars, unless treated promptly by skin grafting. Keloids form in some persons,
Without intervention, the epidermis in superficial burns regenerates rapidly from uninjured epidermal e hair follicles, and sweat glands; little scarring results unless infection develops. With deep burns in wh epidermis and much of the dermis are destroyed, reepithelialization starts from the edges of the woun the scattered remains of integument, or from remaining dermal appendages. The process is slow, and excessive granulation tissue forms before epithelium covers the area. Such wounds generally contract disfiguring or disabling scars, unless treated promptly by skin grafting. Keloids form in some persons, especially in blacks.
With deep burns in which the entire dermis and epidermis are destroyed and the area is too large to b by contracture (because the dermis does not regenerate), spontaneous healing does not occur. Witho excision, such burns separate and slough wound eschar over time, leaving a raw wound bed.
Burns of > 40% BSA, age > 60 yr, and presence of inhalation injury are risk factors for death. The mor rate is 0.3% with no risk factors, 3% with one, 33% with two, and about 87% with three.
Treatment
In general, a burn wound should be cleaned and debrided; topical and/or systemic antibiotics are used depending on the severity of the burn. Splinting and positioning of the injured extremity as well as othe physical therapy may be necessary. Home care instructions are given, and outpatient follow-up is arra
About 85% of burn patients have minor burns and may be treated as outpatients. The general criteria outpatient suitability are first-degree and superficial second-degree burns of < 10% BSA, moderate to second-degree burns of < 5% BSA, and third-degree burns of < 1% BSA as long as there is no inhalat injury. More extensively burned patients and patients with very small deep burns of the hands, face, fe perineum must be hospitalized. Hospitalization is required for very small deep burns of these areas be even minor infection may result in severe impairment of appearance and function. A patient initially tre an outpatient is hospitalized if the wound is not expected to heal spontaneously within 3 wk. Hospitaliz may also be required if poor compliance with elevation, dressing changes, or physician instruction is anticipated or if the patient is < 2 yr or > 60 yr.
Initial emergency treatment: At the rescue site, the victim of an acute thermal, chemical, or electrica must be immediately removed from the burning process, including removing all clothing, especially sm material (eg, melted synthetic shirts, hot tar-laden material). All chemical agents should be flushed off and burns caused by acids, alkalis, or organic compounds (eg, phenols, cresols) should be flushed wi copious amounts of water continuously over an extended time. Phosphorus burns should be immersed immediately in water to avoid contact with air. Phosphorus particles are removed gently under water; t wound is washed with 1% copper sulfate solution to coat any residual particles with a protective film of phosphide (these fluoresce and can be readily removed in a darkened room). Excess absorption of co must be prevented.
At an emergency facility, immediate care includes establishing an adequate airway, stopping the burni process, replacing lost fluid (plasma), recognizing and managing associated life-threatening major trau diagnosing metabolic abnormalities, assessing the possibility of bacterial infection from contamination admission, and protecting the patient from further bacterial contamination.
Topical burn wound care: Small burns should be immediately immersed in cold water, if possible. Th wound should be cleaned with soap and water, and all debris carefully removed. For deeply embedde the wound may be anesthetized with a local infiltration of 1 or 2% lidocaine and scrubbed with a stiff b soap.
Blisters should be sharply debrided if they are already broken or are likely to be broken. If burn depth i unknown, blisters should be removed, and the wound base examined to determine if the injury is full th
wound should be cleaned with soap and water, and all debris carefully removed. For deeply embedde the wound may be anesthetized with a local infiltration of 1 or 2% lidocaine and scrubbed with a stiff b soap.
Blisters should be sharply debrided if they are already broken or are likely to be broken. If burn depth i unknown, blisters should be removed, and the wound base examined to determine if the injury is full th
After cleansing and under aseptic conditions, the burned surface is treated with an appropriate topical and covered with sterile dressings. Commonly used topical antibacterials include 0.5% silver nitrate so mafenide acetate, and 1% silver sulfadiazine. After the wounds are covered with up to eight layers of c roll bandages, silver nitrate is poured over the dressing q 2 h. This process keeps the dressing moist a concentration of silver nitrate on the skin at about 0.5%. A lower concentration is probably not bacteric higher concentration, which can result from evaporation, may further burn the skin. When applied to a burned area, silver nitrate may leach excessive amounts of Na, Cl, and K into the dressing, leading to hypokalemia, hypochloremia, alkalosis, or methemoglobinuria. Mafenide acetate or silver sulfadiazine applied directly to the wound in one layer, then the wound may be covered with a few layers of cotton bandages; residual cream should be removed before applying fresh bandages. Mafenide acetate crea inhibits carbonic anhydrase activity and may produce compensated metabolic acidosis and, occasiona proximal renal tubular acidosis. Silver sulfadiazine should be used with caution in patients who are sen sulfonamides; it may cause hematologic abnormalities.
Drugs: For minor burns, oral narcotics (eg, codeine), with or without an NSAID or aspirin, can provide analgesia. For severe burns, IV narcotics (eg, morphine, meperidine) are usually needed. A tetanus to booster, 0.5 to 1 mL sc or IM, may be given to patients immunized within 4 to 5 yr; otherwise, tetanus globulin 250 U IM should be given (and repeated q 6 wk as necessary), and concomitant active immun should be started.
Respiratory care: For significant thermal injury, care includes supplemental O2 to raise the O2 conten blood and to begin to displace carbon monoxide. Inadequate ventilation is managed with intubation (p nasotracheal) and mechanical support. Absolute indications for intubation include rapid, shallow ventil with tachypnea of 30 to 40 breaths/min; bradypnea of < 8 to 10 breaths/min; mechanical airway obstru due to trauma, edema, or laryngospasm; and signs of respiratory failure with arterial pH < 7.2, PO2 < 6 Hg, or PCO2 > 50 mm Hg. Relative indications include exposure to an enclosed-space explosion or fir nasal hairs or oral mucosa; erythema of the palate; soot in the mouth, larynx, or sputum; edema assoc with a burn of the face or neck; and signs of respiratory distress (eg, nasal flaring, respiratory crowing stridor, anxiety, agitation, combativeness).
Initial fluid replacement: Immediate therapy is vital. Adequate fluid replacement prevents peripheral vasoconstriction and hypoperfusion, ensuring intact local host defense. Use of a colloid solution, eg, fr frozen plasma (which contains antibacterial substances including antibody), protects against bacterial by organisms contaminating the burn before the start of treatment.
When shock is anticipated (as it should be in all third-degree and second-degree burns of > 10% BSA when Hct is above normal, fluid replacement should be begun immediately. A 14- to 16-gauge venous is placed in one or two peripheral veins (see Invasive Procedures in Ch. 198). Although central lines m be necessary initially, later placement may be difficult because of extensive wound edema; thus early placement may be best. If necessary, central or peripheral lines may be placed through burn eschar. A cutdown is not recommended because it can destroy the vein and has a high risk of infection. Blood sh drawn to determine Hb, Hct, blood type, and cross-match.
The emergency resuscitation fluid should be the most readily available sodium-containing IV fluid, usu followed by a colloid solution (eg, fresh frozen plasma, albumin) when it becomes available. Use of co depends on the size, depth, and position of the burn, the patient's age, and concomitant disorders. Co
cutdown is not recommended because it can destroy the vein and has a high risk of infection. Blood sh drawn to determine Hb, Hct, blood type, and cross-match.
The emergency resuscitation fluid should be the most readily available sodium-containing IV fluid, usu followed by a colloid solution (eg, fresh frozen plasma, albumin) when it becomes available. Use of co depends on the size, depth, and position of the burn, the patient's age, and concomitant disorders. Co required as soon as possible by patients who have medium or large burns; who are very young or elde have deep burns on the hands, face, or perineum; who have heart disease; or whose Hct is increased indicating imminent burn hypovolemia. If fluid replacement is delayed > 2 h after the burn, colloid shou administered as soon as it is available.
The fluid volume needed is related to the extent and depth of the burn. Initially, the infusion rate may b estimated after a brief physical examination and initial determination of the extent of the burn using the nines or the Lund-Browder chart. Usually, 2 to 4 mL/kg/% BSA of sodium-containing IV fluid is require first 24 h after the injury. Adding colloid usually reduces the volume of sodium-containing fluid needed
Ongoing fluid replacement: Because the exact volume of fluid and infusion rate depend on the patie response to fluid delivery, ongoing fluid replacement is based on close monitoring of the patient. The g maintain an adequate BP and Hct and a urine output of > 50 to 100 mL/h (0.5 to 1 mL/kg/h) in an adul mL/kg/h in a child while avoiding circulatory overload. Hb is determined q 3 to 4 h for the first 72 h, and is regulated to keep Hb levels between 11 and 16 g/dL. Hct should be maintained between 30 and 45% Patients whose urine output is inadequate despite administration of a large volume of sodium-containi often respond to an increased volume of this fluid to which colloid is added.
Precalculated figures are seldom correct for the total period of resuscitation; formulas are used only as guide. A general formula for the first 24 h is 0.5 mL/kg/% BSA of colloid and 1.5 mL/kg/% BSA of lacta Ringer's solution along with 100 mL/h maintenance of lactated Ringer's solution. One fourth of the fluid in the first 4 h, 1/4 in the second 4 hr, 1/4 in the next 8 h, and 1/4 in the last 8 h--measured from the tim injury, not from the time of arrival at the emergency facility, because large amounts of intravascular flu move into tissues, leading to shock, which begins immediately after injury.
For example, a 70-kg man with a 40% BSA burn is given 1400 mL of colloid, 4200 mL of lactated Ring solution, and 2400 mL maintenance of lactated Ringer's solution, for a total of 8000 mL of fluid during 24 h. One fourth of the amount (350 mL of colloid, 1050 mL of lactated Ringer's solution, and 100 mL/ maintenance of lactated Ringer's solution) is given during the first 4 h, the second 4 h, the next 8 h, an last 8 h. If the patient is admitted immediately after the injury, sample orders (with calculations rounded that the following IV solutions be given: for the first 8 h, fresh frozen plasma at 87.5 mL/h and lactated solution at 360 mL/h and, for the next 16 h, fresh frozen plasma at 45 mL/h and lactated Ringer's solu 220 mL/h.
Many parameters must be closely monitored to detect insufficient or excessive fluid replacement and t prevent related problems. Use of a flowchart listing the parameters discussed here helps. Insufficient replacement is indicated by decreased urine output, increased Hct, and symptoms of shock. An indwe Foley catheter should be used to monitor urine output. Excessive replacement (resulting in pulmonary and heart failure) is indicated by increased pulse, respiration, and BP; by neck vein distention; or by in central venous pressure. The lung bases should be auscultated frequently for rales.
For patients with preexisting cardiovascular-renal disease, use of fluid, electrolytes, and colloid should limited to amounts sufficient to produce minimal adequate urinary output (25 mL/h), and the patient sh observed for signs of circulatory overload.
Prevention of burn wound infection: Effective preventive care must begin as soon as possible after and must be rigorously continued until the wound has healed. Topical antibacterials are used to maint normal systemic physiology and to prevent further bacterial seeding of the wound.
limited to amounts sufficient to produce minimal adequate urinary output (25 mL/h), and the patient sh observed for signs of circulatory overload.
Prevention of burn wound infection: Effective preventive care must begin as soon as possible after and must be rigorously continued until the wound has healed. Topical antibacterials are used to maint normal systemic physiology and to prevent further bacterial seeding of the wound.
As prophylaxis for streptococcal cellulitis, a rare but life-threatening infection (due to -hemolytic strepto patients with second- or third-degree burns are often given penicillin V 1 to 2 g/day po in 4 divided dos the first few days. Erythromycin 1 to 2 g/day po in 4 divided doses may be used for patients allergic to penicillin. For extensive burns, penicillin G 5 million U IM or IV is given daily for 3 days as prophylaxis streptococcal cellulitis. Other routine use of antibiotics is not generally recommended to avoid promoti bacterial resistance.
Nutrition: Aggressive nutritional support is indicated for patients with a burn of > 20% BSA, preinjury malnutrition, such complications as sepsis or associated injury (eg, fracture), or a weight loss of > 10% last three are associated with increased mortality.
Nutritional support (see Ch. 1) is started 1 to 2 days after the fluid replacement phase of burn therapy. feeding is preferred because it has fewer complications and costs less; however, anorexia, facial burn dysphagia may make it difficult or impossible. If oral feeding is inadequate but GI motility and absorptio normal, enteral (tube) feedings are used to supplement feedings or supply total nutrition. Parenteral nu indicated for patients with prolonged gastric and colonic ileus related to the burn wound, repeated ope or sepsis. Complications are more likely in parenteral than in enteral nutrition.
Operative management: Eschars in circumferential third-degree burns may require escharotomy--eg previously palpable pulse is lost or pulse is nonpalpable in a single extremity but is easily palpable in t remaining extremities. Peripheral ischemia is suspected when a single extremity is cooler than the oth has a poor capillary refilling time; Doppler ultrasonography confirms ischemia. Even if Doppler pulses present, a tense eschar is released when peripheral ischemia is strongly suspected. For skin injuries t not affect deeper tissue, the escharotomy incision extends only through the dermis, excluding the hypo and fat. The incision should extend well beyond the tense area of eschar to ensure complete release. apparently full-thickness eschars retain partial pain sensation, making the releasing incision painful. Anesthesia with 1% lidocaine is effective.
Deep second-degree and all third-degree burns must be closed by prompt surgical excision or remova burn eschar, best performed during the first 1 to 4 days after the burn. Excision removes devitalized tis avoids subeschar sepsis, and allows the wound to be closed early, shortening hospitalization and impr the functional result. Areas that are not expected to heal in 3 wk and that therefore require excision are identified, and the sequence in which they should be excised is determined. If the injury is large and p survival is in question, the largest affected areas should be removed first to expeditiously reduce the v open burn wound. The areas most likely to be treated initially and to accept grafts successfully are the chest, and abdomen. No more than 30% BSA, including donor sites, should be excised at one time. W issue is not survival but cosmetic appearance or optimization of function, eschars of the hands, arms, legs are excised first and in that order. Traditionally, eschars on the face are conservatively excised, re as much of the soft tissue as possible; prompt excision on the face has been recommended.
After excision, the wound bed requires closure with a graft. Grafts may be autografts (the patient's skin allografts (viable skin usually from cadaver donors); or xenografts (skin from porcine sources). Autogra which are permanent, can be transplanted as sheet (a solid piece of skin) or mesh grafts (a sheet of d in which small incisions are made at regular intervals with a skin meshing instrument, allowing the graf cover a larger area). Mesh grafts are used when donor skin is scarce, but not for burns of < 20% BSA. grafts heal with an uneven gridlike appearance, sometimes with excessive hypertrophic scarring. Suffi autograft material is usually not available for deep burns of > 40% BSA. However, material may be tak the same donor site repeatedly at 14-day intervals, expanding the autograft supply over time. Allograft
allografts (viable skin usually from cadaver donors); or xenografts (skin from porcine sources). Autogra which are permanent, can be transplanted as sheet (a solid piece of skin) or mesh grafts (a sheet of d in which small incisions are made at regular intervals with a skin meshing instrument, allowing the graf cover a larger area). Mesh grafts are used when donor skin is scarce, but not for burns of < 20% BSA. grafts heal with an uneven gridlike appearance, sometimes with excessive hypertrophic scarring. Suffi autograft material is usually not available for deep burns of > 40% BSA. However, material may be tak the same donor site repeatedly at 14-day intervals, expanding the autograft supply over time. Allograft xenografts are temporary, may be rejected as early as 10 to 14 days later, and must be replaced with autografts. However, they may be lifesaving for patients with massive burns. An alternative is a skin replacement system with an artificial dermal regeneration template. The template is biodegraded as it the formation of completely new skin (so-called neodermis), created by the patient's cells, which is per
Physical therapy: Early physical therapy is important. Positioning, splinting, exercise, and pressure ga help preserve function and appearance as burn wounds heal. Body surfaces with high skin tension an movement (eg, face, hands, joints, upper legs, chest) are most susceptible to scarring and contracture
The most important therapeutic maneuver is elevation of the extremity, especially for patients with a le hand burn. The extremity should be placed above heart level at all times except for periods of <= 20 m during the day. Because bed rest with elevation is difficult for an outpatient, hospitalization is often req when the legs are burned.
Splinting is required for second- or third-degree burns that affect a joint. Each finger is wrapped individ with cotton roll gauze over the hand and wrist in a figure-8 pattern. The palm should receive extra pad maintain the metacarpophalangeal and interphalangeal joints in slight flexion. The wrist or elbow may splinted with an arm sling. For outpatients, the legs are not usually splinted.
For extensive burns, splints to keep joints in functional position should be applied as soon as possible admission. They must be fitted properly and constantly assessed in the early stages of treatment to av constriction of the extremity, which may increase edema. As edema subsides, splints often need to be remodeled for a closer fit. Splints are worn continuously until the area is grafted and heals substantiall Throughout convalescence, joints are maintained in functional position with dressings and blanket rolls
Joints are put through active and passive range-of-motion exercises once or twice a day before graftin preserve function. Exercise and positioning become easier as the initial edema subsides. After skin gr the affected part is usually kept immobile for 5 to 10 days, so that the graft can stabilize before postop exercises are begun.
Follow-up care: The patient is advised to keep the wound clean, dry, and elevated; to change the dre twice daily as directed; to clean the wound completely with water, removing all residual topical medica before applying a new layer; to take antibiotics as directed; and to return for follow-up. Outpatient follo visits are required to monitor compliance with wound care; to debride the wound; to look for cellulitis; t assess burn depth; to evaluate and arrange for ambulatory, occupational, and physical therapy; and to consider excisional therapy. For less severe burns, the first follow-up visit is usually within 24 to 48 h o burn. Subsequent outpatient visits are q 24 to 72 h, as necessary, depending on the severity and dept burn and the ability of the patient to care for the wound.
Section 20. Disorders Due To Physical Agents Chapter 281. Altitude Sickness Topics
[General]
[General]
Altitude sickness (mountain sickness; soroche; puna; mareo): Syndromes due to decreased O2 at high altitudes.
Atmospheric pressure decreases as altitude increases, while the percentage of O2 in air remains cons thus, the partial pressure of O2 decreases with altitude and at 18,000 ft (5500 m) is about 1/2 that at s About 20% of persons ascending above 8000 ft (2500 m) in < 1 day develop some form of altitude sic Persons who have had one attack are slightly more susceptible to another if conditions are similar, bu effects of high altitude vary greatly among and within individuals. Young children are most susceptible incidence decreases linearly with increasing age. Abrupt exposure to high altitude (eg, depressurizatio aircraft, balloon ascent) causes acute severe hypoxia and loss of consciousness rather than altitude s
Most persons acclimatize to altitudes of up to 10,000 ft (3000 m) in a few days. The higher the altitude longer full acclimatization takes. Above 17,000 ft (5100 m), deterioration is more rapid; no one can live altitude permanently. Acclimatization is an integrated series of responses that gradually restore tissue oxygenation toward normal in persons exposed to altitude. Features of acclimatization include sustain hyperventilation with persistent partially compensated alkalosis, an initial increase in cardiac output (w lower than normal maximum cardiac output), increased RBC mass, and increased tolerance for anaer work. After many generations at altitude, some ethnic groups have acclimatized in slightly different wa
Hypoxia stimulates breathing, increasing tissue oxygenation but also causing respiratory alkalosis, wh contributes to symptoms until loss of HCO3 in urine partially compensates. The basic pathophysiology altitude sickness is disturbance of water and electrolyte balance. Capillary permeability is increased, a fluid to accumulate in various locations; the cause is thought to be vascular endothelial damage. In su persons, increased ADH secretion results in tissue fluid retention, and plasma volume is decreased, s an increase in Hct. A low hypoxic ventilatory response is not associated with altitude sickness. The rol atrial natriuretic peptide, aldosterone, renin, and angiotensin are unclear.
altitude sickness is disturbance of water and electrolyte balance. Capillary permeability is increased, a fluid to accumulate in various locations; the cause is thought to be vascular endothelial damage. In su persons, increased ADH secretion results in tissue fluid retention, and plasma volume is decreased, s an increase in Hct. A low hypoxic ventilatory response is not associated with altitude sickness. The rol atrial natriuretic peptide, aldosterone, renin, and angiotensin are unclear.
Hypoxia increases pulmonary vascular resistance and pulmonary artery pressure, but systemic resista arterial pressure usually change little. Cerebral blood flow is decreased by hypocapnia, is increased by hypoxia, and consequently varies with the balance between arterial CO2 and O2 . The role of this varia symptomatology is unclear.
Peripheral or facial edema may be due to high altitude or, as at sea level, to strenuous exertion. Thrombophlebitis may occur at extremely high altitude, especially if a person is dehydrated and inactiv Dimmed vision, hemianopsia, scotomata, and even transient blindness have been reported. Some of t symptoms may be explained by "anencephalalgic" migraine (migraine without headache); others may grouped as hypoxic amaurosis. Persons who have had radial keratotomy may have significant visual disturbances at altitudes > 16,000 ft (> 5000 m) or even as low as 10,000 ft (3000 m). These alarming symptoms disappear rapidly after descent, unless due to intracranial pathology, which is rare.
Retinal hemorrhages may develop at altitudes as low as 9000 ft (2700 m); they are common above 16 They are usually asymptomatic unless in the macular region and resolve rapidly without sequelae. Sm hemorrhages may also occur under the nails, in the kidneys, and in the brain.
The various clinical forms of altitude sickness are not separate entities but parts of a spectrum in whic more may be present in different degrees. CNS dysfunction is considered a factor in several forms. No can reliably predict development of altitude sickness.
Acute mountain sickness (AMS): This form is the most common and may develop at altitudes as low 6500 ft (2000 m). It is characterized by headache, fatigue, nausea, dyspnea, and sleep disturbance. E aggravates the symptoms. AMS usually subsides in 24 to 48 h but occasionally evolves into high-altitu pulmonary edema, high-altitude cerebral edema, or both. Laboratory studies are nonspecific and are n helpful in diagnosis.
High-altitude pulmonary edema (HAPE): This form is less common but more serious, usually develo to 96 h after rapid ascent above 8000 ft (2500 m). When most persons ascend above 8000 ft, fluid accumulates in lung interstitial tissues and is usually drained away by the lymphatics. When fluid accu more rapidly than it is drained, frank alveolar edema develops.
Persons who have had one episode of HAPE are likely to have another and should be so warned. Res infections, even minor ones, appear to increase the risk of HAPE. Recently identified persons who hav repeated episodes of HAPE are described as HAPE-S (susceptible); the reason for their susceptibility unknown. Men are 5 times more likely than women to develop HAPE, but AMS and high-altitude cereb edema affect men and women equally. Children appear to be at a slightly greater risk, as are longtime high-altitude residents when they return after a brief stay at low altitude. The absence of one pulmona is a rare congenital anomaly that greatly increases the risk of HAPE, even at altitudes as low as 5000 m). Persons who develop HAPE repeatedly or at an unusually low altitude should be evaluated for pul artery pathology or old pulmonary embolism.
HAPE is a high-pressure edema with increased microvascular permeability. Excessive vasoconstrictio some areas causes overperfusion in others, and the resulting ventilation/perfusion mismatch is consid precipitating cause. There is new evidence that a decrease in alveolar nitric oxide, perhaps due to abs
m). Persons who develop HAPE repeatedly or at an unusually low altitude should be evaluated for pul artery pathology or old pulmonary embolism.
HAPE is a high-pressure edema with increased microvascular permeability. Excessive vasoconstrictio some areas causes overperfusion in others, and the resulting ventilation/perfusion mismatch is consid precipitating cause. There is new evidence that a decrease in alveolar nitric oxide, perhaps due to abs nitric oxide synthase, is an important factor in susceptibility to HAPE.
HAPE is characterized by increasing dyspnea; irritative cough that produces frothy, often bloody sputu weakness; ataxia; and, later, coma. Cyanosis, tachycardia, and low-grade fever are common and, with coarse pulmonary rales (often audible without a stethoscope), may lead to a misdiagnosis of pneumon Chest x-ray shows Kerley lines and patchy edema unlike that in heart failure. Atrial pressure is normal pulmonary artery pressure is greater than that in healthy persons experiencing hypoxia. HAPE may wo rapidly; coma and death may occur within hours.
High-altitude cerebral edema (HACE): Cerebral edema is believed to be present to a mild degree in of altitude sickness. Diffuse or patchy edema of the brain, seen on CT scans, is thought to contribute t and to AMS. Severe edema is manifested as ataxia, headache, mental confusion, and hallucinations. neck does not occur, and papilledema is not necessary for diagnosis. CSF pressure may be elevated, fluid is normal. Gait ataxia is a reliable early warning sign. Coma and death may develop within a few h the first symptoms. HACE must be differentiated from other causes of coma (eg, infection, vascular ac ketoacidosis) by the history, absence of significant fever or paralysis, and normal blood and CSF studi
Subacute infantile mountain sickness: This syndrome has been described in Han Chinese infants b brought to high altitude. A similar syndrome has been described among troops stationed above 20,000 m) for months. Both syndromes are characterized by right heart failure and require descent to prevent
Chronic mountain sickness (Monge's disease): This uncommon disorder affects longtime high-altit residents; it is characterized by fatigue, dyspnea, aches and pains, excessive polycythemia, and thromboembolism. The disorder resembles alveolar hypoventilation (formerly called pickwickian syndr both are thought to be caused by an inadequately sensitive respiratory center. The patient should des sea level; recovery is slow, and return to altitude may cause recurrence. Repeated phlebotomy to redu polycythemia may help but is not the most desirable treatment.
Prophylaxis
Altitude sickness is best prevented by slow ascent, but the safe rate of ascent varies among individual can ascend to 5000 ft (1500 m) in 1 day without symptoms, but many are affected by ascending to 80 (2500 m). Above this level, a rate of 1500 ft (460 m)/day is advisable. Climbers should learn how fast t ascend without developing symptoms; a climbing party should be paced for its slowest member. Altho physical fitness enables greater exertion with less O2 consumption, it does not protect against any form altitude sickness. Strenuous effort should be avoided for 24 to 36 h after the ascent is completed, but is less beneficial than mild exercise.
Drinking much more water than usual is important, because overbreathing dry air at altitude greatly inc water loss, and dehydration with some degree of hypovolemia aggravates symptoms. Additional salt s avoided. Alcohol seems to worsen AMS and diminishes nocturnal ventilation, thus accentuating sleep disturbance. Eating frequent small meals that are high in easily digested carbohydrates (eg, fruits, jam starches) improves altitude tolerance and is recommended for the first few days.
Acetazolamide 125 mg at bedtime (for most persons) or 125 mg q 8 h is an effective prophylactic for A Sustained-release capsules (500 mg once daily) are also available. Starting acetazolamide before the has no advantage. Acetazolamide inhibits carbonic anhydrase, increasing ventilation and allowing bett
disturbance. Eating frequent small meals that are high in easily digested carbohydrates (eg, fruits, jam starches) improves altitude tolerance and is recommended for the first few days.
Acetazolamide 125 mg at bedtime (for most persons) or 125 mg q 8 h is an effective prophylactic for A Sustained-release capsules (500 mg once daily) are also available. Starting acetazolamide before the has no advantage. Acetazolamide inhibits carbonic anhydrase, increasing ventilation and allowing bett transport with less alkalosis; it eliminates periodic breathing (almost universal during sleep at high altit thus preventing sharp falls in blood O2. Acetazolamide should not be given to patients allergic to sulfa Low-flow O2 during sleep has the same effect but is inconvenient. Analogs of acetazolamide offer no advantage. Antacids are useless for prevention. Dexamethasone, which minimizes symptoms of AMS recommended for prevention.
Treatment
Retinal hemorrhages require no treatment, generally resolving while the climber remains at high altitu
AMS seldom requires treatment other than fluids, analgesics, a light diet, mild activity, and (rarely) des Dexamethasone 4 mg po q 6 h is effective; acetazolamide 250 mg po q 6 h may alleviate symptoms. Ibuprofen, which decreases platelet aggregation, is more effective than aspirin for altitude headache b also cause easy bruising.
When HAPE is suspected, bed rest and O2 may be tried, but if the condition worsens, immediate desc essential. If descent is not possible, the person can be placed in a large hyperbaric bag in which the p can be increased, simulating descent. This measure helps buy time in an emergency but is not a subs descent. Nifedipine 20 mg sublingually followed by a 30-mg slow-release tablet lowers pulmonary arte hypertension and is beneficial. Strong diuretics (eg, furosemide) are contraindicated. Although morphi effective, the resulting respiratory depression may outweigh the drug's value. Because the heart is nor HAPE, digitalis is of no value; however, in the subacute form of infantile and adult mountain sickness, fails, and digitalis and descent are necessary to save life. Once the patient is hospitalized, other cause pulmonary disease are ruled out, and the patient is treated with adequate oxygenation (sometimes by intubation and positive end-expiratory pressure), bed rest, judicious diuresis, postural drainage, and, if superimposed infection is suspected, antibiotics. When promptly treated, patients usually recover from within 24 to 48 h.
Severe HACE requires immediate descent. Supplementary oxygen or pressurization in a hyperbaric b time but does not cure. Dexamethasone 8 mg IV q 4 h helps but not dramatically. Its value in an altitud emergency is dubious.
Section 20. Disorders Due To Physical Agents Chapter 277. Electric Injury Topics
[General]
[General]
Electric injury: Injury caused by an electric current passing through the body.
The electric current may be atmospheric (lightning) or man-made (eg, from high- or low-voltage lines).
Pathogenesis
The type of current affects the severity of the injury. In general, direct current (DC), which has zero fr but may be intermittent or pulsating, is less dangerous than alternating current (AC), which is generally the USA. The effects of AC on the body depend largely on the frequency. Low-frequency currents of 5 Hz (cycles/sec), which are commonly used, are usually more dangerous than high-frequency currents 3 to 5 times more dangerous than DC of the same voltage and amperage. DC tends to cause a convu contraction, often forcing the victim away from the current's source. AC at 60 Hz (household current) p muscle tetany, often freezing the hand to the current's source; prolonged exposure may result, with se burns if the voltage is high.
Generally, the higher the voltage and amperage, the greater the damage from either type of current. High-voltage (> 500 to 1000 V) currents tend to cause deep burns, and low-voltage to cause freezing t circuit. The threshold of perception for current entering the hand is about 5 to 10 milliamperes (mA) fo about 1 to 10 mA for AC at 60 Hz. The maximum amperage that can cause the flexors of the arm to co but that allows a person to release his hand from the current's source is termed the let-go current. For let-go current is about 75 mA for a 70-kg man; for AC, it is about 15 mA, varying with muscle mass. A low-voltage (110 to 220 V), 60-Hz AC current traveling through the chest for a fraction of a second ma ventricular fibrillation at amperage as low as 60 to 100 mA; about 300 to 500 mA of DC is required. If t current has a direct pathway to the heart (eg, via a cardiac catheter or pacemaker electrodes), a much amperage (< 1 mA, AC or DC) can produce fibrillation.
Body resistance (measured in ohms/cm2 ) is concentrated primarily in the skin and varies directly with skin's condition. The resistance of dry, well-keratinized, intact skin averages 20,000 to 30,000 ohms/cm thickly calloused palm or sole, it may be 2 to 3 million ohms/cm2. The resistance of moist, thin skin is a
amperage (< 1 mA, AC or DC) can produce fibrillation.
Body resistance (measured in ohms/cm2 ) is concentrated primarily in the skin and varies directly with skin's condition. The resistance of dry, well-keratinized, intact skin averages 20,000 to 30,000 ohms/cm thickly calloused palm or sole, it may be 2 to 3 million ohms/cm2. The resistance of moist, thin skin is a 500 ohms/cm2 . If the skin is punctured (eg, from a cut or abrasion or by a needle) or if current is applie moist mucous membranes (eg, mouth, rectum, vagina), resistance may be as low as 200 to 300 ohms skin resistance is low, few, if any, extensive burns occur, although cardiac arrest may occur if the curre reaches the heart. If skin resistance is high, much energy may be dissipated at the surface as current through the skin, and large surface burns can result at the entry and exit points, with charring of tissue between (heat = amperage2 resistance). Internal tissues are burned depending on their resistance; n blood vessels, and muscles conduct electricity more readily than denser tissues (eg, fat, tendon, bone preferentially damaged.
The pathway of current through the body determines the nature of injury. Current traveling from arm between an arm and a foot is likely to traverse the heart and so is much more dangerous than current between a leg and the ground. Electrical injuries to the head may cause seizures, intraventricular hem respiratory arrest, ventricular fibrillation or asystole, and, as a late effect, cataracts.
The most common entry point for electricity is the hand, followed by the head. The most common exit the foot. With AC, exit and entry are misnomers, because which site is the entry and which is the exit c be determined. More appropriate terms are "source" and "ground."
Generally, the duration of current flow through the body is directly proportional to the extent of injury because longer exposure breaks tissues down, allowing internal current flow. The current flow produce damaging internal tissues.
Symptoms and Signs
The clinical manifestations of electrical injuries depend on the complex interaction of the factors discus above. Physiologic functions may be altered, resulting in severe involuntary muscular contractions, se ventricular fibrillation, or respiratory arrest (apnea) due to CNS injury or muscle paralysis. Thermal, electrochemical, or other damage (eg, hemolysis, protein coagulation, vascular thrombosis, dehydratio muscle and tendon avulsion) may occur. Often a combination of these effects occurs. Burns may be s demarcated on the skin and extend well into deeper tissues. High voltage may cause coagulation necr muscle or other internal tissues between source and ground points of the current. Massive edema ma as the veins coagulate and the muscles swell, with resulting compartment syndromes. Hypotension, flu electrolyte disturbances, and severe myoglobinuria may cause acute renal failure. Dislocations, verteb other fractures, blunt injuries, and loss of consciousness may result from powerful muscle contractions secondary to the electric shock (eg, electricity can startle a person, causing a fall).
In "bathtub accidents" (typically, when a wet [grounded] person contacts a 110-V circuit--eg, from a ha or radio), cardiac arrest may occur without burns.
Lightning rarely, if ever, produces entry and exit wounds and seldom causes muscle damage or myoglobulinuria, because the duration of current is too short to break down the skin and tissues. Light flashes over the person, producing little internal damage other than electrical short-circuiting of system heart asystole, brain confusion, loss of consciousness, neuropsychologic sequelae). Some form of am generally results. Neuropsychologic damage, pain syndromes, and sympathetic nervous system dama the most common long-term sequelae. Cardiopulmonary arrest is the most common cause of death. Toddlers who suck on extension cords can burn their mouth and lips. Such burns may cause not only
myoglobulinuria, because the duration of current is too short to break down the skin and tissues. Light flashes over the person, producing little internal damage other than electrical short-circuiting of system heart asystole, brain confusion, loss of consciousness, neuropsychologic sequelae). Some form of am generally results. Neuropsychologic damage, pain syndromes, and sympathetic nervous system dama the most common long-term sequelae. Cardiopulmonary arrest is the most common cause of death.
Toddlers who suck on extension cords can burn their mouth and lips. Such burns may cause not only deformities but also growth problems of the teeth, mandible, and maxilla. An added danger is labial ar hemorrhage, which results when the eschar separates 7 to 10 days after the injury; hemorrhage occur to 10% of cases.
Prevention
Education about and respect for electricity as well as common sense are essential. Any electric device touches or may be touched by the body and may be life threatening should be properly grounded and incorporated into circuits containing protective circuit-breaking equipment. Ground-fault circuit breaker trip when as little as 5 mA of current leaks to ground, are excellent and are readily available. Preventin lightning strikes involves using common sense and proper protection devices, knowing the weather for and having an escape route to an appropriate shelter in storms.
Treatment
Contact between the victim and the current source must be broken. The best method is to shut off the if it can be done rapidly (eg, by throwing a circuit breaker or switch, by disconnecting the device from i electrical outlet); otherwise, the victim must be removed from contact with the current. For low-voltage 220 V) currents, the rescuer should first well insulate himself from ground and then use an insulating m (eg, cloth, dry wood, rubber, leather belt) to pull the victim free. If lines could be high voltage, no attem disengage the victim should be made until the power is shut off. High- and low-voltage lines are not alw easily differentiated, particularly outdoors.
Once the victim can be safely touched, he should be rapidly examined for vital functions (eg, radial, fe carotid pulse; respiratory function; level of consciousness). Airway stabilization is the first priority. If spontaneous respiration is not observed or cardiac arrest has occurred, immediate resuscitation is req (see Ch. 206). Treatment of shock and other manifestations of massive burns is discussed in Ch. 276
Once vital functions have been reestablished, the full nature and extent of the injury must be evaluate treated. Dislocations, fractures, and cervical-spinal and blunt injuries should be sought. If myoglobinur present, fluid replacement and alkalinization therapy is essential to reduce the risk of renal tubular myo precipitation (see Ch. 276). Mannitol or furosemide may be indicated to increase renal flow. Tetanus prophylaxis is required for any burn.
Baseline assessment for all electric injuries includes an ECG, cardiac enzymes, a CBC, and urinalysis especially for myoglobin. Cardiac monitoring for 12 h is indicated if there is any suggestion of cardiac d arrhythmias, or chest pain. Any deterioration in the level of consciousness mandates a CT or MRI sca out intracranial hemorrhage.
Victims of lightning injuries may require cardiac resuscitation, monitoring, and supportive care. Fluid re is the rule because of potential brain edema. Children with lip burns should be referred to a pedodontist or oral surgeon familiar with the evaluation long-term care of such injuries.
Section 20. Disorders Due To Physical Agents Chapter 282. Motion Sickness Topics
[General]
[General]
Sea, air, car, train, and swing sickness and the space adaptation syndrome are specific forms.
Motion sickness: Nausea, vomiting, and related symptoms caused by repetitive angular and linear acc and deceleration.
Etiology
Excessive stimulation of the vestibular apparatus by motion is the primary cause. Individual susceptibi varies greatly. Afferent pathways from the labyrinth to the vomiting center in the medulla are undefined motion sickness occurs only when the 8th nerve and cerebellar vestibular tracts are intact. Visual stim moving horizon), poor ventilation (with fumes, smoke, or carbon monoxide), and emotional factors (eg anxiety) commonly act with motion to precipitate an attack.
In the space adaptation syndrome (motion sickness during space travel), weightlessness (zero gravi etiologic factor. This syndrome reduces the efficiency of astronauts during the first few days of space f adaptation occurs over several days.
Symptoms and Signs
Cyclic nausea and vomiting are characteristic. They may be preceded by yawning, hyperventilation, sa pallor, profuse cold sweating, and somnolence. Aerophagia, dizziness, headache, general discomfort, fatigue may also occur. Once nausea and vomiting develop, the patient is weak and unable to concen With prolonged exposure to motion, the patient may adapt and gradually return to well-being. Howeve symptoms may recur if motion increases or recurs after a short respite. Prolonged motion sickness with vomiting may lead to arterial hypotension, dehydration, inanition, and depression. Motion sickness can be a serious complication in patients with other illnesses.
symptoms may recur if motion increases or recurs after a short respite. Prolonged motion sickness with vomiting may lead to arterial hypotension, dehydration, inanition, and depression. Motion sickness can be a serious complication in patients with other illnesses.
Prevention is easier than treatment. When motion is unavoidable, susceptible persons should minimiz exposure by positioning themselves where motion is the least (eg, in the middle of a ship close to wate over the wings in airplanes). A supine or semirecumbent position with the head supported is best. Rea should be avoided. Keeping the axis of vision at a 45 angle above the horizon reduces susceptibility. visual fixation on waves or other moving objects is helpful to some. On a ship, a well-ventilated cabin i important, and going out on deck for a breath of fresh air helps. Alcoholic or dietary excesses before o travel increase the likelihood of motion sickness. Small amounts of fluids and simple food should be co frequently during extended travel; if air travel time is short, food and fluids should be avoided. In the sp adaptation syndrome, movement, which aggravates the symptoms, should be avoided.
Prophylactic drugs should be given before nausea and vomiting occur. One hour before departure, su persons may be given dimenhydrinate, diphenhydramine, meclizine, or cyclizine 50 mg po; promethaz mg po; diazepam 5 to 10 mg po; or scopolamine 0.6 mg po (where available) to minimize vagal-media symptoms. However, all of these drugs except diazepam are anticholinergic and cause adverse effect especially in the elderly. A dermal patch can deliver a smaller dose of scopolamine; it is applied 4 h be departure and releases 0.5 mg over 3 days. If emotional factors are significant, phenobarbital 15 to 30 may be given 1 h before departure. All dosages should be appropriately modified for prolonged travel. vomiting occurs, a drug must be given rectally or parenterally to be effective. If vomiting is prolonged, I and electrolytes may be required for replacement and maintenance.
Section 20. Disorders Due To Physical Agents Chapter 278. Radiation Reactions And Injurie Topics
[General]
[General]
Radiation reactions and injuries: Damage--acute, delayed, or chronic--to body tissues produced by ion radiation.
Ionizing radiation (eg, x-rays, neutrons, protons, or particles, -rays) damages tissue directly or by seco reactions. High doses of radiation can produce observable somatic effects within days. Many years lat changes due to smaller doses may lead to chronic disease in exposed persons or to a genetic defect i offspring. Relationships between the degree of damage and the healing or death of a cell are complex
Harmful sources of ionizing radiation include high-energy x-rays used for diagnosis and therapy, radiu other naturally occurring radioactive materials (eg, radon), nuclear reactors, cyclotrons, linear accelera alternating gradient synchrotrons, sealed cobalt and cesium sources for cancer therapy, and numerou artificially produced radioactive materials used in medicine and industry.
Large amounts of radiation have accidentally escaped from reactors several times--eg, the well-public accidents at Three Mile Island in Pennsylvania in 1979 and at Chernobyl in the Ukraine in 1986. The la resulted in > 30 deaths and many radiation injuries; significant radiation was detected in most of Easte Europe and in parts of Western Europe, Asia, and the USA.
Commonly used units of measurement are the roentgen, gray, and sievert. The roentgen (R) is the am x or ionizing radiation in air. The gray (Gy) is the amount of energy absorbed by a tissue or substance applies to all types of radiation. The R and the centigray (cGy) are essentially equivalent. The sievert ( equals the Gy adjusted by a quality factor to account for the biologic effect. It is used because differen of radiation have different biologic effects for a given amount of energy; eg, neutrons have a greater e x and radiation, the Sv equals the Gy. The Gy and Sv have replaced the rad and rem (Gy = 100 rad; S rem) in current nomenclature. Radiation is often characterized in the lay press as low level (0.2 to 0.3 high level (> 0.3 Gy). Medical doses are usually < 0.05 Gy and frequently < 0.01 Gy. The low levels of background radioactivity in the earth and its atmosphere have no detectable effects (see Table 278-1)
Somatic or genetic effects depend on several factors, including total dose and dose rate (radiation do of time). The probability of measurable effects increases as total dose or dose rate increases. An obse
rem) in current nomenclature. Radiation is often characterized in the lay press as low level (0.2 to 0.3 high level (> 0.3 Gy). Medical doses are usually < 0.05 Gy and frequently < 0.01 Gy. The low levels of background radioactivity in the earth and its atmosphere have no detectable effects (see Table 278-1)
Somatic or genetic effects depend on several factors, including total dose and dose rate (radiation do of time). The probability of measurable effects increases as total dose or dose rate increases. An obse effect is likely after a single rapid dose of several Gy, but the same dose given over weeks or months tolerated with little measurable acute effect.
Radiation effects also depend on the amount of body area exposed. The entire human body can prob absorb a single dose of up to 2 Gy without death; however, as the whole-body dose approaches 4.5 G death rate is about 50% (lethal dose [LD] 50), and a whole-body dose of > 6 Gy given in a very short tim almost certainly fatal. In contrast, tens of Gy can be tolerated when delivered over a long period to a s area of tissue (eg, for cancer therapy).
Distribution of the dose within the body is also important. Generally, the more rapid the turnover of th the greater its sensitivity to radiation. Most sensitive are lymphoid cells, followed by (in descending ord gonads, proliferating bone marrow cells, bowel epithelial cells, epidermis, hepatic cells, epithelium of lu alveoli and biliary passages, kidney epithelial cells, endothelial cells (pleura and peritoneum), nerve ce cells, and muscle and connective tissue cells. During radiation therapy, vulnerable areas (eg, bowel, b marrow) are shielded so that high whole-body doses, which would otherwise be fatal, can be used.
Pathophysiology
At sufficiently high doses, cell necrosis occurs. High but sublethal doses may interfere with cell prolifer decreasing the rate of mitosis, by slowing DNA synthesis, or by causing cells to become polypoid. In ti that normally undergo continual renewal (eg, bowel epithelium, bone marrow, gonads), radiation produ dose-dependent progressive hypoplasia, atrophy, and eventually fibrosis. Some cells, injured but still c of mitosis, may pass through one or two generative cycles, producing abnormal progeny (eg, giant metamyelocytes, hypersegmented neutrophils) before dying.
The somatic and genetic effects of doses < 100 mGy are usually estimated by linear extrapolation from of higher doses, because few objective data on the effects of very low doses are available. Some rese postulate a threshold effect, which is not fully understood. Studies in which animals exposed to extrem levels of additional radiation survived longer than animals exposed only to background radiation have reported.
Symptoms and Signs
Acute radiation syndromes: Syndromes can be divided into cerebral, GI, and hematopoietic depend dose, dose rate, body area, and time after exposure.
The cerebral syndrome, produced by extremely high whole-body doses of radiation (> 30 Gy), is alwa It consists of three phases: a prodromal period of nausea and vomiting; listlessness and drowsiness, r from apathy to prostration (possibly due to nonbacterial inflammatory foci in the brain or to radiation-in toxic products); and tremors, convulsions, ataxia, and death within a few hours to a few days.
The GI syndrome is produced by whole-body doses of >= 4 Gy. It is characterized by intractable naus vomiting, and diarrhea that lead to severe dehydration, diminished plasma volume, and vascular collap GI syndrome results from tissue necrosis and is perpetuated by progressive atrophy of GI mucosa. Ba due to necrotic bowel also occurs. Ultimately, the intestinal villi are denuded, with massive loss of plas the intestine. GI epithelial cells may regenerate after 4 to 6 days if there is massive plasma replaceme
The GI syndrome is produced by whole-body doses of >= 4 Gy. It is characterized by intractable naus vomiting, and diarrhea that lead to severe dehydration, diminished plasma volume, and vascular collap GI syndrome results from tissue necrosis and is perpetuated by progressive atrophy of GI mucosa. Ba due to necrotic bowel also occurs. Ultimately, the intestinal villi are denuded, with massive loss of plas the intestine. GI epithelial cells may regenerate after 4 to 6 days if there is massive plasma replaceme antibiotics may keep patients alive during this period. However, hematopoietic failure ensues within 2 o and is usually fatal.
The hematopoietic syndrome is produced by whole-body doses of 2 to 10 Gy and initially causes an apathy, nausea, and vomiting. These symptoms may be maximal within 6 to 12 h, subsiding complete 24 to 36 h after exposure. However, during this period of relative well-being, lymph nodes, spleen, and marrow begin to atrophy, leading to pancytopenia. Atrophy results from direct killing of radiosensitive c from inhibition of new cell production. In the peripheral blood, lymphopenia develops immediately, bec maximal within 24 to 36 h. Neutropenia develops more slowly. Thrombocytopenia may be prominent w or 4 wk.
In the hematopoietic syndrome, susceptibility to infection (by saprophytic and pathogenic organisms) i because of a dose-dependent decrease in circulating granulocytes and lymphocytes, dose-dependent impairment of antibody production, impairment of granulocyte migration and phagocytosis, decreased the reticuloendothelial system to kill phagocytized bacteria, diminished resistance to bacterial spread i subcutaneous tissues, and development of hemorrhagic areas (due mainly to thrombocytopenia) in th and bowel, which enable bacteria to enter and grow.
Acute radiation sickness: This disorder develops in a small proportion of patients after radiation ther (particularly to the abdomen). Its cause is not understood. Nausea, vomiting, diarrhea, anorexia, head malaise, and tachycardia of varying severity typically occur, then subside within a few hours or days.
Intermediate delayed effects: Prolonged or repeated exposure at a low-dose rate from internally dep external sources of radiation may produce amenorrhea and decreased libido in women and decreased anemia, leukopenia, thrombocytopenia, and cataracts in both sexes. Higher doses or highly localized e causes loss of hair, skin atrophy and ulceration, keratosis, and telangiectasia. Ultimately, squamous c carcinomas may develop. Osteosarcomas may appear years after ingestion of radioactive bone-seeki nuclides (eg, radium salts).
Extensive radiation therapy for cancer can occasionally cause serious injury to exposed organs. If the are irradiated, GFR and renal tubular function may decrease. Extremely high doses may result in the a onset of clinical manifestations (eg, proteinuria, renal insufficiency of varying degree, anemia, hyperten after a latent period of 6 mo to 1 yr. When cumulative kidney exposure is > 20 Gy in < 5 wk, radiation f and oliguric renal failure develop in about 37% of patients. In the remainder, various changes develop prolonged period. Large accumulated doses to muscles may result in painful myopathy with atrophy a calcification. Very rarely, neoplastic changes (eg, sarcoma) follow. After irradiation for lung cancer, sev radiation pneumonitis and subsequent pulmonary fibrosis may develop and can be fatal after a cumula dose of > 30 Gy if treatment is not spread over a long enough period. Extensive radiation therapy to th mediastinum can produce radiation pericarditis and myocarditis. Catastrophic myelopathy may develo cumulative dose of > 50 Gy to a segment of the spinal cord. However, this risk can be minimized by lim dose rate to 2 Gy/day. If the rate is 8 Gy/day, myelopathy may occur at a cumulative dose as low as 1 (after 2 days of treatment). After extensive radiation of abdominal lymph nodes (eg, for seminoma, lym or ovarian carcinoma), chronic ulceration, fibrosis, and perforation of the bowel may develop. The use high-energy photons (which penetrate deeply into tissues) in cobalt-60 units and linear accelerators ha virtually eliminated the skin erythema and ulceration that occurred when orthovoltage x-ray therapy wa
Late somatic and genetic effects: Radiation of somatic cells may result in diseases--such as cancer leukemia; thyroid, skin, or bone cancer) and cataracts--or, as suggested by animal models, in nonspec shortening of life. Thyroid cancer may occur 20 to 30 yr after x-ray therapy for adenoid and tonsillar
or ovarian carcinoma), chronic ulceration, fibrosis, and perforation of the bowel may develop. The use high-energy photons (which penetrate deeply into tissues) in cobalt-60 units and linear accelerators ha virtually eliminated the skin erythema and ulceration that occurred when orthovoltage x-ray therapy wa
Late somatic and genetic effects: Radiation of somatic cells may result in diseases--such as cancer leukemia; thyroid, skin, or bone cancer) and cataracts--or, as suggested by animal models, in nonspec shortening of life. Thyroid cancer may occur 20 to 30 yr after x-ray therapy for adenoid and tonsillar hypertrophy. Externally delivered radiation appears to have a greater biologic effect than radioiodine.
Radiation to germ cells affects the genes, and mutations increase. Procreation perpetuates the mutati resulting in an increased number of genetic defectives in subsequent generations. The long-term prob a measurable genetic or somatic effect appearing in a given individual is estimated to be 10-2/Gy.
Diagnosis and Prognosis
When the cerebral or GI syndrome is present, diagnosis is simple, but the prognosis is grave. Death re within hours to a few days in the cerebral syndrome and usually in 3 to 10 days in the GI syndrome. In hematopoietic syndrome, death may occur in 8 to 50 days, in 2 to 4 wk due to a supervening infection to 6 wk due to massive hemorrhage. GI or hematopoietic malfunction is fatal if the acute whole-body d 6 Gy, but if the dose is < 6 Gy, survival is possible and is inversely related to total dose.
For a person who is receiving radiation therapy or has been exposed during a radiation accident, diagn obvious. Prognosis depends on dose, dose rate, and body distribution. Serial hematologic and bone m studies to gauge the severity of bone marrow injury provide additional prognostic information.
For chronic radiation injury in which external exposure is unknown or overlooked, a diagnosis may be or impossible. Possible occupational exposure must be sought. In institutions licensed by federal or st governments, records of exposure to radiation are maintained. Serial chromosome studies can be per to detect types and frequency of chromosomal abnormalities likely to occur after significant exposure, these abnormalities may have preexisted or have other causes.
Periodic examination for cataracts is appropriate if the eyes are habitually exposed to radiation, espec neutrons. Exposed patients may be monitored using handheld rate-meter probes or sophisticated who counting. Urine should be analyzed for non--emitting radionuclides if exposure to these agents is susp Radon breath analysis can be performed if radium ingestion is suspected.
In cases of alleged radiation exposure, exact diagnosis is probably impossible unless the person has r a documented external or internal dose. If hematologic values are normal and no objective clinical dise found, the patient and others concerned can be reassured.
Prophylaxis
Many drugs and chemicals (eg, sulfhydryl compounds) increase survival rate in animals if given before irradiation. However, none are practical for humans. The only way to minimize fatal or serious overexp to rigorously enforce protective measures and to adhere to maximum permissible dose levels. These l described in U.S. Nuclear Regulatory Commission, Code of Federal Regulations-Energy, Part 20, Title (10CFR20), Standards for Protection Against Radiation, published by the Office of the Federal Registe Government Printing Office Superintendent of Documents, Washington, DC 20452.
Treatment
Radioactive materials contaminating the skin should be immediately removed using copious water irrig
Government Printing Office Superintendent of Documents, Washington, DC 20452.
Treatment
Radioactive materials contaminating the skin should be immediately removed using copious water irrig and special chelating solutions containing ethylenediaminetetraacetic acid (EDTA--eg, Radiac Wash) available. Small puncture wounds must be cleaned vigorously, using irrigation and debridement, until t wound is free of radioactivity. Ingested radioactive material should be removed promptly by inducing v or, if exposure is recent, by lavage. If radioiodine is inhaled or ingested in large quantities, the patient be given Lugol's (strong iodine) solution or saturated solution of potassium iodide for days to weeks to thyroid uptake, and diuresis should be promoted. Patients with an iodine allergy should not be given L solution.
Because the acute cerebral syndrome is fatal, treatment is palliative and includes managing shock and relieving pain and anxiety, and giving sedatives to control convulsions.
For the GI syndrome, antiemetics, sedatives, and antibiotics may suffice if exposure was modest. If or feeding can be started, a bland diet is tolerated best. Fluids, electrolytes, and plasma, by appropriate r may be required in large amounts. Amount and type are dictated by blood chemistry (especially electro and proteins), BP, pulse, fluid exchange, and skin turgor.
For the hematopoietic syndrome, with potentially lethal infection, hemorrhage, and anemia, managem similar to that of marrow hypoplasia and pancytopenia, regardless of cause (see Aplastic Anemia in C Antibiotics, fresh blood, and platelet transfusions are the main therapies. Aseptic technique must be u during all skin-puncturing procedures, and the patient must be isolated to prevent exposure to pathoge
Concurrent antineoplastic chemotherapy or use of other marrow-suppressing drugs, unless strongly in because of a preexisting disorder or sudden complication, should be avoided because bone marrow m suppressed further.
If a person may have received a dose of > 2 Gy, tissue type should be determined, and a compatible b marrow donor should be sought. A marrow transplant from an identical twin increases the likelihood of If granulocytes and platelets fall to < 500/L and < 20,000/L, respectively, homotransplantation of ma should be considered, although the likelihood of success is small and transplantation may be followed potentially fatal immunologic graft-vs.-host reaction (see Bone Marrow Transplantation in Ch. 149).
Symptoms of radiation sickness due to radiation therapy of the abdomen can be reduced by an antiem prochlorperazine 5 to 10 mg po or IM qid) and may be prevented by prior administration. Ondansetron granisetron, used for symptoms caused by chemotherapy, may also help in radiation sickness but are more expensive. The radiotherapist and referring physician must cooperate closely, giving attention to and fluid balance. Careful planning of overall management (eg, dose, interval between treatments, sup therapy) can prevent most problems.
For severe chronic exposure, removing the patient from the radiation source is the first step. If radium, or radiostrontium is deposited in the body, prompt administration of oral and parenteral chelating drugs EDTA) increases excretion. However, in the late stages, these drugs are useless. Radiation ulcers and cancers require surgical removal and plastic repair. Radiation-induced leukemia is treated in the same a similar spontaneous leukemia. Whole-blood transfusion can correct anemia, and platelet transfusion reduce thrombocytopenic bleeding. However, the value of these measures is only temporary because probability that extensively damaged bone marrow will regenerate is slight. No effective treatment of s of ovarian and testicular dysfunction, except for hormonal supplementation, is available.
Section 20. Disorders Due To Physical Agents Chapter 283. Medical Aspects Of Air And Foreign Topics
Air Travel Foreign Travel
Air Travel
Modern aircraft impose infrequent but important medical and environmental risks. For persons living n airports, high-level noise and air pollution can aggravate various medical and psychologic conditions. Physicians in agricultural communities should know the toxic manifestations of the chemicals used in a spraying, which may accidentally contaminate farm workers or persons in nearby areas. Local disaste near airports should be prepared to provide initial management of major trauma and burns among air survivors.
Traveling by air can cause or worsen certain medical problems. Very few medical conditions absolutel air travel; however, some patients must plan and take precautions. During a flight, physicians may be help in cases of illness; all U.S. domestic commercial aircraft have first aid and limited medical supplie
Physiologic Effects
Changes in barometric pressure: Some small airplanes, which usually fly at < 10,000 ft (< 3050 m), unpressurized. In modern jet aircraft, the cabin pressure is equivalent to atmospheric pressure at 5000 ft (1525 to 2440 m), regardless of altitude. At such pressures, free air in body cavities expands by abo this expansion may aggravate certain medical conditions. Upper respiratory inflammation or allergy ma in obstructed eustachian tubes, and sinus ostia may result in barotitis media (see Ch. 84) or barosinus Facial pain of dental origin may occur when air pressure changes. Frequent yawning or closed-nose swallowing during descent, use of decongestant nasal sprays, or use of antihistamines before or durin often prevents or relieves these conditions. Children are particularly susceptible to barotitis media and be given fluids or food during descent to encourage swallowing. Sudden accidental loss of cabin press which occurs occasionally, can cause additional problems.
Air travel is contraindicated for patients who have or are likely to develop pneumothorax (eg, who have pulmonary blebs or cavities) and for those in whom air or gas is trapped (eg, those with an incarcerate recent [< 10 days] chest or abdominal surgery, or intraocular gas injection), because even modest exp may cause pain or stress tissue. Patients with a colostomy should wear a large bag and expect freque
Air travel is contraindicated for patients who have or are likely to develop pneumothorax (eg, who have pulmonary blebs or cavities) and for those in whom air or gas is trapped (eg, those with an incarcerate recent [< 10 days] chest or abdominal surgery, or intraocular gas injection), because even modest exp may cause pain or stress tissue. Patients with a colostomy should wear a large bag and expect freque
Decreased O 2 tension: Cabin pressure equivalent to pressure at 7500 ft (2640 m) results in a PaO2 o 70 mm Hg, which is well tolerated by healthy travelers. In general, anyone who can walk 50 yd (46 m) one flight of stairs and whose disease is stable can tolerate normal cabin conditions without additional However, problems may arise for patients with such conditions as moderate or severe pulmonary dise asthma, emphysema, cystic fibrosis), heart failure, anemia with Hb < 8.5 g/dL, severe angina pectoris, cell disease (but not trait--see Ch. 127), and some congenital heart diseases. Such patients can usual safely with specially designed continuous O2 equipment, which must be provided by the airline; 72-h a notice is required. Patients recovering from MI may fly when stable, often within 10 to 14 days. Mild an edema due to venous stasis commonly develops during long flights and should not be confused with h failure. Smoking can aggravate mild hypoxia and should be avoided before flying. Hypoxia and fatigue increase the effects of alcohol.
Turbulence: Turbulence may cause air sickness (see Ch. 282) or injury. While seated, passengers sh keep their seat belts fastened at all times.
Circadian dysrhythmia (jet lag): Rapid travel across multiple time zones disrupts the normal circadia rhythm. Because bright sunlight resets the internal clock, exposure to bright late-afternoon light delays onset of normal time of sleep, and early-morning light advances the biologic clock (time of sleep is ear usual). Melatonin, a hormone secreted by the pineal gland, provides a time-of-night cue (see Insomnia 173); if a person traveling east across several time zones takes melatonin 0.5 to 5.0 mg in the evening arrival at his destination, his usual time of sleep may be earlier. Melatonin's effectiveness depends on coordinating its administration with the destination's time pattern.
Some therapeutic regimens must be altered to compensate for circadian dysrhythmia; eg, insulin dosa timing may require modification depending on the number of time zones traversed, time spent at desti available food, and activity; glucose must be monitored frequently. Regimens may require modification on elapsed rather than local time.
Psychologic stress: Fear of flying and claustrophobia are psychologic and not influenced by reason; hypnosis and behavioral modification have reduced the fear of flying in some persons. Fearful passen may benefit from mild sedation before and during flight. Hyperventilation commonly simulates heart dis and may cause tetany-like symptoms or altered awareness. Psychotic tendencies may become more a and troublesome during flight. Patients with violent or unpredictable tendencies must be accompanied attendant and appropriately sedated.
Precautions
Deep vein thrombosis may develop in anyone sitting for long periods, especially pregnant women and with venous disease, and may result in a pulmonary embolus. Frequent (q 1 to 2 h) walks around the c and short-movement exercises while seated are recommended.
Dehydration may develop because of very low cabin humidity and can be avoided by adequate intake and avoidance of alcohol. Contact lens wearers should instill artificial tears frequently to avoid corneal resulting from low cabin humidity.
Communicable disease may endanger others in a crowded aircraft. International immunization require change frequently; current information may be obtained from local or state health departments.
Dehydration may develop because of very low cabin humidity and can be avoided by adequate intake and avoidance of alcohol. Contact lens wearers should instill artificial tears frequently to avoid corneal resulting from low cabin humidity.
Communicable disease may endanger others in a crowded aircraft. International immunization require change frequently; current information may be obtained from local or state health departments.
Travelers should carry an adequate supply of medication on their person to ensure continued therapy of lost baggage, delayed arrival, theft in hotels, or local unavailability. Patients who must carry narcotic unusually large amounts of any medication should have a verifying letter from a physician to avoid pos security or customs complications. A summary of a patient's medical record (including ECG) is invalua patient becomes ill away from home. Patients subject to disabling illness (eg, epilepsy) or those with c disease should wear a medical (eg, Medic Alert [800-633-4260]) identification bracelet or necklace. Ha a dental checkup recently and taking extra glasses and hearing-aid batteries are wise. Maxillofacial injury immobilized by fixed wires, unless fitted with a special quick-release device, is a contraindication to air travel because air sickness may result in aspiration of vomitus.
Newer pacemaker models are effectively shielded from interference from security devices. The metal of pacemakers and orthopedic prostheses and braces may trigger a security alarm; a physician's lette be carried to avoid security difficulties.
Uncomplicated pregnancy through 36 wk is not a contraindication to air travel; high-risk pregnant wom be individually evaluated. Flight during the 9th mo usually requires a physician's written approval dated 72 h of departure and indicating expected delivery date. Pregnant women should wear seat belts belo abdomen, across the hips. Thrombophlebitis is a specific risk.
Children < 7 days of age are not permitted to fly. For children with chronic disease (eg, congenital hea disease, chronic lung disease, anemia), the same precautions apply as for adults.
With advance notice, airlines make reasonable efforts to accommodate patients with handicaps, includ those in wheelchairs and litters. If patients cannot be accommodated on a commercial aircraft, air amb service is necessary. Some airlines accept patients requiring special equipment (eg, IV fluids, respirato provided that appropriate personnel accompany the patient and arrangements have been made in adv Special foods, including low-sodium, low-fat, and diabetic diets, are available if requested in advance.
Further information about air travel may be obtained from the medical department of major airlines or Federal Aviation Administration Regional Flight Surgeon. Special arrangements (eg, O2 , wheelchair) c made through regular reservations clerks, but at least 72 h notice is usually required.
Section 20. Disorders Due To Physical Agents Chapter 279. Heat Disorders Topics
[General] Heatstroke Heat Exhaustion Heat Cramps
[General]
Heat disorders: Mild to grave reactions to high environmental temperature due to inadequate or inappr responses of heat-regulating mechanisms.
Exposure to high ambient temperature without efficient heat loss may lead to heat cramps, heatstroke exhaustion. Acute (eg, 3 to 4 h of strenuous effort) or prolonged (10 to 12 days) exposure to heat with excessive sweating uncompensated by fluid intake leads to dehydration, sodium and potassium deple hypovolemia. Associated vomiting and diarrhea contribute to fluid loss. Evaporation, the most importan of heat loss, depends on relative humidity: The higher the humidity, the less efficient the heat loss. Th high ambient humidity (which decreases the cooling effect of sweating) and prolonged strenuous exer (which increases heat production by muscle) increase the risk of developing heat disorders. Age, obes chronic alcoholism, debility, and many drugs (eg, anticholinergics, antihistamines, phenothiazines, num psychoactive drugs, alcohol, cocaine) increase susceptibility to heat disorders, particularly heatstroke. Heatstroke and heat exhaustion both occur in hot, humid environments, but they are markedly differen disorders (see Table 279-1).
Prophylaxis
Using common sense is best. Strenuous exertion in a very hot environment or in an inadequately vent space should be avoided, and heavy insulating clothing should not be worn. If exertion in a hot environ unavoidable, fluid and electrolytes (often lost imperceptibly in very hot, very dry air) should be replaced frequently drinking fluids slightly salty to taste (ie, near isotonic), and evaporation, which helps keep th cool, should be facilitated by wearing open mesh clothing or using fans. Thirst is a poor indicator of dehydration. During strenuous exercise, fluids should be drunk every hour regardless of thirst. Salt tab which are less desirable than lightly salted beverages and foods, should not be taken unless large am fluids are consumed. Depletion of potassium, magnesium, and calcium is hazardous only when heat e is prolonged.
Section 20. Disorders Due To Physical Agents Chapter 284. Near Drowning Topics
[General]
[General]
Ventilatory insufficiency is the most critical problem for near-drowning victims. Severe hypoxia is due t aspiration of fluid or to acute reflex laryngospasm, which may result in asphyxia without aspiration of fl Aspiration of fluid and particulate matter may cause chemical pneumonitis, damaging cells lining the a and may impair alveolar secretion of surfactant, resulting in patchy atelectasis. The perfusion of nonae atelectatic areas of the lungs leads to intrapulmonary shunting of blood, aggravating the hypoxemia; a fluid is aspirated, surfactant loss increases, and atelectasis and hypoxemia worsen. Sizable areas of atelectasis may result in stiff noncompliant lungs and respiratory failure (see Ch. 66). Respiratory acid hypercapnia can occur. A concomitant metabolic acidosis may result from tissue hypoxia. Alveolar and hypoxia can result in pulmonary and cerebral edema. Pulmonary edema due to near drowning is thoug result directly from alveolar hypoxia, analogous to high-altitude pulmonary edema (see Ch. 281); ie, it noncardiogenic. Pulmonary edema and atelectasis may coexist.
Other problems include changes in electrolytes and blood volume, which vary in magnitude depending type and volume of aspirated fluid. Seawater may cause a mild elevation of Na and Cl, but the levels a life threatening. In contrast, large quantities of fresh water can cause a profound electrolyte imbalance sudden increase in blood volume, and hemolysis. Asphyxia and ventricular fibrillation may result, caus death at the scene. Cardiac arrest, usually preceded by fibrillation, causes many of the deaths attribut drowning.
The mammalian diving reflex may allow victims of near drowning to survive long periods of submersion water. First identified in seagoing mammals, this reflex slows the heartbeat and constricts the peripher arteries, shunting oxygenated blood away from the extremities and the gut to the heart and brain. Also water, the O 2 needs of the tissues are reduced, extending the possible time of survival.
Prevention
A large meal should not be eaten shortly before swimming because it increases the risk of vomiting, a and airway obstruction. Alcohol consumption is a major risk factor for near drowning in teenagers and and should be avoided. Children must be supervised at beaches and near pools or ponds. All swimme should be accompanied by an experienced swimmer or swim only in guarded areas. Wearing flotation
Prevention
A large meal should not be eaten shortly before swimming because it increases the risk of vomiting, a and airway obstruction. Alcohol consumption is a major risk factor for near drowning in teenagers and and should be avoided. Children must be supervised at beaches and near pools or ponds. All swimme should be accompanied by an experienced swimmer or swim only in guarded areas. Wearing flotation when in boats is encouraged for all persons and required for nonswimmers and for small children, who also wear them when playing near bodies of water. Children should be taught to swim as early as poss and adults and children > 12 yr should be familiar with the basics of resuscitation. All swimming pools be adequately fenced (>= 4 ft [>= 1.2 m] in height). Infants, children, the debilitated, and the elderly sh be left unattended in bathtubs. When swimming or boating, persons with a history of a seizure disorde other medical problems should identify their problems to others and should be taught to take appropria precautions.
Treatment
The key factors that affect the chance of surviving submersion without permanent injury are duration o submersion, water temperature, the victim's age (the diving reflex is more active in children), and spee resuscitation. Survival depends more on the prompt correction of hypoxemia and acidosis (due to ven insufficiency) than on correction of electrolyte imbalance; the goal is to prevent pulmonary and cerebra due to hypoxia.
If near drowning occurs in very cold water, the victim may be hypothermic. Because of the mammalian reflex and the reduced metabolic needs associated with hypothermia, vigorous attempts should be ma resuscitate victims (especially children), even if they have been submerged for >= 1 h. Basic life suppo prompt correction of hypothermia (see Ch. 280) are important because a hypothermic heart may be le responsive to resuscitation techniques.
If the victim is apneic, mouth-to-mouth rescue breathing should be started immediately--in the water, if necessary. If heartbeat and carotid pulse cannot be detected, external (closed-chest) cardiac compres also started (see Ch. 206). Advanced cardiac life support, including intubation, is then performed expe As soon as a mechanical ventilator is available, it should be used to increase inspired O2 concentratio Electrical defibrillation and/or cardioversion may be necessary to correct dysrhythmias unresponsive to adequate ventilation and oxygenation.
If the victim dove into water, traumatic neck injury should be suspected. The victim's neck should be s in a neutral position without flexion or extension, and rescue breathing should be performed using a ja without head tilt or chin lift.
Trying to drain fresh water from the lungs wastes time because fresh water, being hypotonic, passes r into the circulation. Seawater, being hypertonic, draws plasma into the lungs, so drainage should be attempted; Trendelenburg's position may help.
All victims must be hospitalized. Resuscitation should continue during transport, regardless of the pati condition, because pulmonary injury and hypoxia may develop several hours after submersion. Consc is therefore not synonymous with recovery.
In the hospital, treatment should focus on intensive pulmonary care to achieve adequate arterial blood acid-base levels. Required measures range from simple O2 administration (for a spontaneously breath patient) to intubation and continuous mechanical ventilation (for an apneic patient). Adequate alveolar ventilation and restoration of tissue perfusion are crucial for optimizing acid-base balance during cardi in near-drowning victims. The use and timing of pharmacologic buffers are controversial. Sodium bicar IV may be considered if alveolar ventilation is adequate, because metabolic acidosis almost invariably
In the hospital, treatment should focus on intensive pulmonary care to achieve adequate arterial blood acid-base levels. Required measures range from simple O2 administration (for a spontaneously breath patient) to intubation and continuous mechanical ventilation (for an apneic patient). Adequate alveolar ventilation and restoration of tissue perfusion are crucial for optimizing acid-base balance during cardi in near-drowning victims. The use and timing of pharmacologic buffers are controversial. Sodium bicar IV may be considered if alveolar ventilation is adequate, because metabolic acidosis almost invariably accompanies tissue and cellular hypoxia. Monitoring blood gases helps determine oxygenation and ac status: whether bicarbonate should be used, whether ventilatory support should be continued, and wh inspired O2 concentrations should be. High supplemental O 2 concentrations must be continued until a blood gas studies indicate that lesser O2 concentrations are adequate.
Manual hyperinflation of the lungs is indicated to reexpand atelectatic alveoli. How frequently it is perfo based on clinical response. Standard doses of 2-agonists given by inhalation or injection help reduce bronchospasm. Because near drowning with fluid aspiration is a form of aspiration pneumonitis, cortic and antibiotics may be considered.
A patient who develops acute respiratory distress syndrome requires mechanical ventilation. Positive end-expiratory pressure (see Ch. 66) may help maintain alveolar patency, prevent alveolar collapse, a expand collapsed alveoli. Pulmonary care may be necessary for hours or days, depending on arterial b gas and pH analyses.
Fluid and electrolyte solutions are required to correct significant electrolyte imbalance. A large quantity may be extravasated into the lungs during seawater submersion, reducing blood volume and sometim lowering central venous pressure; infusion of volume expanders may be indicated. Fluid restriction is u not advisable, because the pulmonary and cerebral edema caused by hypoxia is related to direct pulm epithelial damage or osmotic gradients rather than to circulatory overload as in heart failure. RBC repla to increase the O2-carrying capacity of blood and forced diuresis to facilitate excretion of free plasma H be necessary if hemolysis is significant.
Permanent brain damage from hypoxemia and tissue hypoxia is a residual problem in some patients. Hyperventilation or hyperoxygenation in hyperbaric chambers (see Ch. 292) may be beneficial but has risks. No single drug or therapeutic modality has proved to be beneficial after global brain ischemia. Th general brain-oriented intensive care measures (in the American Heart Association's Advanced Life Su guidelines) should be followed (see Ch. 206).
Section 20. Disorders Due To Physical Agents Chapter 280. Cold Injury Topics
[General] Frostnip Frostbite Hypothermia Immersion Foot Chilblains
[General]
Cold injury (exposure): Injury due to cold causing structural and functional disturbances in small blood cells, nerves, and skin.
Susceptibility to cold injury is increased by substance abuse, exhaustion, hunger, dehydration, hypoxia impaired cardiovascular function, and contact with moisture or metal. The elderly, the very young, and intoxicated with alcohol are particularly at risk.
Preventive measures, although obvious, are often ignored. Several layers of warm clothing and protec against moisture and wind are important even when the weather does not seem to threaten cold injury and socks should be kept as dry as possible, and insulated boots that do not impede circulation shoul worn in very cold weather. A warm head covering is particularly important, because 30% of heat loss o from the head. Consuming ample fluids and food helps sustain metabolic heat production. Being alert parts becoming cold and numb and immediately warming them may prevent damage. As the body coo shivering, exertion, warm clothing, and hot drinks may prevent hypothermia.
Section 20. Disorders Due To Physical Agents Chapter 285. Injury During Diving Or Work In Compr Topics
[General] Decompression Illness Recompression
[General]
Deep-sea and scuba (self-contained underwater breathing apparatus) divers can develop medical pro due to high pressure, as can construction workers in tunnels or caissons (pressurized work areas). A p with almost any disorder that develops during or especially after exposure to high pressure may have decompression illness (arterial gas embolism or decompression sickness) and urgently needs recomp Physicians who see such patients must be alert for these problems and may seek advice from the Div Network (DAN), coordinated by the Duke University Medical Center, at any hour (919-684-8111).
High pressure at depth results from the weight of water above, just as barometric pressure on land res the weight of the air above. Pressures in diving are often expressed in units of depth or atmospheres a (atm abs). A diver at 33 ft (10 m) in seawater is exposed to a pressure of 14.7 lb/sq in (760 mm Hg, 1 higher than the barometric pressure at the surface. The total pressure at 33 ft is 2 atm abs, which is th of the water plus the barometric pressure at the surface. Every additional 33 ft of descent adds 1 atm. pressure in a caisson or tunnel (in which compressed air is used to exclude water from the work site) r the pressure of the water outside. The pressure in atm abs is lower at higher altitude--an important fac diving in lakes at high altitude.
Pathophysiology of Increased Pressure
Local differences in pressure ("squeeze"): As external pressure on the body increases with depth, the pressure of gas in the lungs and airways. If the eustachian tubes open normally (eg, by swallowing yawning), pressure in the middle ear can be kept equal to increasing external pressure. If a structural a allergic or vasomotor rhinitis, or URI prevents such equalization, the excess external pressure is exerte directly on the eardrum. The external pressure is also fully transmitted to all blood vessels of the body pressure in the middle ear space remains lower than the external pressure, capillaries in the mucosa m dilate, leak, and rupture. If edema fluid and extravasated blood do not occupy enough space to equali pressure, the eardrum may rupture (see also Barotitis Media in Ch. 84). Middle ear infection often follo injury. Squeeze may also cause injury in the paranasal sinuses, signaled by local pain or, in the sphen sinuses, by pain referred to the occiput, vertex, or frontal area. Mucosal congestion preventing equaliz pressure in the ears or sinuses may respond to local or systemic decongestants. Without free equaliza
directly on the eardrum. The external pressure is also fully transmitted to all blood vessels of the body pressure in the middle ear space remains lower than the external pressure, capillaries in the mucosa m dilate, leak, and rupture. If edema fluid and extravasated blood do not occupy enough space to equali pressure, the eardrum may rupture (see also Barotitis Media in Ch. 84). Middle ear infection often follo injury. Squeeze may also cause injury in the paranasal sinuses, signaled by local pain or, in the sphen sinuses, by pain referred to the occiput, vertex, or frontal area. Mucosal congestion preventing equaliz pressure in the ears or sinuses may respond to local or systemic decongestants. Without free equaliza pressure, continuing to dive usually produces some injury.
Local squeeze can also occur when a rigid or semirigid airspace is attached to the body. Pressure in fa masks is equalized by air from the nose, but pressure in goggles and some diving suits is not equalize sometimes causing discomfort, local hemorrhage, and tissue damage. Earplugs form a closed space i auditory canal, preventing pressure equalization, and must not be used in diving.
Vertigo can result from changes in pressure and gas volume in the middle ear by at least three differen mechanisms. (1) If the eardrum of a bareheaded diver ruptures in cold water, the results resemble tho caloric test (see Clinical Evaluation of the Vestibular Apparatus in Ch. 82): severe and potentially disas vertigo, disorientation, nausea, and vomiting. (2) Unequalized pressure in the middle ear may affect th ear via the round window, producing alternobaric vertigo, which may cause the disequilibrium sometim experienced by divers when starting to ascend. (3) Perilymph fistula, with leakage of perilymph throug round or oval window, is an uncommon but serious cause of vertigo and requires prompt surgical repa be confused with vestibular decompression sickness when vertigo develops after a dive.
Compression and expansion of gas: Boyle's law states that volume of a given mass of gas changes inversely with absolute pressure; eg, 1 L of air at the surface (1 atm abs) is compressed to 1/2 L at 33 depth (2 atm abs). The pressure in body airspaces during descent must be equalized to compensate f compression. Breathing from a diving helmet or scuba regulator compensates for compression of gas respiratory system.
Gas density increases proportionally with the pressure in atm abs, but the breathing rate and tidal volu scuba diver at depth are nearly the same as those at the surface (for comparable work). Thus, the num gas molecules respired per minute at depth increases in proportion to the pressure; eg, the number of molecules respired at 2 atm abs is twice that at the surface. Consequently, the duration of the diver's a decreases proportionately, and breathing becomes increasingly difficult at greater depths because res to gas flow in the diver's airways and in the breathing apparatus increases. Such changes can accentu overexertion, respiratory exhaustion, and general fatigue--potentially significant problems of diving eve ideal conditions.
Expansion of pulmonary gas during ascent can cause life-threatening complications. If a diver inspires single breath of air or other gas at depth and does not let it escape freely during ascent, the expanding may overinflate the lungs. Possible consequences include pneumothorax, mediastinal and subcutaneo emphysema, and arterial gas (air) embolism; gas embolism is an extreme emergency and a leading ca death among scuba divers (see below and Table 285-1).
Partial-pressure effects: The partial pressure (P) of a gas is determined by the concentration of the g by the ambient pressure; eg, the concentration of O2 in air is about 21%, and the partial pressure of O in air at surface (1 atm abs) is about 0.21 atm. The concentration of O2 in air remains the same at dep PO2 increases, reflecting the increasing pressure and compression of the gas. At 2 atm abs, the numb molecules per unit volume (density) and the PO2 are twice what they are at surface.
Inert gases (eg, N 2 , helium) are taken up in the blood and tissues whenever their partial pressure is in During ascent, when the surrounding pressure decreases, bubbles may form, causing various problem Decompression Sickness, below).
molecules per unit volume (density) and the PO2 are twice what they are at surface.
Inert gases (eg, N 2 , helium) are taken up in the blood and tissues whenever their partial pressure is in During ascent, when the surrounding pressure decreases, bubbles may form, causing various problem Decompression Sickness, below).
The physiologic effects of gases are related to their partial pressure, changing with depth. Extended e to a PO2 > 0.5 atm (equivalent to 50% O 2 at surface or 25% O 2 at 33 ft) can result in pulmonary oxyge toxicity. CNS oxygen toxicity, occurring primarily during working dives, may cause convulsions if the PO approaches or exceeds 2 atm (eg, 100% O 2 at 33 ft or 50% O 2 at 99 ft [30 m, 4 atm abs]) or even is a 1.6 atm (eg, 100% O2 at 20 ft [6 m]).
Nitrogen narcosis, which resembles alcohol intoxication, occurs when the partial pressure of N2 incre divers who breathe compressed air, this effect may become noticeable at 100 ft (30 m) or less and is g incapacitating at about 300 ft (90 m) or 10 atm abs, at which its anesthetic effect resembles that of 30% oxide at surface. Because helium lacks this anesthetic property, it is used instead of N2 to dilute O2 for diving.
During breath-hold diving and underwater swimming without a breathing apparatus, PO2 and PCO2 in gas are modified. The impulse to return to the surface and resume breathing depends largely on CO2 in the body rather than on O2 deficit. Hyperventilating before a breath-hold dive can extend time under because it blows off CO2, but it adds little to O2 stores. Thus unconsciousness from hypoxia may occu warning before arterial PCO2 rises enough to stimulate the need to breathe. Diving to significant depth breath holding elevates alveolar PO 2, allowing increased O2 uptake at depth. Thus a diver who pushe limits may lose consciousness when alveolar PO2 falls to a low level during ascent. This phenomenon probably responsible for many unexplained drownings among spearfishing competitors and others wh extensive breath-hold diving. The term shallow-water blackout is sometimes used but is best reserved original meaning: unconsciousness from CO2 buildup in rebreathing types of scuba, in which CO 2 rem depends on active chemical absorption.
Hydrostatic pressure: High-pressure neurologic syndrome is attributed to hydrostatic pressure wit reference to gas compression or partial pressures. It is characterized by neuromuscular and cerebral abnormalities, which may develop at about 600 ft (180 m) during descent. It has no evident medical importance at shallower depths.
Other Problems
Hypoxia can result if O2 in rebreathing units is displaced by an excess of N2 or another gas. Rebreathi mixtures (eg, N2 -O2 combinations other than air) requires exceptional precautions.
Carbon dioxide poisoning: On land, hyperpnea or breathlessness normally provides ample warning increased CO 2 in inspired gas. Such a response does not necessarily occur underwater, especially wh arterial PO2 and exertion are also factors. Some persons spontaneously retain CO2 during exertion be pulmonary ventilation does not increase adequately. Whatever the source, abnormally high arterial PC cause loss or impairment of consciousness at depth (shallow-water blackout), increase the likelihood o convulsions, and worsen nitrogen narcosis. The tendency to retain CO 2 must be suspected in divers w frequently have dive-related headaches or pride themselves on low air-use rates.
pulmonary ventilation does not increase adequately. Whatever the source, abnormally high arterial PC cause loss or impairment of consciousness at depth (shallow-water blackout), increase the likelihood o convulsions, and worsen nitrogen narcosis. The tendency to retain CO 2 must be suspected in divers w frequently have dive-related headaches or pride themselves on low air-use rates.
Carbon monoxide (CO) poisoning: If air in the breathing apparatus is contaminated with CO, divers become incapacitated or die (see also Ch. 292). CO poisoning should be suspected if a diver complain nausea or headache or shows weakness, clumsiness, or mental changes. Cherry-red skin is not a reli sign. Common causes of CO in divers' air are an air compressor intake placed too close to engine exh "flashing" of lubricating oil in a malfunctioning compressor. Divers' air must be tested periodically for C other contaminants.
Complicating factors: Poor visibility, currents requiring excessive effort, and cold may cause or wors medical problems during a dive. Hypothermia can develop rapidly in water; early effects may include c loss of judgment and dexterity. Cold water can trigger fatal cardiac arrhythmias in susceptible persons
Hypoglycemia is a hazard for divers with insulin-dependent diabetes and probably for those who consu excess alcohol while neglecting adequate food intake. Drugs, including prescription or illicit drugs and may have unpredictable or unanticipated effects at depth.
Evaluation of Fitness for Diving
Physicians are often asked to judge a person's fitness for diving or related pursuits. If possible, deferri recognized expert is advisable. Usually, physicians cannot bar anyone from diving and function largely advisors. They should explain unwelcome findings and their implications. Making such findings a matte record with signed acknowledgment by the person concerned is prudent. Evaluation of professional di divers with a medical history of certain disorders warrants special procedures (eg, pulmonary function stress ECG, audiometry, bone x-rays).
Present knowledge suggests that fit and healthy women, with a few possible exceptions, can dive as s men. However, some studies suggest that women are more susceptible to decompression sickness an should be more careful than men. Some evidence suggests that diving increases the incidence of birth and fetal death. Because safe limits of exposure cannot be specified, women who are or may be preg advised not to dive. Physical and psychologic fitness for diving, discussed in diving manuals and texts, has some basic requirements:
Divers must be able to take care of themselves in a wide range of conditions. Diving can involve exertion, even when no arduous activities are anticipated. Air cylinders are heavy, and current can req unexpectedly vigorous swimming. Therefore, divers should be free of significant cardiac or pulmonary and should have above-average aerobic capacity. Family history and coronary risk factors are relevan cardiac arrhythmias, including some that are accepted in other pursuits, should rule out diving. Patent ovale may allow decompression bubbles to escape filtration in the lungs and may explain some cases cerebral decompression sickness or apparent gas embolism. It should be ruled out before a person di again. Gross obesity is often associated with poor exercise tolerance and increased susceptibility to decompression sickness. Rigid age limits are unreasonable, but older divers deserve special scrutiny, especially as to cardiopulmonary fitness. Physical handicaps must be evaluated in terms of ability to a diving buddy as well as to care for self. Divers must be able to equalize pressure readily in all body airspaces. Pulmonary disorders that air trapping may cause gas embolism during ascent. Absolute contraindications include lung cysts,
decompression sickness. Rigid age limits are unreasonable, but older divers deserve special scrutiny, especially as to cardiopulmonary fitness. Physical handicaps must be evaluated in terms of ability to a diving buddy as well as to care for self.
Divers must be able to equalize pressure readily in all body airspaces. Pulmonary disorders that air trapping may cause gas embolism during ascent. Absolute contraindications include lung cysts, emphysema, active asthma, and a history of pneumothorax. A history of asthma is a concern because of an underwater attack. Chronic nasal congestion, perforated tympanic membrane, and certain otolog surgical procedures are contraindications. Diving should be avoided during respiratory infections and exacerbations of vasomotor or allergic rhinitis. Persons who habitually swallow air or have a tendency regurgitate may have problems during diving.
Divers must not be subject to impairment of consciousness, alertness, or judgment. Lapses, ev momentary, can lead to underwater mishaps endangering divers and their companions. Epilepsy, sync alcoholism, and drug abuse are incompatible with diving. Insulin-dependent diabetes is a concern bec exertion can result in hypoglycemia. Divers should not take drugs that cause drowsiness or reduce ale such drugs may also potentiate nitrogen narcosis. Emotional instability is perilous for divers and their companions. Adequate training is necessary for safe diving; courses offered by national diving organiz are widely available.

