Part 18: Poisoning, Drug Overdose, and Envenomation
that low-level arsenic may cause neurodevelopmental delays in chil-
472e Heavy Metal Poisoning
Howard Hu
Metals pose a significant threat to health through low-level environ-
mental as well as occupational exposures. One indication of their
importance relative to other potential hazards is their ranking by the
U.S. Agency for Toxic Substances and Disease Registry, which main-
tains an updated list of all hazards present in toxic waste sites according
to their prevalence and the severity of their toxicity. The first, second,
third, and seventh hazards on the list are heavy metals: lead, mercury,
arsenic, and cadmium, respectively (http://www.atsdr.cdc.gov/spl/).
Specific information pertaining to each of these metals, including
sources and metabolism, toxic effects produced, diagnosis, and the
appropriate treatment for poisoning, is summarized in Table 472e-1.
Metals are inhaled primarily as dusts and fumes (the latter defined
as tiny particles generated by combustion). Metal poisoning can also
result from exposure to vapors (e.g., mercury vapor in creating dental
amalgams). When metals are ingested in contaminated food or drink
or by hand-to-mouth activity (implicated especially in children), their
gastrointestinal absorption varies greatly with the specific chemical
form of the metal and the nutritional status of the host. Once a metal is
absorbed, blood is the main medium for its transport, with the precise
kinetics dependent on diffusibility, protein binding, rates of biotrans-
formation, availability of intracellular ligands, and other factors. Some
organs (e.g., bone, liver, and kidney) sequester metals in relatively high
concentrations for years. Most metals are excreted through renal clear-
ance and gastrointestinal excretion; some proportion is also excreted
through salivation, perspiration, exhalation, lactation, skin exfoliation,
and loss of hair and nails. The intrinsic stability of metals facilitates
tracing and measurement in biologic material, although the clinical
significance of the levels measured is not always clear.
Some metals, such as copper and selenium, are essential to normal
metabolic function as trace elements (Chap. 96e) but are toxic at high
levels of exposure. Others, such as lead and mercury, are xenobiotic and
theoretically are capable of exerting toxic effects at any level of expo-
sure. Indeed, much research is currently focused on the contribution of
low-level xenobiotic metal exposure to chronic diseases and to subtle
changes in health that may have significant public health consequences.
Genetic factors, such as polymorphisms that encode for variant
enzymes with altered properties in terms of metal binding, transport,
and effects, also may modify the impact of metals on health and thereby
account, at least in part, for individual susceptibility to metal effects.
The most important component of treatment for metal toxicity is
the termination of exposure. Chelating agents are used to bind met-
als into stable cyclic compounds with relatively low toxicity and to
enhance their excretion. The principal chelating agents are dimer-
caprol (British anti-Lewisite [BAL]), ethylenediamine tetraacetic acid
(EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicilla-
mine; their specific use depends on the metal involved and the clinical
circumstances. Activated charcoal does not bind metals and thus is of
limited usefulness in cases of acute metal ingestion.
In addition to the information provided in Table 472e-1, several
other aspects of exposure, toxicity, or management are worthy of
discussion with respect to the four most hazardous toxicants (arsenic,
cadmium, lead, and mercury).
Arsenic, even at moderate levels of exposure, has been clearly linked
with increased risks for cancer of the skin, bladder, renal pelvis, ureter,
kidney, liver, and lung. These risks appear to be modified by smoking,
folate and selenium status, genetic traits (such as ability to methylate
arsenic), and other factors. Studies in community-based populations
are beginning to demonstrate that arsenic exposure is a risk factor for
increased coronary heart disease and stroke. Evidence is also emerging
472e-1
dren and possibly diabetes, but the evidence remains uneven.
Serious cadmium poisoning from the contamination of food and
water by mining effluents in Japan contributed to the 1946 outbreak
of “itai-itai” (“ouch-ouch”) disease, so named because of cadmium-
induced bone toxicity that led to painful bone fractures. Modest expo-
sures from environmental contamination have recently been associ-
CHAPTER 472e Heavy Metal Poisoning
ated in some studies with a lower bone density, a higher incidence
of fractures, and a faster decline in height in both men and women,
effects that may be related to cadmium’s calciuric effect on the kidney.