Section 9. Dental And Oral Disorders Chapter 103. Dentistry In Medicine Topics
[General]
[General]
A dentist should consult a physician when a systemic disorder is suspected, when a person's ability to withstand general anesthesia or extensive oral surgery must be evaluated, or when an emergency occ dental office.
A physician should consult a dentist when a child has abnormal growth manifested by peculiar facies, tooth eruption, or gross malformation or malalignment of teeth as well as when a patient has a cleft lip palate, a jaw fracture, an oral neoplasm, or a newly discovered lump in the neck. A prosthodontist exp in maxillofacial prostheses can help mask or compensate for congenital or acquired facial or intraoral d Other reasons for a dental consultation include obscure facial pain, unexplained swelling or cellulitis o neck that may have originated in an infected tooth, and infection of the parapharyngeal space that ma indicate an abscess of a lower posterior tooth. In FUO or a systemic infection of inapparent cause, a d cause of bacteremia should be considered.
A medical-dental consultation may be necessary to identify obscure causes of face, head, and neck p malocclusion, poorly fitting dental appliances, temporomandibular (also called temporomandibular join disorders, giant cell (temporal) arteritis, unilateral mastication, spasm of the masticatory muscles (see Myofascial Pain Syndrome in Ch. 108), occult cavities in the jawbones, and trigeminal neuralgia. Pain to the ear may arise from an inflamed gingival flap around a partly erupted mandibular third molar or fr back of the tongue in glossopharyngeal neuralgia. Conversely, percussion tenderness in several maxi teeth may result from nasal or antral disease adjacent to the root tips. Facial numbness or paresthesia be due to a neoplasm of the antrum or nasopharynx, a vascular accident, metastasis to the brain stem multiple sclerosis. However, paresthesia most commonly affects the lower lip, usually when extraction mandibular molar causes damage to the inferior alveolar nerve. Rarely, it indicates an oral neoplasm.
An oral or dental problem, as well as systemic disorders, may cause involuntary weight loss. For exam person may be unable to chew food well because of too few, loose, or painful teeth; poorly fitting dent appliances; stomatitis (see in Ch. 105); a temporomandibular disorder (see Ch. 108); or fatigue of the masticatory muscles. Masticatory fatigue may be caused by a congenital muscular or neuromuscular d in younger persons or by poor circulation in the masticatory musculature (jaw claudication) or by poorl occluding artificial dentures in older persons.
person may be unable to chew food well because of too few, loose, or painful teeth; poorly fitting dent appliances; stomatitis (see in Ch. 105); a temporomandibular disorder (see Ch. 108); or fatigue of the masticatory muscles. Masticatory fatigue may be caused by a congenital muscular or neuromuscular d in younger persons or by poor circulation in the masticatory musculature (jaw claudication) or by poorl occluding artificial dentures in older persons.
Dental Care of Patients with Systemic Disorders
All persons should practice preventive oral hygiene to minimize tooth decay and gingivitis and should h their teeth filled when decay occurs. Infections may follow dental procedures, such as tooth extraction particularly of abscessed or periodontally affected teeth. Bacteremia may also follow preparation of too surfaces for an artificial crown. Bacteria cause caries, which can kill the dental pulp and form an absce abscessed tooth is not removed (to allow drainage), the infection spreads (see Pulpitis in Ch. 106) and can result. Patients whose condition makes them prone to infection should be given appropriate antibi before periodontal treatment, including routine prophylaxis and scaling (removal of calculus), oral surg root canal therapy.
Drugs: Certain drugs, such as corticosteroids, immunosuppressive drugs, and antineoplastic drugs, in normal inflammation required for healing. As a result, hemorrhage, delayed healing, local infection, an septicemia may occur after dental procedures. When possible, such procedures should be performed for healing allowed before these drugs are given.
Hematologic disorders: Persons who have bleeding disorders should have carious teeth filled to avo subsequent extractions. Cavity preparation before filling a tooth is almost always a bloodless procedur the minimal bleeding from any gingival lacerations is controlled by pressure. However, for hemophiliac persons with related disorders, factor VIII or whichever factor is lacking should be administered before and after an extraction to avoid extensive postextraction bleeding. Performing such oral surgery in the in consultation with a hematologist is preferable. Persons with congenital bleeding disorders should re lifelong close dental supervision with preventive measures, such as topical fluoride and plastic sealant avoid extractions.
In patients with acute forms of leukemia, thrombocytopenia, or hepatitis, extractions should be delayed the condition improves or stabilizes. Spontaneous gingival bleeding or prolonged bleeding after an ext or a periodontal procedure may occur in patients with polycythemia vera or macroglobulinemia, platele disorders, severe liver disease with diminished vitamin K-associated coagulation factors, or increased fibrinolytic activity. Patients taking aspirin should discontinue it for a week before such dental procedur performed and should not resume taking it until healing occurs. The dose of an anticoagulant may hav reduced before a tooth is extracted. In patients with leukemia or agranulocytosis, infection may follow extraction despite antibiotics.
For persons on hemodialysis, dental procedures should, if possible, be performed the day after dialysi heparinization has subsided. The use of possibly nephrotoxic drugs should be minimized.
Cardiovascular disorders: After a myocardial infarction, dental procedures should be delayed for 3 m possible. Patients with lung or heart disease who require inhalation anesthesia for dental procedures s be treated in a hospital. Patients with mitral valve prolapse, congenital or rheumatic heart disease, or a prosthetic cardiac valve--all of whom are predisposed to bacterial endocarditis--and those with congen or great vessel disease should receive oral amoxicillin 2.0 g, or for children 50 mg/kg, 1 h before tooth extraction, scaling, dental implant placement, endodontic procedures beyond the root apex, and period surgery and root planing, all of which can result in bacteremia. They should also receive antibiotics be initial placement of orthodontic bands, prophylactic cleaning where bleeding is likely, and intraligamen anesthetic injections. Clindamycin should be considered for penicillin-sensitive patients.
or great vessel disease should receive oral amoxicillin 2.0 g, or for children 50 mg/kg, 1 h before tooth extraction, scaling, dental implant placement, endodontic procedures beyond the root apex, and period surgery and root planing, all of which can result in bacteremia. They should also receive antibiotics be initial placement of orthodontic bands, prophylactic cleaning where bleeding is likely, and intraligamen anesthetic injections. Clindamycin should be considered for penicillin-sensitive patients.
In some cardiovascular patients, epinephrine, used as a vasoconstrictor to potentiate the duration of lo anesthetics, may cause arrhythmias or ischemia or exacerbate hypertension. Often, its use can be avo Electrical equipment, such as a cautery, pulp tester, or dental drill, can interfere with pacemakers. Pat heart failure may be unable to tolerate the horizontal position of a dental chair, and those taking antihypertensive drugs may develop orthostatic hypotension when they arise.
Cancer: Some antineoplastic drugs (eg, doxorubicin, 5-fluorouracil, bleomycin, dactinomycin, cytosine arabinoside, methotrexate) cause stomatitis; the severity is often related to the severity of preexisting periodontal disease. Before such drugs are instituted, a cancer patient should have calculus (tartar) re Improving the health of periodontal tissue (eg, with proper toothbrushing and flossing) can reduce ging hemorrhage, tissue sloughing, oral pain, the consequent poor food intake, and the likelihood of stoma
Before radiation therapy of the oral region, patients should have any necessary oral surgery, periodon treatment, and dental restorations, with time allowed for healing. Sealants and topical fluoride should b applied because xerostomia secondary to irradiation and destruction of the salivary glands promotes c Extraction of teeth from irradiated tissues is commonly followed by osteoradionecrosis of the jaws, a catastrophic complication (see Ch. 292). Thus, extraction should be avoided, if possible, by using dent restorations, dental splints, or root canal therapy. Such patients must practice lifelong good oral hygien should use a fluoride gel and mouth rinse (after removing any partial dentures) daily and see a dentist because caries develops rapidly in irradiated patients. Viscous lidocaine may enable a patient with sen oral tissues to brush and floss the teeth. Irradiated tissue under dentures is likely to break down, so de should be checked and adjusted whenever discomfort is noted. Irradiated patients may develop muco hypogeusia as well as trismus due to fibrosis of the masticatory muscles. Trismus may be minimized b exercises, such as opening and closing the mouth widely 20 times three or four times a day.
Extracting a tooth adjacent to a carcinoma of the gingiva, palate, or antrum facilitates invasion of the a (tooth socket) by the neoplasm. Thus, it should be extracted only in the course of definitive treatment.
Immunosuppression: Persons with compromised immune systems--whether congenital or due to AID immunosuppressive drugs, or chemotherapy--are prone to severe mucosal and periodontal infections Candida sp, herpesvirus, or bacteria. The infections may be accompanied by hemorrhage, delayed he and septicemia. After a few years of immunosuppression, oral leukoplakia, mucosal dysplasia, or a ne often in an oral location, may develop. Bilateral parotid gland enlargement may be a presenting sign o (see Ch. 163). Persons with AIDS may develop Kaposi's sarcoma, hairy leukoplakia, candidiasis, apht ulcers, progressive periodontal disease, and non-Hodgkin's lymphoma. AIDS is believed to have been transmitted by deep kissing in two partners, both of whom had bleeding gingivae, allowing infectivity b contaminating the saliva and penetrating the inflamed gingivae.
Endocrine disorders: Usually, dental treatment should be postponed until the disorder is well control example, persons with hyperthyroidism may develop tachycardia and excessive anxiety. One exceptio patients with poorly controlled diabetes, for whom improved oral hygiene is vital. Such patients are pro periodontal disease and xerostomia. Even in well-controlled diabetics, oral infections should be treated promptly. When food intake is limited because of pain after oral surgery, diabetics may require adjustm insulin dosage and diet or parenteral fluids. Extractions, dental restorations, and periodontal surgery s not be performed on both sides of the mouth in one visit, to avoid undue interference with food intake.
Patients with adrenocortical insufficiency may require supplemental corticosteroids during major denta procedures, and persons receiving low-dose corticosteroid therapy may need their dose doubled on th
promptly. When food intake is limited because of pain after oral surgery, diabetics may require adjustm insulin dosage and diet or parenteral fluids. Extractions, dental restorations, and periodontal surgery s not be performed on both sides of the mouth in one visit, to avoid undue interference with food intake.
Patients with adrenocortical insufficiency may require supplemental corticosteroids during major denta procedures, and persons receiving low-dose corticosteroid therapy may need their dose doubled on th their dental appointment. Persons who have Cushing's syndrome or who are receiving corticosteroids have alveolar bone loss, delayed wound healing, and increased capillary fragility.
Neurologic disorders: Persons with Bell's palsy lose the natural cleansing action of the lip and cheek tooth surfaces of the affected side, resulting in unilateral decay unless oral hygiene is scrupulous and and sealant treatments are repeated. Persons with convulsive disorders should be fitted with nonremo small dental appliances that cannot be swallowed or aspirated. Persons with appreciable upper extrem weakness or tremor and some with arthritis of the upper limbs cannot maintain optimal oral hygiene un their caregivers are very conscientious. Consequently, unexplained fever may have an oral basis.
People with obstructive sleep apnea can often benefit from a removable dental appliance that position mandible anteriorly so the tongue cannot block the airway (see Ch. 173).
Allergies: Persons with allergies may, despite interrogation, receive an offending antibiotic, local anes other drug during dental treatment.
Gastrointestinal disorders: Because strains of Helicobacter pylori isolated from saliva and dental pla generally identical to those isolated from the stomach, the mouth may be a source of reinfection.
Orthopedic disorders: People with joint replacements, particularly during the first 2 yr after the proce may be at risk of joint infection after extraction or root canal. Prophylactic antibiotics are advisable.
Obstetrics: Pregnant women with severe periodontal disease are more likely to deliver preterm low-birth-weight babies. Whether this can be prevented by treating the oral problem during pregnancy unknown.
Oral Findings in Systemic Disorders
Although abnormal taste sensations may be due to psychiatric disorders, local causes should alway sought. A bitter taste may indicate pus originating from a periodontal or alveolar abscess; a salty taste indicate bleeding or seepage of tissue fluid from beneath poorly fitting dentures or from inflamed perio tissues into the normally sodium-poor oral environment. A sour taste may be caused by an electrolytic between adjacent fillings of dissimilar metals. When such underlying dental problems are corrected, th symptom disappears. Persons receiving gold compounds for RA may complain of a metallic taste, whi be a prelude to stomatitis. An unpleasant, sweet taste may indicate small cell carcinoma of the lung.
The most severe xerostomia (dryness of the mouth) occurs in Sjgren's syndrome (see Ch. 50). Xero may also be caused by certain drugs, particularly diuretics and anticholinergics; by salivary gland disor dehydration; or by mouth breathing. If feasible, giving a drug that causes xerostomia before bedtime--b the patient is unaware of the dryness during sleep--may reduce daytime symptoms. Because xerostom prevent the desired dissolution of sublingual nitroglycerin tablets, a few drops of water should be sippe taking the drug. Oral dryness occurs with the Eaton-Lambert syndrome (a rare cancer-associated diso which acetylcholine release is decreased at nerve endings in skeletal muscles and in salivary glands. Appreciable tooth decay is common among persons with xerostomia, such as patients with poorly con diabetes, because of reduced salivary flow. Because saliva aids denture retention, a complaint of poor dentures may indicate xerostomia, as well as bony changes as occur with acromegaly, Paget's diseas jaw tumor.
prevent the desired dissolution of sublingual nitroglycerin tablets, a few drops of water should be sippe taking the drug. Oral dryness occurs with the Eaton-Lambert syndrome (a rare cancer-associated diso which acetylcholine release is decreased at nerve endings in skeletal muscles and in salivary glands. Appreciable tooth decay is common among persons with xerostomia, such as patients with poorly con diabetes, because of reduced salivary flow. Because saliva aids denture retention, a complaint of poor dentures may indicate xerostomia, as well as bony changes as occur with acromegaly, Paget's diseas jaw tumor.
Xerostomia interferes with speech and swallowing, causes fetid breath, and, because the reduced sali no longer washes away bacteria, makes oral hygiene difficult to maintain. Patients with xerostomia sho avoid decongestants and antihistamines and pay fastidious attention to oral hygiene. Sipping sugarles frequently, chewing xylitol-containing gum, and using a saliva substitute containing carboxymethylcellu a mouthwash may help, as may pilocarpine 5-mg tablets tid (after ophthalmologic and cardiorespirator contraindications are excluded).
Slight facial asymmetry is universal. It may be due to preferential chewing on one side causing unilat enlargement of the masticatory muscles, differences in the contour of the dental arches or in angulatio teeth on one side compared with the other, or a combination of these. Marked facial asymmetry occur persons with lipodystrophy, hemiatrophy or hemihypertrophy of the face, or a congenitally absent cond the mandible. Because of the psychologic trauma associated with facial malformation, the patient shou referred for possible facial surgery.
Children with congenital craniofacial deformities frequently have septal defects of the heart or transpos great vessels. Occlusal abnormalities often develop in persons with craniofacial skeletal disorders. Pe with orofacial dyskinesia, sometimes associated with tardive dyskinesia, may benefit from correcting ja relationships, even if malocclusion is due to poorly fitting complete dentures. In such cases, replacing dentures should be considered.
Once formed, teeth are never remodeled by systemic influences, only by local ones. So, the examiner find defects in tooth form, calcification, or color (see Ch. 106), suggesting childhood exanthems, developmental disorders, or endocrinopathies. Hypopituitarism or hypothyroidism can delay the eruptio teeth.
Rampant caries of deciduous teeth frequently indicates that the teeth were in prolonged contact with sweetened infant formula, perhaps while the infant napped (nursing bottle caries). A metabolizable sugar-based vehicle should not be used for oral drugs regularly given to children, to minimize the incid caries. Development of rampant caries after childhood may indicate regular use of marijuana, which is accompanied by a craving for sweets and inattention to oral hygiene. Autistic children love sweets and poor oral hygiene so they have severe caries. Caries at the gumline, particularly when the area is stain brown, suggests the use of snuff (smokeless tobacco).
Rarely, no or minimal tooth decay indicates hereditary fructose intolerance, characterized by an aversi sweets. Shed deciduous teeth can be analyzed for lead content for epidemiologic studies of lead poiso
The color of soft tissues can reflect anemia, polycythemia, cyanosis, or jaundice. An examiner looks generalized inflammation (stomatitis) and localized areas of inflammation, ulceration, petechiae, or thic Darkly pigmented areas may be a racial characteristic or pigmented nevi or may indicate Addison's dis very rarely, melanoma, particularly if on the gingiva or palate. Violaceous lesions of Kaposi's sarcoma common oral finding in AIDS.
Development of keratotic lichenoid patches in the oral mucosa of an organ transplant recipient may be sign of graft-vs.-host disease. Palatal petechiae may result from infectious mononucleosis, endocardit dyscrasias, or oral sex. Acute uvulitis may occur with acute epiglottitis, a potentially lethal condition.
common oral finding in AIDS.
Development of keratotic lichenoid patches in the oral mucosa of an organ transplant recipient may be sign of graft-vs.-host disease. Palatal petechiae may result from infectious mononucleosis, endocardit dyscrasias, or oral sex. Acute uvulitis may occur with acute epiglottitis, a potentially lethal condition.
Neurologic disorders may have oral signs. For example, if the soft palate does not rise when a person "ah," the patient may be a wind instrument player who has "lost his seal" (ie, a temporary paralysis of t palate) or may have pathology affecting the glossopharyngeal nerve, often where it exits the base of th Fasciculations of the tongue occur in progressive bulbar palsy.
Local and systemic infections may have an oral origin. For example, aspiration of fragments of teeth o can cause lung abscess, and persons who dissolve illicit drugs in saliva before injecting them IV may disseminate oral bacteria systemically.
Oral Changes in the Elderly
With aging, changes in the oral tissues occur. Resting salivary secretion diminishes, sometimes exace by drugs, although meal-stimulated salivary flow is usually adequate to form a bolus. The flattened cus worn teeth and weakness of the masticatory muscles may make chewing tiresome, impairing food inta of bone mass in the jaws (particularly the alveolar portion), dryness of the mouth, thinning of the oral m and impaired coordination of lip, cheek, and tongue movements may make denture retention progress difficult. Additionally, the taste buds become less sensitive, so the elderly may add abundant seasonin particularly salt (which is deleterious for many of them), or they may desire very hot foods for more tas sometimes burning the often atrophic oral mucosa. In the elderly, gingival recession exposes the dent adjacent to the crown, making root caries common.

Section 9. Dental And Oral Disorders Chapter 106. Teeth And Periodontium Topics
[General] Caries Pulpitis Malocclusion Gingival Disorders Periodontitis
[General]
A detailed examination of the teeth and periodontium may not be a routine part of a physician's exami Yet, all health care providers should know certain aspects of it. (See also Table 256-5.)
The common numbering system for permanent teeth uses numbers 1 to 32; it starts at the maxillary rig molar (#1), goes sequentially around to the maxillary left third molar (#16), drops down to the mandibu third molar (#17), and continues around to the mandibular right third molar (#32). Deciduous teeth are identified using letters A to T. Another method identifies teeth in each quadrant of the mouth (see Fig. Tooth anatomy is shown in Fig. 106-2. Pain felt when teeth are tapped with a tongue depressor suggests extensive caries (tooth decay) or periodontal disease.
Loose teeth usually indicate severe periodontal disease but can be caused by bruxism or trauma, whi damage otherwise normal periodontium. Rarely, teeth become loose when alveolar bone is eroded by underlying mass (eg, ameloblastoma, eosinophilic granuloma of histiocytosis X). A tumor or systemic c alveolar bone loss, such as diabetes mellitus, hyperparathyroidism, osteoporosis, or Cushing's syndro should be suspected when teeth are loose and heavy plaque and calculus are absent.
Calculus (calcified plaque, tartar), when present, is deposited predominantly on the buccal surfaces o maxillary molars near the parotid duct orifices and on the lingual surfaces of the mandibular anterior te the submandibular and sublingual duct orifices.
Bruxism (clenching or grinding of teeth) can abrade and eventually wear down dental crowns, and tee loosen. Most of the grinding and clenching occurs during sleep, so the patient may be oblivious to it, b members may notice. Treatment requires that the patient consciously overcome the habit while awake perhaps with the help of mild anxiolytics and plastic mouthpieces (night guards) that cover the teeth of
the submandibular and sublingual duct orifices.
Bruxism (clenching or grinding of teeth) can abrade and eventually wear down dental crowns, and tee loosen. Most of the grinding and clenching occurs during sleep, so the patient may be oblivious to it, b members may notice. Treatment requires that the patient consciously overcome the habit while awake perhaps with the help of mild anxiolytics and plastic mouthpieces (night guards) that cover the teeth of jaw, preventing occlusal contact. The latter are also used during sleep.
Attrition (wearing of biting surfaces) can be caused by an abrasive diet or by the wear that accompan aging, but it usually indicates bruxism. Attrition makes chewing less effective, and the diminished enam exposes the underlying dentin (which is sensitive to touch and temperature changes), causing noncari teeth to become painful. A dentist can desensitize such teeth or restore the dental anatomy by placing or onlays on badly worn teeth.
Trauma to a tooth may be obvious or difficult to recognize. A dislodged tooth or tooth fragment may be embedded at another site where it may be located radiographically. If a missing tooth cannot be found and abdominal x-rays should be taken to determine whether it was aspirated or swallowed. Injuries ma during contact sports; for example, a maloccluded (malpositioned) incisor may be struck and chipped. However, the use of athletic mouth guards has greatly reduced trauma to the teeth. Maxillary incisor fr are common in children with neurologic disorders, who often fall and do not extend their arms to break impact. If several teeth are fractured and the history does not explain the physical findings, child abuse be considered. A torn labial frenum, which attaches the lip or buccal mucosa to the alveolar mucosa o used to be considered an indication of abuse--the result of force-feeding--but many other causes are p
Defects in tooth form may indicate a developmental or endocrine disorder. In congenital syphilis, the are constricted at the incisal third, producing a pegged or screwdriver shape, with a notch in the cente incisal edge (Hutchinson's incisors); the first molar is dwarfed, with a small occlusal surface and rough lobulated, often hypoplastic enamel (mulberry molar). In congenital ectodermal dysplasia, teeth are ab conical so that from childhood, partial dentures are needed. Dentinogenesis imperfecta, an autosomal dominant disorder, produces abnormal dentin that is dull bluish brown and opalescent and does not cu the overlying enamel adequately. Such teeth cannot withstand occlusal stresses and rapidly become w Congenitally narrow lateral incisors are not associated with systemic disease. Pituitary dwarfs and per with congenital hypoparathyroidism have small dental roots; persons with gigantism have large ones. Acromegaly produces hypercementosis of the roots as well as enlargement of the jaws, so teeth beco widely spaced.
Defects in tooth color must be differentiated from the darkening or yellowing that occurs with age an particularly with smoking. A tooth may appear gray because of pulpal necrosis, usually due to extensiv penetrating the pulp, or because of hemosiderin deposited in the pulp after trauma, which may or may have devitalized the pulp. A child's teeth darken appreciably and permanently after even short-term us tetracyclines by the mother during the second half of pregnancy or by the child during odontogenesis ( development), until age 9. Minocycline can cause permanent discoloration of fully formed teeth in adu also darkens bone, apparent as discoloration of the overlying gingiva and mucosa if they are thin. In u light, affected teeth fluoresce a color characteristic of the specific tetracycline given, rather than white. congenital porphyria, both the deciduous and permanent teeth are brown but fluoresce red from the pi deposited in the dentin. Congenital hyperbilirubinemia causes a yellowish tooth discoloration.
Defects in tooth enamel may be caused by the abnormal calcium metabolism associated with rickets results in enamel hypoplasia. A rough, irregular band forms in the enamel when abnormal calcification Any prolonged febrile illness during odontogenesis can produce a permanent narrow zone of chalky, p enamel, visible after the tooth erupts. Thus, the age at which the disease occurred and its duration can estimated from the location and height of the band. Amelogenesis imperfecta, an autosomal dominant disease, causes severe enamel hypoplasia. Chronic vomiting (as in bulimia) decalcifies the dental crow primarily the lingual surfaces of the lower anterior teeth. Chronic snorting of cocaine can result in wide
results in enamel hypoplasia. A rough, irregular band forms in the enamel when abnormal calcification Any prolonged febrile illness during odontogenesis can produce a permanent narrow zone of chalky, p enamel, visible after the tooth erupts. Thus, the age at which the disease occurred and its duration can estimated from the location and height of the band. Amelogenesis imperfecta, an autosomal dominant disease, causes severe enamel hypoplasia. Chronic vomiting (as in bulimia) decalcifies the dental crow primarily the lingual surfaces of the lower anterior teeth. Chronic snorting of cocaine can result in wide decalcification of teeth, because in saliva, the drug dissociates into a base and hydrochloride, often ab when the user massages the oral mucosa to hasten drug absorption. Treatment of all these conditions consists of extensive restorative dentistry, particularly artificial crowns, after the cause is removed or c Swimmers who spend much time in overchlorinated pools lose considerable amounts of enamel. If the water is buffered, brown calculus deposits form; they can be removed by dental cleanings.
Fluorosis (mottled enamel) may develop in children who drink water containing > 1 ppm of fluoride du period of tooth development. The likelihood of fluorosis increases with concentration of fluoride and am fluoridated water ingested. Enamel changes range from irregular whitish opaque areas to severe brow discoloration of the entire crown with a roughened surface. Such teeth, although unsightly, are highly r to dental caries. Mild discoloration can be treated by bleaching with 10% carbamide peroxide. More se discoloration requires placing resin or porcelain veneers or crowns on the teeth.
Rampant caries in deciduous teeth suggests prolonged contact with a sweetened infant formula, typ when an infant goes to bed with a bottle (baby or nursing bottle caries). Premature loss of such teet to result in orthodontic problems as the adjacent teeth shift, preventing eruption of their permanent suc To help prevent caries of deciduous teeth, caregivers should not give a child a nursing bottle containin anything other than water at bedtime after teeth have erupted.
Atrophy of the alveolar process (senile atrophy) begins as soon as teeth are lost. Alveolar bone res diminishing the stability of an artificial full denture, particularly a lower one. Oral surgical procedures ca enlarge the alveolar ridge, or dental implants can be used instead of dentures.

Section 9. Dental And Oral Disorders Chapter 104. Oral Examination Topics
[General]
[General]
Examination of the oral cavity is part of every general physical examination (see also Ch. 105). Oral fin many systemic diseases are unique, are sometimes pathognomonic, and may be the first sign of the d (see Ch. 103). Early detection of oral cancer may be possible.
A dental history is obtained first. It may indicate a particular dental problem or neglect of dental care. A complaint of difficulty in chewing food suggests insufficient teeth for proper mastication, loose or painf poorly fitting dental appliances, or disorders of the temporomandibular joint or the masticatory muscles bleeding after brushing suggests mild gingivitis; frequent, spontaneous, or profuse bleeding may indica blood dyscrasia. Recurring oral infections may indicate diabetes mellitus (the most common cause), agranulocytosis, neutropenia, leukemia, immunoglobulin defects, or disorders of leukocyte function. Immunosuppressed persons may experience painful reactivation of oral herpes simplex or other infect with pain, oral ulcerations, and consequent interference with food intake.
A thorough evaluation requires good illumination, a tongue blade, gloves, and a gauze pad. A dental o laryngeal mirror, if available, is helpful.
The examiner initially looks at the face for appreciable asymmetry, skin lesions, and other abnormalitie as restricted movement during speech, as occurs in scleroderma or acromegaly. Numerous congenita syndromes produce characteristic facies. For example, a very thin upper lip suggests the fetal alcohol syndrome or Prader-Willi syndrome. Trauma in youth, particularly blunt trauma to the point of the chin damage growth centers in the condyles and lead to unilateral or bilateral impairment of mandibular gro Idiopathic hypertrophy of one or both sides of the mandible or other parts of the face may distort the fa may acromegaly or a salivary gland or jaw tumor. If the posterior teeth or dental prostheses are missin cheeks may be sunken, producing a prematurely aged or cachectic appearance. One or both cheeks m appear swollen due to cherubism, parotitis, Sjgren's syndrome, tumor, an excessively thick denture fl cellulitis from an abscessed tooth. Multiple basal cell carcinomas on the face may indicate the nevoid cell carcinoma syndrome, which alerts the examiner to look for multiple odontogenic keratocysts on x-
The lips are palpated. With the patient's mouth open, the buccal mucosa and vestibules are examined tongue blade; then the hard and soft palates, uvula, and oropharynx are viewed. The patient is asked extend the tongue as far as possible, exposing the dorsum, and to move the extended tongue as far a
cellulitis from an abscessed tooth. Multiple basal cell carcinomas on the face may indicate the nevoid cell carcinoma syndrome, which alerts the examiner to look for multiple odontogenic keratocysts on x-
The lips are palpated. With the patient's mouth open, the buccal mucosa and vestibules are examined tongue blade; then the hard and soft palates, uvula, and oropharynx are viewed. The patient is asked extend the tongue as far as possible, exposing the dorsum, and to move the extended tongue as far a possible to each side, so that its posterolateral surfaces can be seen. If a patient does not extend the far enough for the circumvallate papillae to be seen, the examiner uses a gauze pad to grasp the tip o tongue and extend it to the desired position. The tongue is then raised to view the ventral surface and of the mouth. The teeth and gingivae should be viewed.
With gloved hand, the examiner palpates the vestibules and the area over the roots of the teeth with o and the cheek with two fingers. The index finger of the dominant hand is inserted inside the mouth, an contents of the floor of the mouth are compressed gently between it and the fingers of the other hand. make palpitation more comfortable, the examiner asks the patient to relax the mouth, keeping it open enough to allow access. The cervical lymph nodes should also be palpated.
The temporomandibular joint (TMJ) is assessed by looking for jaw deviation during opening and by pa the head of the condyle, anterior to the ear (see Ch. 108). The examiner then places his little fingers intrameatally while the patient opens widely and closes three times. The patient should be able to com open wide enough to fit three fingers between the incisors. Trismus, the inability to open the mouth, m indicate scleroderma, arthritis, ankylosis of the TMJ, dislocation of the temporomandibular disk, tetanu tonsillar abscess. Unusually wide opening suggests subluxation or type III Ehlers-Danlos syndrome.
Malodor of exhaled breath may have many causes (see also Halitosis in Ch. 21). Fetor oris originates mouth. Most commonly, it is caused by volatile sulfur compounds resulting from bacterial metabolism, particularly when oral hygiene is poor or xerostomia is present. Halitosis may follow eructation from the or may be caused by systemic metabolic conditions--eg, an acetone odor with diabetes mellitus, a mo with liver failure, and a urinous odor with kidney failure. Halitosis may also originate from the nose, sin nasopharynx, and lungs, particularly when infections or necrotic neoplasms are present. A patient who breath frequently smells of mouthwash may be masking halitosis or may have parosmia (a perversion sense of smell, usually involving smelling unpleasant odors that do not exist).

Section 9. Dental And Oral Disorders Chapter 107. Dental Emergencies Topics
[General] Toothache/Infection Postextraction Problems Fractured And Avulsed Teeth Fractures Of The Jaw And Contiguous Structures Dislocated Mandible
[General]
Emergency dental treatment by a physician is sometimes required when a dentist is unavailable. A de should be consulted as soon as possible.
Section 9. Dental And Oral Disorders Chapter 105. Disorders Of The Oral Region Topics
[General] Inflammation Of The Oral Mucosa Neoplasms
[General]
The skin and mucosa of the lips are demarcated by the vermilion border. The mucosa seen on viewin face is keratinized and dry; the mucosa of the inner aspect of the lips is nonkeratinized and moist.
The buccal mucosa, including the vestibule and nonkeratinized alveolar mucosa, is usually smooth, m and pink. Innocuous entities, such as linea alba (a thin white line, typically bilateral, on the level of the plane, where the cheek is bitten), Fordyce's granules (which also occur on the lips), and white sponge (thick white folds over most of the buccal mucosa, except the gingivae) can be seen in this region. Rec them avoids needless biopsy and apprehension. The orifices of the parotid ducts are opposite the max first molar on each side.
An abnormal distribution of keratinized and nonkeratinized oral mucosa demands attention. A patient w complete or partial dentures is asked to remove them so that the underlying soft tissues can be seen. Normally, keratinized epithelium occurs on the facial aspect of the lips, dorsum of the tongue, hard pa gingiva around the base of dental crowns and overlying the alveolar bone covering part of the roots of Nonkeratinized mucosa occurs over alveolar bone furthest from the crowns of teeth, inside the lips, in cheeks, on the sides and undersurface of the tongue, on the soft palate, and on the floor of the mouth Keratinized tissue that occurs in normally nonkeratinized areas appears white. This abnormal condition leukoplakia, requires a biopsy because it may be precancerous.
The palate is involved in normal vocal resonance and articulation. The anterior hard palate is the site incisive papilla behind the central incisors. Behind it are the rugae, firm ridges that keep food from slip the tongue moves beneath it. The boneless soft palate should rise symmetrically when a patient says
The uvula hangs in the midline at the far end of the soft palate. It varies greatly in length. A long uvula excess velopharyngeal tissue is associated with snoring and in some persons may predispose to obst sleep apnea (see Sleep Apnea Syndromes in Ch. 173).
The dorsal surface of the tongue is covered by numerous whitish elevations, the filiform papillae. Inter
The uvula hangs in the midline at the far end of the soft palate. It varies greatly in length. A long uvula excess velopharyngeal tissue is associated with snoring and in some persons may predispose to obst sleep apnea (see Sleep Apnea Syndromes in Ch. 173).
The dorsal surface of the tongue is covered by numerous whitish elevations, the filiform papillae. Inter among them are isolated reddish prominences, the fungiform papillae, occurring mostly on the anterio the tongue. The circumvallate papillae, which are considerably larger, lie posteriorly. They do not proje the tongue but are surrounded by a trench. The foliate papillae appear as a series of parallel slitlike fo the lateral borders of the tongue, near the anterior pillars of the fauces. They vary in length and can ea confused with lesions. Lingual tonsils may be considered components of Waldeyer's ring and are seen posteriorly at the back of the tongue.
The lingual nerves (branches of the 5th cranial nerves) supply general sensory innervation, and the ch tympani fibers (of the 7th cranial nerves) innervate the taste buds of the anterior 2/3 of the tongue. Be circumvallate papillae, the glossopharyngeal nerves (9th cranial nerves) provide the sensations of touc taste. Nerve integrity can be determined by testing taste on both sides of the dorsum of the tongue wit salt, vinegar, and quinine. Sweet and salty taste receptors are located at and near the tip; sour, on the and bitter, on the most posterior part of the tongue. The hypoglossal nerves (12th cranial nerves) cont movement of the tongue.
On each side, the floor of the mouth is marked anteriorly near the midline by the opening of Wharton which drains the ipsilateral submandibular and sublingual glands.
The major salivary glands are the paired parotid, submandibular, and sublingual glands. Most oral m surfaces contain many minor mucus-secreting salivary glands. Abnormal sublingual and submandibula can be felt when the floor of the mouth is palpated bimanually. A parotid enlargement occurs preauricu overlying the mandibular ramus.
Many disorders can affect the oral region (see Table 105-1 and elsewhere in The Manual). Benign les the oral region are often bilateral; bilateral oral cancers are rare. Cleft lip and cleft palate are discussed 261.
Section 9. Dental And Oral Disorders Chapter 108. Temporomandibular Disorders Topics
[General] Internal Joint Derangement Myofascial Pain Syndrome Agenesis Of The Jaw Condylar Hypoplasia Condylar Hyperplasia Ankylosis Arthritis
[General]
Temporomandibular disorders: Pain in the jaw and face, often in or around the temporomandibular join including the masticatory and other muscles, fascia, or a combination of areas.
Temporomandibular disorders are typically multifactorial in origin. The discomfort a patient feels may o not be related to pathosis within the joint. These disorders are diagnosed only if a patient has pain or l of movement sufficient to force him to seek professional care. Comfortable patients, regardless of wha be found radiographically or during incidental physical examination, are not considered to have a temporomandibular disorder. Otherwise, most persons would have the disorder during at least part of
Commonly, temporomandibular disorders cause or reflect disturbed movement of the mandibular cond the glenoid fossa or against the articular cartilaginous disk (the cushion between them). Disorders of th temporomandibular joint (TMJ) itself must be distinguished from the many conditions that mimic them Table 108-1) and can often be identified when the pain they cause is exacerbated by finger pressure o joint when the mouth is opened.
The patient is asked to point to and describe which areas hurt. Each of the major muscle groups involv mastication and the occipital muscles are palpated for general tenderness and trigger points (spots tha pain to another area). The patient is observed opening the mouth as wide as is comfortable. With the of the maxillary and mandibular central incisors (typically in the midline) lined up against a vertical stra edge, the patient is observed while opening and closing the mouth. Typically, the mandibular midline d toward the painful side. The joint is palpated and auscultated during opening and closing. Condylar mo best be palpated by placing the fifth finger of each hand intrameatally and exerting very gentle forward
mastication and the occipital muscles are palpated for general tenderness and trigger points (spots tha pain to another area). The patient is observed opening the mouth as wide as is comfortable. With the of the maxillary and mandibular central incisors (typically in the midline) lined up against a vertical stra edge, the patient is observed while opening and closing the mouth. Typically, the mandibular midline d toward the painful side. The joint is palpated and auscultated during opening and closing. Condylar mo best be palpated by placing the fifth finger of each hand intrameatally and exerting very gentle forward pressure as the patient moves the jaw.
Section 21. Special Subjects Chapter 286. General Principles Of Medical Gen Topics
[General] Inheritance Of Single-Gene Defects Multifactorial Inheritance Nontraditional Inheritance Chromosomal Disorders Mitochondrial DNA Abnormalities Cancer Genetics Immunogenetics Forensic Genetics Genetic Therapy
[General]
Human development depends on genetic and environmental factors. A person's genetic composition ( is established at conception. The genetic information is carried in the DNA of the chromosomes and mitochondria. Most diseases probably have some genetic component, the extent of which varies. Environmental factors may alter genetic information through mutation or other structural alteration and affect classic genetic disorders (eg, dietary management in phenylketonuria, drugs for hypercholestero
DNA's capacity to replicate constitutes the basis of hereditary transmission. DNA also provides the ge code, which determines cell development and metabolism by controlling RNA synthesis. The sequenc elements (nucleotides) that comprise DNA and RNA determines protein composition and thus its funct
Genes (between 60,000 and 100,000 in humans) are carried by the chromosomes (rodlike structures cell nuclei) and mitochondria (circular structures in cell cytoplasm present in multiple copies). In human somatic (nongerm) cells normally have 46 chromosomes, occurring as 23 pairs. Each pair consists of chromosome from the mother and one from the father. One pair, the sex chromosomes, determines a sex. Women have two X chromosomes in every somatic cell nucleus, whereas men have one X and o chromosome (ie, heterologous chromosomes). The X chromosome carries genes responsible for man hereditary traits, whereas the small, differently shaped Y chromosome carries the genes that initiate m determination. The remaining 22 chromosome pairs, the autosomes, are usually homologous (ie, iden size, shape, and position and number of genes). Germ cells (egg and sperm) undergo meiosis, which the number of chromosomes to 23--half that of somatic cells (46)--so that when an egg is fertilized by at conception, the normal number of chromosomes is reconstituted. In meiosis, the genetic information inherited from a person's mother and father is recombined through crossing over or exchange between homologous chromosomes.
determination. The remaining 22 chromosome pairs, the autosomes, are usually homologous (ie, iden size, shape, and position and number of genes). Germ cells (egg and sperm) undergo meiosis, which the number of chromosomes to 23--half that of somatic cells (46)--so that when an egg is fertilized by at conception, the normal number of chromosomes is reconstituted. In meiosis, the genetic information inherited from a person's mother and father is recombined through crossing over or exchange between homologous chromosomes.
Genes, the basic units of heredity, are arranged linearly within the DNA along the chromosomes; each has a specific location (locus) or position on the chromosomes. The number and arrangement of loci o homologous chromosomes are usually identical. However, the structure of a specific gene may have m variations (polymorphisms) without causing disease. The specific nucleotide sequence of the genes th occupy the two homologous loci along the two chromosomes of a pair are called alleles. The two allele the one inherited from the mother and the one inherited from the father) may have slightly different nu sequences or may be the same. A person with a pair of identical alleles for a particular gene is a homo a person with a pair of dissimilar alleles is a heterozygote.
If a trait or disorder occurs when only one allele is abnormal, the disorder is said to be dominant. A dis said to be recessive if it occurs only when both alleles at the loci on both chromosomes are abnormal. genes are located in the mitochondrial DNA (see below). Many copies of mitochondrial DNA are prese cytoplasm and may have the same DNA structure (homoplasmy) or different structures (heteroplasmy
There are three types of genetic disorders: Mendelian, or single-gene, mutations are inherited in recog patterns; multifactorial conditions involve > 1 gene and environmental factors interacting in ways that a always clearly recognizable but that have been described by observation (empirically); and chromosom abnormalities include structural defects and deviations from the normal number (see Ch. 247). More re mitochondrial and nontraditional patterns of inheritance have been recognized.
Humans vary phenotypically and genotypically. Heterogeneity results from different alleles and mutatio the multiple genes, which are part of almost all biochemical pathways. Mutations in different parts of a may cause different disorders. For instance, mutations in different locations along the gene for one typ collagen can produce tall stature, arthritis, and deafness or lethal dwarfism. More than 60 specific cau congenital deafness have been identified; some are genetic (involving nuclear and mitochondrial gene whereas others result from rubella virus or other environmental agents. Concern about the teratogenic of drugs taken during pregnancy is growing. For instance, women who consume alcohol during pregna at increased risk of having infants with mental retardation and behavioral disturbances, intrauterine gro retardation, and congenital malformations (see Fetal Alcohol Syndrome under Metabolic Problems in t Newborn in Ch. 260).
Thus, phenotypically similar conditions may be due to mutations in different genes, nongenetic factors To establish the cause of the person's problem and best determine the risk to future offspring, the phy must take a thorough family history and inquire about possible environmental factors, keeping heterog mind. Identifying the specific causative agent is not always possible.
Powerful molecular genetic techniques have made it possible to study the structure of DNA and to trac changes during development and in different tissues. The structure of a gene is complex and includes elements (eg, promoters, enhancers), expressed elements (exons), intervening elements that are not expressed (introns), and a termination signal. The configuration of the DNA of a gene in a tissue that d express the gene is likely to be different (eg, methylated, condensed) than that of a gene that is active expressing.
The human genome project is a large collaborative international project that began in 1991. The goa map specific genes to specific locations on chromosomes and determine their exact nucleotide seque genome of a human) by 2005. Mapping can be done through family studies, using the known location markers, and involves isolating small stretches of DNA and sequencing the genes and the other DNA area.
The human genome project is a large collaborative international project that began in 1991. The goa map specific genes to specific locations on chromosomes and determine their exact nucleotide seque genome of a human) by 2005. Mapping can be done through family studies, using the known location markers, and involves isolating small stretches of DNA and sequencing the genes and the other DNA area.
Genetic Screening
Genetic screening may be used in populations at risk for a particular genetic disorder. Genetic screeni only appropriate when the natural history of the disease is understood; the screening tests are valid an reliable; sensitivity, specificity, false-negative, and false-positive rates are acceptable; and effective the available. A sufficient benefit must be derived from a screening program to justify its cost.
Heterozygote screening: Screening a susceptible population (eg, Tay-Sachs disease in Ashkenazic sickle cell anemia in blacks, thalassemia in various ethnic groups) may be appropriate because of the frequency of heterozygotes. Heterozygote screening can determine if a person is a carrier for a specifi disorder. If the partner is also a heterozygote, the couple is at risk of having an affected child. Screenin the couple to make informed reproductive choices.
Presymptomatic genetic screening: Presymptomatic genetic screening may be appropriate for pers a family history of a dominantly inherited disorder (eg, Huntington's disease, breast cancer). Identifying definite carrier of the genetic disorder may allow the patient to make informed decisions (eg, monitorin case of breast cancer, reproductive choices in the case of Huntington's disease or adult polycystic kidn disease).
Prenatal diagnosis: Amniocentesis, chorionic villus sampling, umbilical cord blood sampling, materna sampling, maternal serum screening, and fetal visualization with ultrasound and radiography are usefu prenatal diagnosis (see Ch. 247). Common reasons for prenatal screening include maternal age > 35 family history of a condition that can be diagnosed by prenatal techniques, abnormal maternal serum screening results, and certain complications of pregnancy.
Newborn screening: Screening for phenylketonuria, galactosemia, and hypothyroidism in the newbor prophylaxis (ie, special diet or replacement therapy) to be initiated early enough to prevent severe complications.
Construction of a Family Pedigree
The family history is often key to determining genetic risk. It is most easily recorded in a family pedigre tree), which uses conventional symbols (see Fig. 286-1). The pedigree provides a ready view of proble illnesses within the family and facilitates analysis of inheritance patterns, including the range and degr affliction and variation among persons and generations. Some familial disorders with identical phenoty have several patterns of inheritance. For example, cleft palate can have an autosomal dominant, auto recessive, or X-linked recessive pattern of inheritance, or it may be multifactorial (ie, familial but with n precisely predictable inheritance pattern).
Generations in the family pedigree are numbered with Roman numerals (see Figs. 286-2 to 286-5,) wi generations at the top and the most recent at the bottom. Within each generation, persons are numbe left to right with Arabic numerals. Siblings are usually listed by age, with the oldest on the left. Thus, ea member of the pedigree can be identified by two numbers (eg, II, 4). A spouse is also assigned an ide
precisely predictable inheritance pattern).
Generations in the family pedigree are numbered with Roman numerals (see Figs. 286-2 to 286-5,) wi generations at the top and the most recent at the bottom. Within each generation, persons are numbe left to right with Arabic numerals. Siblings are usually listed by age, with the oldest on the left. Thus, ea member of the pedigree can be identified by two numbers (eg, II, 4). A spouse is also assigned an ide number (eg, II, 6 in Fig. 286-2).
Study of a trait or disease begins with the affected person (the proband, propositus [male], proposita [ or index case). When taking a family history, the physician usually draws the pedigree as the relatives described. The inquiry begins with the siblings of the proband and proceeds to the parents; relatives o parents, including brothers, sisters, nephews, and nieces; grandparents; and so on. The number of rel included in the pedigree is determined by the inheritance pattern of the condition and by the extent of informant's memory or knowledge. Usually, at least 3 generations are included. Illnesses, hospitalizati causes of death, miscarriages, abortions, congenital anomalies, and any other unusual features are re
Genetic Counseling
Genetic counseling involves obtaining a thorough family history and addressing the family's concerns a questions by gathering appropriate information from the literature and from genetic specialists; consult with an expert concerning the specific condition is often important. The information provided should inc diagnosis and diagnostic methods, including identification of carriers; the natural history of the disorde complications; the recurrence risk for the patient and various family members; potential therapies; and reproductive options. Communicating genetic risks and options is an involved process that often requir follow-up visits and written communication.
Many family support groups exist for specific genetic diseases. Most have regular meetings with chapt numerous locales and publish useful information.
Genetic counseling centers exist at medical schools in the USA and Canada. Patients and families can referred for diagnosis, counseling, management, and information. A working relationship between the center and the family physician is essential for the family's best interest and for follow-up.

Section 21. Special Subjects Chapter 292. Hyperbaric Oxygen Therapy Topics
[General] Indications Contraindications Adverse Effects
[General]
Hyperbaric oxygen therapy: A medical treatment in which the patient is entirely enclosed in a pressure chamber breathing 100% O2 at > 1.4 times atmospheric pressure.
Hyperbaric oxygen (HBO) therapy uses a monoplace (single-person) chamber pressurized with pure O larger multiplace chamber pressurized with compressed air in which the patient receives pure O2 by m head tent, or endotracheal tube. The indications for, contraindications to, and adverse effects of HBO been established by the Committee on Hyperbaric Oxygenation of the Undersea and Hyperbaric Medi Society (UHMS) and are discussed below.
To locate HBO facilities in the USA, Canada, and the Caribbean in an emergency, call the Divers Aler Network at Duke University, 919-684-8111.
Section 21. Special Subjects Chapter 287. Syndromes Of Uncertain Origin Topics
[General] Gulf War Syndrome Multiple Chemical Sensitivity Syndrome Chronic Fatigue Syndrome
[General]
Many persons suffer greatly from syndromes for which no specific cause can be found. Some physicia these syndromes as the result of psychologic factors, although most persons with symptoms reject a psychologic cause. Some data--often incomplete, inconsistent, or contradictory--suggest a physical ca
Some patients may have scattered, unrelated symptoms that do not form a syndrome, but some of the patients may have physical disease that cannot be diagnosed. Better definitions may allow better case recognition; research is needed to clarify the origins and significance of these syndromes, produce acc diagnoses, and define optimum care.
The first responsibility of the physician confronted by such a patient is to obtain a thorough history of e and to exclude specific, potentially treatable causes. If no cause is identified, supportive, sympathetic is required.

Section 21. Special Subjects Chapter 293. Geriatric Medicine Topics
[General] Health Care Delivery Disorders Common Only In The Elderly Disorders With Unusual Presentations In The Elderly Drug Use Advance Medical Directives
[General]
Geriatric medicine (Geriatrics): An interdisciplinary approach to management of sickness and disability health promotion and disease prevention in the elderly that involves gerontology (the study of changes normal aging as differentiated from disease effects).
Most age-related biologic functions peak at < 30 yr of age and may gradually decline in a linear fashio Table 293-1); although this later decline may be critical during stress, it has no effect on daily activity. disease, rather than normal aging, is the prime determinant of functional loss in old age.
Many decrements reportedly caused by aging are often attributable to lifestyle, behavior, diet, or enviro which can be modified. For example, aerobic exercise can partially reverse declines in o2 max, muscle strength, and glucose tolerance in healthy but sedentary older persons. The effects of aging may be le dramatic than thought, and healthier, more vigorous aging may be possible for many persons.
Cross-sectional studies comparing persons of different ages are relatively easy to do but may be less than longitudinal studies comparing persons over time to their younger selves. Such studies are difficu because of the long duration and high dropout rate; also, it is hard to find healthy aging subjects.
Demographics: At the turn of the century, persons > 65 yr accounted for 4% of the U.S. population; c they account for > 12% (33 million, with a net gain of > 1000/day). It is estimated that in 2030, when post-World War II baby boomers reach age 80, > 70 million Americans (> 20%) will be aged > 65 yr, a increase in the percentage of persons aged > 85 yr will be greater.
Life expectancy: At age 65 yr, a man has a 13-yr life expectancy but at age 75 yr still has a 9-yr life expectancy. At age 65 yr, a woman has a 20-yr life expectancy but at age 75 yr still has a 12-yr life expectancy. Overall, women live about 8 yr longer than men, probably the result of genetic, biologic, a environmental factors; thus, there are more elderly women than men. Survival differences have not de
increase in the percentage of persons aged > 85 yr will be greater.
Life expectancy: At age 65 yr, a man has a 13-yr life expectancy but at age 75 yr still has a 9-yr life expectancy. At age 65 yr, a woman has a 20-yr life expectancy but at age 75 yr still has a 12-yr life expectancy. Overall, women live about 8 yr longer than men, probably the result of genetic, biologic, a environmental factors; thus, there are more elderly women than men. Survival differences have not de despite women smoking more and moving into traditionally male job markets. The maximum human lif (estimated at 110 to 120 yr) has increased modestly compared with the major increase in average life expectancy during this century, but increases continue. Persons aged > 65 yr are in better health than predecessors. However, with all cohorts, the oldest old decline most.