There is some evidence for synergy between the adverse impacts of
cadmium and lead on kidney function. Environmental exposures have
also been linked to lower lung function (even after adjusting for smok-
ing cigarettes, which contain cadmium) as well as increased risk of
cardiovascular disease and mortality, stroke, and heart failure. Several
studies have also raised concerns that cadmium may be carcinogenic
and contribute to elevated risks of prostate, breast, and pancreatic
cancer. Overall, this growing body of research indicates that cadmium
exposure may be contributing significantly to morbidity and mortality
rates in the general population.
Advances in our understanding of lead toxicity have recently ben-
efited by the development of K x-ray fluorescence (KXRF) instruments
for making safe in vivo measurements of lead levels in bone (which, in
turn, reflect cumulative exposure over many years, as opposed to blood
lead levels, which mostly reflect recent exposure). Higher bone lead
levels measured by KXRF have been linked to increased risk of hyper-
tension and accelerated declines in cognition in both men and women
from an urban population. Upon reviewing these studies in conjunc-
tion with other epidemiologic and toxicologic studies, a recent federal
expert panel concluded that the impact of lead exposure on hyperten-
sion and cognition in adults was causal. Prospective studies have also
demonstrated that higher bone lead levels are a major risk factor for
increased cardiovascular morbidity and mortality rates in both com-
munity-based and occupational-exposed populations. Lead exposure
at community levels has also been recently associated with increased
risks of hearing loss, Parkinson’s disease, and amyotrophic lateral scle-
rosis. With respect to pregnancy-associated risks, high maternal bone
lead levels were found to predict lower birth weight, head circumfer-
ence, birth length, and neurodevelopmental performance in offspring
by age 2 years. In a randomized trial, calcium supplementation (1200
mg daily) was found to significantly reduce the mobilization of lead
from maternal bone into blood during pregnancy.
The toxicity of low-level organic mercury exposure (as manifested by
neurobehavioral performance) is of increasing concern based on stud-
ies of the offspring of mothers who ingested mercury-contaminated
fish. With respect to whether the consumption of fish by women during
pregnancy is good or bad for offspring neurodevelopment, balancing
the trade-offs of the beneficial effects of the omega-3-fatty acids (FAs)
in fish versus the adverse effects of mercury contamination in fish has
led to some confusion and inconsistency in public health recommenda-
tions. Overall, it would appear that it would be best for pregnant women
to either limit fish consumption to those species known to be low in
mercury contamination but high in omega-3-FAs (such as sardines or
mackerel) or to avoid fish and obtain omega-3-FAs through supple-
ments or other dietary sources. Current evidence has not supported the
recent contention that ethyl mercury, used as a preservative in multiuse
vaccines administered in early childhood, has played a significant role
in causing neurodevelopmental problems such as autism. With regard
to adults, there is conflicting evidence as to whether mercury exposure
is associated with increased risk of hypertension and cardiovascular
disease. At this point, conclusions cannot be drawn.
Heavy metals pose risks to health that are especially burden-
some in selected parts of the world. For example, arsenic expo-
sure from natural contamination of shallow tube wells inserted
for drinking water is a major environmental problem for millions of
 472e-2   TABLE 472e-1    Heavy Metals
Main Sources Metabolism
Arsenic
Smelting and micro- Organic arsenic (arseno-
electronics industries; betaine, arsenocholine)
wood preservatives, is ingested in seafood
pesticides, herbicides, and fish, but is nontoxic;
fungicides; contami- inorganic arsenic is
nant of deep-water readily absorbed (lung
wells; folk remedies; and GI); sequesters in
and coal; incineration liver, spleen, kidneys,
of these products. lungs, and GI tract;
residues persist in skin,
PART 18
hair, and nails; biometh-
ylation results in detoxi-
fication, but this process
saturates.