Section 21. Special Subjects Chapter 288. Sarcoidosis Topics
[General]
[General]
Sarcoidosis: A multisystem granulomatous disorder of unknown etiology, characterized histologically b noncaseating epithelioid granulomas involving various organs or tissues, with symptoms dependent on and degree of involvement.
Sarcoidosis occurs mainly in persons aged 20 to 40 yr and is most common in Northern Europeans an American blacks. The lifetime risk of developing sarcoidosis is particularly high among Swedish men ( Swedish women (1.6%), and American blacks (2.4%).
A single provoking agent or disordered defense reactions triggered by various insults may be responsi genetic factors may be important. The characteristic histopathologic findings are multiple noncaseating epithelioid granulomas, with little or no necrosis, occurring commonly in mediastinal and peripheral lym nodes, lungs, liver, eyes, and skin and less often in the spleen, bones, joints, skeletal muscle, heart, a These granulomas may resolve completely or proceed to fibrosis. Although similar granulomas can oc various infections, hypersensitivity reactions, pneumonia, and foreign body reactions, characteristic pa involvement indicate sarcoidosis.
Symptoms and Signs
Symptoms depend on the site of involvement and may be absent, slight, or severe. Fever, weight loss arthralgias may occur initially. Persistent fever is common with liver involvement. Peripheral lymphade is common and usually asymptomatic; even insignificant nodes may contain granulomas. Organ functi be impaired by the active granulomatous disease or by secondary fibrosis. Cough and dyspnea may b minimal or absent.
Skin lesions (plaques, papules, subcutaneous nodules) are frequently present in patients with chronic sarcoidosis, and nasal and conjunctival mucosal granulomas may occur. Erythema nodosum, often wi and arthralgias, is commonly the presenting symptom in Europeans but less commonly in Americans.
Hepatic granulomas are found on percutaneous biopsy in 70% of patients, who may be asymptomatic normal liver function tests. Hepatomegaly is noted in < 10% of patients; progressive and severe liver
Skin lesions (plaques, papules, subcutaneous nodules) are frequently present in patients with chronic sarcoidosis, and nasal and conjunctival mucosal granulomas may occur. Erythema nodosum, often wi and arthralgias, is commonly the presenting symptom in Europeans but less commonly in Americans.
Hepatic granulomas are found on percutaneous biopsy in 70% of patients, who may be asymptomatic normal liver function tests. Hepatomegaly is noted in < 10% of patients; progressive and severe liver dysfunction with jaundice is rare.
Granulomatous uveitis occurs in 15% of patients; it is usually bilateral and, if untreated, may cause se vision loss due to retinal involvement, severe vitreitis, or secondary glaucoma. Lacrimal gland enlargem conjunctival and eyelid infiltrations, and keratitis sicca occasionally are present.
Myocardial involvement, noted in 5 to 10% of patients, may cause angina, heart failure, or fatal conduc abnormalities.
Acute polyarthritis may be prominent; chronic periarticular swelling and tenderness may be due to oss changes in the phalanges. Acute periarticular ankle inflammation often occurs without cutaneous lesio is often not recognized as a presentation of sarcoidosis. CNS involvement is of almost any type, but cranial nerve palsies (especially facial paralysis) are most common, affecting 5% of patients.
Diabetes insipidus may occur. Hypercalcemia and hypercalciuria (the result of increased 1,25-dihydrox D production by alveolar macrophages and sarcoid granulomas) may cause renal calculi or nephrocal with consequent renal failure, but prednisone has reduced the frequency of disordered Ca metabolism Hyperparathyroidism appears to be unusually frequent and should be considered when hypercalcemia not promptly respond to corticosteroids.
Laboratory Findings and Diagnosis
Chest x-ray abnormalities occur in 90% of patients. Mediastinal adenopathy often is discovered on rou chest x-ray. X-ray findings of bilateral hilar and right paratracheal adenopathy are virtually universal (9 patients), although adenopathy occasionally is unilateral. Pulmonary infiltration may have a diffuse, fin ground-glass appearance on x-ray. It may accompany or follow adenopathy; occur without visible aden occur as reticular or miliary lesions; or be present as confluent infiltrations or large nodules resembling metastases. Cough and dyspnea may be minimal or absent. Pulmonary fibrosis, cystic changes, and c pulmonale are late results of progressive disease.
Leukopenia is frequently present, and serum uric acid elevation is common, but gout is rare. Serum al phosphatase and -glutamyl transpeptidase levels may be elevated as a result of liver involvement. Dep of delayed hypersensitivity is characteristic, but a negative second-strength tuberculin reaction reliably excludes complicating TB. Hypergammaglobulinemia is common in blacks.
Pulmonary function tests show restriction, decreased compliance, and impaired diffusing capacity. CO retention is uncommon, although airway obstruction is common in patients with endobronchial disease late stages with pulmonary fibrosis or bullae. Serial pulmonary function tests are important for assessi disease progression and guiding treatment.
Sarcoidosis may be diagnosed in asymptomatic patients with typical chest x-ray findings but should al considered with normal findings when the symptoms and signs described above occur. Because the differential diagnosis includes lymphoma and fungal infections (eg, histoplasmosis, coccidioidomycosi biopsy with microbiologic and histologic examination is essential if symptoms are present and if cortico
disease progression and guiding treatment.
Sarcoidosis may be diagnosed in asymptomatic patients with typical chest x-ray findings but should al considered with normal findings when the symptoms and signs described above occur. Because the differential diagnosis includes lymphoma and fungal infections (eg, histoplasmosis, coccidioidomycosi biopsy with microbiologic and histologic examination is essential if symptoms are present and if cortico therapy is indicated. When superficial or palpable lesions (eg, in skin, lymph nodes, or conjunctiva) are present, biopsy is positive for sarcoidosis in > 85% of such specimens.
When peripheral sites are not available for biopsy, transbronchial biopsy by fiberoptic bronchoscopy is initial procedure for securing histologic evidence of sarcoidosis; granulomas can be seen in 50 to 80% patients regardless of whether the chest x-ray reveals pulmonary infiltration or hilar adenopathy alone. tissue can also be sampled via thoracoscopy.
Other possible biopsy sites include normal-appearing conjunctiva or the mediastinum, which can be approached by mediastinotomy or mediastinoscopy. Liver biopsy shows granulomas in 70% of cases. sarcoid reactions in a single organ (eg, liver) and pulmonary granulomas due to infection, hypersensiti reaction, or foreign body reaction must be excluded. In questionable cases, more than one site should biopsied to thoroughly search for an infection or foreign body reaction.
The Kveim reaction, a granulomatous reaction appearing 4 wk after intradermal injection of sarcoid sp lymph node extracts, is positive in 50 to 60% of patients, but reliable antigens are not available in the U because of FDA restrictions on the use of human material for diagnostic testing.
Serum ACE activity is elevated (> 2 standard deviations) in 60% of patients, presumably reflecting macrophage activity. It can also be elevated in patients with histoplasmosis, acute miliary TB, hepatitis lymphoma and is thus nonspecific. Liver disease slows the metabolic excretion of serum ACE and res increased ACE activity. Increased CSF ACE may be useful in diagnosing CNS sarcoidosis. Tissue AC is highest in sarcoid lymph nodes rather than in pulmonary tissues.
Bronchoalveolar lavage shows lymphocytosis in most patients with active sarcoidosis but is rarely indic because patients with hypersensitivity pneumonitis show similar lymphocytosis. However, the CD4/CD on bronchoalveolar lavage is elevated in sarcoidosis and reduced in hypersensitivity pneumonitis. Bronchoalveolar lavage analyses were advocated to determine the need for corticosteroid therapy, bu studies do not support this use.
Whole-body gallium scanning, a sensitive but nonspecific indicator of sarcoidal inflammation, may be diagnosis in patients with normal chest x-rays or otherwise atypical presentations. Patients with symm increased uptake in mediastinal and hilar nodes (lambda sign) and in lacrimal, parotid, and salivary gla (panda sign) have a pattern pathognomonic for sarcoidosis. Gallium scanning may indicate useful site biopsy and may help determine whether radiologic densities represent reversible inflammation or fibro long-standing pulmonary sarcoidosis. Gallium uptake is extremely sensitive to corticosteroids; a negat in patients taking prednisone is unreliable.
TB, aspergillosis, cryptococcosis, histoplasmosis, coccidioidomycosis, and Hodgkin's disease must be differentiated from sarcoidosis. It is uncertain whether the typical sarcoid granulomas found in 5% of li biopsies performed for staging of Hodgkin's disease indicate two concurrent diseases or a sarcoid rea the neoplasm.
Clinical Course and Prognosis
Evaluating treatment is difficult because spontaneous improvement or clearing is common. Even mass adenopathy and extensive infiltrates may disappear in a few months or years. Mediastinal adenopathy sometimes persist without change for many years. In one study, recovery was observed on x-ray at the
Clinical Course and Prognosis
Evaluating treatment is difficult because spontaneous improvement or clearing is common. Even mass adenopathy and extensive infiltrates may disappear in a few months or years. Mediastinal adenopathy sometimes persist without change for many years. In one study, recovery was observed on x-ray at the 5 yr in 82% of Swedish patients with hilar adenopathy alone and in 57% of patients with pulmonary op In another study, recovery was observed at the end of 9 yr in 85% of white patients and 65% of black with pulmonary sarcoidosis. Race and extrapulmonary sarcoidosis help predict the likelihood of recove patients with pulmonary sarcoidosis: 89.4% in whites with no extrathoracic disease; 69.7% in whites w extrathoracic disease; 76% in blacks with no extrathoracic disease; and 46.4% in blacks with extrathor disease.
The prognosis is better for patients who have adenopathy without radiologic evidence of pulmonary di The most reliable indicator of a favorable outcome of sarcoidosis is onset with erythema nodosum.
About 10% of patients develop serious disability from ocular, respiratory, or other organ damage, but m from sarcoidosis is < 3%. Pulmonary fibrosis leading to cardiorespiratory failure is the most common c death, followed by pulmonary hemorrhage from aspergilloma.
Treatment
Patients with few or no symptoms should not be treated, regardless of radiologic or laboratory abnorm (except for sustained hypercalcemia). Abnormal ACE activity, gallium scanning, and other laboratory t useful in assessing symptoms, but abnormal test results alone do not justify therapy. No available drug consistently prevented pulmonary fibrosis.
Corticosteroids accelerate clearance of symptoms, physiologic disturbances, and x-ray changes. How little difference is demonstrable in long-term outcome between treated and untreated patients, and rela common when treatment ends. Corticosteroids should be given to suppress severe symptoms (eg, dys arthralgia, fever) or hepatic insufficiency, cardiac arrhythmia, CNS involvement, hypercalcemia, ocular uncontrolled by local drugs, or disfiguring skin lesions. A good starting dose is prednisone 15 to 20 mg or methylprednisolone 12 to 16 mg/day po. Prednisone 60 mg/day po or methylprednisolone 48 mg/da often used when a prompt effect is desired, but such doses are poorly tolerated by many patients. Pat with acute disease (eg, severe erythema nodosum) may need treatment for only a few weeks, but mos those requiring therapy have chronic sarcoidosis and need treatment for >= 1 yr. Maintenance doses o prednisone as low as 5 mg/day po control symptoms and radiologic lesions and may be needed indefi a few patients. Inhaled corticosteroids may provide palliation of mild or moderate respiratory symptom Because relapse occurs in 50% of cases, clinical and laboratory examination should be repeated ever mo after the drug is stopped.
About 10% of patients requiring therapy are unresponsive to tolerable doses of a corticosteroid and sh given a 6-mo trial of methotrexate starting at 2.5 mg/wk po and increasing in increments of 2.5 mg/wk of 10 to 15 mg/wk as tolerated by a WBC > 3000/mm 3. After 8 wk of methotrexate, the corticosteroid c reduced and then often discontinued. Serial blood counts and liver enzyme tests should be performed wk.
Although immunosuppressive drugs are often more effective in refractory cases, relapse is frequent af cessation. The safety of long-term use of drugs other than methotrexate has not been established. Immunosuppressive drugs are frequently required in patients with neurosarcoidosis and other severe f the disease. Hydroxychloroquine 200 mg bid po is more effective than corticosteroids for treatment of disfiguring skin sarcoids. Retinal damage is rare, but serial ophthalmologic examination should be perf every 6 mo.
Although immunosuppressive drugs are often more effective in refractory cases, relapse is frequent af cessation. The safety of long-term use of drugs other than methotrexate has not been established. Immunosuppressive drugs are frequently required in patients with neurosarcoidosis and other severe f the disease. Hydroxychloroquine 200 mg bid po is more effective than corticosteroids for treatment of disfiguring skin sarcoids. Retinal damage is rare, but serial ophthalmologic examination should be perf every 6 mo.

Section 21. Special Subjects Chapter 294. Care Of The Dying Patient Topics
[General] Symptom Control Psychologic Interventions Societal Concerns Managing Death
[General]
Helping a patient and family find comfort in the experience of dying is often more important than adher medical routines or correcting symptomless physiologic abnormalities. Distressing symptoms, howeve be prevented or relieved as effectively as possible. It is also important to prevent suffering, a global pe of distress due to factors that together undermine quality of life (eg, pain; physical impairment; psycho disturbances; social, family, financial, and spiritual concerns).
People differ in what they consider important, especially when facing death. Some people search for c they reach out to friends and family to share time and to express their love; they complete projects imp their lives; and they tie up loose ends. Often, the time and manner of death allows a satisfying close. O are unable to accept their imminent mortality and avoid such closure. For some, life is to be prolonged the cost of pain, marked confusion, or severe respiratory distress. For others, quality of life is the overa concern: they would prefer comfort measures to enduring prolonged disability and struggle.
The patient's preferences are paramount in planning care. A patient who fears dementia more than de should be treated differently from one who cherishes every moment of life, regardless of its quality. A knowledge of local law and institutional policy governing living wills, durable power of attorney, and pro for resuscitation and hospitalization is also important to ensure that patients' wishes are followed when are no longer able to direct their own care.
Supportive care may be the only realistic goal for a dying patient. Medical management of troubling sy can enable patients and families to avoid needless suffering and to share valuable time. Yet, to say th patient's care has changed from curative to supportive care, or from treatment to palliation, is an oversimplification of a complex decision process.
Sometimes, aggressive treatment may be appropriate. A dying patient may benefit from attempts at cu rehabilitative, or preventive care, just as a person not near death may benefit from symptom control an psychologic counseling.
patient's care has changed from curative to supportive care, or from treatment to palliation, is an oversimplification of a complex decision process.
Sometimes, aggressive treatment may be appropriate. A dying patient may benefit from attempts at cu rehabilitative, or preventive care, just as a person not near death may benefit from symptom control an psychologic counseling.
Section 21. Special Subjects Chapter 289. Familial Mediterranean Fever Topics
[General]
[General]
Familial mediterranean fever (familial paroxysmal peritonitis): An inherited disorder characterized by re fever and peritonitis and less frequently by pleuritis, arthritis, skin lesions, and pericarditis.
Most frequently, but not exclusively, persons of Mediterranean origin (eg, Sephardic Jews, Arabs, Arm Turks) are affected. A sufficient number of cases have occurred in other groups, particularly Ashkenaz to caution against excluding the diagnosis on the basis of atypical ancestry. About 50% of patients hav family history of the disorder.
The disorder is inherited as an autosomal recessive trait; the causative gene on the short arm of chrom 16 has been cloned. The gene product, a 781 amino acid protein called pyrin by one group of discove marenostrin by another, appears to be expressed only in circulating neutrophils. It is believed to attenu transcription of proinflammatory promoters by these cells.
Onset is usually between the ages of 5 and 15 but may be much later or even during infancy. Attacks regular pattern of recurrence and vary in the same patient. They usually last 24 to 72 h, but some last Frequency ranges from two attacks per week to one per year (most commonly once every 2 to 4 wk). and frequency tend to decrease with age, during pregnancy, or with amyloidosis. Spontaneous remiss last years.
Fever as high as 40 C (104 F), usually accompanied by peritonitis, is the major manifestation; occas serositis occurs with a low fever. Abdominal pain (usually starting in one quadrant and spreading to the abdomen) occurs in about 95% of patients and can vary in severity with each attack. Decreased bowe distention, guarding, and rebound tenderness are likely to occur at the peak of an attack and cannot b differentiated from a perforated viscus on physical examination. Consequently, many patients have un urgent laparotomy before the correct diagnosis was made. With diaphragmatic involvement, splinting o chest and pain in one or both shoulders may occur. Other symptoms include acute pleuritic pain (in 75 acute arthritis involving the large joints (in 25%), and an erysipeloid rash of the lower leg. Recurrent pe with chest pain is relatively rare.
abdomen) occurs in about 95% of patients and can vary in severity with each attack. Decreased bowe distention, guarding, and rebound tenderness are likely to occur at the peak of an attack and cannot b differentiated from a perforated viscus on physical examination. Consequently, many patients have un urgent laparotomy before the correct diagnosis was made. With diaphragmatic involvement, splinting o chest and pain in one or both shoulders may occur. Other symptoms include acute pleuritic pain (in 75 acute arthritis involving the large joints (in 25%), and an erysipeloid rash of the lower leg. Recurrent pe with chest pain is relatively rare.
No laboratory test is diagnostic. No specific pathologic changes are found. Laparotomy at the peak of attack may yield a small amount of peritoneal fluid containing neutrophils; serosal biopsy may show fib deposition. Amyloidosis may develop (most frequently in patients in the Mediterranean region) due to perivascular deposition of serum amyloid A protein; it is much less common since the advent of colchi During acute attacks, polymorphonuclear leukocytosis is frequently, but not invariably, found. Results phase reactant tests (ESR, serum fibrinogen, C-reactive protein) are likely to be elevated. Results of o laboratory tests are normal.
Consequently, diagnosis is made more on the basis of clinical than on laboratory findings, including a presentation (appropriate ethnicity; a positive family history; recurrent, self-limited peritonitis; excellent between episodes).
Prognosis, Prophylaxis, and Treatment
Despite the severity of symptoms during acute attacks, most patients recover swiftly and remain free o until their next attack. Widespread use of prophylactic colchicine has been associated with a dramatic reduction in the incidence of amyloidosis and subsequent renal failure.
Prophylactic colchicine 0.6 mg po bid (some patients require qid dosage and others a single daily dose provides complete remission or distinct improvement in about 85% of patients. For patients with infreq attacks having a definite prodromal phase, colchicine can be reserved until initial symptoms occur and begun at 0.6 mg/h po for 4 h, then q 2 h for 4 h, then q 12 h for 48 h. Initiation of colchicine at the peak attack, even if delivered IV, is unlikely to be beneficial. Children often require adult dosages to achieve effective prophylaxis. Colchicine does not add to the increased risk of infertility and miscarriage among affected women, nor does it increase the number of teratogenic events when taken during pregnancy.
Narcotics are sometimes needed for pain relief but should be administered prudently to avoid drug add

Section 21. Special Subjects Chapter 295. Clinical Decision Making Topics
[General] Clinical Rules Reasoning With Probabilities Laboratory Testing Revising Probabilities With Bayes Theorem Making Choices Determining A Threshold For Treating Determining A Threshold For Performing A Test Economic Analyses
[General]
Clinicians must choose from and interpret a huge variety of clinical data while facing pressure to decre uncertainty, risks to patients, and costs. The essence of medical practice is decision making (eg, what information to gather, which tests to order, how to interpret and integrate this information into diagnost hypotheses, what treatments to administer).

Section 21. Special Subjects Chapter 290. Smoking Cessation Topics
[General] Tobacco Addiction Problems Associated With Smoking Cessation
[General]
The huge impact of morbidity and premature mortality caused by tobacco smoking, primarily cigarette smoking, continues. Many teenagers begin smoking despite efforts to discourage them, and about 47 Americans continue to smoke--percentages are increasing among women--despite efforts to help the smokers who want to quit. These smokers are addicted to tobacco and claim that they do not know ho quit.
Although >= 70% of smokers consult their physician at least once per year for some reason, many hav been asked about smoking or advised to quit by their physician. To initiate smoking cessation and to o practical and effective advice about smoking cessation, physicians must first inquire about a patient's s habits. Of patients who quit, 90% do so on their own. But, in any given year, only about 1.7 million smo (3.6%) successfully quit. Studies have shown that a physician's advice to stop smoking, which requires about 3 to 5 min, may achieve a quit rate of 3 to 5%. However, when the physician's advice is support follow-up visits and drugs, quit rates of 20 to 25% may be expected (see below).

Section 21. Special Subjects Chapter 296. Normal Laboratory Values Topics
[General]
[General]
Normal laboratory values: Mean values in a healthy population 2 standard deviations (SD), which inc about 95% of this population.
Because each laboratory test is independent of the others, the probability of a normal person having completely normal results when multiple tests are performed is relatively low; eg, when a sequential m analyzer (SMA) is used, one abnormal test result is expected in almost 1/2 of patients having an SMA in 2/3 having an SMA-20.
Determination of values is complicated by sex, age (see below), diet, malnutrition, drugs, time of day, position of the patient when the specimen is drawn (eg, plasma volume increases when the patient ch from a standing to a supine position, which reduces the plasma concentrations of nondiffusible substa Automated methods tend to be more subject to errors than manual methods, eg, due to a trace of a pr sample remaining in the instrument.
Artifactual errors include high serum K due to cellular release, eg, after prolonged tourniquet constricti serum glucose in patients with high WBC counts; low serum Na or high plasma Hb in patients with hyperlipidemia; and high serum creatinine in patients with diabetic ketoacidosis because acetoacetate interferes with automated methods.
Some cardiac, pulmonary, renal, and metabolic functions progressively decline with age, but at somew different rates. The declines sometimes correlate with changes in laboratory parameters (see Table 29
The normal values and drug therapeutic ranges listed in Tables 296-2 and 296-3 are provided by Que Diagnostics. These ranges apply only to adults, unless indicated otherwise, and are for reference purp only. Any decision regarding diagnosis, treatment, or management of patients should be based on the reference intervals printed on laboratory test result reports. SBCL does not assume responsibility, and specifically disclaims liability, for use of this information. The conversion of normal values and drug the ranges to SI units is the responsibility of The Manual.
Tables 296-4 and 296-5 list commonly measured biochemical values and the effects of various diseas
only. Any decision regarding diagnosis, treatment, or management of patients should be based on the reference intervals printed on laboratory test result reports. SBCL does not assume responsibility, and specifically disclaims liability, for use of this information. The conversion of normal values and drug the ranges to SI units is the responsibility of The Manual.
Tables 296-4 and 296-5 list commonly measured biochemical values and the effects of various diseas them.

Section 21. Special Subjects Chapter 291. Rehabilitation Topics
[General] Physical Therapy Therapeutic And Assistive Devices Treatment Of Pain And Inflammation Rehabilitation For Some Specific Problems
[General]
Rehabilitation: A combination of physical, occupational, and speech therapy; psychologic counseling; social work directed toward helping patients maintain or recover physical capacities.
Rehabilitation is often needed after hip fracture, amputation, stroke, serious cardiac events, or prolong rest that results in deconditioning or as part of the treatment of arthritis or various other illnesses or inj causing varying degrees of functional loss. Usually, for younger patients, the goal is to achieve full, unrestricted function and, for older patients, to restore the ability to perform as many activities of daily possible. Recovery is often rapid for younger patients, but progress may be slow for elderly patients.
Rehabilitation may begin in an acute care hospital, but organized rehabilitation programs rarely exist th Rehabilitation hospitals usually provide the most extensive and intensive care and should be considere patients who have the most potential and who can participate in aggressive intervention (eg, patients m able to tolerate therapy for >= 3 h/day). Many nursing homes have programs that are less intensive (g 1 h/day, < 5 days/wk) and, thus, are better suited to those who need more gentle rehabilitation (eg, fra elderly patients). Rehabilitation programs with less variety and frequency of services may be offered in outpatient settings or at home and are appropriate for many patients.
To initiate formal rehabilitation therapy, a physician must write a referral to a physiatrist, therapist, or rehabilitation center. The referral should establish the goal of therapy and, therefore, should be detaile including relevant information and initial instructions. Although vague instructions (eg, "physical therap evaluate and treat") are often accepted, they are not adequate. Physicians unfamiliar with writing refer should consult with a senior therapist, physiatrist, or orthopedic surgeon.
Disabled patients tend to be depressed and may lose motivation for restoring lost function and returnin community. Mental health specialists may help the patient overcome these adverse emotional states a on functional recovery. The family may have to adjust to the patient's disability and appropriately assis patient. Disability may cause financial hardship to the patient and family. A social worker helps the pat
should consult with a senior therapist, physiatrist, or orthopedic surgeon.
Disabled patients tend to be depressed and may lose motivation for restoring lost function and returnin community. Mental health specialists may help the patient overcome these adverse emotional states a on functional recovery. The family may have to adjust to the patient's disability and appropriately assis patient. Disability may cause financial hardship to the patient and family. A social worker helps the pat family adjust.
Initial evaluation includes discussions on objectives, which generally focus on restoring function for ac of daily living (ADLs). ADLs include personal care such as grooming, bathing, dressing, feeding, and as well as cooking, cleaning, shopping, managing medications, managing finances, using the telephon traveling. The referring physician and rehabilitation team can determine which of these activities are achievable and which are essential for the patient to remain independent.

Section 21. Special Subjects Chapter 297. Ready Reference Guides Topics
[General]
[General]
Milligram-Milliequivalent Conversions
(Note: formula wt = atomic or molecular wt)
The milliequivalent (mEq) expresses the chemical activity, or combining power, of a substance relati activity of 1 mg of hydrogen. Thus, 1 mEq is represented by 1 mg of hydrogen, 23 mg of sodium, 39 m potassium, 20 mg of calcium, and 35 mg of chlorine. Conversion equations are as follows:
The mEq is roughly equivalent to the milliosmole (mOsm), the unit of measure of osmolality or tonicit Normally, the body fluid compartments each contain about 280 mOsm/L of solute/L. TABLE 297-1. METRIC SYSTEM
TABLE 297-2. METRIC-NONMETRIC EQUIVALENTS*
TABLE 297-3. HOUSEHOLD NONMETRIC-METRIC EQUIVALENTS*
TABLE 297-4. ATOMIC WEIGHTS OF SOME COMMON ELEMENTS*
TABLE 297-4. ATOMIC WEIGHTS OF SOME COMMON ELEMENTS*
TABLE 297-5. CENTIGRADE-FAHRENHEIT EQUIVALENTS
Section 10. Dermatologic Disorders Chapter 109. Diagnostic Approach To Skin Dise Topics
[General] Special Diagnostic Methods Primary Skin Lesions Secondary Skin Lesions Pruritus
[General]
Many skin diseases can be diagnosed by a thorough physical examination alone. The physical examin should include examination of the nails and areas unavailable for self-examination (eg, oral mucosa, anogenital area, scalp). Good lighting is essential. Diagnosis requires identification of primary and sec skin lesions by morphology (see below).
The arrangement of lesions may be distinctive. Grouping of tense vesicles is seen in herpes simplex a zoster, with a characteristic linear arrangement in the latter. Annularity (a tendency to form rings) is typ granuloma annulare, erythema multiforme, fixed drug eruption, dermatophyte infections, some forms o disease, and secondary syphilis. Linearity is sometimes seen with epidermal nevi, linear scleroderma, contact dermatitis. In Kbner's phenomenon (isomorphic reaction), lesions in psoriasis, lichen planus, warts mimic the shape of trauma to the skin (eg, from scratching, rubbing, or other injury). Lesion distr usually follows some common pattern (see Table 109-1). The history may also provide valuable clues.

Section 10. Dermatologic Disorders Chapter 118. Inflammatory Reactions Topics
[General] Drug Eruptions Toxic Epidermal Necrolysis Erythema Multiforme Erythema Nodosum Granuloma Annulare
[General]
(See also Pruritic Urticarial Papules and Plaques of Pregnancy in Ch. 252.)
Section 10. Dermatologic Disorders Chapter 110. Principles Of Topical Dermatologic T Topics
[General]
[General]
Topical dermatologic treatments are used as cleansing agents, absorbents, anti-infective agents, anti-inflammatory agents, astringents (drying agents that precipitate protein and shrink and contract th emollients (skin softeners), and keratolytics (agents that soften, loosen, and facilitate exfoliation of the squamous cells of the epidermis).
The base (vehicle or carrier) for a topical formulation may alter the effectiveness of the active ingredie must be selected carefully. Allergic and irritating reactions (eg, contact dermatitis) may be caused by ingredients of the base as well as by the active ingredients.
Topical Preparations
Creams, semisolid emulsions of oil and water, are the mainstay of dermatologic therapy. They are ea applied and vanish when rubbed into the skin.
Ointments are oleaginous and contain little if any water; they feel greasy but are generally well tolerat Ointments are best used to lubricate, especially if applied over hydrated skin; they are preferred for les with thick crusts, lichenification, or heaped-up scales and may be less irritating than cream for some e open lesions (eg, stasis ulcers). Drugs in ointments are often more potent than in creams.
Lotions originally were suspensions of powdered material (eg, calamine) in a water or alcohol base, b modern lotions (eg, some corticosteroids) are water-based emulsions. Convenient to apply, lotions coo dry acute inflammatory and exudative lesions.
Solutions are homogenous mixtures of two or more substances. Like lotions, solutions are drying. Th particularly convenient to apply (especially to the scalp). The most commonly used bases are ethyl alc propylene glycol, polyethylene glycol, and water.
Occlusive therapy is used in such conditions as psoriasis, atopic dermatitis, lupus erythematosus, an chronic hand dermatitis. Covering the treated area with a nonporous occlusive dressing increases the
Solutions are homogenous mixtures of two or more substances. Like lotions, solutions are drying. Th particularly convenient to apply (especially to the scalp). The most commonly used bases are ethyl alc propylene glycol, polyethylene glycol, and water.
Occlusive therapy is used in such conditions as psoriasis, atopic dermatitis, lupus erythematosus, an chronic hand dermatitis. Covering the treated area with a nonporous occlusive dressing increases the absorption and effectiveness of topical corticosteroids. Usually, a polyethylene film (plastic household applied overnight over cream or ointment, which tends to be less irritating than lotion for occlusive ther Plastic tape impregnated with flurandrenolide is especially convenient for treating isolated or recalcitra lesions. Miliaria, atrophic striae, and bacterial or fungal infections may follow occlusive therapy; childre (less often) adults may experience pituitary and adrenal suppression after prolonged occlusive therapy large areas.
Aerosol forms of betamethasone dipropionate and triamcinolone acetonide are available but are seldo because they offer no tangible advantage over creams, lotions, and solutions.
Categories and Indications
Cleansing agents: The principal cleansing agents are detergents and solvents. Soap is the most pop detergent, but synthetic detergents are also used. Baby shampoos are usually well tolerated around th and for cleansing wounds and abrasions; they are useful for removing crusts and scales in psoriasis, e and other forms of dermatitis. However, acute irritated, weeping, or oozing lesions are most comfortab cleansed with only water or isotonic saline.
Various ingredients often are added to detergents and other skin preparations to enhance or provide c properties. For example, zinc pyrithione, selenium sulfide, or tar extracts may be added to shampoo fo antidandruff action.
Water is the principal solvent for cleansing. Using tap-water soaks, baths, or compresses (made from old sheets) for 48 to 72 h (changing them q 1 to 2 h) will generally dry, soothe, cool, and often debride weeping or oozing lesions. Aluminum acetate or magnesium sulfate is seldom better than tap water fo dressings; evaporation may result in caustic concentrations of the dissolved ingredient.
Protectants: Powders are often used to protect intertriginous areas (ie, between the toes; in the interg cleft, axillae, groin, and inframammary areas). Powders dry macerated skin and reduce friction by abs moisture. However, some powders tend to clump and can be irritating if they become moist. Talc is oft than cornstarch, which may promote fungal growth. Powders may be incorporated into protective crea ointments, and lotions. Collodion and other films provide a flexible or semirigid continuous coating. Hy polymers can be applied with a gauze cover. Zinc oxide gelatin (Unna's paste boot) forms an occlusive dressing. Sunscreens help shield the skin from ultraviolet light (see Ch. 119).
Anti-infective agents: Eradication of specific agents causing skin infections (eg, bacteria, fungi, proto discussed elsewhere in The Manual. Topical antibiotics are used to treat acne, and some agents (eg, mupirocin) effectively treat some superficial skin infections. Topical fungicides, scabicides, and pedicu are commonly used, as are systemic antibiotics.
Agents that relieve symptoms (eg, pruritus, burning, pain): In addition to analgesics, camphor 0.5 to menthol 0.1 to 0.2%, or both may be used in creams or ointments. The local anesthetics lidocaine and dibucaine are generally ineffective when used on skin but are sometimes useful on mucosal surfaces. preparations containing pramoxine hydrochloride have been used with some success in the treatment cutaneous pruritus. Additionally, pramoxine is less likely to cause sensitization than diphenhydramine, lidocaine, or dibucaine. Newer eutectic mixtures of local anesthetics (eg, Emla cream) are useful on sk especially if used with occlusive dressings.
menthol 0.1 to 0.2%, or both may be used in creams or ointments. The local anesthetics lidocaine and dibucaine are generally ineffective when used on skin but are sometimes useful on mucosal surfaces. preparations containing pramoxine hydrochloride have been used with some success in the treatment cutaneous pruritus. Additionally, pramoxine is less likely to cause sensitization than diphenhydramine, lidocaine, or dibucaine. Newer eutectic mixtures of local anesthetics (eg, Emla cream) are useful on sk especially if used with occlusive dressings.
Anti-inflammatory agents: Corticosteroids are the most effective topical anti-inflammatory agents. Th devoid of systemic side effects (see Table 110-1 for relative potency) unless used over extensive skin surfaces. Pruritic inflammatory dermatoses usually respond to properly used corticosteroids. However drugs may worsen conditions such as acne, rosacea, and some fungal infections. Corticosteroids and preparations are usually used as creams, ointments, lotions, gels, or solutions and less commonly as and tapes.
Although topical corticosteroids are available in varying strengths, the more potent ones (see Table 11 should generally be prescribed first, except in cases affecting the face or intertriginous areas, where s effects occur most frequently. Mid- and high-potency glucocorticoids should be used only for short inte the face because corticosteroid-induced rosacea, acne, or perioral dermatitis of striking magnitude ma They should be applied sparingly two or three times daily, or more frequently for some dermatoses. Ve potent corticosteroids may be applied less often. For maximum effectiveness, creams should be rubbe gently until they vanish. Hydrocortisone 1% is useful for mild inflammatory dermatoses and is available a prescription. Hydrocortisone, which is nonfluorinated, does not usually induce facial telangiectasia, p dermatitis, atrophy, or striae and is thus usually preferred over a fluorinated corticosteroid for treating f dermatoses. The use of topical antibiotics with topical corticosteroids is seldom warranted. These combinations are no more effective than a corticosteroid alone, and allergic contact dermatitis from top antibiotics, especially neomycin, may complicate the primary problem.
Intralesional injection of a corticosteroid suspension (almost always triamcinolone acetonide) is usef delivering a high concentration of drug to a chronic lesion or to one resistant to topical corticosteroids. suspension may be diluted with sterile saline and is usually used at concentrations of 2.5 to 5 mg/mL t minimize risk of local dermal atrophy and, in black patients, hypopigmentation. Dermal atrophy is usua reversible. Higher concentrations of up to 40 mg/mL may be used to treat keloids.

Section 10. Dermatologic Disorders Chapter 119. Reactions To Sunlight Topics
[General] Sunburn Chronic Effects Of Sunlight Photosensitivity
[General]
Sun Exposure
The skin may respond to excessive sunlight in several ways: sunburn, chronic changes (dermatohelios photosensitivity.
Although the sun emits a wide range of ultraviolet (UV) electromagnetic radiation (ie, UVA, 320 to 400 UVB, 280 to 320 nm; UVC, 10 to 280 nm), only UVA and UVB reach the earth's surface. The characte amount of such radiation vary greatly with the seasons and with changing atmospheric conditions. Exp skin to sunlight depends on multiple factors, eg, clothing, lifestyle, occupation, and geographic factors, altitude and latitude.
Sunburn-producing rays (< 320 nm) are filtered out by glass (eg, windows) and to a great extent by sm smog. Large amounts of sunburn-producing rays may pass through light clouds, fog, or 30 cm (1 ft) of water, causing severe reactions in many unsuspecting persons. Snow, sand, and bright sky enhance e by reflecting the rays. Stratospheric ozone, which filters out shorter wavelengths of UV, is depleted by man-made chlorofluorocarbons (eg, in refrigerants and aerosols). A decreased ozone layer increases inadvertent exposure to UVA and UVB.
Pathophysiology
Sun-tanning lamps use artificial light that is more UVA than UVB, but some long-term deleterious effec should be expected. Even light sources that contain only UVA adversely affect the skin.
After exposure to sunlight, the epidermis thickens and melanocytes produce melanin at an increased r providing some natural protection against future exposure. Furthermore, exposure leads to functional alterations in epidermal Langerhans' cells (which are immunologically important).
should be expected. Even light sources that contain only UVA adversely affect the skin.
After exposure to sunlight, the epidermis thickens and melanocytes produce melanin at an increased r providing some natural protection against future exposure. Furthermore, exposure leads to functional alterations in epidermal Langerhans' cells (which are immunologically important).
Persons differ greatly in their reactivity to sunlight. Pigmentation does not occur in the skin of albinos b of a defect in melanin metabolism, nor does it occur in areas of vitiligo because of the absence of melanocytes. Blacks and other nonwhites are less sensitive to sun exposure than fair-skinned persons they are not immune to the effects of the sun and can become sunburned with prolonged exposure. P with blonde or red hair are especially susceptible. Uneven melanin deposition occurs in many fair-haire persons and results in freckling.

Section 10. Dermatologic Disorders Chapter 111. Dermatitis Topics
[General] Contact Dermatitis Atopic Dermatitis Seborrheic Dermatitis Nummular Dermatitis Chronic Dermatitis Of The Hands And Feet Generalized Exfoliative Dermatitis Stasis Dermatitis Lichen Simplex Chronicus
[General]
Dermatitis (eczema): Superficial skin inflammation, characterized histologically by epidermal edema an clinically by vesicles (when acute), poorly marginated redness, edema, oozing, crusting, scaling, usua pruritus, and lichenification caused by scratching or rubbing.
Authorities generally disagree about how to use the synonymous terms eczema and dermatitis. Often, refers to vesicular dermatitis, but some authorities restrict eczema to mean chronic dermatitis. Some a to dermatitis as spongiotic dermatitis because spongiosis (intraepidermal edema) is a histologic featur

Section 10. Dermatologic Disorders Chapter 120. Bullous Diseases Topics
[General] Pemphigus Bullous Pemphigoid Dermatitis Herpetiformis Linear Immunoglobulin A Disease
[General]
(See also Herpes Gestationis in Ch. 252.)
Section 10. Dermatologic Disorders Chapter 112. Bacterial Infections Of The Skin Topics
[General] Cellulitis Acute Lymphangitis Lymphadenitis Erysipelas Cutaneous Abscesses Necrotizing Subcutaneous Infections Staphylococcal Scalded Skin Syndrome Folliculitis Furuncles Hidradenitis Suppurativa Carbuncles Paronychial Infections Erythrasma
[General]
(See also Erysipelothricosis in Ch. 157.)
When infections are clinically atypical or unresponsive to initial attempts at therapy, the specific bacter causing a skin infection should be identified (see Special Diagnostic Methods in Ch. 109). Knowledge many bacteria normally inhabit the skin (eg, micrococci, diphtheroids, Propionibacterium acnes) helps interpret culture results.
Bacterial infection may be the primary cause of a skin lesion, or infection or colonization may be secon another skin disease. Primary infections (eg, impetigo, erysipelas) usually respond promptly to system antibiotics, whereas secondary infections tend to clear more slowly, requiring more complicated treatm regimens (see Impetigo and Ecthyma under Bacterial Infections in Ch. 265). Recurrent infections shou the physician to a possible underlying systemic disorder, especially diabetes, or an immunodeficient st

Section 10. Dermatologic Disorders Chapter 121. Disorders Of Cornification Topics
Ichthyosis Keratosis Pilaris Calluses And Corns
Ichthyosis
Dry skin.
Ichthyosis ranges from mild but annoying dryness to severe dryness with scales and flaking that becom disfiguring. Several ichthyotic skin diseases are inherited; ichthyosis is a symptom in several rare here syndromes and in several systemic disorders.
Xeroderma (xerosis), the mildest form of ichthyosis, is neither congenital nor associated with systemic abnormalities. It usually occurs on the lower legs of middle-aged or older patients, most often during c weather and in those who bathe too frequently. There may be mild to moderate itching and an associa dermatitis caused by detergents or other irritants.
Inherited ichthyoses, which are characterized by excessive accumulation of scale on the skin surface classified according to clinical and genetic criteria (see Table 121-1). Consultation with a dermatologis recommended to provide genetic counseling and guidance to treatments. Ichthyosis is a symptom in R syndrome (rare hereditary ataxia with polyneuritic changes and deafness caused by a defect in the en phytanic acid hydroxylase) and in Sjgren-Larsson syndrome (hereditary mental deficiency and spasti paralysis); both syndromes are autosomal recessive.
Acquired ichthyosis may be an early manifestation in some systemic diseases (eg, leprosy, hypothyr lymphoma, AIDS). The dry scaling may be fine and localized to the trunk and legs, or it may be thick a widespread. Biopsy of ichthyotic skin is usually not diagnostic; however, there are exceptions, most no sarcoidosis, in which a thick scaling may appear on the legs and biopsy usually shows typical granulom
Treatment
In any ichthyosis, minimizing bathing is helpful. Soaps should be used only in intertriginous areas. Hexachlorophene products should not be used because of increased absorption and toxicity. An emollient--preferably plain petrolatum, mineral oil, or lotions containing urea or -hydroxy acids--should
Treatment
In any ichthyosis, minimizing bathing is helpful. Soaps should be used only in intertriginous areas. Hexachlorophene products should not be used because of increased absorption and toxicity. An emollient--preferably plain petrolatum, mineral oil, or lotions containing urea or -hydroxy acids--should applied twice daily, especially after bathing (for 10 min to hydrate the stratum corneum) while the skin wet. Blotting dry with a towel will remove excess applied oil. Ichthyosis caused by an underlying system disease may slightly improve with lubrication using propylene glycol. However, improvement is greates primary disease can be corrected.
To remove the scale in ichthyosis vulgaris, X-linked ichthyosis, and lamellar ichthyosis, a preparation containing 50% propylene glycol in water under occlusion (eg, thin plastic film or bags) every night afte hydration of the skin is particularly effective. In children, it should be applied twice daily without an occ dressing overnight. After scaling has decreased, less frequent application is required. Other useful age include 5% or 6% salicylic acid gel, hydrophilic petrolatum and water (in equal parts), and cold cream a -hydroxy acids (eg, lactic, glycolic, and pyruvic acids) in various bases.
Patients with epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma) may need long-term cloxacillin 250 mg po tid or qid or erythromycin 250 mg po tid or qid as long as thick intertrig scaling is present to prevent superinfection with painful, foul-smelling pustules. Regular use of soaps containing chlorhexidine may also reduce the bacteria.
The most effective therapies for most ichthyoses are oral synthetic retinoids. Etretinate (see Psoriasis 117) is effective in X-linked ichthyosis and epidermolytic hyperkeratosis. In lamellar ichthyosis, 0.1% tr (vitamin A acid, retinoic acid) cream or oral isotretinoin may be effective. The lowest effective dosage be used. Long-term (>= 1 yr) treatment with oral isotretinoin has resulted in bony exostoses in some p and other long-term side effects may arise. (Caution: Oral retinoids are contraindicated in pregnancy of their teratogenicity, and etretinate should be avoided in women of childbearing potential because of teratogenicity and long half-life.)

Section 10. Dermatologic Disorders Chapter 113. Fungal Skin Infections Topics
Dermatophyte Infections Yeast Infections
Dermatophyte Infections
(Ringworm)
Infections caused by dermatophytes--fungi that invade only dead tissues of the skin or its appendages (stratum corneum, nails, hair).
Trichophyton, Epidermophyton, and Microsporum are most commonly involved, but clinical differentiat dermatophytes is difficult. Transmission is usually from person to person or animal to person. Fomites usually responsible.
Some dermatophytes produce only mild or no inflammation or immune reaction; in such cases, the org may persist indefinitely, causing intermittent remissions and exacerbations of a gradually extending les a scaling, slightly raised border. In other cases, infection may be acute, typically causing a sudden ves and bullous disease of the feet or an inflamed boggy lesion of the scalp (kerion) that results from a str immune reaction to the fungus; such infection is usually followed by remission or cure.
Diagnosis
Diagnosis is made clinically according to site of infection and confirmed by direct microscopic examina scales dissolved in a solution of potassium hydroxide or by culture, demonstrating the pathogenic fung scrapings of lesions (see also Special Diagnostic Methods in Ch. 109).
Treatment
Most skin infections respond very well to topical antifungal preparations, such as the imidazoles (miconazole, clotrimazole, econazole, ketoconazole), ciclopirox, naftifine, or terbinafine. Resistant cas those with widespread involvement require systemic therapy.
Newer systemic drugs include itraconazole and fluconazole, oral triazoles, and terbinafine, a second-generation allylamine. These drugs appear to be safer and more effective than ketoconazole (
Most skin infections respond very well to topical antifungal preparations, such as the imidazoles (miconazole, clotrimazole, econazole, ketoconazole), ciclopirox, naftifine, or terbinafine. Resistant cas those with widespread involvement require systemic therapy.
Newer systemic drugs include itraconazole and fluconazole, oral triazoles, and terbinafine, a second-generation allylamine. These drugs appear to be safer and more effective than ketoconazole ( General Therapeutic Principles in Ch. 158), a broad-spectrum oral imidazole derivative that is effective dermatophyte infections, although occasional liver toxicity (severe or even fatal) limits its use. Itracona interacts with many commonly prescribed drugs. Terbinafine delays gastric emptying, and GI side effe in 3 to 5% of patients. Disturbances of taste occur less frequently, and hematologic and hepatic side e are rare. However, liver function should be evaluated at baseline and periodically thereafter. The new antifungals are more effective than griseofulvin in all dermatophytoses, except possibly tinea capitis.
Until recently, griseofulvin was the most widely used systemic antifungal drug, but its use as first-line t of cutaneous fungal infections is decreasing with the availability of newer drugs. The adult dosage is m griseofulvin 250 mg po bid to qid, best given with a high-fat meal. Ultramicrosize griseofulvin is better a and should be given in a single or divided total dose of 250 to 330 mg po for tinea corporis, capitis, or and 500 to 660 mg po for tinea pedis. Headache is the most common side effect, and the drug occasi causes GI distress, photosensitivity, rashes, or leukopenia. Angioedema has been reported. Vertigo a rarely, exacerbation of lupus erythematosus or transient hearing reduction may occur. Topical imidazo with oral griseofulvin increase the cure rate.
TINEA CORPORIS
(Ringworm of the Body)
Trichophyton sp is usually the cause. The characteristic pink-to-red papulosquamous annular plaques raised borders, expand peripherally, and tend to clear centrally. Differential diagnosis includes pityrias drug eruptions, nummular dermatitis, erythema multiforme, tinea versicolor, erythrasma, psoriasis, and secondary syphilis. A variant form appears as nummular scaling patches studded with small papules o pustules.
For mild-to-moderate lesions, an imidazole, ciclopirox, naftifine, or terbinafine in cream, lotion, or gel fo should be rubbed in twice daily for at least 7 to 10 days after lesions disappear. Inflammatory types of corporis usually respond readily to specific topical antifungal medications. Extensive and resistant lesio occur in patients infected with Trichophyton rubrum and in persons with debilitating systemic diseases extensive or resistant tinea corporis, the most effective therapy is oral itraconazole or terbinafine (see
TINEA PEDIS
(Ringworm of the Feet; Athlete's Foot)
Tinea pedis is common. Trichophyton mentagrophytes infections typically begin in the 3rd and 4th inte spaces and later involve the plantar surface of the arch. Toe web lesions often are macerated and hav scaling borders; they may be vesicular. Acute flare-ups, with many vesicles and bullae, are common d warm weather. Infected toenails become thickened and distorted. T. rubrum produces scaling and thic of the soles, often extending just beyond the plantar surface in a "moccasin" distribution. Itching, pain, inflammation, or vesiculation may be slight or severe. Tinea pedis may be complicated by secondary b infection, cellulitis, or lymphangitis, which may recur. Tinea pedis may be confused with maceration (fr hyperhidrosis and occlusive footgear), contact dermatitis (from sensitivity to various materials in shoes particularly adhesive cement), eczema, or psoriasis.
Itraconazole and terbinafine are the most effective treatments for mycologically proven tinea pedis but
inflammation, or vesiculation may be slight or severe. Tinea pedis may be complicated by secondary b infection, cellulitis, or lymphangitis, which may recur. Tinea pedis may be confused with maceration (fr hyperhidrosis and occlusive footgear), contact dermatitis (from sensitivity to various materials in shoes particularly adhesive cement), eczema, or psoriasis.
Itraconazole and terbinafine are the most effective treatments for mycologically proven tinea pedis but have little immediate effect on an acute inflammatory infection, which is a cell-mediated immune react Either drug may be used to treat chronic infections and prevent acute exacerbations. Interdigital infect be successfully treated with topical agents. Systemic treatment for infected nails (onychomycosis) may therapy for many months and is especially difficult if the toenails are involved. Because of the keratoph characteristics of these newer drugs, itraconazole 200 mg/day for 1 mo or pulse therapy with 200 mg b wk/mo for 1 to 2 mo often cures uncomplicated tinea pedis. Concomitant topical antifungal use may re recurrences.
Good foot hygiene is essential. Interdigital spaces must be dried after bathing, macerated skin gently d and a bland, drying antifungal powder (eg, miconazole) applied. Light permeable footwear is recomme especially during warm weather; many patients even benefit from going barefoot. During acute vesicul flare-ups, bullae may be drained at the margin, but the keratinous blister roof should not be removed. agents include tap water or dilute Burow's solution (twice-daily soaks).
Cure with topical treatment is difficult, but control may be obtained with long-term therapy. Recurrence common after therapy is discontinued.
TINEA UNGUIUM
(Ringworm of the Nails)
This form of onychomycosis is usually caused by Trichophyton sp. Infections of the fingernails are less common than those of the toenails. The nails thicken and become lusterless, and debris accumulates the free edge. The nail plate becomes thickened and separated, and the nail may be destroyed. Differ a Trichophyton infection from psoriasis is particularly important because drug therapy for tinea unguium specific, and long-term treatment is required.
When griseofulvin is used to treat onychomycosis, long-term cure is achieved in < 20% of cases. Ther systemic treatment with oral itraconazole or oral terbinafine is probably the treatment of choice. Itracon 200 mg po bid 1 wk/mo for 4 mo or terbinafine 250 mg/day achieves a high cure rate for fingernail and infections. For onychomycosis of fingernails, the duration of terbinafine treatment is 6 wk, and for toen wk. It is not necessary to treat until all abnormal nail is gone because these drugs remain bound to the plate and continue to be effective after oral administration has ceased. Topical treatments for nail infe are rarely effective, except for the superficial white type, in which infection occurs on the nail surface o
TINEA CAPITIS
(Ringworm of the Scalp)
Tinea capitis mainly affects children. It is contagious and may become epidemic. Trichophyton tonsura common cause in the USA; other Trichophyton sp (eg, Trichophyton violaceum) are common causes elsewhere. T. tonsurans infection of the scalp is often subtle in onset. Inflammation is often low-grade persistent; the lesions are not annular or sharply marginated, so the disorder resembles seborrheic de Characteristic black dots on the scalp result from broken hairs. Inflammatory infections can occur. Trichophyton sp may persist in adults.
elsewhere. T. tonsurans infection of the scalp is often subtle in onset. Inflammation is often low-grade persistent; the lesions are not annular or sharply marginated, so the disorder resembles seborrheic de Characteristic black dots on the scalp result from broken hairs. Inflammatory infections can occur. Trichophyton sp may persist in adults.
Microsporum audouinii and M. canis, once predominant, are less common causes of tinea capitis in th M. audouinii lesions are small, scaly, semi-bald grayish patches with broken, lusterless hairs. Infection limited to a small area or extend and coalesce until the entire scalp is involved; sometimes ringed patc extend beyond the scalp margin. M. canis and M. gypseum usually cause an inflammatory reaction, w shedding of the infected hairs. A raised, inflamed, boggy granuloma (kerion) may also occur and may mistaken for an abscess or a pyoderma; it is followed shortly by healing.
Trichophyton, an endothrix, produces chains of arthrospores that can be seen microscopically within th the hairs do not fluoresce under Wood's light. Diagnosis of a Microsporum infection is facilitated by ex the scalp under Wood's light; infected hairs may fluoresce a light, bright green. Microsporum is also an ectothrix, producing spores to form a sheath around the hair. The sheath can be seen on microscopy. of the fungus is also important in establishing the diagnosis.
Children with Trichophyton infection should be given microsize griseofulvin suspension 10 to 20 mg/kg ultramicrosize griseofulvin 5 to 10 mg/kg/day with meals or milk for at least 4 wk or until all signs of infe are gone. Until tinea capitis is cured, an imidazole or ciclopirox cream should be applied to the scalp to spread, especially to other children, and selenium sulfide 2.5% shampoo should be used daily.
TINEA CRURIS
(Jock Itch)
Tinea cruris, more common in males, may be caused by various dermatophytic organisms. Typically, a lesion extends from the crural fold over the adjacent upper inner thigh. Both sides may be affected. Sc dermatitis and lichenification often occur. Lesions may be complicated by maceration, miliaria, second bacterial or candidal infection, and reactions to treatment. Recurrence is common because fungi may repeatedly infect susceptible persons. Flare-ups occur more often during summer. Tight clothing or ob tends to favor growth of the organisms.
The infection may be confused with contact dermatitis, psoriasis, erythrasma, or candidiasis. In derma infections, scrotal involvement is usually absent or slight; however, the scrotum is often inflamed in ca intertrigo or lichen simplex chronicus.
Topical therapy with a cream or lotion, as in tinea corporis, is often effective. In some cases, itraconaz mg/day or terbinafine 250 mg/day po for 3 to 6 wk may be needed.
TINEA BARBAE
(Ringworm of the Beard; Barber's Itch)
Mycotic infection of the beard area is rare. Infections in this area are more commonly bacterial (see Fo in Ch. 112) but may be fungal, especially in agricultural workers. The causative agent is established microbiologically.
Oral terbinafine is the best treatment. If the lesions are severely inflamed, a short course of prednison be added (to lessen symptoms and perhaps reduce the chance for scarring), starting with 40 mg/day p adults) and tapering the dose over 2 wk.
in Ch. 112) but may be fungal, especially in agricultural workers. The causative agent is established microbiologically.
Oral terbinafine is the best treatment. If the lesions are severely inflamed, a short course of prednison be added (to lessen symptoms and perhaps reduce the chance for scarring), starting with 40 mg/day p adults) and tapering the dose over 2 wk.
DERMATOPHYTIDS OR ID ERUPTIONS
These fungus-free skin lesions are of variable morphology and occur elsewhere on the body during an vesicular or inflammatory dermatophyte infection; they are thought to result from hypersensitivity to a f
Although sometimes caused by a dermatophyte infection or id reaction, vesicular dermatitis of the han most commonly something else (see Chronic Dermatitis of Hands and Feet in Ch. 111). Treatment of reaction consists of diagnosis and treatment of the underlying dermatophyte infection. A topical cortico cream or lotion and an oral antihistamine (eg, hydroxyzine hydrochloride 25 mg qid) may provide some

Section 10. Dermatologic Disorders Chapter 122. Pressure Sores Topics
[General]
[General]
Pressure sores (bedsores; decubitus ulcers; trophic ulcers): Ischemic necrosis and ulceration of tissue overlying a bony prominence that has been subjected to prolonged pressure against an external objec bed, wheelchair, cast, splint).
Pressure sores occur most often in patients with diminished or absent sensation or who are debilitated emaciated, paralyzed, or long bedridden. Tissues over the sacrum, ischia, greater trochanters, externa malleoli, and heels are especially susceptible; other sites may be involved depending on the patient's Pressure sores can also affect muscle and bone.
Etiology
Intrinsic factors include loss of pain and pressure sensations (which ordinarily prompt the patient to s position and relieve the pressure) and minimal fat and muscle padding between bony weight-bearing prominences and skin. Disuse atrophy, malnutrition, anemia, and infection contribute. In a paralyzed p loss of vasomotor control leads to lowered tone in the vascular bed and lowered circulatory rate. Spas especially in patients with spinal cord injuries, can place a shearing force on the blood vessels to furth compromise circulation.
Of extrinsic factors, the most important is pressure due to infrequent shifting of the patient's position; irritation, and pulling of skin from ill-adjusted supports or wrinkled bedding or clothing contribute. The f duration of pressure directly determine the extent of the ulcer. In an immobilized patient, severe press impair local circulation in < 3 h, causing local tissue anoxia that, if unrelieved, progresses to necrosis o skin and subcutaneous tissues. Moisture (eg, from perspiration or incontinence) leads to tissue macer and predisposes to pressure sores. The stages of pressure sore formation correspond to tissue layers (see Table 122-1).
Prophylaxis
and predisposes to pressure sores. The stages of pressure sore formation correspond to tissue layers (see Table 122-1).
Prophylaxis
The best treatment is prevention by relief of pressure on sensitive areas.
In a bedridden patient, position must be changed at least q 2 h until tolerance for longer periods can b demonstrated (by the absence of redness). Air-filled alternating-pressure mattresses, sponge-rubber e mattresses, and silicone gel or water mattresses help decrease pressure on sensitive areas but do no the need for position changes q 2 h. When maximal relief of pressure is needed, other systems, includ flotation mattresses, must be used. A Stryker frame facilitates turning patients with spinal cord injuries Protective padding (eg, sheepskin or a synthetic equivalent) at bony prominences should be used, esp under braces or plaster casts; a window should be cut out of the cast at potential pressure sites.
Wheelchair-bound patients may develop pressure sores. Thus, they must shift position or be shifted q min, even if a pressure-relieving pillow is used.
Inspection under adequate light is important. Pressure points should be checked for erythema or trau least once/day. Patients and families must be taught a routine of daily visual inspection and palpation for potential ulcer formation.
Meticulous care is necessary to prevent maceration and secondary infection. Lying on a sheepskin h keep the patient's skin in good condition and minimize pressure sores. Protective padding, pillows, or sheepskin can be used to separate body surfaces.
Maintaining cleanliness and dryness helps prevent maceration. Bedding and clothing should be cha frequently; sheets should be soft, clean, and free from wrinkles and particulate matter. Sponging the s weather and thorough drying after baths are essential. Special efforts are required for incontinent patie Most areas may be powdered with plain talc.
Oversedation should be avoided and activity encouraged. Physiotherapy, when practicable, may be ca by means of passive and active exercises. Hydrotherapy is also valuable.
A well-balanced diet, high in protein, is important. There is some evidence that supplemental vitamin zinc help healing.
Treatment
The ulcer is analogous to an iceberg; it has a small visible surface with a more extensive unknown bas is no good method to determine the extent of tissue damage.
Incipient pressure sores (stages 1 and 2) require all the prophylactic measures above to prevent necro area should be kept exposed, free from pressure, and dry. Stimulating the circulation by gentle massa accelerate healing.
Ulcers that have not advanced beyond stage 3 may heal spontaneously if the pressure is removed an area is small. New hydrophilic gels and hydrocolloid dressings speed healing.
Stage 4 ulcers require debridement or more extensive surgery. When the ulcers are filled with pus or n debris, dextranomer beads or newer hydrophilic polymers may hasten debridement without surgery.
Ulcers that have not advanced beyond stage 3 may heal spontaneously if the pressure is removed an area is small. New hydrophilic gels and hydrocolloid dressings speed healing.
Stage 4 ulcers require debridement or more extensive surgery. When the ulcers are filled with pus or n debris, dextranomer beads or newer hydrophilic polymers may hasten debridement without surgery. Conservative debridement of necrotic tissue with forceps and scissors should be instituted. Some ulce be debrided by cleansing with 1.5% hydrogen peroxide. Whirlpool baths may assist debridement.
More advanced ulcers with fat and muscle involvement require surgical debridement and closure. Affe bony tissue may require surgical removal; disarticulation of a joint may be needed. The granulation tiss formation that follows debridement may provide a satisfactory base for skin grafts to cover small areas sliding full-thickness skin flap graft is the closure of choice, especially over large bony prominences (eg sacrum, ischia, the trochanters), because scar tissue cannot develop the tolerance to pressure that is For adequate healing, the patient may need to be placed on a bed that redistributes weight, such as o a forced-air system.
For cellulitis, a penicillinase-resistant penicillin or a cephalosporin is necessary. Culture is generally no in choosing an antibiotic, and surface growth is often polymicrobial.
Many new dressings and topical agents are becoming available. No powder, gel, or dressing is univers superior because some are hydrophilic and highly occlusive; prolonged use increases the risk of infect such as Pseudomonas. Others are painful, all are expensive, and controlled clinical trials evaluating th advantages and disadvantages of various dressings often are not available. Valuable advice on the ca decubiti can often be obtained from geriatric nurse practitioners. Plastic surgery consultation is someti needed.

Section 10. Dermatologic Disorders Chapter 114. Parasitic Skin Infections Topics
[General] Scabies Pediculosis Creeping Eruption
[General]
(See also Ch. 161.)

Section 10. Dermatologic Disorders Chapter 123. Pigmentation Disorders Topics
Hypopigmentation Hyperpigmentation
Hypopigmentation
A congenital or acquired decrease in melanin production.
The three main types of hypopigmentation are vitiligo, albinism, and postinflammatory hypopigmentati
Vitiligo affects 1 to 2% of the population. The cause is unknown; although usually acquired, vitiligo is sometimes familial (autosomal dominant, with incomplete penetrance and variable expression). It may unusual physical trauma, especially of the head. The association of vitiligo with Addison's disease, dia mellitus, pernicious anemia, and thyroid dysfunction, as well as a high incidence of serum antibodies t thyroglobulin, adrenal cells, and parietal cells, has led to a postulated immunologic and neurochemica disease. Some patients have antibodies to melanin.
Vitiligo is characterized by depigmented areas, usually sharply demarcated and often symmetric, caus lack of melanocytes. Depigmentation may involve one or two spots or may cover most of the skin surfa in vitiliginous areas is usually white. Skin lesions are accentuated under Wood's light. Lesions are pron sunburn, requiring use of protective clothing, sun avoidance, and repeated applications of a sunscreen sun protective factor (SPF) of >= 15.
Treatment is for the cosmetic disfigurement. Topical corticosteroids occasionally help. Oral and topica psoralens with ultraviolet A (PUVA) have been used, but treatment is protracted and results vary. Khel furanochrome, can be used in combination with PUVA. However, 100 to 200 treatments are required t achieve a satisfactory result. Melagenena, an extract of human placenta, has had variable success in and the Far East. Cover-up cosmetics are much more satisfactory for most when cure is doubtful. Sma lesions may be camouflaged with cosmetic creams or tanning solutions that do not wipe off on clothing last several days.
Albinism is a rare autosomal recessive inherited disorder in which melanocytes are present but do no melanin. There are various forms. In tyrosinase-negative albinism, the hair is white, the skin pale, and pink; nystagmus and errors of refraction are common. Albinos sunburn easily and frequently develop s cancers (see Ch. 126). They should avoid sunlight, use sunglasses, and during daylight hours use a s
last several days.
Albinism is a rare autosomal recessive inherited disorder in which melanocytes are present but do no melanin. There are various forms. In tyrosinase-negative albinism, the hair is white, the skin pale, and pink; nystagmus and errors of refraction are common. Albinos sunburn easily and frequently develop s cancers (see Ch. 126). They should avoid sunlight, use sunglasses, and during daylight hours use a s with an SPF of >= 15.
Postinflammatory hypopigmentation follows healing of certain inflammatory disorders (especially bu dermatoses), burns, and skin infections and appears in scars and atrophic skin. Although pigmentation reduced, the skin may not be ivory-white as in vitiligo, and spontaneous repigmentation may occur. Co cosmetics are most satisfactory.

Section 10. Dermatologic Disorders Chapter 115. Viral Skin Infections Topics
[General] Warts Molluscum Contagiosum
[General]
Herpes simplex and herpes zoster, although considered viral skin infections, are discussed in Ch. 162

Section 10. Dermatologic Disorders Chapter 124. Disorders Of Sweating Topics
Miliaria Hyperhidrosis
Miliaria
(Prickly Heat)
An acute inflammatory pruritic eruption due to blockage of sweat gland ducts and retained sweat.
Miliaria usually occurs in warm humid weather but may occur in cool weather in an overdressed patien horny layer of the epidermis swells, obstructing eccrine sweat gland ducts. Sweat fails to reach the ski surface and is trapped in the epidermis or dermis, where it causes irritation (prickling) and often severe Appearance of the lesions depends on the depth of the obstruction. In miliaria crystallina, ductal obs is in the uppermost epidermis, and the typical minute lesions are tense transparent vesicles that lack inflammation. In miliaria rubra, obstruction with inflammation occurs deeper in the epidermal acrosyri and the lesions are red. In miliaria profunda, ductal obstruction occurs at the entrance of the duct int dermal papillae; it is the deepest and most severe form of miliaria. Miliaria profunda manifests with larg deeper-seated, frequently painful papules. Intertriginous areas are favored.
Treatment
Treatment is symptomatic (cooling and drying the involved areas) and prophylactic (avoiding condition may induce sweating). An air-conditioned environment is ideal. Corticosteroid lotions, sometimes with menthol added, are often used; however, topical therapy is less effective than a change of environmen lighter clothing.
Section 10. Dermatologic Disorders Chapter 116. Disorders Of Hair Follicles And Seba Glands Topics
Acne Rosacea Perioral Dermatitis Hypertrichosis Alopecia Pseudofolliculitis Barbae Keratinous Cyst
Acne
Pathogenesis
A common inflammatory disease of the pilosebaceous glands characterized by comedones, papules, p inflamed nodules, superficial pus-filled cysts, and (in extreme cases) canalizing and deep, inflamed, so purulent sacs.
An interaction among hormones, keratin, sebum, and bacteria determines the course and severity. Ac usually begins at puberty, when an increase in androgens causes an increase in the size and activity o pilosebaceous glands. Inflammatory acne lesions include papules, pustules, and nodules or cysts. Noninflammatory lesions include open and closed comedones (ie, blackheads and whiteheads). First, intrafollicular hyperkeratosis leads to blockage of the pilosebaceous follicle; consequently, comedones composed of sebum, keratin, and microorganisms, particularly Propionibacterium acnes. Lipases from acnes break down triglycerides in the sebum to free fatty acids (FFA), which irritate the follicular wall. R of sebaceous secretions and dilation of the follicle may lead to cyst formation. Rupture of the follicle, w release into the tissues of FFA, bacterial products, and keratin, induces an inflammatory reaction that results in an abscess. These abscesses heal, with scarring in severe cases. Acne usually spontaneou remits, but the time of remittence cannot be predicted.
Symptoms and Signs
Acne is often worse in winter and improved in summer, probably because of the benefits of sunlight. D little effect; however, if a food is suspected, it should be omitted for several weeks and then eaten in substantial quantities to determine if acne worsens. Acne may cycle with the menses, and it may impr
Symptoms and Signs
Acne is often worse in winter and improved in summer, probably because of the benefits of sunlight. D little effect; however, if a food is suspected, it should be omitted for several weeks and then eaten in substantial quantities to determine if acne worsens. Acne may cycle with the menses, and it may impr worsen during pregnancy. Although cosmetics rarely aggravate acne, the traditional advice to avoid gr preparations seems prudent.
Superficial acne: Blackheads (open comedones) or whiteheads (closed comedones), inflamed papul pustules, and superficial cysts are characteristic. Large cysts occur occasionally, sometimes after man or trauma to an otherwise uninflamed blackhead. The prognosis for healing without scars is good in su acne, but attempts to extrude blackheads or superficial cysts and scratching of ruptured lesions may in scarring.
Deep acne: This form is characterized by the above findings with deep inflamed nodules and pus-fille which often rupture and become abscesses. Some of the abscesses open on the skin surface and dis their contents. Lesions are most common on the face, but the neck, chest, upper back, and shoulders also be affected. Scarring is frequent.
Diagnosis
Comedones are almost always present, and lesions at various stages of development are seen simultaneously. Differential diagnosis includes rosacea, which does not have comedones, and corticosteroid-induced acneiform lesions, which usually have follicular pustules in the same stage of development and no comedones.
Treatment
Although acne is almost universal, it may embarrass adolescents, who may withdraw, using the acne a excuse to avoid difficult personal adjustments. Supportive counseling for patients and parents may be Misconceptions about a relationship between acne and diet, athletics, or sex are common and warran discussion. Treatment depends on the severity of the lesions.
Superficial acne: Although washing lesions several times a day has little effect, the appearance of an face often improves. Any good toilet soap may be used. Antibacterial soaps are of no benefit, and irrita from abrasive soaps makes it difficult to use follicular drugs (see below).
In superficial pustular acne, topical clindamycin or erythromycin alone or with one of the follicular dru mentioned below is probably most useful. Sunlight causes mild dryness and slight scaling and is usua helpful. However, sunlight is not always available, and its benefit may be difficult to duplicate with a su Azelaic acid cream 20%, which has antiproliferative and antibacterial effects, may be effective in come inflammatory acne.
Topical tretinoin (retinoic acid) in 0.025%, 0.05%, or 0.1% cream, 0.05% liquid, or 0.01% or 0.025% ge often effective. A new topical retinoid, adapalene 0.1% gel, was recently approved in the USA. It may slightly less irritating than topical tretinoin. These retinoids must be applied carefully and at night (ever night if irritation is excessive), going over the entire affected area only once. The eyes, nasolabial folds creases of the mouth should be avoided. The liquid form of tretinoin should be applied with a cotton-tip applicator. Exposure to sunlight and use of other drugs are restricted to prevent severe irritation. With or adapalene, acne may worsen at first; improvement usually requires >= 3 to 4 wk.
slightly less irritating than topical tretinoin. These retinoids must be applied carefully and at night (ever night if irritation is excessive), going over the entire affected area only once. The eyes, nasolabial folds creases of the mouth should be avoided. The liquid form of tretinoin should be applied with a cotton-tip applicator. Exposure to sunlight and use of other drugs are restricted to prevent severe irritation. With or adapalene, acne may worsen at first; improvement usually requires >= 3 to 4 wk.
Other topical drugs include 5% to 10% benzoyl peroxide, OTC drugs, and various sulfur-resorcinol combinations; they are usually applied twice daily or one preparation at night and another in the morni antibiotics may also be helpful in superficial pustular acne.
Deep acne: Vigorous management is required to reduce residual scarring. For severe, deep lesions, t treatment is unsatisfactory; a broad-spectrum oral antibiotic is usually effective because it reduces ba organisms. The most cost-effective is tetracycline; 250 mg qid or 500 mg bid (between meals and at b should be continued for >= 4 wk and then decreased to the lowest effective dose. Occasionally the do must be increased to 500 mg qid. Because relapse ordinarily follows short-term treatment, therapy mu continued for months to years, although tetracycline 250 or 500 mg/day is often sufficient. Many dermatologists consider the more costly minocycline to be the systemic antimicrobial of choice becaus efficacy, lack of GI side effects, simplified dosing with regard to meals, and lack of photosensitization. effects include dizziness and pigmentation of the skin and mucous membranes. Other systemic antim that may be used include erythromycin and doxycycline. Both can cause GI side effects, and doxycycl frequent photosensitizer. Full-dose systemic antibiotics (tetracycline 500 mg bid, minocycline 100 mg b doxycycline 100 mg bid, and erythromycin 333 mg tid) should be continued for >= 4 wk before tapering Optimal therapeutic results are achieved in 6 to 12 wk.
The most common adverse effect of prolonged antibiotic use in women is candidal vaginitis. If local an systemic therapy does not eradicate this problem, antibiotic therapy for acne must be stopped. Long-te of antibiotics may also produce a gram-negative pustular folliculitis around the nose and in the center face. This uncommon superinfection may be difficult to clear and is best treated with oral isotretinoin a discontinuing the oral antibiotic.
Oral isotretinoin is the best treatment for patients in whom antibiotics are unsuccessful or in patients severe deep acne. This drug has revolutionized therapy for acne but should be used only by physician are familiar with its adverse effects. Because isotretinoin is teratogenic, women at risk of pregnancy m two methods of contraception for 1 mo before taking the drug, while taking the drug, and at least 1 mo discontinuing it. Pregnancy tests before beginning therapy and at monthly intervals are still recommen
The dosage of isotretinoin is usually 1 mg/kg/day for 20 wk. In recalcitrant cases, the dosage may be increased to 2 mg/kg/day. If side effects make this dosage intolerable, it may be reduced to 0.5 mg/kg After therapy, acne may continue to improve. Most patients do not require a second course of treatme needed, it should be resumed only after the drug has been stopped for 4 mo. Re-treatment is required often if the initial dosage is low (0.5 mg/kg/day). With this dosage (which is very popular in Europe), fe effects occur; however, prolonged therapy is usually required.
Side effects occur in virtually all patients; the most common are dryness of conjunctivae and mucosae genitalia and chapped lips. Petrolatum usually alleviates mucosal and cutaneous dryness. Musculoske symptoms (pain or stiffness of large joints or of the lower back) occur in about 15% of patients. CBC, l function, and triglyceride and cholesterol levels should be determined before treatment. Except for the each should be reassessed at 4 wk and, unless abnormalities are noted, need not be repeated until th treatment. Triglycerides rarely increase to a level at which the drug should be discontinued. Liver funct seldom affected.
For firm (cystic) acne lesions, injection of 0.1 mL triamcinolone acetonide suspension 2.5 mg/mL (t mg/mL suspension must be diluted) into an inflamed cyst or abscess is helpful; local atrophy (resulting the corticosteroid or destruction of tissue by the cyst) is usually transient. For isolated, very boggy lesio incision and drainage are often beneficial but may result in residual scarring.
treatment. Triglycerides rarely increase to a level at which the drug should be discontinued. Liver funct seldom affected.
For firm (cystic) acne lesions, injection of 0.1 mL triamcinolone acetonide suspension 2.5 mg/mL (t mg/mL suspension must be diluted) into an inflamed cyst or abscess is helpful; local atrophy (resulting the corticosteroid or destruction of tissue by the cyst) is usually transient. For isolated, very boggy lesio incision and drainage are often beneficial but may result in residual scarring.
Dermabrasion for small scars is sometimes useful, but its permanent effect is controversial. X-ray ther not justified. Topical corticosteroids, especially if fluorinated, may worsen acne. When other measures acne seems related to menses, an oral estrogen-dominant estrogen-progesterone-containing contrace may be tried; therapy >= 6 mo is needed to evaluate the effect.

Section 10. Dermatologic Disorders Chapter 125. Benign Tumors Topics
[General] Moles Dysplastic Nevi Skin Tags Lipomas Angiomas Pyogenic Granuloma Seborrheic Keratoses Dermatofibroma Keratoacanthoma Keloid
[General]
(See also Warts in Ch. 115, Keratinous Cyst in Ch. 116, and Genital Warts in Ch. 164.)

Section 10. Dermatologic Disorders Chapter 117. Scaling Papular Diseases Topics
[General] Psoriasis Pityriasis Rosea Lichen Planus Pityriasis Rubra Pilaris
[General]
Scaling papular diseases are either eczemas (see Ch. 111) or papulosquamous diseases. Unlike ecze papulosquamous diseases typically have sharp margins and lack signs of epithelial disruption, such as wetness, crusts, fissures, and excoriations.

Section 10. Dermatologic Disorders Chapter 126. Malignant Tumors Topics
[General] Basal Cell Carcinoma Squamous Cell Carcinoma Malignant Melanoma Paget's Disease Of The Nipples Kaposi's Sarcoma
[General]
Skin cancers, which are usually curable, are the most common type of cancer; most arise in sun-expo areas of skin (see also Ch. 119). The incidence is highest in outdoor workers, sportsmen, and sunbath is inversely related to the amount of melanin skin pigmentation; light-skinned persons are most suscep Skin cancers may also develop years after x-ray or radium burns or arsenic ingestion. Skin cancers inc basal cell and squamous cell carcinomas, malignant melanoma, Paget's disease of the nipple or extramammary Paget's (usually near the anus), Kaposi's sarcoma, tumors of adnexae, and cutaneous lymphoma (mycosis fungoides--see Ch. 139).

Section 22. Clinical Pharmacology Chapter 298. Drug Input And Disposition Topics
[General] Absorption Bioavailability Distribution Elimination
[General]
Drugs are almost always compounds foreign to the body. As such, they, unlike endogenous substance not continually being formed and eliminated. Drug absorption, bioavailability, distribution, and eliminati therefore determinants of onset, duration, and intensity of drug effect.

Section 22. Clinical Pharmacology Chapter 303. Monitoring Drug Treatment Topics
[General] Therapeutic Window Evaluation Of An Observed Concentration
[General]
Directly measuring the desired therapeutic effect is not always possible. For many drugs, surrogate en are used; they include biochemical markers or, occasionally, signs of toxicity (eg, tinnitus for salicylate nystagmus for phenytoin).
Monitoring plasma drug concentration is an easier, faster way to estimate dosage requirements than o drug effects only. Monitoring can determine when a target concentration range is reached and help en it is maintained.
A strategy for drug administration can sometimes be guided primarily by plasma drug concentrations ( Table 303-1). Whether plasma drug concentration monitoring is used may depend on the drug (see Ta 303-2) or on the clinical situation (see Table 303-3).
Frequency of monitoring depends on the drug, accuracy of previous measurements, and presumed ch factors affecting drug response. For example, for a patient with heart failure, digoxin levels need be m only occasionally if the patient's health is stable and drug therapy is not changed, but levels must be m more frequently if health deteriorates or if drugs known to interact with digoxin (eg, amiodarone, quinid added. Theophylline serum concentrations should probably be monitored daily for patients in ICUs, es if they have heart failure, pulmonary edema, or severe constrictive airway disease. In this setting, meta of the drug is reduced and varies extensively over time in the same patient.

Section 22. Clinical Pharmacology Chapter 299. Pharmacokinetics Topics
[General] Basic Pharmacokinetic Parameters Drug Administration Variability In Parameter Values
[General]
Pharmacokinetics: Study of the time course of a drug and its metabolites in the body after administrati any route.
An appropriate response to a drug requires the appropriate concentration of drug at the site of action. dosage regimen required to attain and maintain the appropriate concentration depends on pharmacok The appropriate concentration and dosage regimen depend on the patient's clinical state, severity of th disorder, presence of concurrent disease, use of other drugs, and other factors.
Because of individual differences, drug administration must be based on each patient's needs--traditio empirically adjusting dosage until the therapeutic objective is met. This approach is frequently inadequ because optimal response may be delayed or serious toxic reactions may occur. Alternatively, a drug administered according to its expected absorption and disposition (distribution and elimination--see als 298) in a patient, and dosage can be adjusted by monitoring plasma drug concentration and drug effe approach requires knowledge of the drug's pharmacokinetics as a function of the patient's age and we the kinetic consequences of concurrent diseases (eg, renal, hepatic, or cardiovascular disease or a combination of diseases).

Section 22. Clinical Pharmacology Chapter 304. Drug Therapy In The Elderly Topics
[General] Pharmacokinetics Pharmacodynamics Adverse Drug Reactions Considerations For Effective Pharmacotherapy
[General]
Safe, effective pharmacotherapy remains one of the greatest challenges in clinical geriatrics. The elde many chronic disorders and consequently use more drugs than any other age group. Their diminished physiologic reserves can be further depleted by effects of drugs and acute or chronic disease. Aging a pharmacodynamics and pharmacokinetics, affecting the choice, dose, and frequency of many drugs. I addition, pharmacotherapy may be complicated by an elderly patient's inability to purchase or obtain d to comply with drug regimens.
In the USA, about 2/3 of persons >= 65 yr take prescription and nonprescription (OTC) drugs. Women more drugs than men because they are on average older and because they use more psychoactive an antiarthritic drugs. At any given time, an average older person uses four to five prescription drugs and drugs and fills 12 to 17 prescriptions a year. The frail elderly use the most drugs. Drug use is greater in hospitals and nursing homes than in the community; typically, a nursing home resident receives seven drugs.
The type of drug used most often by the elderly varies with the setting. Community dwellers use analg diuretics, cardiovascular drugs, and sedatives most often; nursing home residents use antipsychotics a sedative-hypnotics most commonly, followed by diuretics, antihypertensives, analgesics, cardiac drugs antibiotics. Psychoactive drugs are prescribed for 65% of nursing home patients and for 55% of reside care patients; 7% of patients in nursing homes receive three or more psychoactive drugs concurrently.
Many drugs benefit the elderly. Some can save life--eg, antibiotics and thrombolytic therapy in acute il Oral hypoglycemic drugs can improve independence and quality of life while controlling chronic diseas Antihypertensive drugs and influenza vaccines can help prevent or decrease morbidity. Analgesics an antidepressants can control debilitating symptoms. Therefore, appropriateness--whether the potentia benefits outweigh the potential risks--should guide therapy. Polypharmacy (concurrent use of many drugs) alone is not an accurate measure of appropriateness
Oral hypoglycemic drugs can improve independence and quality of life while controlling chronic diseas Antihypertensive drugs and influenza vaccines can help prevent or decrease morbidity. Analgesics an antidepressants can control debilitating symptoms. Therefore, appropriateness--whether the potentia benefits outweigh the potential risks--should guide therapy.
Polypharmacy (concurrent use of many drugs) alone is not an accurate measure of appropriateness therapy because older persons often have many disorders requiring treatment; however, it may reflect inappropriate prescribing. Many older patients in hospitals and nursing homes routinely receive drugs (including hypnotics, analgesics, H2 blockers, antibiotics, and laxatives) that are not essential and can harm, directly or through interactions. A thorough review of drugs can often reduce the number of drug and, according to limited data, improve patient outcomes.
Underuse of some drugs is also a significant problem among elderly patients. For example, antidepre use in nursing homes is much lower than the high prevalence of depression warrants. Drugs for incont and preventive treatments (eg, drugs for glaucoma, influenza and pneumococcal vaccines) are also underused.

Section 22. Clinical Pharmacology Chapter 300. Pharmacodynamics Topics
[General] Drug-Receptor Interactions Dose-Response Relationships
[General]
Pharmacodynamics: Study of the biochemical and physiologic effects of drugs and their mechanisms o
Many drugs produce pharmacologic responses by interacting with (binding to) specific macromolecule usually complex proteins, on or within cells. Some drug classes react directly with endogenous or exog nonprotein substances; included are some cancer chemotherapeutic drugs that interact with nucleic a metal chelating drugs (eg, calcium disodium edetate, dimercaprol, deferoxamine), and antacids used t chemically neutralize gastric acid.

Section 22. Clinical Pharmacology Chapter 305. Anabolic Steroid Use Topics
[General]
[General]
Anabolic steroids are synthetic derivatives of testosterone (see Table 305-1). Testosterone has androg (masculinizing) effects (eg, changes in hair or in libido, aggressiveness) and anabolic (tissue-building) (eg, increased protein utilization, muscle mass changes). The androgenic effect cannot be separated f anabolic, but anabolic steroids have been synthesized to minimize the androgenic effects.
Scientific as well as significant anecdotal evidence indicates that with resistive training and proper diet muscle mass and strength increase more in persons using anabolic steroids. However, there is no dire evidence that anabolic steroid use increases endurance or speed. Substantial anecdotal evidence sug that athletes taking anabolic steroids can perform more frequent high-intensity workouts, although no s support this effect and no mechanism for it is known. The enhanced athletic performance may be only perceived.
In the USA, the reported rate of anabolic steroid use is 6 to 11% among high-school-aged males, inclu unexpected number of nonathletes, and about 2.5% among high-school-aged females. In a national s the most common reason given for anabolic steroid use was improvement of athletic performance; sec improvement of appearance.
A typical user is a male (95%) athlete (65%), usually a football player, heavyweight wrestler, or weight is more likely to attend a metropolitan school of > 700 students, to be a minority student, and to have r steroids from a black-market source (60%). He is less likely to have a parent who finished high school
Athletes may take steroids for a period of time, discontinue them, then start again (cycling) several tim year. Intermittent discontinuation is believed to allow endogenous testosterone levels, sperm count, an hypothalamic-pituitary-gonadal axis to return to normal. Anecdotal evidence suggests that cycling may decrease harmful effects and the need for increasing drug doses to attain the desired effect.
Athletes frequently use many drugs simultaneously (a practice called stacking) and alternate routes of administration (oral, IM, or transdermal). Increasing the dose through a cycle (pyramiding) may result i 5 to 100 times the physiologic dose. Stacking and pyramiding are intended to increase receptor bindin minimize adverse effects, but these benefits have not been proved.
decrease harmful effects and the need for increasing drug doses to attain the desired effect.
Athletes frequently use many drugs simultaneously (a practice called stacking) and alternate routes of administration (oral, IM, or transdermal). Increasing the dose through a cycle (pyramiding) may result i 5 to 100 times the physiologic dose. Stacking and pyramiding are intended to increase receptor bindin minimize adverse effects, but these benefits have not been proved.
Anabolic steroids also have medicinal uses. Because they are anticatabolic and improve protein utiliza they are given to burn, bedridden, or other debilitated patients to prevent muscle wasting.
Symptoms and Signs
The most characteristic sign is a dramatic, rapid increase in body bulk. If the user trains with weights a a high-calorie, high-protein diet while taking anabolic steroids, strength and muscle bulk usually increa Increases in energy level and libido (in men) occur but are more difficult to identify.
The overall safety of anabolic steroids is controversial. Methyltestosterone 200 mg/wk does not produc adverse effects (not even on personality), except for a mild increase in acne. Most adverse effects occ with doses of > 200 mg methyltestosterone equivalent per week. The effects of long-term use have no studied, nor have the extraordinarily high doses used by some athletes, especially bodybuilders, who sometimes use the equivalent of several grams of methyltestosterone per week.
Psychologic effects (generally only with very high doses) are often noticed by the family; effects includ and erratic mood swings, irrational behavior, increased aggressiveness ("steroid rage"), irritability, dep and dependency.
Increased acne, a common complaint, is one of the few adverse effects for which an adolescent may s medical attention. Jaundice, indicating liver dysfunction, may occur, but usually only with oral anabolic Musculotendinous injuries and liver dysfunction or tumors (benign and malignant) may occur. In prepu and pubertal users, bony epiphyses may close prematurely, possibly decreasing final height. Hyperten increased low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) chol may increase cardiovascular risk. Males may develop gynecomastia, testicular atrophy, and azoosperm
Some virilizing effects in females may be irreversible--eg, alopecia, enlarged clitoris, hirsutism, and de voice. Breast size may decrease; vaginal mucosa may atrophy; menstruation may change or stop; libid increase, or, less commonly, decrease; and aggressiveness and appetite may increase.
Diagnosis and Prevention
A urine screen usually detects users of anabolic steroids. Metabolites of anabolic steroids can be dete urine up to 6 mo (even longer for some types of anabolic steroids) after the drugs are discontinued.
Education about anabolic steroids should start by the beginning of middle school. School principals, te coaches (especially of football, wrestling, basketball, and track and field), and school health care offici should be taught as well as adolescents and their parents.
Section 22. Clinical Pharmacology Chapter 301. Factors Affecting Drug Respons Topics
Pharmacogenetics Drug Interactions Placebos Patient Compliance
Pharmacogenetics
Pharmacogenetics concerns genetic variations in drug response. Among normal subjects, kinetic para (eg, Michaelis constant [Km], maximum rate of reaction [V max]) of drug-metabolizing enzymes often d widely, and drug elimination rates measured in vivo vary by fourfold to more than fortyfold, depending drug and population studied. Numerous twin and family studies have shown that genetic factors are m responsible for these large interindividual variations.
Pharmacogenetics has clinical consequences and biologic significance. When prescribing drugs, phys must consider that the inherent capacity to clear a drug may differ among patients. A patient with rapid metabolism may require larger, more frequent doses to achieve therapeutic concentrations; a patient w metabolism may need lower, less frequent doses to avoid toxicity, particularly for drugs with a narrow m safety.
Many environmental and developmental factors can interact with each other and with genetic factors t drug response (see Fig. 301-1). For example, increasing age affects other factors, thereby complicatin disposition.
PHARMACOKINETIC VARIATION
Acetylation: In about 50% of the U.S. population, drug inactivation by hepatic N-acetyltransferase is s Such persons (slow acetylators) require a longer time to metabolize drugs that are acetylated and are therefore more susceptible to adverse effects of such drugs (eg, peripheral neuritis with isoniazid, lupu erythematosus with hydralazine or procainamide, sedation and nausea with phenelzine).
In the rest of the population, acetylation is rapid. Compared with slow acetylators, such persons requir or more frequent doses of drugs that are acetylated (eg, isoniazid) to obtain the desired therapeutic re They are also more likely to develop hepatotoxicity due to acetylhydrazine accumulation.
therefore more susceptible to adverse effects of such drugs (eg, peripheral neuritis with isoniazid, lupu erythematosus with hydralazine or procainamide, sedation and nausea with phenelzine).
In the rest of the population, acetylation is rapid. Compared with slow acetylators, such persons requir or more frequent doses of drugs that are acetylated (eg, isoniazid) to obtain the desired therapeutic re They are also more likely to develop hepatotoxicity due to acetylhydrazine accumulation.
Hydrolysis: About 1 in 1500 persons has plasma pseudocholinesterase deficiency, which decrease succinylcholine inactivation. When conventional doses of succinylcholine are given, prolonged paralys respiratory muscles results. Persistent apnea may require mechanical ventilation until the drug can be eliminated by alternate pathways.
Oxidation: In about 5 to 10% of whites in North America and Europe, oxidative biotransformation of debrisoquin is decreased; if such persons take debrisoquin for hypertension, they are at increased risk toxicity (eg, orthostatic hypotension). Reduced hydroxylation may cause an unusually large therapeutic response to -receptor blockade with metoprolol or timolol or increased toxicity (eg, excessive CNS dep with nortriptyline or phenytoin. Other drugs apparently affected by reduced hydroxylation include some antiarrhythmics (eg, encainide, flecainide), tricyclic antidepressants (eg, amitriptyline, desipramine), an dextromethorphan, an antitussive drug.
About 4% of whites in North America metabolize mephenytoin slowly, increasing their risk of its main a effect, transient sedation. In such persons, the activity of other drugs biotransformed to some extent b same enzyme as mephenytoin may be increased; these drugs include mephobarbital (an anticonvulsa proguanil (an antimalarial), and possibly diazepam (an anxiolytic).
About 50% of Japanese, Chinese, and other Asian populations lack aldehyde dehydrogenase-2, an en involved in ethanol metabolism. In such persons, alcohol ingestion results in marked elevations of bloo acetaldehyde and in adverse effects (eg, facial flushing, increased heart rate, diaphoresis, muscle wea elevated acetaldehyde can lead to catecholamine-mediated vasodilation with euphoric and dystrophic symptoms.
In about 85% of Japanese, Chinese, and other Asian populations; in 5 to 10% of the English; in 9 to 1 the German; and in 20% of the Swiss, alcohol dehydrogenase (another enzyme involved in ethanol metabolism) operates about 5 times faster than normal. When such persons ingest alcohol, acetaldeh accumulates, resulting in extensive vasodilation, facial flushing, and compensatory tachycardia.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency: G6PD is essential for RBC reduction rea that maintain cytoskeletal integrity. Patients with G6PD deficiency, which occurs in about 10% of black are at increased risk of developing hemolytic anemia when given oxidant drugs, such as antimalarials chloroquine, pamaquine, primaquine), aspirin, probenecid, and vitamin K.
Glutathione synthetase deficiency: In patients with RBC glutathione synthetase deficiency (which is to but much rarer than G6PD deficiency), oxidant drugs cause hemolytic anemia. Patients with low lev RBC glutathione synthetase in hepatocytes are at increased risk of liver damage if given such drugs a acetaminophen and nitrofurantoin.
PHARMACODYNAMIC VARIATION
Reduced warfarin activity: In certain persons, anticoagulant activity after usual therapeutic doses of is substantially reduced; a dose up to 20 times greater than usual may be necessary to produce the de effect. Biotransformation of warfarin is not abnormal in such persons; reduced activity may be due to a genetically controlled reduction in binding affinity of the warfarin receptor.
Reduced warfarin activity: In certain persons, anticoagulant activity after usual therapeutic doses of is substantially reduced; a dose up to 20 times greater than usual may be necessary to produce the de effect. Biotransformation of warfarin is not abnormal in such persons; reduced activity may be due to a genetically controlled reduction in binding affinity of the warfarin receptor.
Malignant hyperthermia: This disorder causes a life-threatening elevation in body temperature; it res a hypermetabolic response to a combination of a depolarizing muscle relaxant (usually succinylcholine potent, volatile inhalational general anesthetic (eg, halothane [most commonly], isoflurane, sevoflurane combination produces a similar reaction in some patients with muscular dystrophy and myotonia.
Malignant hyperthermia affects about 1 in 20,000 patients. Susceptibility to the disorder is inherited in autosomal dominant pattern. Mutations in the gene that encodes the ryanodine receptor (calcium relea channel) may cause the disorder. The mechanism appears to be related to halothane-induced potenti Ca activity in the sarcoplasmic reticulum of skeletal muscle; in susceptible patients, this tissue is hyper to Ca. As a result, Ca-induced biochemical reactions are accelerated, causing severe muscle contract an elevated metabolic rate.
Malignant hyperthermia may develop during anesthesia or in the early postoperative period. Clinical presentation varies, depending on the drug used and the patient's susceptibility. Muscular rigidity is of first sign, followed by tachycardia, other arrhythmias, acidosis, shock, and hyperthermia. Hyperkalemia respiratory and metabolic acidosis, hypocalcemia, CK elevation, myoglobinemia, and coagulation abnormalities (particularly disseminated intravascular coagulation) can develop.
The mortality rate in developed countries is about 7%. Early diagnosis and prompt treatment are requi reduce morbidity and mortality. The in vitro caffeine-halothane contracture test is a specific diagnostic malignant hyperthermia but is available at few centers in North America. Muscle biopsy and elevated c kinase levels may be used to identify sensitive members of the patient's family. Treatment with dantro sodium (starting with 2.5 mg/kg IV) must be initiated immediately after symptoms develop. Surgery an anesthesia should be discontinued as rapidly as possible. Corrective therapy also includes manageme metabolic acidosis, core and surface cooling, and hyperventilation.
Section 22. Clinical Pharmacology Chapter 306. Trade Names Of Some Commonly Use Topics
[General]
[General]
Throughout The Manual, generic (nonproprietary) names for drugs are used whenever possible. Most prescription drugs have trade names (also called proprietary, brand, or specialty names) to distinguish being produced and marketed by a particular manufacturer. In the USA, these names are usually regis trademarks with the Patent Office, which confers certain legal rights with respect to their use. A trade n may be registered for a product containing a single active ingredient (with or without additives) or two o active ingredients (combination drugs). A chemical substance marketed by several manufacturers may several trade names. A drug may be marketed under different trade names in different countries.
Trade names are found in many publications and are used extensively in clinical medicine. For conven Table 306-1 lists trade names for most drugs mentioned throughout The Manual, primarily those mark the USA. The table is not all-inclusive and does not list every trade name for each drug. A few drugs in table are investigational and may subsequently be approved by the FDA. The inclusion of a drug does indicate approval of its use for any indication, nor does it imply efficacy or safety of its action. The inclu a trade name in Table 306-1 indicates neither endorsement nor preference by The Manual.

Section 22. Clinical Pharmacology Chapter 302. Drug Toxicity Topics
Evaluation Of Drug Toxicity Adverse Drug Reactions Carcinogenesis Benefit-To-Risk Ratio
Evaluation Of Drug Toxicity
In the USA, the Food and Drug Administration (FDA) regulates the investigation of drugs. Pharmacolo toxicologic data from animal (preclinical) studies are submitted to the FDA as part of an application for investigational new drug (IND). If these data demonstrate that the drug is sufficiently safe and effective (clinical) studies are conducted in three phases; data from these studies are submitted as part of a ne application (NDA). Although the FDA is required to take action on an NDA within 6 mo, actual approva NDA usually takes 2 to 3 yr. Total time for drug development, from filing of an IND to final approval of averages 8 to 9 yr.
ANIMAL STUDIES
The pharmacokinetic, pharmacodynamic, and toxicologic properties of a drug must be evaluated and documented in animals according to FDA regulations (Good Laboratory Practices) before study in hum Two main assumptions are made: The effects of chemicals in appropriately selected laboratory anima to humans; and the use of high doses in these animals is a necessary and valid method for discoverin possible toxicity in humans. High doses are necessary because of the relatively small number of anim and the need to detect low-incidence toxic responses.
The safety of a drug is determined by studying the acute, subchronic, and chronic toxicity of the drug i animal species.
Acute Toxicity
The safety of a drug is determined by studying the acute, subchronic, and chronic toxicity of the drug i animal species.
Acute Toxicity
Initial acute toxicity studies are conducted to determine the lethal dose (LD50 or LD90--the dose requir 50% or 90%, respectively, of the laboratory animals), toxic symptoms, and the time symptoms appear at least three species of animals (including one nonrodent) are used, and acute toxicity is determined than one administration route. In recent years, fewer animals have been used to determine lethality, w corresponding reduction in precision. The greater precision is not necessary for overall toxicity assess humans, because the LD50 or LD90 has little predictive value unless accompanied by data from longer studies using toxicity measures other than death.
Subchronic Toxicity
Subchronic toxicity studies, conducted in at least two animal species, usually consist of daily administr the drug for up to 90 days. In each species, at least three dose levels are used, varying from expected therapeutic levels to levels high enough to produce toxicity. Ideally, the drug is given by the route to be human studies. Physical examinations and laboratory tests are performed throughout the study. At the the study, the animals are killed, and pathologic examinations are performed to identify affected organ
Chronic Toxicity
Chronic toxicity studies, conducted in at least two species (including one nonrodent), usually last the li the animal (up to 2 yr in a rodent or longer in a nonrodent), but duration may depend on the intended d of drug administration to humans. Three dose levels are used, varying from a nontoxic low-level dose dose that is higher than the expected therapeutic dose and that is toxic when given long-term. Physica examinations and laboratory tests are performed at intervals throughout the period of drug administrat Some animals are killed periodically for gross and histologic examination. On the basis of these result investigators determine which organs are affected and whether the drug is potentially carcinogenic.
In addition, extensive reproductive tests are conducted in rats and rabbits to detect alterations in the reproductive cycle and teratogenic effects. These tests and chronic toxicity studies may be conducted concurrently with initial studies in humans, particularly when the drug is intended only for short-term hu use.
IN VITRO STUDIES
Interest in in vitro toxicity studies, which provide more rapid results than animal studies and are more cost-effective, is growing. The focus is on mutagenicity; the most popular test is the Ames bioassay. A chemical shown to be a bacterial mutagen may be a mammalian carcinogen. In vitro toxicity tests are substitutes for animal studies and provide only supportive information in the regulatory process; pharmaceutical companies use them to focus on specific chemicals for additional in vivo studies and f pharmacologic development. However, the role of in vitro studies in drug development has expanded. studies are used to predict drug metabolism pathways in humans, which may differ from those in labor animals. Use of in vitro cell lines expressing the major human drug metabolizing enzymes may help pr novel metabolites in humans that animal studies would not detect. In vitro data may be submitted as a supplement to traditional absorption, distribution, metabolism, and excretion studies.
pharmacologic development. However, the role of in vitro studies in drug development has expanded. studies are used to predict drug metabolism pathways in humans, which may differ from those in labor animals. Use of in vitro cell lines expressing the major human drug metabolizing enzymes may help pr novel metabolites in humans that animal studies would not detect. In vitro data may be submitted as a supplement to traditional absorption, distribution, metabolism, and excretion studies.
HUMAN STUDIES
Human studies must be conducted in three phases before the FDA approves a new drug for marketing (Studies of the drug's general use after approval and postmarketing surveillance can be regarded as a phase.) Human studies are necessary because estimatedly >= 50% of the most common adverse effe depression, heartburn, headaches, ringing in the ears) cannot be discerned in animal studies. Becaus drug effects and increasing severity of symptoms due to ineffective drugs are risks in all human studie safeguards--such as institutional review boards (IRBs) and informed consent--are required to protect t of study participants.
Phase 1
In phase 1 studies, a new drug is first given to humans, usually to a small number (20 to 80) of healthy volunteers aged 18 to 45 yr. The purpose is to document the dose level at which signs of toxicity first a humans and thereby determine a safe tolerated dose. Because the end point of these studies is toxici informed consent is a prerequisite, and participants must be closely supervised by medical personnel access to emergency facilities. Before phase 1 can begin, a protocol that describes the conditions and personnel involved in the clinical study and that is approved by the IRB is submitted to the FDA; if the approves the protocol, it issues an IND exemption permit.
Initially, each participant receives a single dose of the drug and is closely monitored for adverse drug reactions. If none occur, the dose of the drug is progressively increased until a predetermined dose or level is achieved or until toxicity occurs. Absorption, metabolism, and excretion may also be measured
Phase 2
Phase 2 studies begin after satisfactory preliminary evidence of safety has been obtained. They involv supervised administration of the drug to about 80 to 100 patients for treatment of or prophylaxis again disorder for which the drug is intended. Ideally, patients should have no health problems other than the intended disorder. Usually, phase 2 studies are randomized, comparing the new drug with the prototyp if one exists, for the intended disorder. Often, they provide the first opportunity to observe the effect of long-term administration of the drug to humans. The purpose of phase 2 is to determine an optimal dose-response range for the new drug and to verify its efficacy for the intended disorder. Participants a monitored for adverse effects; because this test population is larger, additional adverse effects may be detected. This phase is the most crucial, because its data are used to determine whether to proceed w extensive studies in large populations.
Phase 3
After phases 1 and 2 have provided reasonable evidence of safety and efficacy, phase 3 studies begin continue until the drug is released for general use. They may involve many practicing physicians who m supervise several hundred to several thousand patients. The purpose is to verify the efficacy of the dru detect effects that may not have occurred during phases 1 and 2, so that the sponsor and FDA can de that the drug is safe and effective for its intended use.
After phases 1 and 2 have provided reasonable evidence of safety and efficacy, phase 3 studies begin continue until the drug is released for general use. They may involve many practicing physicians who m supervise several hundred to several thousand patients. The purpose is to verify the efficacy of the dru detect effects that may not have occurred during phases 1 and 2, so that the sponsor and FDA can de that the drug is safe and effective for its intended use.
There are no definitive rules for what constitutes safety and efficacy, which must be judged in relation disorder being treated and to alternative treatments. When sufficient data have been collected to justif continued use of the drug, an NDA is submitted. Usually, >= 4 yr have elapsed between the drug's sel (on the basis of the original pharmacologic screen) and the filing of the NDA.
Phase 4
Phase 4 studies are conducted after the drug is approved; they are ongoing studies in large population Often, special subpopulations, such as pregnant women, children, or the elderly, are included; the incl such populations in studies before drug approval might be unethical (eg, exposing unborn children to r unscientific (eg, introducing unknown variables).
Phase 4 studies can detect low-incidence adverse effects. Preclinical and clinical studies are relatively insensitive, capable of detecting adverse drug reactions with a frequency of > 1 in 1000 administration many drugs, a frequency of 1 in 10,000 or 1 in 50,000 may be clinically relevant and can be determine with postmarketing surveillance after NDA approval. New therapeutic or toxic effects, including rare or long-term effects indiscernible in a small number of patients, may be discovered.
The sponsor's claims of drug safety and efficacy that are to appear in brochures and advertising are re and approved by the FDA. Reports from ongoing phase 4 studies must be sent to the FDA every 3 mo the first year, every 6 mo during the second year, and annually thereafter. The reports must include information about the quantity of drug distributed as well as copies of mailing pieces, labeling, and adv The sponsor must notify the FDA of any unexpected adverse effects, injury, and toxic or allergic reacti Thus, the FDA continues to monitor and ensure the safety and efficacy of drugs after marketing.

Section 11. Hematology And Oncology Chapter 127. Anemias Topics
[General] Anemias Caused By Blood Loss Anemias Caused By Deficient Erythropoiesis Anemias Caused By Excessive Hemolysis
[General]
Anemias: Decreases in numbers of RBCs or Hb content caused by blood loss, deficient erythropoiesis excessive hemolysis, or a combination of these changes.
The term anemia has been used incorrectly as a diagnosis; more properly, it denotes a complex of sig symptoms. The type of anemia defines its pathophysiologic mechanism and its essential nature, allow appropriate therapy. Not investigating mild anemia is a serious error; its presence indicates an underly disorder, and its severity reveals little about its genesis or true clinical significance.
The symptoms and signs of anemia represent cardiovascular-pulmonary compensatory responses to severity and duration of tissue hypoxia. Severe anemia (eg, Hb < 7 g/dL) can be associated with weak vertigo, headache, tinnitus, spots before the eyes, fatigability, drowsiness, irritability, and even bizarre behavior. Amenorrhea, loss of libido, GI complaints, and sometimes jaundice and splenomegaly can o Finally, heart failure or shock can result. Abbreviations Used in This Chapter AdoCbl Adenosylcobalamin ag AIHA ATG C3 CBC EDTA Attogram Autoimmune hemolytic anemia Equine antihymocyte globulin Complement Complete blood count Ethylenediaminetetraacetic acid Hct MCH MCV NaCl O2 PCH Hematocrit Mean corpuscular Hb Mean corpuscular volume Sodium chloride Oxygen Paroxysmal cold hemoglobinuria
MCHC Mean corpuscular Hb concentration MeCbl Methylcobalamin
EDTA EPO Fe G6PD Hb
Ethylenediaminetetraacetic acid Erythropoietin Iron Hemoglobin
PCH PO2 RBC WBC
Paroxysmal cold hemoglobinuria Partial pressure of oxygen Red blood cell RBC volume distribution width White blood cell
ELISA Enzyme-linked immunosorbent assay PNH
Paroxysmal nocturnal hemoglobinuria
Glucose-6-phosphate dehydrogenase RDW
General diagnostic patterns can expedite the differential diagnosis (see Table 127-1). Anemia results f or more of three basic mechanisms: blood loss, deficient erythropoiesis (RBC production), and exc hemolysis (RBC destruction). Blood loss should be the first consideration. Once it is ruled out, only th two mechanisms need to be considered. Because RBC survival is 120 days, maintenance of a steady population requires daily renewal of 1/120 of the cells. Complete cessation of erythropoiesis results in decline of about 10%/wk (1%/day) of RBCs. Deficient erythropoiesis results in relative or absolute reticulocytopenia. When RBC values fall > 10%/wk (ie, 500,000 RBCs/L) without blood loss, hemolys causative factor.
A convenient approach to most anemias that result from deficient erythropoiesis is to examine change size and shape. Thus, microcytic anemias (see Laboratory Tests, below) suggest altered heme or glob synthesis (eg, iron [Fe] deficiency, thalassemia and related Hb-synthesis defects, anemia of chronic d In contrast, normochromic-normocytic anemias suggest a hypoproliferative or hypoplastic mechanism. anemias are characterized by macrocytes (large RBCs), which suggest a defect in DNA synthesis. The anemias are usually caused by defective vitamin B 12 or folic acid metabolism or by an interference wit synthesis by chemotherapeutic cytoreductive drugs. Adequate marrow response to anemia is evidenc peripheral blood reticulocytosis or polychromatophilia.
Similarly, a few common mechanisms of increased destruction (eg, sequestration by the spleen, antibody-mediated hemolysis, defective RBC membrane function, abnormal Hb) greatly aid in the diffe diagnosis of hemolytic anemias.
A critical tenet in managing anemias is to give specific therapy, which implies that a specific diagnosis necessary. The response to therapy corroborates the diagnosis. Although multidrug (or "shotgun") the may provide transient repair of the anemia, such therapy is not justifiable because it risks serious sequ RBC transfusion provides a form of instant repair that should be reserved for patients with cardiopulmo symptoms, signs of active uncontrollable blood loss, or some form of hypoxemic end-organ failure. Tra procedures and blood components are discussed in Ch. 129. Table 127-2 classifies anemias according to cause.
Laboratory Tests
Laboratory tests quantitate the severity of anemia and provide data for diagnosis.
Blood specimen collection: Blood is preferably collected by venipuncture, although fingertip punctur sterile lancet may sometimes suffice. The specific tests determine which anticoagulant, if any, should collection tubes. Vacuum tubes are available with double-pointed needles to facilitate collection; they c
Laboratory tests quantitate the severity of anemia and provide data for diagnosis.
Blood specimen collection: Blood is preferably collected by venipuncture, although fingertip punctur sterile lancet may sometimes suffice. The specific tests determine which anticoagulant, if any, should collection tubes. Vacuum tubes are available with double-pointed needles to facilitate collection; they c anticoagulants for most routine tests. However, most commercially available vacuum tubes are nonste backflow of blood from the filled tube to the vein may permit bacteria to enter. To avoid such infections tourniquet should be removed before blood flow into the tube stops; the patient's arm should not be m during collection (even a few centimeters' elevation after the tube draw is complete may lower venous sufficiently to produce backflow); and no pressure should be exerted on the stopper end of the tube. W possible, sterile tubes or needle and tube arrangements that have a check valve should be used.
Ethylenediaminetetraacetic acid (EDTA) is the preferred anticoagulant for blood collection because the morphology is less distorted and platelets are better preserved. It can be added to clean test tubes, or tubes containing EDTA may be obtained commercially. Slides should be prepared within 3 to 4 h after obtaining blood, or within 1 to 2 h for platelet counts.
For small amounts of blood or when venipuncture is infeasible, the finger, the earlobe, or, in infants, th plantar surface of the heel is punctured quickly with a sterile disposable lancet, piercing deeply enough ensure spontaneous flow of blood. Undue pressure that might cause tissue fluids to dilute the blood sh avoided during collection.
In some circumstances, EDTA tubes are used for coagulation testing. Regardless of the anticoagulant because significant anemia (Hct < 20%) or polycythemia (Hct > 50%) may affect coagulation results, th sample volume must be adjusted after CBC data are known. For significant anemia, less blood can be to the fixed amount of anticoagulant by drawing the blood in a syringe; for polycythemia, the amount o anticoagulant must be reduced (see Table 127-3).
Complete blood count: The CBC is a basic evaluation that usually includes Hb, Hct, WBC count, WB differential count, platelet count, a description of the blood smear relative to RBC morphology and deg polychromatophilia, and platelet spread and architecture. An RBC count is often included, especially w calculation of RBC indices is desired.
Indications for a CBC include suspected hematologic, inflammatory, neoplastic, or infectious disease a screening of infants < 1 yr, pregnant women, the institutionalized elderly, and patients with nutritional abnormalities. Its value during routine patient evaluation on hospital admission is controversial.
Anemia, erythrocytosis, leukemia, bone marrow failure, infection, inflammation, or adverse drug reacti be detected. Blood smear examination can help detect other abnormalities (eg, thrombocytopenia, ma and other parasites, significant formation of rouleaux, nucleated RBCs or immature granulocytes, inclu RBCs or granulocytes) that may occur despite normal counts. Evaluation of the blood smear is importa assess RBC morphology and abnormal WBCs.
Through automated technology, the RBC count, Hb, Hct, and platelet count are available in about 30 s rare cases, blood counts can also be measured by mixing a measured volume of blood with an approp diluent or lysing agent and counting in a chamber under the microscope. Hb can be measured colorim after treatment with dilute hydrochloric acid, which permits colorimetric or spectrophotometric comparis standards of hematin or cyanmethemoglobin, respectively. Hct can be measured by centrifuging a volu blood and determining the percentage of RBCs relative to total blood volume. The WBC differential co measured by staining a drop of blood on a glass slide with a metachromatic stain (eg, Wright's) and ex it with oil immersion microscopy. A minimum of 100 WBCs are counted; each type is reported as a pe Some automated instruments also measure differential counts by pattern recognition. The platelet num be estimated on the blood smear (using 20,000/L for each platelet seen in a given [90] oil immersio
after treatment with dilute hydrochloric acid, which permits colorimetric or spectrophotometric comparis standards of hematin or cyanmethemoglobin, respectively. Hct can be measured by centrifuging a volu blood and determining the percentage of RBCs relative to total blood volume. The WBC differential co measured by staining a drop of blood on a glass slide with a metachromatic stain (eg, Wright's) and ex it with oil immersion microscopy. A minimum of 100 WBCs are counted; each type is reported as a pe Some automated instruments also measure differential counts by pattern recognition. The platelet num be estimated on the blood smear (using 20,000/L for each platelet seen in a given [90] oil immersio
Normal values for the total WBC count range between 4,300 and 10,800/L; normal values for the diff WBC count are as follows: segmented neutrophils, 34 to 75%; band neutrophils, <= 8%; lymphocytes, 50%; monocytes, 3 to 15%; eosinophils, <= 5%; and basophils, <= 3%.
RBC counts: The normal range at sea level is 5.4 0.8 million/L for men and 4.8 0.6 million/L for At birth, this count is slightly higher; by the 3rd month, it falls to about 4.5 0.7 million/L and slowly in after age 4 through puberty.
Normal Hb is 16 2 g/dL for men and 14 2 g/dL for women. Hct (ie, the volume of packed RBCs) is for men and 42 5% for women. The diagnostic criterion for anemia in men is RBC < 4.5 million/L, H g/dL, or Hct < 42%; for women this criterion is RBC < 4 million/L, Hb < 12 g/dL, or Hct < 37%.
Reticulocyte count: Daily RBC replacement (40,000 to 50,000/L) represents 0.5 to 1.5% of the tota count. These cells can be identified as polychromatophilic cells on routine staining (eg, Wright's or Gie stain colors remnants of RNA) or as reticulocytes on supravital staining, which recognizes endoplasmi reticular material within the cells. The reticulocyte count is done by taking a few drops of blood initially with fresh methylene blue, then counterstained with Wright's stain. Under oil immersion, the number o consecutive RBCs having a blue-staining reticulum are counted and expressed as a percentage (norm to 1.5%). Reticulocytes may be enumerated using automated differential counters.
Because reticulocytes represent a young cell population, reticulocyte count is an important criterion of activity that can be considered a response to a need for RBC renewal. An increased reticulocyte coun (reticulocytosis) suggests a restoration response after acute blood loss or specific therapy for anemias by deficient erythropoiesis (ie, vitamin B12, folic acid, and Fe-deficiency anemias). Reticulocytosis is particularly prominent in hemolytic anemias and in acute and severe bleeding. A normal reticulocyte co anemia indicates failure of the bone marrow to respond appropriately. Such a reticulocytopenia is usua caused by a nutrient or hormonal deficiency resulting in deficient erythropoiesis; one dramatic mechan the presence of viral infections (especially human parvovirus B19) as a cause for severe, but transient decreased RBC production.
RBC indices: The type of anemia may be indicated by the RBC indices: mean corpuscular volume (M mean corpuscular Hb (MCH), and mean corpuscular Hb concentration (MCHC). RBC populations are microcytic (MCV < 80 fL) or macrocytic (MCV > 95 fL). The term hypochromia refers to RBC popul with MCH < 27 pg/RBC or MCHC < 30%. These quantitative relationships can usually be recognized o peripheral blood smear and, together with the indices, permit a classification of anemias that correlate etiologic classification (see Table 127-1) and greatly aids diagnosis.
Automated electronic techniques directly measure Hb, RBC count, and MCV, whereas Hct, MCH, and are derived from these data. Thus, the MCV has become the most important RBC index in the differen diagnosis of anemias, and confidence in the derived figures (especially Hct) has declined. Automatedcytometry provides a new parameter in differential diagnosis: A histogram of anisocytosis (variation in can be automatically expressed as the coefficient of variation of the RBC volume distribution width (RD
Poikilocytosis (variation in shape) may also occur. RBC injury may be identified by finding RBC fragme portions of disrupted cells (schistocytes), or evidence of significant membrane alterations from oval-sh cells (ovalocytes) or spherocytic cells. Target cells (thin RBCs with a central dot of Hb) are RBCs with
cytometry provides a new parameter in differential diagnosis: A histogram of anisocytosis (variation in can be automatically expressed as the coefficient of variation of the RBC volume distribution width (RD
Poikilocytosis (variation in shape) may also occur. RBC injury may be identified by finding RBC fragme portions of disrupted cells (schistocytes), or evidence of significant membrane alterations from oval-sh cells (ovalocytes) or spherocytic cells. Target cells (thin RBCs with a central dot of Hb) are RBCs with insufficient Hb or excess membrane.
Bone marrow aspiration and biopsy: These studies provide direct observation of erythroid activity a maturation of the RBC precursors; abnormal maturity (dyspoiesis) of the cells; and semiquantitation of amount, distribution, and cellular pattern of Fe content. These are helpful in anemias, other cytopenias unexplained leukocytosis, and thrombocytosis and when leukemia or myelophthisis is suspected. Simultaneous culture of the bone marrow aspirate is an excellent diagnostic tool in patients with FUO. Cytogenetic and molecular analyses can be performed on aspirate material in hemopoietic or other ne or in suspected congenital lesions. Flow cytometry can be performed in suspected lymphoproliferative myeloproliferative states to define the immunophenotype.
Because bone marrow aspiration and biopsy are not difficult nor do they pose significant invasive risk, should be performed early in suspected hematologic diseases. In general, both can be performed as a procedure. Because biopsy requires adequate bone depth, usually the posterior (or less commonly, an iliac crest is used. After the biopsy needle is inserted, a small amount of marrow (preferably < 0.5 mL) aspirated into a syringe. A few drops are smeared directly onto slides, stained with metachromatic stai May-Grnwald, Giemsa, Wright's), and examined under a microscope. The remaining aspirate can be in heparin for subsequent study or cytogenetic analysis; a portion can be permitted to clot and is hand surgical tissue. If bone marrow culture is desired, 1 mL is aspirated through the same implanted needl the histologic material has been obtained. The core biopsy can be obtained by advancing the same ne cm and performing rotatory cutting. The core must be decalcified and handled as surgical tissue. If on aspiration is sought, the sternum or dorsal lumbar vertebral spine may be used. Aspiration of > 2 mL o marrow should be avoided because dilution with peripheral blood makes interpretation difficult.
RBC fragility (osmotic fragility): Twelve small test tubes containing sodium chloride (NaCl) solutions from 0.28 to 0.5% in 0.02% increments are prepared. A drop of the patient's blood is placed in each tu the blood of a normal control is added to another series of tubes. The percentage of NaCl at which he begins (normally <= 0.44 0.04%) and the percentage at which the first tube shows complete hemolys (usually about 0.32 0.04%) are noted. If many spherocytes are present, as in familial hemolytic jaund congenital spherocytosis), hemolysis appears at higher concentrations because of the increased fragil predominating cell is abnormally thin, as in -thalassemia major, hemolysis first appears at lower conce and may never be complete.
Other tests are discussed below under specific anemias and bleeding disorders. For tests of hemostas bleeding time, clot retraction and observation, fibrin and fibrinogen degradation products, partial thromboplastin time and prothrombin time), see Table 131-2.

Section 11. Hematology And Oncology Chapter 137. Histiocytic Syndromes Topics
[General] Langerhans' Cell Histiocytosis
[General]
Histiocytic syndromes: A broad grouping of disorders characterized by abnormal proliferation of macro or histiocyte-like cells.
Classifying these disorders is difficult because of the ubiquitous nature of the macrophage, its extraord metabolic capabilities, its role as a regulator of hematopoiesis, and its prominence in the immune and inflammatory response and because of uncertainty regarding monocyte, macrophage, histiocyte, and cell ontogeny. However, three "classes" of histiocytic syndromes have been defined (see Table 137-1) chapter discusses class I histiocytoses (Langerhans' cell histiocytosis).

Section 11. Hematology And Oncology Chapter 128. Iron Overload (Hemosiderosis; Hemochromatosis) Topics
[General]
[General]
(For acute iron poisoning, see Table 307-3)
Chronic iron (Fe) overload is characterized by increased focal or generalized deposition within the tiss tissue examination, this has been commonly termed hemosiderosis. When excess Fe deposition is associated with tissue injury or the total body Fe estimate is > 5 g, the term hemochromatosis has be applied (see Table 128-1). Hemochromatosis, an HLA-linked genetic Fe overload disorder, must be differentiated from other inherited disorders accompanied by increased Fe stores (eg, aceruloplasmine hypotransferrinemia/atransransferrinemia) and from nongenetic Fe overload and Fe overload of undet etiology.
Hemochromatosis in its primary form is a genetic disorder with a homozygous frequency of 1:200 and heterozygous frequency of 1:8. The hemochromatosis gene (HLA-H) was recently identified on the sho of chromosome 6 as a single point mutation in which the amino acid cysteine at position 282 changes tyrosine (nt 845A, 845A; Cys 282 Tyr). Of patients with clinical hemochromatosis, 83% are homozygou this mutation, which encodes for an HLA-A-like molecule. A mutation at nt 187C(His 63 Asp) linked to major histocompatibility complex has also been found; these changes have been termed hemochromatosis-associated mutations.
Finding these mutations does not explain the pathophysiologic mechanism of the increased Fe absorp Increased Fe absorption from the GI tract appears to cause the overload. Because physiologic mecha for Fe excretion are limited, Fe accumulates in the body. Total body Fe content can reach as high as 5 compared with the normal levels of about 2.5 g in women and 3.5 g in men.
Symptoms and Signs
Focal hemosiderosis chiefly occurs in the lungs and kidneys and is the result of other obvious diseas processes. Pulmonary hemosiderosis caused by recurrent pulmonary hemorrhage occurs as an idiopa entity, as part of Goodpasture's syndrome, or in severe mitral stenosis. Occasionally, the Fe loss from episodes of hemorrhage into the lungs causes Fe-deficiency anemia because Fe cannot be reutilized.
Symptoms and Signs
Focal hemosiderosis chiefly occurs in the lungs and kidneys and is the result of other obvious diseas processes. Pulmonary hemosiderosis caused by recurrent pulmonary hemorrhage occurs as an idiopa entity, as part of Goodpasture's syndrome, or in severe mitral stenosis. Occasionally, the Fe loss from episodes of hemorrhage into the lungs causes Fe-deficiency anemia because Fe cannot be reutilized. hemosiderosis can result from extensive intravascular hemolysis caused by trauma to RBCs (eg, chro disseminated intravascular coagulation, defective or torn heart valve leaflets, prosthetic mechanical he valves) or in paroxysmal nocturnal hemoglobinuria. Free Hb is filtered at the glomerulus, and renal Fe deposition occurs with saturation of haptoglobin. The renal parenchyma is not damaged, but severe hemosiderinuria may result in Fe deficiency.
Genetic hemochromatosis is uncommonly symptomatic before middle age. Of affected men, 80 to 9 total body Fe stores > 10 g before symptoms develop. In women, symptoms more commonly develop menopause because Fe loss during menses and pregnancy provides some protection. Thus, hepatic F content is higher in women whose menopause occurs before age 50.
Despite blood loss during pregnancy and menses, women have the full phenotypic clinical expression hemochromatosis. The clinical event leading to the diagnosis is usually incidental because clinical seq Fe overload are late manifestations; clinical-laboratory evaluation early in Fe accumulation is the best approach. In women, fatigue and nonspecific constitutional symptoms are early findings; in men, cirrho diabetes is often the initial presentation. The clinical findings of advanced Fe deposition can include hepatocellular dysfunction and even cirrhosis, bronze skin pigmentation, diabetes mellitus (overt in 50 of patients), and cardiomyopathy manifested by cardiomegaly, heart failure, and arrhythmias or condu disturbances. Pituitary failure is common and may be the cause of testicular atrophy and loss of libido, are frequent. Abdominal pain, arthritis, and chondrocalcinosis occur less often. These changes are ca parenchymal Fe deposition, although an increased familial incidence of diabetes mellitus suggests tha other than pancreatic siderosis may play a role. Hepatocellular carcinoma occurs more frequently in long-standing hemochromatosis than in any form of cirrhosis; approximate incidence is 14%.
Diagnosis
Hemochromatosis is often diagnosed late in the course of disease after significant tissue injury is pres because the clinical symptoms are insidious and the extent of organ involvement varies; thus, the full c picture evolves slowly. Other nongenetic mechanisms of Fe overload, such as congenital hemolytic sta sickle cell anemia, thalassemia), must be appropriately ruled out.
In genetic hemochromatosis, the serum Fe is elevated (> 300 mg/dL). The serum transferrin saturat sensitive parameter of increased Fe and merits evaluation when > 50%. The serum ferritin is increase RBC ferritin is increased to > 200 attograms/RBC. Urinary Fe excretion is markedly increased (> 2 mg the chelating drug deferoxamine (500 to 1000 mg IM based on the size of the patient), and this has be as a diagnostic test in some circumstances when the diagnosis is uncertain. In addition, when the Fe c in the liver is significantly increased, an MRI may reflect this change. Liver biopsy had been the gold s in diagnosis; it now serves only to provide evidence of fibrosis (cirrhosis). Gene assay is the diagnostic choice. Demonstration of hepatic siderosis and a quantitative increase in liver content (mean hepatic F > 2; mean hepatic Fe concentration, > 250 mol/g) confirms the diagnosis.
Genotypic clinical diagnosis and appropriate screening of first-degree relatives has been simplified wit availability of testing for C282Y, the most prevalent mutation, and H63D, a lesser mutation; these gene mutations account for > 95% of hemochromatosis cases.
Treatment
Genotypic clinical diagnosis and appropriate screening of first-degree relatives has been simplified wit availability of testing for C282Y, the most prevalent mutation, and H63D, a lesser mutation; these gene mutations account for > 95% of hemochromatosis cases.
Treatment
Phlebotomy is the simplest method for removing excess Fe in patients with hemochromatosis and im survival but does not alter the incidence of hepatocellular carcinoma. Phlebotomy is best initiated as s the diagnosis is made. About 500 mL/wk of blood (about 250 mg of Fe) is removed until serum Fe leve normal and transferrin saturation is well below 50%. Usually, phlebotomy can be performed weekly. W stores are normal, further phlebotomy can be performed to maintain transferrin saturation at < 10%. T serum ferritin level is a less valid parameter during Fe unloading. Diabetes mellitus, cardiac abnormali impotency, and other secondary manifestations are treated as indicated.
Genetic Iron Overload
Two very rare inherited diseases, hypotransferrinemia/atransferrinemia and aceruloplasminemia, accompanied by increased Fe stores. In transferrin deficiency, absorbed Fe enters the portal system a nontransferrin-bound Fe and is deposited in the liver. Subsequent transfer to the erythron for physiolog needs is reduced because of the reduced transport system. In ceruloplasmin deficiency, the lack of fe results in defective conversion of Fe2+ to Fe3+, which is necessary for binding to transferrin; this impai process reduces the movement of Fe from intracellular stores to plasma transport with accumulation o the tissues.
These transport defects are diagnosed by measurement of serum transferrin (ie, Fe-binding capacity) ceruloplasmin (see Wilson's Disease in Ch. 4). Although replacement therapy with transferrin or with ceruloplasmin (depending on the diagnosis) would be ideal, these products are not available for therap
Nongenetic Iron Overload
Transfusion Fe overload and Fe overload that occurs with increased nonabsorption due to defective erythropoiesis (eg, in congenital hemolytic anemias or hemoglobinopathies) can generally be identified clinical history. Because these circumstances (sometimes termed secondary hemochromatosis) are associated with anemia, phlebotomy may not be possible.
Deferoxamine 20 to 40 mg/kg/24 h as a slow sc or IV infusion given overnight by a small portable pum effectively reduces Fe stores. Because tachyphylaxis occurs with deferoxamine therapy, continued eff must be evaluated (usually by urine Fe measurement). Alternatively, salmon-colored urine confirms > mg/day of Fe in the urine.
Iron Overload of Undetermined Origin
Parenchymal liver diseases, especially alcoholic liver disease, nonalcoholic steatohepatitis, and chron hepatitis C infection, can be associated with increased Fe storage. The mechanisms for this are unkno although genetic hemochromatosis must always be considered a potential background etiologic factor evaluated. Fe unloading does not appear to improve the liver dysfunction in these patients who do not genetic hemochromatosis.
Parenchymal liver diseases, especially alcoholic liver disease, nonalcoholic steatohepatitis, and chron hepatitis C infection, can be associated with increased Fe storage. The mechanisms for this are unkno although genetic hemochromatosis must always be considered a potential background etiologic factor evaluated. Fe unloading does not appear to improve the liver dysfunction in these patients who do not genetic hemochromatosis.

Section 11. Hematology And Oncology Chapter 138. Leukemias Topics
[General] Acute Leukemia Chronic Leukemia Myelodysplastic Syndrome
[General]
Leukemias: Malignant neoplasms of blood-forming tissues.
Although viruses cause several forms of leukemia in animals, their role in humans is uncertain; only tw associations are identified: (1) Epstein-Barr virus, a DNA virus, is associated with Burkitt's lymphoma ( 139), and (2) human T-cell lymphotropic virus type I, called human T-cell leukemia/lymphoma virus, an retrovirus, is associated with some T-cell leukemias and lymphomas, most commonly identified in Jap the Caribbean. Exposure to ionizing radiation and certain chemicals (eg, benzene, some antineoplasti is associated with an increased risk of leukemia. Some genetic defects (eg, Down syndrome, Fanconi anemia) also predispose to leukemia.
Transformation to malignancy (through two or more steps) occurs in a single cell, with subsequent pro and clonal expansion. Usually, transformation occurs at the pluripotent stem cell level, but sometimes involve a committed stem cell with capacity for more limited differentiation. The clone tends to be gene unstable with features of heterogeneity and phenotypic evolution. In general, leukemic cells divide with cell cycles and smaller growth fractions than normal bone marrow cells, but they accumulate because slowed apoptosis (programmed cell death).
Clinical and laboratory features of leukemia are caused by suppression of normal blood cell formation organ infiltration. Inhibitory factors produced by leukemic cells or replacement of marrow space may s normal hematopoiesis, with ensuing anemia, thrombocytopenia, and granulocytopenia. Organ infiltrati results in enlargement of the liver, spleen, and lymph nodes, with occasional kidney and gonadal invol Meningeal infiltration results in clinical features associated with increasing intracranial pressure (eg, cr nerve palsies).
Classification
normal hematopoiesis, with ensuing anemia, thrombocytopenia, and granulocytopenia. Organ infiltrati results in enlargement of the liver, spleen, and lymph nodes, with occasional kidney and gonadal invol Meningeal infiltration results in clinical features associated with increasing intracranial pressure (eg, cr nerve palsies).
Classification
Leukemias were originally termed acute or chronic based on life expectancy but now are classified acc to cellular maturity. Acute leukemias consist of predominantly immature cells (usually blast forms); chr leukemias, more mature cells.
Acute leukemias are divided into lymphoblastic (ALL) and myelogenous (AML) types, which may be f subdivided by morphologic and cytochemical appearance according to the French-American-British (F classification (see Table 138-1) or immunophenotype (see Table 138-2). The specific B-cell and T-cell myeloid-antigen monoclonal antibodies, together with flow cytometry, are very helpful for classifying A versus AML, which is critical for treatment.
Chronic leukemias are described as lymphocytic (CLL) or myelocytic (CML). General features of ALL CLL, and CML are shown in Table 138-3.
Myelodysplastic syndromes represent progressive bone marrow failure but with an insufficient propo blast cells (< 30%) for definite diagnosis of AML; 40 to 60% of cases evolve into AML.

Section 11. Hematology And Oncology Chapter 129. Transfusion Medicine Topics
[General] Blood Collection Pretransfusion Testing Blood Products Technique Complications Therapeutic Hemapheresis
[General]
As many as 15 million transfusions are given yearly in the USA. The decision to transfuse is a clinical that requires weighing the possible benefits and known hazards against alternative treatments. Althou transfusion is probably safer than ever, risk and the public's perception of risk and fear of disease tran mandate informed consent.

Section 11. Hematology And Oncology Chapter 139. Lymphomas Topics
[General] Hodgkin's Disease Non-Hodgkin's Lymphomas Mycosis Fungoides
[General]
The major types are Hodgkin's disease and non-Hodgkin's lymphoma. An uncommon type is mycosis fungoides.
Lymphomas: A heterogeneous group of neoplasms arising in the reticuloendothelial and lymphatic sys

Section 11. Hematology And Oncology Chapter 130. Myeloproliferative Disorders Topics
[General] Polycythemia Vera Myelofibrosis Primary Thrombocythemia
[General]
Myeloproliferative disorders: A group of disorders characterized by abnormal proliferation of one or mo hematopoietic cell lines or connective tissue elements.
The myeloproliferative disorders include polycythemia vera, myelofibrosis, chronic myelogenous (mye leukemia (see Ch. 138), and primary thrombocythemia. Some hematologists also include acute leukem especially erythroleukemia, and paroxysmal nocturnal hemoglobinuria; however, most argue that thes disorders are sufficiently different from the basic four and omit them.
Each disorder is identified according to its predominant feature or site of proliferation (see Table 130-1 Despite overlap, each has a somewhat typical constellation of clinical features, laboratory findings, an Although proliferation of one cell line may dominate the clinical picture, cytogenetic markers and isoen studies have shown that each disorder is caused by clonal proliferation arising at the level of a pluripo cell, causing varying degrees of abnormal proliferation of erythroid, myeloid, and megakaryocytic prec the bone marrow. Peripheral RBCs, granulocytes, and platelets arise from this abnormal clone, but the marrow fibroblast does not. Myeloproliferative disorders sometimes terminate in acute leukemia.

Section 11. Hematology And Oncology Chapter 140. Plasma Cell Dyscrasias Topics
[General] Monoclonal Gammopathy Of Undetermined Significance Macroglobulinemia Multiple Myeloma Heavy Chain Diseases
[General]
Pathogenesis and Classification
Plasma cell dyscrasias: A group of clinically and biochemically diverse disorders of unknown etiology characterized by the disproportionate proliferation of one clone of B cells and the presence of a structu and electrophoretically homogeneous (monoclonal) immunoglobulin or polypeptide subunit in serum o
(For structural features and classification of the immunoglobulins, see under B Cells and Humoral Imm Ch. 146.)
Normally, immunoglobulin production is heterogeneous (polyclonal), with each plasma cell clone secre one heavy chain (gamma [], mu [], alpha [], delta [], or epsilon []) and one light chain (kappa [] or lamb during its life span. A slight excess of light chains is normally produced, and small amounts of free pol light chains (<= 40 mg/24 h) are excreted in the urine of healthy persons.
Disproportionate proliferation of one clone results in a corresponding increase in the serum level of its molecular product, the monoclonal immunoglobulin protein (M protein). The M protein is readily detect tall homogeneous symmetric spike (M spike) with 2, , or mobility on electrophoresis of serum or urine. Immunofixation or immunoelectrophoresis is required to identify the heavy and light chain class of the The magnitude of the M spike is related to the number of cells in the body producing the M protein; thu proteins are markers for B-cell clones.
Most M proteins appear to be normal products of a single clone that has become overabundant; they a qualitatively abnormal. Some M proteins show antibody activity, most frequently directed toward autoa and bacterial antigens. Recent analysis suggests that expression of the immunoglobulin genes that lea production of M proteins occurs in an antigenically driven fashion.
Most M proteins appear to be normal products of a single clone that has become overabundant; they a qualitatively abnormal. Some M proteins show antibody activity, most frequently directed toward autoa and bacterial antigens. Recent analysis suggests that expression of the immunoglobulin genes that lea production of M proteins occurs in an antigenically driven fashion.
Serum levels of immunoglobulins other than the monoclonal immunoglobulin are commonly reduced. T impaired immunoglobulin production in multiple myeloma may be due to the presence of a monocyte o macrophage that suppresses the maturation of normal B cells into antibody-secreting plasma cells.
Plasma cell dyscrasias vary from asymptomatic, apparently stable conditions (in which only the protein present) to clinically symptomatic and progressive neoplasms (eg, multiple myeloma). Rarely, transien cell dyscrasias have been described in patients with drug hypersensitivity (sulfonamide, phenytoin, an penicillin), presumed viral infections, and cardiac surgery. Plasma cell dyscrasias are classified in Tab
Section 11. Hematology And Oncology Chapter 131. Hemostasis And Coagulation Diso Topics
[General] Hemostasis Hereditary Coagulation Disorders Acquired Coagulation Disorders
[General]
Hemostasis and coagulation disorders: Disorders characterized by a tendency to bleed.

Section 11. Hematology And Oncology Chapter 141. Disorders Of The Spleen Topics
[General] Hypersplenism Splenomegalic Syndromes Splenic Rupture
[General]
(See also Splenic Deficiency Syndromes in Ch. 147.)
By structure and function the spleen is like two organs--an immune one, the white pulp, consisting of periarterial lymphatic sheaths and germinal centers, and a phagocytic one, the red pulp, consisting of macrophages and granulocytes lining vascular spaces (the cords and sinusoids).
Functions of the white pulp: The white pulp generates protective humoral antibodies (inappropriate autoantibodies to circulating blood elements also may be synthesized, as in immune thrombocytopeni purpura [ITP] or Coombs'-positive immune hemolytic anemias). Production and maturation of B and T and plasma cells also occur in the white pulp, as in other lymphoid organs.
Functions of the red pulp: The red pulp removes unwanted particulate matter (eg, bacteria, senesce elements). In immune cytopenias (ITP, Coombs'-positive hemolytic anemias, some neutropenias), phagocytosis of antibody-coated cells by red pulp macrophages and granulocytes underlies their destr The red pulp also serves as a reservoir for blood elements, especially WBCs and platelets. Culling and removes inclusion bodies in RBCs, such as Heinz bodies (precipitates of insoluble globin), Howell-Joll (nuclear fragments), and whole nuclei from RBCs; thus, after splenectomy, circulating nucleated RBCs Howell-Jolly bodies are commonly encountered. Hematopoiesis, another function of red pulp, normally in the spleen only during fetal life. Beyond fetal life, injury to marrow sinusoids (eg, by fibrosis or tumor allow hematopoietic stem cells to circulate and repopulate the adult spleen and liver (see Myelofibrosis 130 and Myelodysplastic Syndrome in Ch. 138).

Section 11. Hematology And Oncology Chapter 132. Thrombotic Disorders Topics
[General]
[General]
Thrombotic disorders: Diseases characterized by formation of a thrombus that obstructs vascular bloo locally or detaches and embolizes to occlude blood flow downstream (thromboembolism).
Thrombi are mechanical masses that form within the cardiovascular system on denuded endovascular prosthetic flow surfaces. They are composed of insoluble fibrin, deposited platelets, accumulating WB entrapped RBCs in variable flow-dependent patterns.
Thrombus formation is a multifactorial process involving many mutually interactive genetic and environ factors. Thrombotic predisposition is usually identified clinically. The most important features are famil recurrence, young age, severity of provocation, and unusual sites of thrombosis.
Suspected arterial or venous thrombosis or thromboembolism requires objective confirmation. Angiogr the diagnostic reference standard. However, ultrasonography performed by skilled personnel is suitab superficial vessels and for cardiac assessment.
Of patients with venographically proven spontaneous deep vein thrombosis, 25 to 50% have a genetic predisposing factor. A genetically impaired anticoagulant mechanism (eg, factor V resistance to activa protein C, hyperhomocysteinemia, protein C deficiency, protein S deficiency, antithrombin deficiency, fibrinolysis), when combined with a thrombotic stimulus (eg, surgery, pregnancy, oral contraceptive us antiphospholipid antibodies), is sufficient to develop a venous thromboembolism. Persons with more th abnormality experience thrombosis earlier, more frequently, and more severely than those with single
Antithrombotic therapy involves the use of thrombolytic drugs, antiplatelet drugs, and anticoagulants. Thrombolytic drug therapy is the first consideration when formulating an antithrombotic strategy becau thrombolytic drugs can remove an established thrombus. Subsequent antithrombotic therapy varies de on whether the venous or arterial circulatory system is involved; the size and location of the involved v the risks of extension, embolization, or recurrence; and the relative antithrombotic benefits and hemor risks.
Mechanical measures for restoring vascular patency include balloon catheter and surgical embolectom
thrombolytic drugs can remove an established thrombus. Subsequent antithrombotic therapy varies de on whether the venous or arterial circulatory system is involved; the size and location of the involved v the risks of extension, embolization, or recurrence; and the relative antithrombotic benefits and hemor risks.
Mechanical measures for restoring vascular patency include balloon catheter and surgical embolectom Indications and complications related to antithrombotic regimens for specific disorders (eg, MI, venous thrombosis, pulmonary embolism, cerebrovascular accident, prosthetic heart valves, arterial embolism summarized elsewhere in The Manual.
Factor V Resistance to Activated Protein C
Resistance to activated protein C (APC) results from the genetic point mutation factor V Leiden. This d the most common genetic risk factor associated with familial predisposition to venous thrombosis. Its prevalence in European populations is 5%, but it rarely occurs in native Asian or African populations. A resistance phenotype is found in 20 to 60% of patients with spontaneous venous thrombosis. Mutated is activated by thrombin or factor Xa in the usual way, but its inactivation by APC is impaired.
Hyperhomocysteinemia
Plasma homocysteine levels are elevated tenfold or greater in homozygous cystathionine -synthase de these patients are at great risk of arterial and venous thromboembolism. Hyperhomocysteinemia is als strongly correlated with atherosclerotic thrombosis (including coronary artery disease--see Ch. 201). M cases occur in heterozygous cystathionine -synthase deficiency and in other abnormalities of folate metabolism, including methyltetrahydrofolate dehydrogenase deficiency. Homocysteine levels may be normalized by dietary supplementation with folate and, if needed, pyridoxine, but this has not been sho reduce the risk of thrombosis.
Protein C Deficiency
Heterozygous deficiency of plasma protein C is transmitted in an autosomal dominant fashion, with a prevalence of 0.2 to 0.5%; about 75% of persons with this defect will experience a venous thromboem (50% by age 50 yr). Homozygous or doubly heterozygous deficiency presents in the newborn as purpu fulminans or disseminated intravascular coagulation (DIC) and is fatal without replacement therapy an anticoagulation. Acquired decreases are observed in patients with liver disease, severe infection, or D during cancer chemotherapy (including L-asparaginase); after surgery; and with warfarin therapy. Labo screening involves use of functional assays. In patients with symptomatic thrombosis, it is important to antithrombotic therapy with full heparin anticoagulation before beginning warfarin because of the dang skin necrosis. Warfarin occasionally causes thrombotic skin infarction by lowering protein C levels befo decreasing the majority of vitamin K-dependent clotting factors.
Protein S Deficiency
Heterozygous deficiency of plasma protein S is similar to protein C deficiency in genetic transmission, prevalence, incidence, and laboratory screening. Acquired deficiencies are observed during pregnancy infection, DIC, HIV, oral contraceptive use, and warfarin therapy and after L-asparaginase administrati treatment precautions are the same as those for protein C deficiency.
Heterozygous deficiency of plasma protein S is similar to protein C deficiency in genetic transmission, prevalence, incidence, and laboratory screening. Acquired deficiencies are observed during pregnancy infection, DIC, HIV, oral contraceptive use, and warfarin therapy and after L-asparaginase administrati treatment precautions are the same as those for protein C deficiency.
Antithrombin Deficiency
Heterozygous deficiency of plasma antithrombin is inherited in an autosomal dominant fashion with a prevalence of about 0.2 to 0.4%; about half of these persons experience venous thrombotic episodes. Acquired deficiencies in antithrombin levels are observed in patients with acute thrombosis, DIC, liver or nephrotic syndrome and during heparin therapy, estrogen therapy (including contraceptive use), or L-asparaginase therapy. Laboratory screening should involve use of an antithrombin-heparin cofactor because it detects all different subtypes. Oral anticoagulation is highly effective prophylaxis for patient have experienced or are at risk of thrombosis.
Defective Fibrinolysis
Inherited disorders of plasminogen--decreased tissue plasminogen activator levels or increased plasm activator inhibitor levels--are rare. They have been associated with unexplained venous thromboembo younger patients. Screening produces many false-positive and false-negative results. Possible heredit fibrinolytic abnormalities should be investigated in a research setting.
Phospholipid Syndrome
(Antiphospholipid Syndrome; Antiphospholipid Antibodies; Anticardiolipin Antibodies; Lupus Anticoagulant)
This syndrome includes thromboembolism (particularly involving CNS vasculature), thrombocytopenia fetal loss in association with autoimmune antibodies directed against phospholipid membrane constitu vitro clotting tests are prolonged. The mechanism of action may involve antibody-induced platelet activ yielding phosphatidylserine-rich procoagulant surfaces and thrombocytopenia.
Atherosclerosis
(See also Ch. 201.)
Patients with symptomatic atherosclerosis are at significant risk of stroke, MI, and peripheral artery occ which primarily develop at sites of preexisting stenosis. Atherosclerotic plaques rupture and expose tis factor-rich plaque contents to blood. This initiates thrombin-mediated, platelet-rich thrombus formation Increases in fibrinogen levels correlate with thrombotic events. High levels may be an independent risk for arterial thromboembolism or a nonspecific inflammatory marker of ruptured plaques.
Thrombocytosis
In patients undergoing invasive vascular procedures (eg, saphenous vein bypass grafts, small-caliber grafts), the frequency of thrombotic complications correlates with the peripheral platelet concentration. However, in the absence of vascular disruption, there is little relationship between arterial thrombosis a
Thrombocytosis
In patients undergoing invasive vascular procedures (eg, saphenous vein bypass grafts, small-caliber grafts), the frequency of thrombotic complications correlates with the peripheral platelet concentration. However, in the absence of vascular disruption, there is little relationship between arterial thrombosis a thrombocytosis, even if peripheral platelet counts are very high, especially in young asymptomatic per
Other Predisposing Factors

Stasis is associated with increased venous thromboembolism in surgery, orthopedic or paralytic immobilization, congestive heart failure, pregnancy, varicosities, and obesity.
Tissue injury from trauma and surgery increases the frequency of venous thromboembolism. Coag serine proteases are activated, and platelets are triggered by the exposure of tissue factor to flowing b
Neoplastic cells may activate platelets, coagulation proteases, or both by secreting adenosine diphosphate-like activating substances and expressing tissue factor on exposed membrane surfaces. resultant circulating activated species trigger thrombus formation at vulnerable sites of vascular stasis Malignancies associated with increased thrombotic predisposition include promyelocytic leukemia and involving lung, breast, prostate, GI tract, and other sites. Advanced metastatic disease may induce DIC extensive search to identify the underlying disease is not indicated because the malignancy is usually
When exposed to flowing blood, chronic inflammatory processes that are associated with tissue fac expression by monocytes or macrophages may initiate thrombosis.
Cardiovascular prosthetic devices may induce chronic monocyte or macrophage accumulation in re their flow surfaces, enhancing the risk of thrombotic device failure.
Oral contraceptive drugs that contain estrogen are associated with venous thromboembolism. These patients often have a coexisting genetic factor predisposing them to venous thrombosis, particularly fa resistance to APC or deficiency of protein C or S.

Section 11. Hematology And Oncology Chapter 142. Overview Of Cancer Topics
[General] Metastatic Carcinoma Of Unknown Primary Origin
[General]
Cancer: A proliferation of cells whose unique trait--loss of normal controls--results in unregulated grow of differentiation, local tissue invasion, and metastasis.
Cancer (malignancy) can develop in any tissue of any organ at any age. Most cancers are potentially c detected at an early stage. By performing self-examinations, patients can help recognize early signs o possible malignancies. Diagnostic testing and therapy are essential for optimal results. When cure or reasonable palliation is likely, physicians must discuss all therapeutic options.
Patients with cancer that is unlikely to be cured need to be informed about what treatment is likely to accomplish and the side effects it may produce. Intensive care may be needed for treatment-related complications. Psychologic support from the physician and the health care team (which may include a psychiatrist and a social worker) helps patients through therapy (see Complications, below).
Physicians must be truthful, yet convey a sense of optimism. Some patients may need to be advised a health care practitioners who falsely promise cure. The patient should feel that members of the health team are concerned and available to answer questions. The physician should initiate frank discussions end-of-life care and advance medical directives at an appropriate time (see Ch. 294).
Cellular Kinetics
Generation time is the time it takes for cells to enter the cell cycle (see Fig. 142-1) and give rise to two daughter cells. Malignant cells usually have a shorter cycle than nonmalignant cells. Most nonmaligna have a larger percentage of cells in G0 (resting phase), so that there is a smaller proliferation fraction. exponential tumor growth is followed by a plateau phase when cell death equals the rate of formation daughter cells. Compared with large tumors, small tumors have a greater percentage of cells in cycle a greater proliferation.
Cellular kinetics are important in the design of antineoplastic drug regimens. Many antineoplastic drug effective only if cells are in cell cycle, and some drugs work only during a specific phase of the cycle. C
exponential tumor growth is followed by a plateau phase when cell death equals the rate of formation daughter cells. Compared with large tumors, small tumors have a greater percentage of cells in cycle a greater proliferation.
Cellular kinetics are important in the design of antineoplastic drug regimens. Many antineoplastic drug effective only if cells are in cell cycle, and some drugs work only during a specific phase of the cycle. C kinetics may influence the dosage schedules and timing of treatment.
Tumor Growth and Metastasis
As a tumor grows, nutrients are provided by direct diffusion from the circulation. Local tissue invasion result in pressure on normal tissues, which can lead to inflammation, or the tumor may produce substa (eg, collagenase) that lead to enzymatic destruction of tissues. Subsequently, synthesis of tumor angio factor causes formation of an independent vascular supply to the tumor. Almost from inception, a tumo shed cells into the circulation. From animal models, it is estimated that a 1-cm tumor sheds > 1 million h into the venous circulation. In animals, circulating tumor cells usually die as a result of intravascular the longer a tumor cell spends in the circulation, the greater the chance of its death. The probability th circulating tumor cell will become a metastatic tumor is estimated at < 1:1 million.
Metastases develop when tumor cells adhere to vascular endothelium and penetrate into surrounding surviving and spawning independent tumors at distant sites. Thus, tumor growth resumes, disrupting n tissue and organ function. Metastatic tumors can give rise to other metastases.
Experiments suggest that metastasis is not a random event and that the primary tumor may regulate t growth of metastatic tumors (eg, in renal cell carcinoma, the rate of growth is often similar in the prima metastatic nodules). Theoretically, removal of the primary tumor can result in rapid growth of the meta
Molecular Abnormalities
Mutations in genes are partially responsible for the growth or reproduction of malignant cells. These m alter the quantity or behavior of the proteins encoded by growth-regulating genes and alter cell division major categories of mutated genes are oncogenes and tumor suppressor genes.
Oncogenes are abnormal forms of the genes that normally regulate cell growth. For example, the ras abnormal in about 25% of human cancers. The Ras protein (encoded by the ras gene) regulates or sig division. In most situations the gene is inactive, but in these malignant cells the Ras protein is active a signals cells to divide, even though they should not.
Another example of oncogene activity involves protein kinases, enzymes that help regulate many cellu activities, particularly signaling from the cell membrane to the nucleus, thus initiating the cell's entranc cell cycle and controlling several other functions. Several human cancers (eg, bladder cancer, breast c chronic myelocytic leukemia [CML]) contain structurally altered protein kinase enzymes. When overpro or altered, the kinase stimulates cell division continuously.
Cellular oncogenes are amplified in several human malignancies (eg, C-myc and N-myc in small cell lu cancer, N-myc in neuroblastoma, C-erb B-2 in breast cancer). The activation of oncogenes is not entir understood, but many factors may contribute, including chemical carcinogens (eg, in tobacco smoke) infectious agents (eg, viruses).
Activation may result from chromosomal (DNA) rearrangements. In Burkitt's lymphoma, t(8;14) moves C-myc locus on chromosome 8 to a position distal to the immunoglobulin heavy chain locus on chrom 14, increasing immunoglobulin synthesis. In CML, the t(9;22) results in a chimeric protein--a fusion of
understood, but many factors may contribute, including chemical carcinogens (eg, in tobacco smoke) infectious agents (eg, viruses).
Activation may result from chromosomal (DNA) rearrangements. In Burkitt's lymphoma, t(8;14) moves C-myc locus on chromosome 8 to a position distal to the immunoglobulin heavy chain locus on chrom 14, increasing immunoglobulin synthesis. In CML, the t(9;22) results in a chimeric protein--a fusion of terminal portion of bcr and the C terminal portion of abl. These translocations of DNA are located near genes responsible for cell growth and proliferation.
Tumor suppressor genes normally suppress the development of malignancies by encoding for prote suppress tumor initiation and growth. For example, the retinoblastoma (RB) gene encodes for the prot which regulates the cell cycle by stopping DNA replication. Mutations in the RB gene occur in 30 to 40 human cancers, allowing affected cells to divide continuously.
Another important regulatory protein, p53, prevents replication of damaged DNA in normal cells and p cell death (apoptosis) in cells with abnormal DNA. Inactive or altered p53 allows cells with abnormal D survive and divide. Mutations are passed to daughter cells, conferring a high probability of neoplasm. T gene appears defective in most human cancers.
Chromosomal abnormalities (see also Ch. 286): Although phenotypic heterogeneity occurs with any malignancy, genotypically a given cancer is believed to arise from a clone of transformed cells. The fa ultimately cause genic or chromosomal changes are unknown; however, the deletion, translocation, or duplication of important genes gives a cancer cell a proliferative advantage over normal cells, and a tu develop.
Chromosomal abnormalities are found in certain human cancers (see Table 142-1); eg, about 80% of with CML have the Philadelphia (Ph) t(9;22)chromosome (see Chronic Myelocytic Leukemia in Ch. 13 G6PD as a protein marker, only a single isoenzyme is present in RBCs and WBCs of patients with CM whereas fibroblasts from these patients contain both isoenzymes. These findings indicate that a chrom change is present in the malignant cells. The loss of alleles located on chromosomes 17p and 18q app important in the etiology of colorectal cancer. The loss of alleles on chromosome 17p has also been im in breast cancer, gliomas, lung carcinoma, and osteosarcoma. The sites 17p and 18q have been sugg the location of tumor suppressor genes.
A chromosomal mechanism of the conversion of normal epithelium to cancer has been proposed for fa polyposis of the colon. First, loss of a suppressor gene on chromosome 5 makes the epithelium hyperproliferative. A DNA methylation change results in an early adenoma that ras oncogene converts intermediate adenoma; loss of a suppressor gene on chromosome 18 converts it to a late adenoma, a of a gene on chromosome 17 converts it to cancer. Other genetic changes may be required for the can metastasize.
Chromosomal analysis of cancer cells may provide prognostic or therapeutic information; eg, patients acute myelogenous leukemia and normal chromosomes have a better prognosis than those with abno chromosomes. Similarly, patients with a translocation of chromosomes t(15;17) always develop acute promyelocytic leukemia.
In some congenital diseases, chromosomes break easily, putting children at high risk of developing ac leukemia and other cancers. These include Bloom's syndrome (a rare autosomal recessive disorder w dwarfism, a photosensitive telangiectatic facial erythema, and characteristic facies), Fanconi's syndrom Down syndrome (trisomy 21).
Environmental Factors
leukemia and other cancers. These include Bloom's syndrome (a rare autosomal recessive disorder w dwarfism, a photosensitive telangiectatic facial erythema, and characteristic facies), Fanconi's syndrom Down syndrome (trisomy 21).
Environmental Factors
Viruses linked with human malignancies include human papillomaviruses (cervical carcinoma), cytomegalovirus (Kaposi's sarcoma), Epstein-Barr virus (Burkitt's lymphoma, immunoblastic lymphoma nasopharyngeal carcinoma), and hepatitis B virus (hepatocellular carcinoma). Human retroviruses hav linked to T-cell lymphomas (human T-cell lymphotrophic virus [HTLV-1]), which have a predilection for bone involvement, hypercalcemia, and a leukemic phase. The mechanism of HTLV-1 neoplastic transformation is integration of the provirus (double-stranded DNA copy of the viral RNA genome) into cellular genome. HTLV-2 has been tenuously associated with an unusual form of hairy cell leukemia o linkage. HIV types I and II are pathogenically linked to AIDS (see Ch. 163). Patients with AIDS are pre to Kaposi's sarcoma and lymphoma, which may be viral in origin.
Of parasites, Schistosoma haematobium has been linked to bladder cancer, which usually develops a chronic inflammation and fibrosis. Opisthorchis sinensis has been linked to carcinoma of the pancreas ducts.
Chemical carcinogenesis is a multistep process: (1) In initiation, a cell that experiences a carcinogen can potentially develop into a neoplastic clone. (2) In promotion, which is reversible, continued existen neoplastic clonal proliferation depends on a chemical or agent with little carcinogenic activity. (3) In progression, irreversible growth of altered (neoplastic) cells occurs. An agent that possesses little or n carcinogenic potency (a cocarcinogen) enhances the carcinogenic effect of another agent when expos simultaneous. Chemical carcinogenesis is influenced by age, endocrine status, diet, other exogenous (cocarcinogens or promoters), and immunologic status. Common chemical carcinogens are listed in T 142-2.
Ultraviolet radiation is a definite cause of skin cancer (ie, basal and squamous cell carcinoma, melan and especially in xeroderma pigmentosum).
Ionizing radiation is carcinogenic; eg, survivors of the atomic bomb drop in Hiroshima and Nagasaki higher-than-expected incidence of leukemia and several other cancers. Similarly, when ionizing radiati form of x-rays is used to treat nonmalignant disease (acne, thymic or adenoid enlargement, and ankyl spondylitis), the incidence of cancer increases, including acute and chronic leukemias; Hodgkin's and non-Hodgkin's lymphomas; multiple myeloma; aplastic anemia terminating in acute nonlymphocytic leu (ANLL); myelofibrosis; melanoma; and thyroid cancer. Industrial exposure (eg, to uranium by mine wo linked to development of lung cancer after a 15- to 20-yr latency. Long-term exposure to occupational irradiation or to internally deposited thorium dioxide predisposes persons to angiosarcomas and ANLL
Chronic irritation to skin leads to chronic dermatitis and on rare occasions ultimately to squamous c carcinoma.
Immunologic Disorders
Patients with immunologic disorders are predisposed to lymphoreticular neoplasia and should be scre periodically; development of new or suspicious lymphadenopathy should be evaluated by biopsy. In pa with ataxia-telangiectasia, the incidence of acute lymphoblastic leukemia (ALL), brain tumors, and gas cancer exceeds that of the normal population. Patients with Wiskott-Aldrich syndrome and X-linked agammaglobulinemia are also at high risk for lymphoma and ALL.
Patients with immunologic disorders are predisposed to lymphoreticular neoplasia and should be scre periodically; development of new or suspicious lymphadenopathy should be evaluated by biopsy. In pa with ataxia-telangiectasia, the incidence of acute lymphoblastic leukemia (ALL), brain tumors, and gas cancer exceeds that of the normal population. Patients with Wiskott-Aldrich syndrome and X-linked agammaglobulinemia are also at high risk for lymphoma and ALL.
Patients with immune deficiency, either as a result of immunosuppressive drugs or HIV infection, are a various neoplasms, especially large cell lymphoma and Kaposi's sarcoma. Similarly, patients with SLE Sjgren's syndrome are at risk for lymphoma, usually the B-cell type, presumably related to the altered immunologic status.
Diagnosis and Screening
A complete history and physical examination are prerequisites to early diagnosis. Physicians must be predisposing factors and must specifically ask about familial cancer, environmental exposure, and prio (eg, autoimmune diseases, previous immunosuppressive therapy, AIDS). The review of systems is im and should address symptoms of fatigue, weight loss, fevers or night sweats, cough, hemoptysis, hematemesis or hematochezia, change in bowel habits, and persistent pain. The physical examination direct particular attention to skin, lymph nodes, lungs, breasts, abdomen, and testes and to the prosta and vaginal examinations.
The principal objectives of cancer screening and early diagnosis are to decrease cancer mortality, allo less radical therapy, and reduce financial costs. Screening procedures that have decreased cancer mo are the Papanicolaou (Pap) smear (cervical cancer) and breast self-examination and mammography ( cancer). For screening procedures recommended by the American Cancer Society, see Table 142-3. However, screening has its own risks: physical and psychologic morbidity from false-positive results, fa reassurance for patients with false-negative findings, and morbidity from the screening procedure.
Tumors may synthesize proteins that produce no clinical symptoms, eg, -human chorionic gonadotrop -fetoprotein, carcinoembryonic antigen, CA 125, and CA 153. These protein products may be used as markers in the serial evaluation of patients for determining disease recurrence or response to therapy 143).
Staging
Once a histologic diagnosis is made, staging (ie, determination of the extent of disease) helps determi treatment decisions and prognosis. Clinical staging uses data from the patient's history, physical exam and noninvasive studies. Pathologic staging requires tissue specimens. For staging of specific neoplas details elsewhere in The Manual.
Mediastinoscopy (see Ch. 65) is especially valuable in the staging of non-small cell lung cancer; if it s mediastinal lymph node involvement, the patient would not usually benefit from a thoracotomy and lun resection.
Bone marrow biopsy is especially useful in determining metastases from malignant lymphoma and s lung cancer. Marrow biopsy will be positive in 50 to 70% of patients with malignant lymphoma (low and intermediate grade) and in 15 to 18% of patients with small cell lung cancer at diagnosis.
Axillary lymph node removal with histopathologic examination for metastases (part of surgical therap in staging breast cancer.
Laparotomy in colon carcinoma allows for therapeutic intervention and operative staging. Laparotomy
intermediate grade) and in 15 to 18% of patients with small cell lung cancer at diagnosis.
Axillary lymph node removal with histopathologic examination for metastases (part of surgical therap in staging breast cancer.
Laparotomy in colon carcinoma allows for therapeutic intervention and operative staging. Laparotomy splenectomy, lymph node removal, and liver biopsy is an integral part of the staging of Hodgkin's disea certain patients (see Ch. 139).
Serum chemistries and enzymes may help staging. Elevation of liver enzymes (alkaline phosphatas and ALT) suggests the presence of liver metastases. Elevated alkaline phosphatase and serum Ca m first evidence of bone metastases. Elevated acid phosphatase (tartrate inhibited) suggests extracapsu extension of prostate cancer. Fasting hypoglycemia may indicate an insulinoma, hepatocellular carcino retroperitoneal sarcoma. Elevated BUN or creatinine levels may indicate an obstructive uropathy seco a pelvic mass, intrarenal obstruction from tubular precipitation of myeloma protein, or uric acid nephro from lymphoma or other cancers. Elevated uric acid levels often occur in myeloproliferative and lymphoproliferative disorders. -Fetoprotein may be elevated in hepatocellular carcinoma and testicular carcinomas, carcinoembryonic antigen-S in colon cancer, -human chorionic gonadotropin in choriocarc and testicular carcinoma, serum immunoglobulins in multiple myeloma, and DNA probes (bcr probe to the chromosome 22 change) in CML.
Imaging studies, especially CT and MRI, can detect metastases to brain, lung, spinal cord, or abdom viscera, including the adrenal glands, retroperitoneal lymph nodes, liver, and spleen. MRI (with gadolin the procedure of choice for recognition and evaluation of brain tumors.
Ultrasonography can be used to study orbital, thyroid, cardiac, pericardial, hepatic, pancreatic, renal, retroperitoneal areas. It may guide percutaneous biopsies and differentiate renal cell carcinoma from a renal cyst. Lymphangiography reveals enlarged pelvic and low lumbar lymph nodes and is useful in t clinical staging of patients with Hodgkin's disease, but it has generally been replaced by CT.
Liver-spleen scans can identify liver metastases and splenomegaly. Bone scans are sensitive in ide metastases before they are evident on x-ray. Because a positive scan requires new bony formation (ie osteoblastic activity), this technique is useless in neoplasms that are purely lytic (eg, multiple myeloma routine bone x-rays are the study of choice in such diseases. Gallium scans can help in staging lymph neoplasms. Radiolabeled monoclonal antibodies (eg, to carcinoembryonic antigen, small cell lung can provide important staging data in various neoplasms (eg, colon cancer, small cell lung cancer).
Complications
Malignancy may lead to pain, wasting, neuropathy, nausea, anorexia, seizures, hypercalcemia, hyperu obstruction, and organ failure.
Cardiac tamponade often occurs precipitously. The most common causes are breast and lung cance lymphoma. Because a malignant pericardial effusion precedes cardiac tamponade, patient history usu reveals ill-defined chest pain or pressure that is worse when supine and better when sitting up (see Ch For diagnostic and therapeutic purposes, a pericardiocentesis must be done and a pleuropericardial w pericardiectomy considered. Pleural effusions, if present, should be drained if symptomatic and follow reaccumulation. If the effusion reaccumulates rapidly, thoracostomy tube drainage and sclerosing age should be used (see Ch. 65). Spinal cord compression requires immediate attention to avoid morbid Ch. 182). Hypercalcemia can be caused by malignancy (see Ch. 12). Superior vena cava syndrom dramatic clinical situation, requires urgent but not emergency care (see Ch. 81).
Pain in patients with metastatic cancer frequently results from bone metastases, nerve or plexus invol
reaccumulation. If the effusion reaccumulates rapidly, thoracostomy tube drainage and sclerosing age should be used (see Ch. 65). Spinal cord compression requires immediate attention to avoid morbid Ch. 182). Hypercalcemia can be caused by malignancy (see Ch. 12). Superior vena cava syndrom dramatic clinical situation, requires urgent but not emergency care (see Ch. 81).
Pain in patients with metastatic cancer frequently results from bone metastases, nerve or plexus invol or pressure exerted by a tumor mass or effusion. Treatment of pain is discussed in Ch. 167.
Paraneoplastic syndromes: The paraneoplastic syndromes (see also under Symptoms and Signs in Hypercalcemia in Ch. 12; and Ch. 177) may be a result of excessive or ectopic hormones synthesized tumor, immune complexes, ectopic receptor production, release of physiologically active compounds, unknown causes. Hormone production by tumor cells includes fasting hypoglycemia (insulin from insu diarrhea (vasoactive intestinal polypeptide from a neuroendocrine tumor, ie, islet cell tumor), and hype (epinephrine and norepinephrine from pheochromocytoma). Ectopic hormone synthesis includes ectop ACTH and ADH (from small cell and non-small cell lung cancer), parathyroid hormone (from squamou lung cancer, head and neck cancer, bladder cancer), calcitonin (from breast cancer, small cell lung ca and medullary thyroid carcinoma), and thyroid-stimulating hormone (from gestational choriocarcinoma Manifestations vary with the type of hormone produced. Successful treatment is best obtained by cont the underlying malignancy, but symptoms can be palliated with drugs, eg, minocycline for ectopic ADH cyproheptadine for carcinoid syndrome, or pamidronate and corticosteroids for hypercalcemia.
Clinical syndromes associated with malignancies with no identifiable products are truly paraneoplastic involve various organ systems. Neurologic paraneoplastic syndromes (see Ch. 177) include subacu cerebellar degeneration, amyotrophic lateral sclerosis, sensory or sensory-motor peripheral neuropath Guillain-Barr syndrome, dermatomyositis, polymyositis, myasthenia gravis, and Eaton-Lambert syndr Most carcinomatous polyneuropathies are of unknown cause and have no specific therapy, although myasthenia gravis can be treated with neostigmine or prednisone.
Hematologic paraneoplastic syndromes are pure RBC aplasia, anemia of chronic disease, leukocy (leukemoid reaction), thrombocytosis, eosinophilia, basophilia, and disseminated intravascular coagula addition, idiopathic thrombocytopenic purpura and a Coombs'-positive hemolytic anemia can complica course of patients with lymphoid malignancies and Hodgkin's disease.
Renal paraneoplastic syndrome (membranous glomerulitis) may occur in patients with colon cancer cancer, and lymphoma as a result of circulating immune complexes.
Pigmented skin lesions or keratoses associated with malignancy include acanthosis nigricans (GI malignancy), generalized melanosis (lymphoma, melanoma, hepatocellular carcinoma), Bowen's disea (lung, GI, and GU malignancy), and large multiple seborrheic keratoses, ie, the sign of Leser-Trlat (lymphoma, GI malignancy).
Other miscellaneous paraneoplastic complications include fever, lactic acidosis (leukemia, lympho hyperlipidemia (myeloma), and hypertrophic pulmonary osteoarthropathy (lung cancer or lung metasta renal cancer, thymoma, sarcoma, and Hodgkin's disease). For prognosis and treatment of cancer, see Ch. 144.

Section 11. Hematology And Oncology Chapter 133. Platelet Disorders Topics
[General] Thrombocytopenia Platelet Dysfunction
[General]
Platelet disorders may cause defective formation of hemostatic plugs and bleeding because of decrea platelet numbers (thrombocytopenia) or because of decreased function despite adequate platelet num (platelet dysfunction).

Section 11. Hematology And Oncology Chapter 143. Tumor Immunology Topics
[General] Tumor Antigens Host Response To Tumors Tumor Immunodiagnosis Immunotherapy
[General]
Understanding of the mechanisms involved in the induction of immunity and the recognition of antigen effector cells has improved dramatically in the past decade as molecular biology has joined forces with tumor immunology. This improved molecular understanding has led to many new therapeutic approac example, immune responses can be dramatically altered by single amino acid changes in either antige receptors.
A tumor-associated antigen (TAA) is an antigen that is relatively restricted to tumor cells. Tumor-spe antigens (TSAs) are antigens unique to tumor cells. The development of tumors despite the presence antigens, the significance of immune recognition in the pathogenesis of tumors, and the potential for therapeutic augmentation of immune responses are the subjects of intense investigation.

Section 11. Hematology And Oncology Chapter 134. Vascular Bleeding Disorders Topics
[General] Purpura Simplex Senile Purpura Hereditary Hemorrhagic Telangiectasia Henoch-Schnlein Purpura Vascular Purpura Caused By Dysproteinemias Leukocytoclastic Vasculitis Autoerythrocyte Sensitization
[General]
Vascular disorders may cause petechiae, purpura, and bruising but seldom lead to serious blood loss. However, bleeding may result from deficiencies of vascular and perivascular collagen in Ehlers-Danlos syndrome and other rare hereditary connective tissue disorders, eg, pseudoxanthoma elasticum, oste imperfecta, and Marfan's syndrome (see under Inherited Connective Tissue Disorders in Ch. 270). Hemorrhage may be a prominent feature of scurvy (see Vitamin C Deficiency in Ch. 3). In vascular ble disorders, tests of hemostasis are usually normal. The diagnosis is made from other clinical findings.
Section 11. Hematology And Oncology Chapter 144. Principles Of Cancer Therapy Topics
[General] Surgery Radiotherapy Chemotherapy Multimodality And Adjuvant Therapy Other Modalities Management Of Adverse Effects Incurable Cancer
[General]
Successful treatment of cancer requires elimination of all cancer cells, whether at the primary site, ext local-regional areas, or metastatic to other regions of the body. The major modalities of therapy are su and radiotherapy (for local and local-regional disease) and chemotherapy (for systemic sites). Other im methods include endocrine therapy (for selected cancers, eg, prostate, breast, endometrium, liver), immunotherapy (biologic response modifiers to enhance endogenous immune cell kill and tumor vacci and thermotherapy (cryotherapy and heat). Multimodality therapy combines the assets of each of thes
Clinical definitions of oncologic terms help clarify the goals and progress of therapy. For a potential cu complete remission or complete response must be achieved, which requires disappearance of clini evident disease. Such patients may appear to be cured but may still have viable neoplastic cells that w time, cause relapse. A partial response is a > 50% reduction in the size of a tumor mass or masses; response may lead to significant palliation and prolongation of life, but tumor regrowth is inevitable. A may also have no response.
The interval between disappearance of cancer and relapse is termed the disease-free interval or disease-free survival. Similarly, the duration of response is the time from partial response to the tim overt progression. Survival is the time from diagnosis to death.
Section 11. Hematology And Oncology Chapter 135. Leukopenia And Lymphocytopen Topics
Leukopenia Lymphocytopenia
Leukopenia
A reduction in the circulating WBC count to < 4000/L.
Leukopenia is usually characterized by a reduced number of blood neutrophils, although a reduced nu lymphocytes, monocytes, eosinophils, or basophils may also contribute to the decreased total cell cou Neutropenia accompanied by monocytopenia and lymphocytopenia is often a more serious disorder th neutropenia alone.
NEUTROPENIA
(Granulocytopenia; Agranulocytosis)
A reduction in the blood neutrophil (granulocyte) count, often leading to increased susceptibility to bac and fungal infections.
Blacks have somewhat lower neutrophil counts (lower limit of normal, about 1200/L) compared with w 1500/L). Neutropenia may be classified by the neutrophil count (total WBC % neutrophils and band the relative risk of infection: mild (1000 to 1500/L), moderate (500 to 1000/L), or severe (< 500/L). severe neutropenia caused by impaired neutrophil production is often life-threatening in immunocomp patients (see Ch. 151).
Etiology
Acute neutropenia (occurring over a few days) often develops when neutrophil use is rapid and produc impaired. Chronic neutropenia (lasting months or years) usually arises from reduced production or exc splenic sequestration of neutrophils. Neutropenia may be classified by whether it arises secondary to f extrinsic to marrow myeloid cells or whether an intrinsic defect appears to be present in the myeloid progenitors (see Table 135-1).
Acute neutropenia (occurring over a few days) often develops when neutrophil use is rapid and produc impaired. Chronic neutropenia (lasting months or years) usually arises from reduced production or exc splenic sequestration of neutrophils. Neutropenia may be classified by whether it arises secondary to f extrinsic to marrow myeloid cells or whether an intrinsic defect appears to be present in the myeloid progenitors (see Table 135-1).
Secondary neutropenia: Drugs are one of the most common causes of neutropenia. The incidence o drug-induced neutropenia increases precipitously with age; only 10% of cases occur in children and yo adults, and > 50% occur in adults.
Drug-induced neutropenia has several underlying mechanisms (immune, toxic, idiosyncratic, or hypersensitivity reactions) and should be differentiated from the severe neutropenia that predictably oc after large doses of cytoreductive cancer drugs or radiotherapy (see below) and from that caused by v infections (see below). Cytotoxic chemotherapy induces neutropenia because of the high proliferative neutrophil precursors and the rapid turnover of blood neutrophils.
Immune-mediated neutropenia, thought to arise from drugs that act as haptens to stimulate antibody formation, usually lasts for 1 wk. It may occur when aminopyrine, propylthiouracil, or penicillin is used. drugs (eg, phenothiazines) can cause neutropenia when given in toxic amounts. In contrast, idiosyncra reactions are unpredictable with regard to dose or duration of use and occur with drugs such as chloramphenicol. Acute hypersensitivity reactions (eg, those caused by phenytoin or phenobarbital) m for only a few days, but chronic hypersensitivity with chronic reactions may last for months or years. Hypersensitivity reactions are rare and occasionally may involve arene oxide metabolites (generated in liver) of aromatic anticonvulsants, ie, phenytoin, phenobarbital. Often, fever, rash, lymphadenopathy, h nephritis, pneumonitis, or aplastic anemia may be associated with hypersensitivity-induced neutropeni Occasionally, drug-induced neutropenia may be asymptomatic despite the neutropenia, especially in p whose blood cell counts are regularly monitored during drug therapy.
Diminished neutrophil production is a frequent and often early feature of megaloblastic anemias cause vitamin B12 or folate deficiency, although it is usually accompanied by macrocytic anemia and sometim mild thrombocytopenia. Alcohol may inhibit the response of the marrow to infection when patients dev diseases such as pneumococcal pneumonia.
Impaired neutrophil production can occur when leukemia, myeloma, lymphoma, or metastatic solid tum breast, prostate) infiltrate and replace the bone marrow. Tumor-induced myelofibrosis may further exte neutropenia. Myelofibrosis can also occur from granulomatous infections, Gaucher's disease, and radiotherapy. Neutropenia can also result from bone marrow failure, as seen in rare conditions (eg, Schwachman-Diamond syndrome, cartilage-hair hypoplasia, dyskeratosis congenita, glycogen storage type IB). Neutropenia is also a prominent feature of myelodysplasia and is accompanied by megalobla features in the bone marrow (see Ch. 130). Splenomegaly of any cause (see Ch. 141) can lead to mod neutropenia, thrombocytopenia, and anemia.
Transient neutropenia often accompanies viral infections (eg, early-stage infectious mononucleosis), a sepsis is a particularly serious cause of neutropenia. Neutropenia associated with common childhood diseases occurs during the first 1 to 2 days of illness and may persist for 3 to 8 days. It usually corresp a period of acute viremia and is related to virus-induced redistribution of neutrophils from the circulatin marginal pool. Neutrophil sequestration may occur after viral tissue damage. Moderate to severe neutr may also be associated with a wide variety of other infections (see Table 135-2).
Chronic neutropenia often accompanies HIV infection, the result of impaired production of neutrophils accelerated destruction of neutrophils by antibodies (see Ch. 145). Autoimmune neutropenias may be associated with the presence of circulating antineutrophil antibodies and may occur in isolation or with associated diseases.
Chronic neutropenia often accompanies HIV infection, the result of impaired production of neutrophils accelerated destruction of neutrophils by antibodies (see Ch. 145). Autoimmune neutropenias may be associated with the presence of circulating antineutrophil antibodies and may occur in isolation or with associated diseases.
Neutropenia caused by intrinsic defects in myeloid cells or their precursors: This type of neutrop uncommon. Cyclic neutropenia is a rare congenital granulocytopoietic disorder. It may be inherited in a autosomal dominant fashion and is characterized by irregular, periodic oscillations in the number of pe neutrophils. The mean oscillatory period is 21 3 days.
Severe congenital neutropenia (Kostmann syndrome) is a rare disorder that occurs sporadically in the and is characterized by an arrest in myeloid maturation at the promyelocyte stage of the bone marrow resulting in an absolute neutrophil count of < 200/L.
Chronic idiopathic neutropenia represents a group of uncommon, poorly understood disorders involvin committed stem cells of the myeloid series; normal numbers of RBC and platelet precursors are prese Splenomegaly is not present. The degree of susceptibility to infection is about proportional to the blood neutrophil count in patients with absolute neutrophil counts < 500/L.
Symptoms and Signs
Some patients with chronic neutropenia with neutrophil counts < 200/L do not experience many serio infections, probably because the rest of the immune system remains intact. Commonly, however, patie cyclic neutropenia or severe congenital neutropenia have oral ulcers, stomatitis, or pharyngitis associa lymph node enlargement during severe chronic neutropenic states. Pneumonias and chronic periodon often occur.
Patients whose neutropenia is secondary to acquired disorders of production arising from cancer or fro chemotherapy are more likely to develop serious bacterial infections because their overall immune sys compromised. The integrity of the skin and mucous membranes, the vascular supply to tissue, and the nutritional status of the patient also influence the risk of infections in acute neutropenia. Patients with p infections tend to have fever > 38.3 C (101 F). The most frequently occurring pyogenic infections in p with profound neutropenia are cutaneous cellulitis, liver abscesses, furunculosis, pneumonia, and sep Stomatitis, gingivitis, perirectal inflammation, colitis, sinusitis, and otitis media often occur.
Diagnosis
The diagnosis of neutropenia is usually suspected in a patient with frequent, severe, or usual infection confirmed with low blood counts. One must then seek the cause and evaluate the risk of the infections Isolated absolute neutropenia has a limited number of causes.
During physical examination, special attention should be directed to the most common primary sites o infection: often the mucosal surfaces, such as the alimentary tract (gums, pharynx), wherein chemotherapy-induced damage may allow for invasion by colonizing organisms, or the skin, where vas catheters may serve as a portal of infection. Other common sites of infection include the lungs, periton bone marrow aspiration and venipuncture sites, and fingernails. The duration and severity of the neutropenia greatly influence the extent of laboratory evaluation.
Acute neutropenia: Evaluation of suspected infection in acute neutropenia is especially difficult becau typical signs of inflammation may be markedly diminished or absent. At least two sets of bacterial and
bone marrow aspiration and venipuncture sites, and fingernails. The duration and severity of the neutropenia greatly influence the extent of laboratory evaluation.
Acute neutropenia: Evaluation of suspected infection in acute neutropenia is especially difficult becau typical signs of inflammation may be markedly diminished or absent. At least two sets of bacterial and blood cultures should be obtained from all febrile patients. If an indwelling IV catheter is present, cultu should be obtained from the lumen and from a peripheral vein. Persistent or chronic drainage should b evaluated for atypical mycobacteria, and suspicious skin lesions should be aspirated or biopsied for cy and culture. Urine cultures are indicated if symptoms or signs of UTI are present. If diarrhea is present should be evaluated for enteric bacterial pathogens and Clostridium difficile toxins.
Radiography of the facial sinuses may be helpful if symptoms or signs of sinusitis (eg, headache, facia swelling, nasal discharge) are present.
Chronic neutropenia: Patients with chronic neutropenia since infancy and a history of recurrent fever chronic gingivitis should have WBC counts and differential counts obtained three times/wk for 6 wk to the periodicity suggestive of cyclic neutropenia. Bone marrow aspirate and biopsy may aid in diagnosi assessment of cellularity. Additional marrow studies (eg, cytogenetic analysis, special stains for detect leukemia and other malignant disorders) should be obtained for patients with suspected intrinsic defec myeloid cells or their precursors and for patients with suspected malignancies. Selection of further lab tests is determined by the duration and severity of the neutropenia and by findings on the physical examination.
Antineutrophil antibodies are associated with immune neutropenia. Various neutrophil antibody assays been used to study patients with suspected autoimmune neutropenia; all assays directly measure anti the patient's neutrophils or indirectly measure antibody in the patient's serum. Their specificity and sen are not well defined.
Treatment
Acute neutropenia: Management of acquired transient neutropenia characteristically associated with malignancies, myelosuppressive chemotherapy (see Ch. 144), or immunosuppressive therapy differs f of congenital or chronic forms of neutropenia. Patients with infections usually present only with fever. Infections are the major cause of death in these patients, who must therefore be approached with a hi of suspicion. Early recognition and treatment of infections may be lifesaving. If the acute neutropenia i suspected to be drug-induced, all potentially offending drugs should be stopped immediately.
Empiric broad-spectrum antibiotics remain the cornerstone of initial management in the acutely febrile neutropenic patient. Such patients should be assumed to have serious bacterial infection and promptly broad-spectrum antibiotics, ordinarily administered IV at maximal doses while diagnostic studies are in progress. In most situations, indwelling vascular catheters may remain in place even if bacteremia is suspected or documented, but they should be removed as soon as possible. Coagulase-negative staphylococci and Staphylococcus aureus are the most common bacterial species causing catheter-as infections. Whereas infections caused by coagulase-negative staphylococci generally respond well to antimicrobial treatment, infections associated with S. aureus, Bacillus sp, Corynebacterium sp, or Can generally require catheter removal and antimicrobial therapy.
The selection of a regimen for any patient should be based on a knowledge of the antimicrobial susce of the predominant pathogens encountered at that particular institution. The potential toxicity of a regim should also be considered when initiating therapy. Table 135-3 lists three available regimens.
Because of the risk of colonization and possible subsequent infections with resistant organisms, indisc
The selection of a regimen for any patient should be based on a knowledge of the antimicrobial susce of the predominant pathogens encountered at that particular institution. The potential toxicity of a regim should also be considered when initiating therapy. Table 135-3 lists three available regimens.
Because of the risk of colonization and possible subsequent infections with resistant organisms, indisc routine inclusion of vancomycin as the initial empiric antimicrobial therapy for fever in neutropenic pati should be discouraged. If cultures are positive, antibiotic therapy is adjusted to match the sensitivity of organisms and usually is continued for at least 7 to 10 days. If a patient defervesces rapidly within 72 antibiotics should be continued for at least 7 days and until the patient is free of significant symptoms signs of infection. Although antibiotic therapy is usually continued until the neutrophil count is > 500/L discontinuation of antimicrobial coverage can be considered in selected patients, especially those in w neutropenia is prolonged and signs and symptoms of inflammation have resolved.
Fever that fails to resolve within 72 h despite empiric broad-spectrum antibiotic therapy suggests a nonbacterial cause or infection with a bacterial species resistant to the chosen empiric regimen, a superinfection with a second bacterial species, inadequate serum or tissue levels of the antibiotics, or infection at a vascular site (eg, an abscess). Neutropenic patients with fever should be rigorously reas on day 4 or 5. If a patient is doing well from a clinical standpoint, the initial antibiotic regimen can be co If the clinical situation is deteriorating, the antibiotic regimen should be altered. In many situations, em addition of vancomycin to the regimen is justified. Because fungal infection is a significant cause of pe fever in neutropenic patients, empiric amphotericin B therapy should be added to the regimen in neutr patients whose fever fails to respond in 7 days to broad-spectrum antibiotic therapy. If a patient fails to defervesce after 3 wk of empiric antibiotic therapy, including 2 wk of amphotericin B, then discontinuat antimicrobial drugs should be considered and the cause of fever reevaluated.
The role of antibiotic prophylaxis in nonfebrile neutropenic patients remains controversial. Trimethoprim-sulfamethoxazole (TMP-SMX) is effective in the prevention of Pneumocystis carinii pneu neutropenic and nonneutropenic patients with impaired cell-mediated immunity. Also, TMP-SMX may the frequency of bacterial infections in patients expected to be profoundly neutropenic for > 1 wk. The disadvantages of TMP-SMX prophylaxis include adverse side effects, potential myelosuppression, and development of resistant bacteria and oral candidiasis. Antifungal prophylaxis with amphotericin B or fluconazole also has been evaluated in neutropenic patients at high risk for developing fungal infection after bone marrow transplantation). However, systemic antifungal prophylaxis is not recommended as component in the management of neutropenic patients.
Using glucocorticoids, androgenic steroids, and vitamins to stimulate the bone marrow to produce mor neutrophils has not proved successful. Two growth factors (cytokines), granulocyte colony-stimulating (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), are widely used to preven and infections in patients with severe neutropenia (eg, after bone marrow transplantation and intensive chemotherapy). Cytokine therapy is expensive; however, if the risk of febrile neutropenia is >= 30%, th G-CSF is justified. In general, most clinical benefit occurs when G-CSF is administered about 24 h afte completion of chemotherapy. Doses of 5 g/kg/day sc are often effective. G-CSF and GM-CSF accele return of the neutrophil count to > 500/L in patients undergoing autologous bone marrow transplantat intensive chemotherapy.
Saline or hydrogen peroxide gargles every few hours, anesthetic lozenges (benzocaine 15 mg q 3 or 4 chlorhexidine mouth rinse (1% solution) may relieve the discomfort associated with oropharyngeal ulce Oral candidiasis is treated with nystatin mouthwash (400,000 to 600,000 U qid). A semisolid or liquid d be necessary during acute mucositis.
Chronic neutropenia: Neutrophil production in congenital, cyclic, and idiopathic neutropenia can be i by administration of G-CSF 3 to 10 g/kg/day sc. This therapy is indicated in patients free from mouth and other types of oropharyngeal inflammation, fever, and cellulitis and other documented bacterial in The benefits are sustained, and patients can be maintained on daily or alternate-day G-CSF for month
be necessary during acute mucositis.
Chronic neutropenia: Neutrophil production in congenital, cyclic, and idiopathic neutropenia can be i by administration of G-CSF 3 to 10 g/kg/day sc. This therapy is indicated in patients free from mouth and other types of oropharyngeal inflammation, fever, and cellulitis and other documented bacterial in The benefits are sustained, and patients can be maintained on daily or alternate-day G-CSF for month years without loss of its effectiveness. Long-term G-CSF has also been used to prevent neutropenia in circumstances, including myelodysplasia, HIV and AIDS, and autoimmune disorders. In general, neutr counts increase, although clinical benefits of this therapy are less clear, especially for patients who do have severe neutropenia. Patients with neutropenia caused by an idiosyncratic drug reaction may also from G-CSF, particularly if a delayed recovery is anticipated. Thus far, however, only uncontrolled trial been reported in the latter situation.
In some patients with accelerated neutrophil turnover caused by autoimmune disorders, corticosteroid (generally prednisone 0.5 to 1.0 mg/kg/day po) will improve the blood neutrophil count. This improvem often be maintained with alternate-day therapy.
Splenectomy raises the neutrophil count in some patients with splenomegaly and splenic sequestratio neutrophils (eg, Felty's syndrome, hairy cell leukemia). However, splenectomy should be reserved for with severe neutropenia (ie, < 500/L) and with serious problems with infections because it predispose patient to infection by encapsulated organisms (see Ch. 141).
Section 11. Hematology And Oncology Chapter 145. Aids-Associated Hematologic Disorde Malignancies Topics
[General] Anemia Thrombocytopenia Leukopenia Antiretroviral Drugs Kaposi's Sarcoma Non-Hodgkin's Lymphomas Primary Central Nervous System Lymphoma Hodgkin's Disease Cervical Cancer Anal Cancer
[General]
Progressive cytopenias (anemia, thrombocytopenia, leukopenia) commonly occur in HIV-infected patie pathophysiologic mechanisms are multifactorial and include direct effects of HIV on hematopoietic pre cells, alterations in the microenvironment of the bone marrow, and immunologic destruction of periphe cells. The severity of these changes relates to the infections or malignancies superimposed on AIDS a myelosuppressive effects of antiretroviral, anti-infective, and antineoplastic therapies.
AIDS has been directly linked to an increased incidence of malignancies. Kaposi's sarcoma, non-Hodg lymphoma, and cervical cancer are AIDS-defining illnesses in HIV-infected patients. Other neoplastic d associated with AIDS include Hodgkin's disease, anal cancer, testicular cancer, melanoma, nonmelan skin cancers, lung cancer, and primary CNS lymphoma. Leiomyosarcoma has been reported as a rare complication of HIV infection in children.
Bone Marrow Evaluation
Indications for bone marrow evaluation in HIV-infected patients include evaluation of cytopenias, stagi malignancies, and culture for occult infections. Bone marrow evaluation can detect M. avium-intracellu tuberculosis, cryptococcus, Histoplasma, Toxoplasma, cytomegalovirus, human parvovirus B19, Pneu carinii, and Leishmania.
Bone marrow morphology in AIDS patients is nonspecific; the majority of patients have normocellular o
Indications for bone marrow evaluation in HIV-infected patients include evaluation of cytopenias, stagi malignancies, and culture for occult infections. Bone marrow evaluation can detect M. avium-intracellu tuberculosis, cryptococcus, Histoplasma, Toxoplasma, cytomegalovirus, human parvovirus B19, Pneu carinii, and Leishmania.
Bone marrow morphology in AIDS patients is nonspecific; the majority of patients have normocellular o hypercellular marrow despite peripheral cytopenia. Mild to moderate plasmacytosis, lymphoid aggrega increased numbers of histiocytes, and dysplastic changes in hematopoietic cells are common. Iron sto usually normal or increased (eg, as in iron-reutilization defect).
Up to 40% of hospitalized AIDS patients have had a positive direct antiglobulin test, representing IgG complement on involved RBCs. This finding is not commonly associated with clinically significant hem
HIV-infected patients may also have a lupus anticoagulant with an associated prolonged activated par thromboplastin time in the absence of bleeding. This may be of greater significance when associated w disorders that may predispose to a bleeding diathesis (thrombocytopenia, qualitative platelet dysfuncti hypoprothrombinemia). The defect may also lead to thrombosis.

Section 11. Hematology And Oncology Chapter 136. Eosinophilic Disorders Topics
[General] Eosinophilia Idiopathic Hypereosinophilic Syndrome
[General]
Eosinophils are granulocytes derived from the same progenitor cells as monocytes-macrophages, neu and basophils. The normal peripheral blood eosinophil count is < 350/L, with diurnal levels that vary i with plasma cortisol levels; the peak occurs at night, and the trough in the morning. The circulating hal eosinophils is 6 to 12 h, with most eosinophils residing in tissues (eg, the upper respiratory and GI trac uterus).
Eosinophilopoiesis appears to be regulated by T lymphocytes through the secretion of the hematopoie growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5). Although GM-CSF and IL-3 also increase the production of other myeloid cells, ILincreases eosinophil production exclusively.
Contents of eosinophil granules: Major basic protein and eosinophil cationic protein are toxic fo parasites and for mammalian cells. These proteins bind heparin and neutralize its anticoagulant activit Eosinophil-derived neurotoxin can severely damage myelinated neurons. Eosinophil peroxidase, differs significantly from peroxidase of other granulocytes, generates oxidizing radicals in the presence hydrogen peroxide and a halide. Charcot-Leyden crystals are primarily composed of phospholipase may be found in sputum, tissues, and feces in disease processes associated with eosinophilia (eg, as eosinophilic pneumonia).
Functions of eosinophils: The precise functions are unknown. No patients or animals without eosino have been described. Although phagocytic, eosinophils are less efficient than neutrophils in killing intra bacteria. No direct evidence shows that eosinophils kill parasites in vivo, but they are toxic to helminth and eosinophilia commonly accompanies helminthic infestations. Eosinophils may modulate immediat hypersensitivity reactions by degrading or inactivating mediators released by mast cells (eg, histamine leukotrienes, lysophospholipids, heparin). Leukotrienes may cause vasoconstriction and bronchocons Prolonged eosinophilia may result in tissue damage by mechanisms that are not entirely clear, althoug basic proteins of eosinophils are cytotoxic.

Section 23. Poisoning Chapter 307. Poisoning Topics
[General] Elimination Of Poisons Specific Poisons
[General]
(For poisoning due to bacterial or other toxins in food, see Ch. 28. For poisoning in children, see Poiso Ch. 263.)
Worldwide, > 13 million natural and synthetic chemicals have been identified; < 3000 cause > 95% of accidental and deliberate poisoning. Suspecting and identifying cases of poisoning and accurately ass poison's potential toxicity are critical to successful management because treatment is merely supportiv a specific toxicologic symptom complex is diagnosed. Poisoning should be considered in the differenti diagnosis of any unexplained symptoms or signs, especially in children < 5 yr and young adults. Poiso may be an attempt at suicide in depressed persons. Other high-risk groups include the elderly (medica mix-ups), hospitalized patients (drug errors), workers exposed to occupational chemicals, and persons exposed to environmental pollution.
A pertinent history should be obtained. The patient, particularly if unconscious, and premises should b inspected for drugs (eg, solid forms with imprint identifications) or traces of drug use (eg, needle tracks alcohol or evidence of alcohol use. (Alcoholism, drug dependence, and other illicit drug uses are discu Ch. 195.) Often, the type and speed of onset will confirm or refute a suspicion of poisoning. As early a possible, blood and urine samples should be collected.
In the USA, Europe, and parts of Asia and South America, information about household and industrial chemicals can be obtained from poison control centers. Consultation with the centers is encouraged b ingredients, first-aid measures, and antidotes printed on product containers may occasionally be inacc out of date, or the container may have been replaced or the package tampered with. The phone numb nearest center is often listed with other emergency numbers in the front of the local telephone book or available from the telephone operator.
Prevention
Widespread use of child-resistant containers with safety caps has reduced poisoning deaths in childre
available from the telephone operator.
Prevention
Widespread use of child-resistant containers with safety caps has reduced poisoning deaths in childre in the USA from about 500 in 1959 to about 50 in 1996. Other measures that prevent poisoning includ labeling of household products and prescription items, use of imprint identifications on solid medicatio elimination of lead from gasoline, use of carbon monoxide detectors, and improved monitoring of toxic exposures within industry and throughout the environment.
Treatment
The adequacy of cardiac and respiratory function must be determined and resuscitation begun if need Chs. 206 and 263). Patients with altered mental status should immediately receive IV glucose, naloxon thiamine after blood is drawn for testing. If possible, the substance ingested, its route of entry into the body, and its toxicity potential should be determined. The need for medical care should be ascertained, recognizing that many substances are (see Table 307-1). Overtreatment may be hazardous and is expensive.
Ingested poison: Early emesis usually removes more of the poison than does later gastric lavage or charcoal. (Caution: Do not induce vomiting if the patient is comatose, is having or is likely to have seiz has ingested corrosive substances. Emesis of petroleum distillates is rarely indicated unless a compou requiring evacuation [eg, parathion] has been dissolved in the distillates.) Ipecac syrup 15 to 30 mL (1 tbsp) taken with water or soft drinks (15 mL/kg for infants or 1 qt [1 L] for adults) immediately induces v the dose of ipecac can be repeated in 30 min if necessary. If ipecac is unavailable and the patient is fa medical facility, vomiting can be induced by giving soapy water (simple detergent). Any containers and appropriate specimens of the product or any vomitus should be saved.
Gastric lavage, if needed (avoid with seizures or if the ingested substance is corrosive), should be pe with the largest tube appropriate for the patient. A cuffed endotracheal tube will prevent aspiration in c or sedated patients > 2 yr. In patients < 2 yr, no cuff is needed because the endotracheal tube fits snu patient should be positioned head-down and given NaCl (for adults, physiologic 0.9% NaCl solution or water; for children, 0.45% solution). Lavage fluids should be introduced in 20- to 30-mL aliquots, which each followed by removal of the stomach contents by siphon or syringe until washings appear free of t (between 500 and 3000 mL of lavage solution). A specific antidote (see below) is then given if availabl otherwise, a slurry of activated charcoal is given.
Activated charcoal, due to its molecular configuration and large surface area, adsorbs significant am many poisons, precluding absorption from the gut. Charcoal is especially effective when the patient is symptomatic and when the compound is reexcreted into the gut (eg, phenobarbital, theophylline). Incr charcoal is being used as the primary management technique in the emergency department.
The earlier charcoal is given, the more effective it is. An amount of charcoal 5 to 10 times that of the s poison ingestion should be used. If the amount of poison is unknown, the usual charcoal dose is 10 to children < 5 yr or 50 to 100 g for older children and adults. Charcoal is administered as a slurry (20 to water), preferably by stomach tube. A dose before gastric lavage may be beneficial. It should not be administered before or immediately after ipecac syrup has been given. About 30% of patients vomit af charcoal administration alone.
The use of cathartics is highly controversial; cathartics may actually enhance absorption rather than p excretion. If used, cathartics are best limited to sodium sulfate 30 g dissolved in 250 mL water, with
water), preferably by stomach tube. A dose before gastric lavage may be beneficial. It should not be administered before or immediately after ipecac syrup has been given. About 30% of patients vomit af charcoal administration alone.
The use of cathartics is highly controversial; cathartics may actually enhance absorption rather than p excretion. If used, cathartics are best limited to sodium sulfate 30 g dissolved in 250 mL water, with proportionally reduced amounts for children, or in sorbitol/charcoal solutions (maximum, 2 doses).
Although not numerous, specific antidotes are remarkably effective--eg, naloxone for opioid overdos atropine for organophosphate toxicity, methylene blue for methemoglobinemia, acetylcysteine for mino toxicity (see Acetaminophen Poisoning in Ch. 263), digoxin immune Fab (Digibind) for digoxin toxicity Ch. 302).
Skin and eye contamination: After removal of contaminated clothing (including shoes and socks), th should be thoroughly washed and the eyes flushed with water or saline (see also Burns in Ch. 91 and emergency treatment in Ch. 276). Helpers should protect themselves from contamination.
Inhaled poison: The patient should be removed from the contaminated environment, and other perso should be protected from contamination. Respiratory support may be needed. Bites and stings: The immediate care of venomous bites and stings is discussed in Ch. 308.
Treatment of Complications
CNS stimulation may require sedation, usually with a benzodiazepine or a barbiturate. In pure amphe poisoning, chlorpromazine or a benzodiazepine may be used. To terminate seizures or prevent their recurrence, a benzodiazepine (eg, diazepam 5 to 10 mg for adults; 0.1 to 0.2 mg/kg for children) is giv slowly IV, or phenobarbital (100 to 200 mg IV or IM for adults; 4 to 7 mg/kg for children) is given. Ideal phenytoin is avoided. O2 saturation should be closely monitored. Refractory seizures very rarely, if eve require general anesthesia.
Severe CNS depression requires circulatory and ventilatory support (see Ch. 66). Endotracheal intub and, rarely, tracheostomy may be necessary. In suspected or known narcotic poisoning, naloxone sho used in repeated doses (see Opioid Dependence in Ch. 195). Stimulants are ineffective and are gene contraindicated.
Cerebral edema is common in poisoning due to sedatives, carbon monoxide, lead, and other CNS depressants. A 20% mannitol solution (5 to 10 mL/kg) is given slowly IV over 30 to 60 min. Corticoster also used (dexamethasone 1 mg/m2 of BSA q 6 h by IV drip). Intracranial monitoring with hyperventila try to alter the degree of cerebral edema is used less frequently. Barbiturate coma in cerebral edema d hypoxic episodes is no longer recommended. Renal failure, if present, may require dialysis. Hepatic failure may warrant transplantation.

Section 23. Poisoning Chapter 308. Bites And Stings Topics
Venomous Snakes Venomous Lizards Spiders Bees, Wasps, Yellow Jackets, Hornets, Ants Other Biting Arthropods Centipedes, Millipedes Scorpions Marine Animals
Venomous Snakes
Only about 15% of the 3000 species of venomous snakes throughout the world are considered poison humans (see Table 308-1). In the USA, about 25 species of snakes are venomous or have toxic saliva secretions. Poisonous snakes are native to every state except Alaska, Maine, and Hawaii. Although in > 8000 persons/yr are bitten by poisonous snakes, fewer than 6 deaths/yr occur, mostly in children, th members of religious sects who handle venomous snakes, and untreated or undertreated cases. Rattl account for most venomous snakebites and for almost all deaths. Most other venomous snakebites ar copperheads and, to a lesser extent, cottonmouths (water moccasins). Coral snakes account for < 1% bites. Imported species of venomous snakes, found in zoos, schools, snake farms, and amateur and professional collections, account for about 100 bites/yr. Most victims are young males, of whom 50% a intoxicated and deliberately handling or molesting the snake. Most bites occur on the extremities.
Venom Chemistry and Pathophysiology
Snake venoms are complex substances, chiefly proteins, with enzymatic activity. Although enzymes p important role, the toxic properties of the venom can be due to certain smaller polypeptides. Most veno components appear to bind with multiple physiologic receptor sites in a victim. Thus, the arbitrary class of snake venoms as "neurotoxins," "hemotoxins," and "cardiotoxins" is superficial and can lead to serio errors in clinical judgment.
The venom of most North American pit vipers (crotalids) contains toxic protein components, which pro local and systemic effects. These effects may include local tissue damage, vascular defects, hemolysi disseminated intravascular coagulation (DIC)-like (defibrination) syndrome (see below), and pulmonar cardiac, renal, and neurologic defects. Crotalid venom alters capillary vessel permeability, causing extravasation of electrolytes, colloid, and RBCs through vessel walls into the envenomated site and in
The venom of most North American pit vipers (crotalids) contains toxic protein components, which pro local and systemic effects. These effects may include local tissue damage, vascular defects, hemolysi disseminated intravascular coagulation (DIC)-like (defibrination) syndrome (see below), and pulmonar cardiac, renal, and neurologic defects. Crotalid venom alters capillary vessel permeability, causing extravasation of electrolytes, colloid, and RBCs through vessel walls into the envenomated site and in organs (eg, lungs, kidneys, heart, rarely CNS). Initially, edema, hypoalbuminemia, and hemoconcentra occur. Later, pooling of blood and fluids in the microcirculation results in shock, hypotension, and lactic acidemia. The fall in effective circulating blood volume may augment cardiac and renal failure. Thrombocytopenia (platelet count < 20,000/L) may occur alone or in combination with other coagulop severe cases of rattlesnake bites. Venom-induced intravascular clotting may trigger the defibrination syndrome, resulting in hematemesis, hematuria, and internal hemorrhage. Renal failure may be due to critical deficit in GFR secondary to hypotension, hemolysis, or a DIC-like syndrome. Proteinuria, hemoglobinuria, and myoglobinuria may be observed in some patients with severe rattlesnake bites. T venom of most North American pit vipers produces very minor changes in neuromuscular conduction, Mojave and Eastern diamondback rattlesnake venom may cause serious neurologic deficits.
Coral snake (elapid) venom contains primarily neurotoxic components, which result in neuromuscular blockade. The lack of significant proteolytic enzyme activity accounts for the minimal symptoms and si seen at the bite site.
Type of snake: The local symptoms and signs of most pit viper envenomations are fang marks, imm burning pain, edema (usually within 10 min, rarely > 30 min), and erythema or ecchymosis of the bite s adjacent tissues. If untreated, edema progresses rapidly and may involve the entire extremity within ho Lymphangitis and enlarged, tender regional lymph nodes may be present along with increased temper over the injured part. Ecchymosis is common in moderate or severe rattlesnake envenomation and ma appear over the bite area within 3 to 6 h. It is most severe after bites by Eastern and Western diamond and by prairie, Pacific, and timber rattlesnakes; it is less severe after copperhead and Mojave rattlesna bites. The skin may appear tense and discolored; vesicles usually appear in the bite area within 8 h, o becoming hemorrhagic. These changes are usually superficial because North American rattlesnake bi to be limited to dermal and subcutaneous tissues. Necrosis around the bite is common in untreated ca surrounding superficial vessels may become thrombosed. Most venom effects peak within 4 days of th
Systemic manifestations may include nausea, vomiting, diaphoresis, fever, generalized weakness, paresthesias, muscle fasciculations, altered mental state, hypotension, and shock. Rattlesnake bite vic may report a rubbery, minty, or metallic taste. Respiratory depression may result from bites by the Moj rattlesnake. Rattlesnake envenomations may induce a wide range of coagulation abnormalities, includ prolongation of prothrombin time (measured by the INR) or activated partial thromboplastin time (aPTT thrombocytopenia, hypofibrinogenemia, elevated fibrin degradation products, or a combination of thes disorders, resembling a DIC-like (defibrination) syndrome. Hemorrhage may occur from the bite site or membranes. Hematemesis, melena, and hematuria may develop. In most cases, a sharp rise in Hct is finding secondary to hemoconcentration. Later, Hct may fall as a result of fluid replacement and blood from coagulopathy. In severe cases, hemolysis may cause a rapid fall in Hct.
In bites from coral snakes, pain and swelling may be minimal or absent and are often transitory. Syst manifestations may be delayed 8 to 24 h. Paresthesia is common around the bite, and some weaknes extremity may become evident within several hours. The patient may report marked weakness and let Altered sensorium, including euphoria and drowsiness, may be observed. Cranial nerve palsies may a including ptosis, diplopia, blurred vision, dysarthria, and dysphagia with increased salivation. Respirato distress and muscle flaccidity may follow. Once the neurotoxic effects of coral snake envenomations b manifest, they are difficult to reverse with antivenom and may last for 3 to 6 days despite treatment. U patients may die of respiratory failure.
extremity may become evident within several hours. The patient may report marked weakness and let Altered sensorium, including euphoria and drowsiness, may be observed. Cranial nerve palsies may a including ptosis, diplopia, blurred vision, dysarthria, and dysphagia with increased salivation. Respirato distress and muscle flaccidity may follow. Once the neurotoxic effects of coral snake envenomations b manifest, they are difficult to reverse with antivenom and may last for 3 to 6 days despite treatment. U patients may die of respiratory failure.
Degree of envenomation: The severity of any snakebite envenomation depends on the size and spe the snake; the amount of venom injected; the number of bites; the location and depth of the bite (eg, b the head and trunk tend to be more severe than bites to the extremities); the age, size, and health of t victim; the time elapsed before treatment; and the victim's susceptibility (response) to the venom.
Numerical grading of envenomation is sometimes described in the literature; however, grading cases a minimal, moderate, or severe (see Table 308-2) based on local changes, systemic symptoms and sign coagulation parameters, and laboratory results is more practical. The grading of the envenomation sho determined by the most severe symptom or sign or laboratory finding. An envenomation may progress from minimal to severe and must be continually reassessed.
Fang marks: Fang marks can suggest the type of offending snake but do not provide positive identific Typical fang-mark patterns, based on the anatomy of the snake's jaw, may not be noticed in the field. Rattlesnakes may leave one or two fang marks or scratches and other teeth marks; single fang marks common. Bites by nonvenomous snakes usually show multiple teeth marks.
Treatment
Venomous snakebites are medical emergencies requiring immediate attention. Before treatment is be must be determined whether the snake is venomous and whether envenomation occurred, because a venomous snake may bite and not inject venom ("dry bites" occur in about 20 to 30% of pit viper bites about 50% of coral snakebites). When no envenomation occurs, or if the bite is inflicted by a nonveno snake, the bite should be treated as a puncture wound. In all envenomations, it is wise to contact a reg poison control center.
In the field: The snakebite victim should move or be moved beyond the snake's striking distance. The should avoid exertion and be reassured, kept warm, and transported to the nearest medical facility as as possible. The injured part should be loosely immobilized in a functional position just below heart lev all rings, watches, and constrictive clothing removed. Stimulants should not be administered. Tourniqu incision and suction, cryotherapy, and electric shock are contraindicated. The pressure immobilization bandages) method is not recommended in the USA for pit viper bites because local necrosis may be increased. The Extractor by Sawyer, applied directly over fang marks, may be of value in pit viper bites applied within a few minutes of the bite and continued for 30 to 60 min.
First responders (eg, paramedics) should support airway and breathing, administer O2 , establish IV ac and immediately transport the victim to the nearest medical facility.
In the emergency department: A detailed history--the time of bite, description of snake, type of field t underlying medical condition, allergy to horse products, history of snakebites and therapy--and a comp physical examination should be performed. All cases of snakebite, whether venomous or nonvenomou should be observed for >= 12 h. In all pit viper bites, except trivial cases, a CBC (including platelets), coagulation profile (prothrombin time, partial thromboplastin time, fibrinogen, fibrin degradation produc electrolytes, BUN, creatinine, and urinalysis should be obtained on arrival. For moderate or severe envenomations, blood typing and cross-match and CK tests should be performed, usually every 4 h fo and then daily. In severe cases, an ECG and a chest x-ray are indicated. If not performed in the field, infusion of normal saline or lactated Ringer's solution should be started in an unaffected extremity and
should be observed for >= 12 h. In all pit viper bites, except trivial cases, a CBC (including platelets), coagulation profile (prothrombin time, partial thromboplastin time, fibrinogen, fibrin degradation produc electrolytes, BUN, creatinine, and urinalysis should be obtained on arrival. For moderate or severe envenomations, blood typing and cross-match and CK tests should be performed, usually every 4 h fo and then daily. In severe cases, an ECG and a chest x-ray are indicated. If not performed in the field, infusion of normal saline or lactated Ringer's solution should be started in an unaffected extremity and patient placed on a cardiac monitor. In coral snakebites, neurotoxic venom effects require monitoring o saturation and baseline and serial pulmonary function (eg, peak flow, vital capacity).
Initial management: Antivenom remains the mainstay of treatment for moderate and severe rattlesn envenomation. Antivenom is given to patients who have evidence of envenomation and progression 3 8 h after the bite. The only commercially approved antivenoms are equine derived, and a skin test for sensitivity to horse serum (included in the package) should be performed only if antivenom will be give negative result does not preclude a hypersensitivity reaction (see Disorders with Type III Hypersensitiv Reactions in Ch. 148). If the skin test result is positive and the envenomation is considered life or limb threatening, pretreatment with H1 and H 2 blockers followed by antivenom should be administered in a care setting equipped to treat anaphylaxis. Early reactions to antivenom are common and usually resu too rapid infusion. If a reaction occurs, antivenom infusion should be stopped immediately. Epinephrin and H2 blockers, and isotonic fluids should be administered. Usually, use of antivenom can be resume further dilution in conjunction with a slower infusion rate.
The effectiveness of antivenom is time- and dose-related; antivenom is most effective within the first 4 less effective after 12 h, although it may reverse coagulopathies after 24 h. The initial dose should be by the severity and progression of local changes, systemic symptoms and signs, or laboratory findings time. Most minimal cases of rattlesnake envenomation do not require antivenom, moderate cases may require 10 to 15 vials (100 to 150 mL), and severe cases may initially require at least 15 vials (>= 150 Patients with profound circulatory collapse should initially receive 20 vials (200 mL). Cottonmouth (wat moccasin) envenomation usually requires smaller doses. Antivenom is unnecessary for copperhead a pygmy rattlesnake bites, except in children, the elderly, and patients with debilitating underlying medic conditions (eg, diabetes mellitus, coronary artery disease).
Reconstituted antivenom should be diluted in 250 to 1000 mL of sterile normal saline or 5% dextrose a given by IV drip, slowly at 50 to 75 mL/h for the first 10 min. If no reaction occurs, the remainder can b infused over 1 h. Antivenom should never be injected into the finger or toe. IV fluids should be minimiz pediatric and geriatric patients, except when shock or hypovolemia is present. Measuring the circumfe the involved extremity at three points proximal to the bite and measuring the advancing border of edem 15 to 30 min can guide additional antivenom dosage. If local findings, symptoms and signs, or laborato changes progress, the initial dose of antivenom is repeated every 1 to 2 h.
When probable coral snake envenomation has been diagnosed, 5 vials of antivenom (Micrurus fulvius be given. If symptoms develop, an additional 10 to 15 vials may be indicated. The patient's condition s monitored in an ICU in the event of respiratory paralysis.
CroFab is a new antivenom obtained from immunizing sheep with North American pit viper venoms, w results in production of IgG. The IgG is then harvested, chemically fractionated, and digested with pap yield purified Fab fragments. Clinical trials at multiple centers in the USA have shown CroFab to be sa effective with a lower incidence of immediate and delayed hypersensitivity reactions.
A regional poison control center or the local zoo is an excellent resource when dealing with a venomou snakebite, including that by a nonnative snake. These facilities maintain a list of consulting physicians as the Antivenin Index, which is published and periodically updated by the American Zoo and Aquarium Association and the American Association of Poison Control Centers. This index catalogs the location number of vials of antivenoms available for all native venomous snakes and most exotic species.
A regional poison control center or the local zoo is an excellent resource when dealing with a venomou snakebite, including that by a nonnative snake. These facilities maintain a list of consulting physicians as the Antivenin Index, which is published and periodically updated by the American Zoo and Aquarium Association and the American Association of Poison Control Centers. This index catalogs the location number of vials of antivenoms available for all native venomous snakes and most exotic species.
Antitetanus therapy should be given when indicated. Antibiotics are given only when clinical signs of in are present; antibiotic choice should be guided by culture of the wound. Signs of hypovolemic shock re isotonic fluid replacement. Severe defects of hemostasis (ie, abnormal clotting or lysis of cells or clots, disturbed platelet activity) may require replacement with packed RBCs, fresh frozen plasma, cryopreci platelets. Blood products should not be administered until an adequate dose of neutralizing antivenom been given. Corticosteroids are of no value during the acute stages and are contraindicated.
At the first sign of respiratory distress, O2 should be given and mechanical support provided (see Ch. Endotracheal intubation or tracheostomy may be needed, particularly if trismus, laryngeal spasm, or e salivation is present. Mild sedation with an IV benzodiazepine is indicated for severe envenomation wh respiratory failure is not a problem. A narcotic may be needed for pain. An extremity should never be i
Surgical debridement of blebs, bloody vesicles, or superficial necrosis, if present, should be carried ou between days 3 and 10 and may need to be done in stages. The wound area should be dressed and examined daily.
Follow-up care: Fasciotomy is usually unnecessary except when severe vascular compromise is evid demonstrated by compartment pressures >= 30 mm Hg over 1 h unresponsive to limb elevation, to ma to 2 g/kg) IV, and to an additional 10 to 15 vials of antivenom. Joint motion, muscle strength, sensation girth should be evaluated within 2 days of the bite. For avoidance of contractures, immobilization is int by frequent periods of gentle exercise, progressing from passive to active. Follow-up care also include whirlpool treatment, debridement as indicated, and daily cleansing of the wound. The wound should be covered with a sterile dressing and a loose bandage when the patient is supine and a reasonably firm when the patient is ambulatory. Serum sickness (type III hypersensitivity reaction--see Ch. 148) in up t of patients occurs 7 to 21 days after administration of >= 5 vials of antivenom. It may manifest as feve arthralgias, rash, lymphadenopathy, and occasional peripheral neuritis. Serum sickness can usually be effectively, on an outpatient basis, with H1 blockers and corticosteroids.

Section 3. Gastrointestinal Disorders Chapter 32. Functional Bowel Disorders Topics
Irritable Bowel Syndrome Gas
Gas
Physiology
(Eructation; Flatulence)
Gas is present in the gut as a result of swallowed air, production in the lumen, or diffusion from the blo the lumen.
Normally, air is swallowed in small amounts (aerophagia) during eating and drinking, but some people unconsciously swallow air repeatedly while eating and at other times, especially when anxious. Most swallowed air is subsequently eructated (belched); only a small amount passes into the small bowel. T quantity of air passed is apparently influenced by position: The esophagus empties into the posterior c aspect of the stomach. In an upright person, air rises above the liquid contents of the stomach, comes contact with the gastroesophageal junction, and is readily belched. In a supine person, air trapped bel stomach fluid tends to be propelled into the duodenum. Excessive salivation may also increase aeroph and may be associated with various GI disorders (gastroesophageal reflux disease), ill-fitting dentures medications, or nausea of any cause. Belching may be associated with use of antacids. Attributing the ulcer symptoms to belching rather than to antacids, the person may continue to belch to relieve distres
Gas is produced in the lumen by several mechanisms. Bacterial metabolism yields significant volum hydrogen (H2 ), methane (CH4), and CO2. Nearly all H2 is produced by bacterial metabolism of ingeste fermentable materials (carbohydrates, amino acids) in the colon and therefore is negligible after a prol fast or after a meal that is completely absorbed in the small bowel. Poorly understood factors (eg, diffe in colonic flora and motility) may also account for variations in gas production. Normal persons incomp absorb carbohydrates in certain common foods. The normally indigestible polysaccharides in fruits and vegetables (eg, fiber, raffinose) may also cause excess gas.
H2 is produced in large quantities after ingestion of certain fruits and vegetables containing indigestible carbohydrates (eg, baked beans) and in patients with malabsorption syndromes. In patients with disaccharidase deficiencies (most commonly lactase deficiency), large amounts of disaccharides pass colon and are fermented to H2 (see Carbohydrate Intolerance in Ch. 30). Celiac disease, tropical spru
vegetables (eg, fiber, raffinose) may also cause excess gas.
H2 is produced in large quantities after ingestion of certain fruits and vegetables containing indigestible carbohydrates (eg, baked beans) and in patients with malabsorption syndromes. In patients with disaccharidase deficiencies (most commonly lactase deficiency), large amounts of disaccharides pass colon and are fermented to H2 (see Carbohydrate Intolerance in Ch. 30). Celiac disease, tropical spru pancreatic insufficiency, and other causes of carbohydrate malabsorption should also be considered in of excess colonic gas.
CH4 is produced by bacterial metabolism of endogenous substances in the colon; the production rate minimally influenced by food ingestion. Some people consistently excrete large quantities of CH4; othe or none. The tendency to produce large quantities is familial, appearing during infancy and persisting f
CO2 may also be produced by bacterial metabolism, but a more important source is the reaction of HC H2 ions, in which 22.4 mL of CO2 is released for each mEq of HCO3 . H2 ions may be derived endogen from gastric hydrochloric acid or exogenously from the fatty acids released during digestion of fats, the sometimes representing several hundred milliequivalents of H2 ion. Theoretically, up to 4 L of CO2 ma released into the duodenum after ingestion of a meal. The acid products released by bacterial ferment unabsorbed carbohydrates in the colon may also react with HCO 3 to produce CO2. Although bloating occasionally occurs, the rapid diffusion of CO2 into the blood prevents intolerable distention.
Gas diffuses between the lumen and the blood in a direction dependent on the difference in partial pressure. The production of H2, CO2, and CH 4 may reduce the partial pressure of N in the lumen to fa that in the blood, which may account for much of the N in the lumen.
Gas is eliminated by belching, diffusion from the lumen into the blood with ultimate excretion by the lu bacterial catabolism, and passage through the anus (flatus, farting).
Excessive intestinal gas is commonly thought to cause abdominal pain, bloating, distention, belching, excessively voluminous or noxious flatus. However, excessive gas has not been clearly linked to these complaints; it is likely that many symptoms are incorrectly attributed to "too much gas." In most norma persons, 1 L/h of gas can be infused into the gut with a minimum of symptoms, whereas persons with symptoms related to gas often cannot tolerate smaller quantities. Similarly, retrograde colonic distentio balloon inflation or during colonoscopy often elicits severe discomfort in patients with IBS but minimal symptoms in others. Thus, the basic abnormality in persons with gas-related problems may be a hypersensitive intestine. Altered motility may contribute further to symptoms; gas may be the inciting a have no role in their pathogenesis.
Repeated belching indicates aerophagia. Some persons with this problem can readily produce a serie belches on command. When aerophagia is suspected, patient education and behavior modification sh undertaken rather than extensive medical evaluation and drug therapy.
In the splenic flexure syndrome, swallowed air becomes trapped in the splenic flexure and may caus diffuse abdominal distention. Left upper quadrant fullness and pressure radiating to the left side of the may result. There is increased tympany in the extreme left lateral aspect of the upper abdomen. Relief with defecation or passage of flatus.
Infantile colic is a syndrome presumably caused by crampy abdominal pain. Colicky infants appear to an excessive amount of gas. However, studies show no increase in H2 production or increase in
diffuse abdominal distention. Left upper quadrant fullness and pressure radiating to the left side of the may result. There is increased tympany in the extreme left lateral aspect of the upper abdomen. Relief with defecation or passage of flatus.
Infantile colic is a syndrome presumably caused by crampy abdominal pain. Colicky infants appear to an excessive amount of gas. However, studies show no increase in H2 production or increase in mouth-to-cecum transit times in colicky infants. Hence, the cause of this syndrome remains unclear.
Flatulence: Among those who are flatulent, the quantity and frequency of gas passage shows great v As with stool frequency, persons who complain of flatulence often have a misconception of what is nor study of eight normal men aged 25 to 35 yr, the average number of gas passages was 13 4/day with upper limit of 21/day, which overlapped with many persons who complained of excess flatus. Hence, objectively recording flatus frequency (using a diary kept by the patient) should be the first step in eval complaint of excessive flatulence.
Despite the flammable nature of the H2 and CH4 in flatulence, working near open flames is not hazard Children have been known to make a game of expelling gas over a match flame. However, gas explos rarely with fatal outcome, has been reported during jejunal and colonic surgery and even when diather used during endoscopic procedures in poorly evacuated patients.
Because symptoms of excessive gas are nonspecific and commonly overlap with IBS (see above) and organic disease, a detailed history is essential to guide the extent of medical evaluation. Long-standin symptoms in a young person who is otherwise well and has not lost weight are unlikely to be caused b serious organic disease. The older person, especially with the onset of new symptoms, merits more th examination before excessive gas, real or imagined, is treated. It is not uncommon for patients with ea disorders (anorexia nervosa, bulimia) to misperceive and be particularly stressed by symptoms such a bloating and belching. Clinicians should explore for the possible presence of an eating disorder in pati particularly young women with these symptoms.
Treatment
Belching, bloating, and distention are difficult to relieve because most complaints are caused by uncon aerophagia or by exaggerated sensitivity to normal amounts of gas. An attempt must be made to redu aerophagia. Aerophagia may be caused by excessive salivation, so the patient should avoid habits su gum chewing or smoking. Upper GI tract diseases (eg, peptic ulcer) that may cause reflex hypersaliva disorders that may cause nausea and reflex salivation should be treated. Carbonated beverages or an should be eliminated if associated with belching. Foods containing unabsorbable carbohydrates shoul avoided. Dairy products should be excluded from the diet of lactose-intolerant patients.
The mechanism of repeated belching should be explained and demonstrated. When aerophagia is troublesome, biofeedback and relaxation therapy can retrain the patients to swallow and chew more e and break the cycle of aerophagia-discomfort-belch-relief.
Few well-controlled studies have demonstrated clear-cut benefit from any drug. Simethicone, an agen breaks up small gas bubbles, has been incorporated into several preparations, and various anticholine drugs have also been used, all with variable results. Some persons with dyspepsia and postprandial u abdominal fullness have benefited from antacids. Cisapride (10 to 20 mg 30 min before meals--Cautio of serious drug interactions) can facilitate gastric emptying and increase lower esophageal sphincter p Complaints of excessive flatus are treated with similar measures to try to minimize the volume of gas i gut. Roughage (eg, bran, psyllium seed) may be added to the diet to try to increase colonic transit; how some patients, worsening of symptoms may result. Activated charcoal can sometimes help reduce gas unpleasant odor created by hydrogen sulfide produced in the bowel. However, its tendency to stain clo and the oral mucosa makes it somewhat awkward to use.
abdominal fullness have benefited from antacids. Cisapride (10 to 20 mg 30 min before meals--Cautio of serious drug interactions) can facilitate gastric emptying and increase lower esophageal sphincter p Complaints of excessive flatus are treated with similar measures to try to minimize the volume of gas i gut. Roughage (eg, bran, psyllium seed) may be added to the diet to try to increase colonic transit; how some patients, worsening of symptoms may result. Activated charcoal can sometimes help reduce gas unpleasant odor created by hydrogen sulfide produced in the bowel. However, its tendency to stain clo and the oral mucosa makes it somewhat awkward to use.
In general, functional bloating, distention, and flatus run an intermittent, chronic course that is only par relieved by therapy. Reassurance that these problems are not detrimental to health is important.
The following piece appeared in the Gastrointestinal section of past editions of The Merck Manual, and being reprinted here because of reader demand.
Flatulence, which can cause great psychosocial distress, is unofficially described according to its salie characteristics: (1) the "slider" (crowded elevator type), which is released slowly and noiselessly, some with devastating effect; (2) the open sphincter, or "pooh" type, which is said to be of higher temperatur more aromatic; (3) the staccato or drumbeat type, pleasantly passed in privacy; and (4) the "bark" type (described in a personal communication) is characterized by a sharp exclamatory eruption that effectiv interrupts (and often concludes) conversation. Aromaticity is not a prominent feature. Rarely, this usua distressing symptom has been turned to advantage, as with a Frenchman referred to as "Le Petomane became affluent as an effluent performer who played tunes with the gas from his rectum on the Moulin stage.

Section 13. Infectious Diseases Chapter 157. Bacterial Diseases Topics
Caused By Gram-Positive Cocci Caused By Gram-Negative, Aerobic Cocci Caused By Gram-Positive Bacilli Caused By Gram-Negative Bacilli Caused By Anaerobic Bacilli Caused By Spirochetes Caused By Mycobacteria
Caused By Gram-Positiv Bacilli

ERYSIPELOTHRICOSIS
Infection caused by Erysipelothrix rhusiopathiae that most often takes the form of erysipeloid, an acu slowly evolving skin affliction.
E. rhusiopathiae (formerly called E. insidiosa), a gram-positive, capsulated, nonsporulating, nonmotile, microaerophilic bacillus with worldwide distribution, is primarily a saprophyte. It may infect a variety of animals, including insects, shellfish, fish, birds, and mammals (especially swine). In humans, infection occupational and typically follows a penetrating wound in persons who handle animal matter, either ed nonedible (infected carcasses, rendered products [grease, fertilizer], bones, and shells). Nondermal in rare, usually occurring as arthritis or endocarditis.
Symptoms and Signs
Within a week of injury, a characteristic raised, purplish red, nonvesiculated, indurated, maculopapular appears, accompanied by itching and burning. Local swelling, though sharply demarcated, may inhibit
Symptoms and Signs
Within a week of injury, a characteristic raised, purplish red, nonvesiculated, indurated, maculopapular appears, accompanied by itching and burning. Local swelling, though sharply demarcated, may inhibit the hand, the usual site of infection. The lesion's border may slowly extend outward, causing discomfo disability that may persist for 3 wk. The disease usually is self-limited, typically without evident regiona lymphatic involvement; it rarely extends to general cutaneous disease. Bacteremia is rare but may res septic arthritis or infective endocarditis even in those without known valvular heart disease.
Diagnosis
Culture of a full-thickness biopsy of the skin is superior to needle aspiration of the advancing edge of a for isolating E. rhusiopathiae; culture of exudate obtained by abrading a florid papule may be diagnost Isolation from synovial fluid or blood is necessary for the diagnosis of erysipelothrical arthritis or endoc Polymerase chain reaction amplification of the DNA sequence of E. rhusiopathiae that codes for 16S r may aid rapid diagnosis.
Treatment
Benzathine penicillin G 1.2 million U IM (a single 600,000-U dose in each buttock) or erythromycin 0.5 for 7 days cures erysipeloid. Endocarditis is treated for 4 wk with penicillin G 25,000 to 30,000 U/kg IV cefazolin 15 to 20 mg/kg IV q 6 h. Although the same drugs and doses are appropriate for arthritis (giv least 1 wk after defervescence or cessation of effusion), repeated needle aspiration drainage of the in joint is necessary.
LISTERIOSIS
Infection caused by Listeria sp. (See also Neonatal Listeriosis under Neonatal Infections in Ch. 260.)
Etiology, Incidence, and Epidemiology
Listeriaceae are gram-positive, non-acid-fast, noncapsulated, nonsporulating, motile, facultatively ana bacilli that are found worldwide in the environment and in the gut of nonhuman mammals, birds, arach and crustaceans. Only those Listeria sp that are hemolytic (chiefly L. monocytogenes, rarely L. ivanov seeligeri) cause disease in humans and domestic and wild animals. Incidence in the USA is >= 7 cases/1,000,000 people/yr, with attack rates highest in newborns and in adults >= 70 yr; infection peak July through August. Infection usually occurs via ingestion of contaminated dairy products and raw veg and is favored by the ability of L. monocytogenes to survive and grow at refrigerator temperatures. Infe may also occur by direct contact (antepartum and intrapartum from mother to child, especially during a [which may be caused by the listerial infection]), and during slaughter from infected animals to butcher abattoir workers. Infection is facilitated by immunoincompetence in up to 2/3 of patients.
Primary listeremia is rare and consists of bacteremia with high fever but without localizing symptoms a
abattoir workers. Infection is facilitated by immunoincompetence in up to 2/3 of patients.
Primary listeremia is rare and consists of bacteremia with high fever but without localizing symptoms a signs. In adults, meningitis is the most common form; unlike in other bacterial meningitides, cerebritis from diffuse encephalitis, or rarely, rhomboencephalitis to abscesses) occurs in up to 20% of cases. Oculoglandular listeriosis, with ophthalmitis and regional lymph node involvement, may follow conjunc inoculation and, if untreated, may progress to bacteremia and meningitis. Listerial dermatitis may follo contact with infected tissues. Endocarditis is rare.
Listerial infections may be suspected clinically, but isolation of Listeria sp is necessary for diagnosis. T laboratory must be informed when specimens are sent for culture of L. monocytogenes because the o is easily confused with diphtheroids. In all listerial infections, IgG agglutinin titers peak 2 to 4 wk after o
Treatment
Listerial meningitis is best treated with penicillin G 75,000 to 100,000 U/kg IV q 4 h and continued for 1 days after defervescence. Cephalosporins are not effective. Both penicillin G (75,000 to 100,000 U/kg and tobramycin (1.7 mg/kg IV q 8 h) should be given for endocarditis (6 wk) and primary listeremia (2 w beyond defervescence). Oculoglandular listeriosis and listerial dermatitis should respond to erythromy estolate 30 mg/kg/day po in 4 equal doses q 6 h, continued until 1 wk after defervescence.
ANTHRAX
This discussion on anthrax has been updated on October 30, 2001, from the printed versi
A highly infectious disease of animals, especially ruminants, transmitted to humans by contact with the or their products.
The causative organism, Bacillus anthracis, is a large, Gram-positive, facultatively anaerobic, encapsu rod. The spores resist destruction by disinfectants and heat and remain viable in soil and animal produ decades. Human infection is usually through the skin but has occurred very rarely in the GI tract after of contaminated meat. Inhaling spores may result in pulmonary anthrax (woolsorter's disease), which i fatal.
Biological Warfare and Terrorism

Biological warfare is the use of microbiological agents for hostile purposes. Such use is contrary to international law and in fact has rarely taken place during formal warfare in modern history, despite the extensive preparations and stockpiling of biological agents carried out in the 20th century by most major
Biological warfare is the use of microbiological agents for hostile purposes. Such use is contrary to international law and in fact has rarely taken place during formal warfare in modern history, despite the extensive preparations and stockpiling of biological agents carried out in the 20th century by most major powers. Currently, the NATO nations have taken biological weapons out of service. Some other nations (including Iraq, Iran, and North Korea) are thought to maintain biological warfare capability. For a variety of reasons--including uncertain military efficacy and the threat of massive retaliation--experts consider the use of biological agents in formal warfare unlikely. The area of most concern is the use of such agents by terrorist groups. Biological agents are thought by some people to be an ideal weapon for terrorists. These agents may be delivered clandestinely, and they have delayed effects--allowing the user to remain undetected. more
Following entry into the body, the spores germinate inside macrophages, and the bacteria are transpo regional lymph nodes, where they multiply. The bacteria produce a variety of toxins; protective antigen target cells and facilitates cellular entry of edema toxin and lethal toxin. Lethal toxin triggers a massive of cytokines from macrophages, which is responsible for the sudden death common in anthrax infectio
Although anthrax is an important animal disease, it is rare in humans and mainly occurs in countries th not prevent industrial or agricultural exposure to infected goats, cattle, sheep, and horses or their prod Anthrax also occurs in exotic wildlife such as hippos, elephants, and cape buffalo.
Symptoms and Signs

The incubation period varies from 12 h to 5 days (generally, 3 to 5 days).
The cutaneous form begins as a painless, pruritic, red-brown papule; as it enlarges, it is surrounded zone of brawny erythema and gelatin-like edema. Considerable peripheral erythema, vesiculation, and induration are present. Central ulceration follows, with serosanguineous exudation and formation of a eschar (see Figure). Local lymphadenopathy may occur, occasionally with malaise, myalgia, headache nausea, and vomiting.
Initial symptoms of pulmonary anthrax are insidious and resemble influenza. Fever increases, and w few days, severe respiratory distress develops, followed by cyanosis, shock, and coma. Severe hemor necrotizing lymphadenitis develops and spreads to the adjacent mediastinal structures. Serosanguine transudation, pulmonary edema, and pleural effusion occur. Hemorrhagic meningoencephalitis and/or anthrax may develop. Lung x-ray may show diffuse patchy infiltration; the mediastinum is widened bec enlarged hemorrhagic lymph nodes.
In GI anthrax, the released toxin induces a hemorrhagic necrosis extending to the draining mesenteric nodes. Septicemia with potentially lethal toxicity ensues.
Diagnosis
The occupational and exposure history is important. Cultures or Gram stains from cutaneous lesions m
nodes. Septicemia with potentially lethal toxicity ensues.
Diagnosis
The occupational and exposure history is important. Cultures or Gram stains from cutaneous lesions m used to isolate B. anthracis, and throat swabs and sputum may be used in the pulmonary form. When cultures do not grow, the organism may be isolated by mouse inoculation. Polymerase chain reaction on blood samples also may be used.
Diagnosis of GI anthrax depends on recognition of clinical symptoms. Occasionally, organisms can be Gram stain of vomitus or feces. Clinically, GI anthrax presents with nausea, vomiting, anorexia, and fe progressing to bowel necrosis with concurrent septicemia and death. An oropharyngeal form of anthra presents as a mucocutaneous lesion in the oral cavity with sore throat, fever, adenopathy, and dyspha which may proceed to necrosis and death.
An anthrax vaccine, composed of a culture filtrate, is available for those at high risk (armed forces per veterinarians, laboratory technicians, employees of textile mills processing imported goat hair). Repea vaccination may be required to ensure protection. Local reactions can occur. A live toxigenic, unencap avirulent animal vaccine is available for veterinary use. Most strains of anthrax are susceptible to penicillin. However, the organism often manifests inducible beta-lactamases, so single-drug therapy with penicillin is not recommended. Cephalosporins are not recommended.
People exposed to inhaled anthrax require prophylactic treatment with oral ciprofloxacin 500 mg bid, o doxycycline 100 mg bid for 60 days. Amoxicillin 500 mg tid is an option where ciprofloxacin and doxyc are contraindicated. Induction of beta-lactam resistance is of less concern with the lower number of or present in prophylactic use.
Cutaneous anthrax is treated with oral ciprofloxacin 500 mg bid, or doxycycline 100 mg bid for 7 days. Treatment is extended to 60 days if there is a possibility of concomitant inhalation exposure. Cutaneou anthrax with significant edema or systemic symptoms, as well as all patients with inhalational anthrax anthrax, requires intravenous treatment with 2 or 3 drugs: ciprofloxacin 400 mg q 12 h or doxycycline 1 12 h along with either penicillin, rifampin, vancomycin, clindamycin, or clarithromycin.
Pulmonary anthrax is frequently fatal, but survival is possible with early treatment and intensive pulmo circulatory support. Corticosteroids may be useful but have not been adequately evaluated. If treatmen delayed (usually because the diagnosis is missed), death is likely.
NOCARDIOSIS
(See also Ch. 158.)
An acute or chronic, often disseminated, granulomatous-suppurative infectious disease usually caused aerobic gram-positive bacillus Nocardia asteroides, a soil saprophyte.
Epidemiology
aerobic gram-positive bacillus Nocardia asteroides, a soil saprophyte. (See also Ch. 158.)
Epidemiology
N. asteroides usually enters the body via the lungs and rarely via the GI tract or skin. Nocardiosis is uncommon and occurs worldwide in all age groups, but incidence is greater among older adults and m Lymphoreticular malignancies, organ transplantation, high-dose corticosteroid or other immunosuppre therapy, and underlying pulmonary disease are predisposing factors, but about half the patients have preexisting disease. Nocardiosis also has been recognized as an opportunistic infection in patients wit advanced HIV infection. Other Nocardia sp sometimes cause localized or, occasionally, systemic infec
Symptoms and Signs
Disseminated nocardiosis usually begins as a pulmonary infection that may resemble actinomycosis, b asteroides is more likely to disseminate hematogenously with abscess formation in the brain or, less frequently, in the kidney or in multiple organs. Skin or subcutaneous abscesses occur frequently, som as a primary site of localized infection. With lung lesions, the most common symptoms--cough, fever, chest pain, weakness, anorexia, and weight loss--are nonspecific and resemble those of TB or suppur pneumonia. Pleural effusion also may occur. Metastatic brain abscesses may occur in as many as 1/3 cases and usually produce severe headaches and focal neurologic abnormalities. Infection may be ac subacute, or chronic.
Diagnosis
Diagnosis is by identification of N. asteroides in tissue or culture from localized lesions identified by ph examination, x-ray, or other imaging studies. Clumps of beaded, branching filaments of gram-positive are often seen, which may be weakly acid-fast (ie, modified acid-fast stains can be decolorized using s acid rather than acid alcohol as with Mycobacterium tuberculosis). N. asteroides does not develop a c appearance as does Actinomyces israelii.
Treatment
Without treatment, nocardiosis caused by N. asteroides is usually fatal. Among patients who are treate appropriate antibacterial antibiotics, the mortality is highest (> 50%) in immunocompromised patients w disseminated infections and lowest (15% mortality) in immunocompetent patients with lesions restricte lungs.
Because most cases respond slowly, sulfonamide in a dose that maintains a blood concentration of 12 mg/dL (eg, with sulfadiazine 4 to 6 g/day po) must be continued for several months. Trimethoprim-sulfamethoxazole or high doses of a sulfonamide alone (sulfadiazine or sulfisoxazole) a When sulfonamide hypersensitivity or refractory infections are present, amikacin, a tetracycline, imipen ceftriaxone, cefotaxime, or cycloserine can be used.

Section 13. Infectious Diseases Chapter 162. Viral Diseases Topics
[General] Respiratory Viral Diseases Herpesvirus Infections Central Nervous System Viral Diseases Arbovirus And Arenavirus Diseases Smallpox
Smallpox
This discussion on smallpox was added to the page on November 12, 2001, and is not contained in the printed version.
Smallpox (variola) is a highly contagious disease caused by the smallpox virus, resulting in severe constitutional symptoms, a classic pustular rash, and frequently death.
No cases of smallpox have occurred in the world since 1977, thanks to a highly successful worldwide vaccination program. In 1980, WHO recommended discontinuation of routine smallpox vaccination. Ro childhood vaccination in the United States ended in 1972. Because humans are the only natural host o smallpox virus, and because the virus cannot survive for longer than 2 days in the environment, the W Health Organization (WHO) has declared the disease eradicated.
Because immunity declines over time, nearly all people--even those previously vaccinated--are now susceptible to smallpox. Recent concerns about terrorist access to existing stockpiles of smallpox viru United States and Russia raise the possibility of a recurrence of this epidemic disease.
There are at least two strains of smallpox virus. The most virulent strain causes variola major; and the virulent results in variola minor (alastrim).
Smallpox is transmitted person to person by direct contact or inhalation of droplet nuclei. Contact with contaminated clothing or bed linens also will transmit the infection. The virus invades the oropharynge respiratory mucosa and multiplies in regional lymph nodes. The virus eventually localizes in small bloo vessels of the dermis and the oropharyngeal mucosa. Other organs are seldom involved, except for an occasional occurrence of encephalitis. Secondary bacterial infection of skin lesions may occur.
Smallpox is transmitted person to person by direct contact or inhalation of droplet nuclei. Contact with contaminated clothing or bed linens also will transmit the infection. The virus invades the oropharynge respiratory mucosa and multiplies in regional lymph nodes. The virus eventually localizes in small bloo vessels of the dermis and the oropharyngeal mucosa. Other organs are seldom involved, except for an occasional occurrence of encephalitis. Secondary bacterial infection of skin lesions may occur.
Patients become infectious only after the appearance of the rash, and remain so for the first 7 to 10 da Once crusts form on the skin lesions, infectivity declines.
Transmission occurs mainly to household and other close personal contacts of an infected person. La outbreaks in schools or the workplace are uncommon. However, because very few virus particles are to initiate infection, as many as 10 to 20 secondary cases may develop from each primary case. Beca the virus's sensitivity to heat and humidity, natural epidemics primarily occurred in the winter and early
Symptoms and Signs
Classic smallpox (variola major) has a 12 to 14 day incubation period (range 7 to 17 days), followed by day prodrome of fever, headache, backache, and extreme malaise. Sometimes, there is severe abdom pain and delirium. Following the prodrome, a maculopapular rash develops on the oropharyngeal muc face, and the arms, spreading shortly thereafter to the trunk and legs. The oropharyngeal lesions quick ulcerate. After 1 or 2 days, the cutaneous lesions become vesicular, and then pustular. The pustules a dense on the face and extremities than on the trunk, and may appear on the palms. The pustules are tense, and appear deeply embedded. The skin lesions of smallpox, unlike those of varicella, are all at same stage of development on a given body part. After 8 or 9 days, the pustules become crusted. Sev residual scarring is typical. Mortality is about 30%, and usually occurs in the second week of illness.
Variola minor results in similar symptoms that are much less severe, with a less extensive rash. Morta less than 1%.
About 10% of people with smallpox develop one of two variant forms; hemorrhagic or malignant. The hemorrhagic form is more common in pregnant women, and manifests with a shorter, more intense pr followed by generalized erythema and cutaneous and mucosal hemorrhage. It is uniformly fatal, with d occurring within 5 or 6 days. The malignant form has a similar, severe prodrome, followed by developm confluent, flat, nonpustular skin lesions. In the rare survivors, the epidermis frequently peels.
Diagnosis
Diagnosis is confirmed by electron microscopy or viral culture of material scraped from skin lesions. Polymerase chain reaction (PCR) testing of blood samples will identify viral strains. Testing should onl performed in laboratories with high level containment capability (BL-4). Once an outbreak is confirmed testing, further cases are diagnosed clinically.
Prevention
There are two arms to smallpox prevention: vaccination and isolation. The current stockpile of smallpo vaccine in the United States is only large enough to cover 6 to 7 million people, but increased producti planned.
Smallpox vaccine consists of live vaccinia virus, which is related to smallpox and provides cross-immu vaccine is administered with a bifurcated needle dipped in reconstituted vaccine. The needle is rapidly 15 times in an area about 5mm in diameter with sufficient force to draw a trace of blood. The vaccine s
vaccine in the United States is only large enough to cover 6 to 7 million people, but increased producti planned.
Smallpox vaccine consists of live vaccinia virus, which is related to smallpox and provides cross-immu vaccine is administered with a bifurcated needle dipped in reconstituted vaccine. The needle is rapidly 15 times in an area about 5mm in diameter with sufficient force to draw a trace of blood. The vaccine s covered with a non-occlusive bandage to prevent spread of the vaccine virus to other body sites. A su vaccination is indicated by development of a pustule by about the seventh day. Revaccination may res in a papule surrounded by erythema, which peaks between 3 and 7 days. People without such a react should be revaccinated.
Preexposure vaccination is likely to be limited to people at high risk for exposure to the virus (such as technicians, healthcare workers, and mortuary attendants) until sufficient supplies of vaccine are avail
Postexposure vaccination can prevent or significantly limit the severity of illness and should be given and close personal contacts of smallpox patients. Early administration is most effective, but some ben realized up to 4 days postexposure.
Complications of vaccination are rare but potentially serious. Postvaccinial encephalitis occurs in 1 300,000 recipients of primary vaccination, typically 8 to 15 days post-vaccination. Symptoms include headache, delirium, coma, seizures, and paralysis. One fourth of cases are fatal. Progressive vaccinia in a nonhealing vaccinial lesion that spreads to adjacent skin and ultimately other skin areas, bones, a viscera. Progressive vaccinia may occur in both primary and revaccination and is occasionally fatal. Ec vaccinatum results in vaccinial skin lesions appearing on areas of active or even healed eczema. Gen vaccinia results from hematogenous dissemination of the vaccinia virus and produces vaccinia lesions multiple locations on the body.
Vaccination mortality is about one per million in primary vaccination and one per 4 million previously vaccinated. On average, serious complications occur in approximately 100 per million primary vaccine People at special risk for complications include people with eczema, people receiving cancer chemoth radiation, people with HIV infection or other immune system suppression, and pregnant women. Serio vaccine complications are treated with vaccinia immune globulin (VIG), 0.6 mL/kg IM in divided doses, repeated after 2 or 3 days if necessary. High-risk patients who require vaccination because of contact smallpox may be simultaneously given VIG 0.3 mL/kg IM. The VIG does not effect the immunogenicity vaccination. VIG is available only from the CDC.
Isolation of people with smallpox is essential to prevent spread of the disease. In limited outbreaks, p may be isolated in a hospital in negative-pressure rooms equipped with high-efficiency particulate filter (HEPA). In mass outbreaks, home isolation may be required. Healthy contacts are not infectious and d require isolation. Contacts should be placed under surveillance, typically with daily temperature measu and isolated at home for temperature >38 C or other sign of illness.
Treatment
Treatment is supportive only, with antibiotics for the occasional secondary bacterial infection. Antivirals marginal activity against smallpox and have never been used clinically.
The Merck Manual of Medical Information--Home Edition Title Page Robert Berkow, M.D., Editor-in-Chief Mark H. Beers, M.D., Associate Editor Andrew J. Fletcher, M.B., B.Chir., Senior Assistant Editor Robert M. Bogin, M.D., Senior Assistant Editor
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The authors, reviewers, editors, and publisher have made extensive efforts to ensure that the informat accurate and conforms to the standards accepted at the time of publication. However, constant chang information resulting from continuing research and clinical experience, reasonable differences in opinio among authorities, unique aspects of individual situations, and the possibility of human error in prepar an extensive text require that the reader exercise judgment when making decisions and consult and co information from other sources. In particular, the reader is advised to discuss information obtained in t with a doctor, pharmacist, nurse, or other health care practitioner.

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