Cadmium
Metal-plating, pig- Absorbed through
Poisoning, Drug Overdose, and Envenomation
ment, smelting, ingestion or inhalation;
battery, and plastics bound by metallo-
industries; tobacco; thionein, filtered at
incineration of these the glomerulus, but
products; ingestion reabsorbed by proximal
of food that con- tubules (thus, poorly
centrates cadmium excreted). Biologic half-
(grains, cereals). life: 10–30 y. Binds cel-
lular sulfhydryl groups,
competes with zinc, cal-
cium for binding sites.
Concentrates in liver
and kidneys.
Lead
Manufacturing of Absorbed through
auto batteries, lead ingestion or inhalation;
crystal, ceramics, organic lead (e.g., tet-
fishing weights, etc.; raethyl lead) absorbed
demolition or sand- dermally. In blood,
ing of lead-painted 95–99% sequestered
houses, bridges; in RBCs—thus, must
stained glass–making, measure lead in whole
plumbing, solder- blood (not serum).
ing; environmental Distributed widely in
exposure to paint soft tissue, with half-life
chips, house dust (in ~30 days; 15% of dose
homes built <1975), sequestered in bone
firing ranges (from with half-life of >20
bullet dust), food or years. Excreted mostly in
water from improperly urine, but also appears
glazed ceramics, lead in other fluids including
pipes; contaminated breast milk. Interferes
herbal remedies, can- with mitochondrial
dies; exposure to the oxidative phosphoryla-
combustion of leaded tion, ATPases, calcium-
fuels. dependent messengers;
enhances oxidation and
cell apoptosis.
Toxicity
Acute arsenic poisoning results in
necrosis of intestinal mucosa with
hemorrhagic gastroenteritis, fluid loss,
hypotension, delayed cardiomyopathy,
acute tubular necrosis, and hemolysis.
Chronic arsenic exposure causes dia-
betes, vasospasm, peripheral vascular
insufficiency and gangrene, peripheral
neuropathy, and cancer of skin, lung,
liver (angiosarcoma), bladder, and
kidney.
Lethal dose: 120–200 mg (adults);
2 mg/kg (children).
Acute cadmium inhalation causes
pneumonitis after 4–24 h; acute inges-
tion causes gastroenteritis.
Chronic exposure causes anosmia,
yellowing of teeth, emphysema, minor
LFT elevations, microcytic hypochro-
mic anemia unresponsive to iron
therapy, proteinuria, increased urinary
β2- microglobulin, calciuria, leading to
chronic renal failure, osteomalacia, and
fractures. Possible risks of cardiovascu-
lar disease and cancer.
Acute exposure with blood lead levels
(BPb) of >60–80 μg/dL can cause
impaired neurotransmission and
neuronal cell death (with central and
peripheral nervous system effects);
impaired hematopoiesis and renal
tubular dysfunction. At higher levels
of exposure (e.g., BPb >80–120 μg/dL),
acute encephalopathy with convul-
sions, coma, and death may occur.
Subclinical exposures in children (BPb
25–60 μg/dL) are associated with ane-
mia; mental retardation; and deficits
in language, motor function, balance,
hearing, behavior, and school perfor-
mance. Impairment of IQ appears to
occur at even lower levels of exposure
with no measurable threshold above
the limit of detection in most assays
of 1 μg/dL.
In adults, chronic subclinical expo-
sures (BPb >40 μg/dL) are associated
with an increased risk of anemia,
demyelinating peripheral neuropathy
(mainly motor), impairments of reac-
tion time and hearing, accelerated
declines in cognition, hypertension,
ECG conduction delays, higher risk
of cardiovascular disease and death,
interstitial nephritis and chronic renal
failure, diminished sperm counts, and
spontaneous abortions.
Diagnosis
Nausea, vomiting, diarrhea, abdomi-
nal pain, delirium, coma, seizures;
garlicky odor on breath; hyperkera-
tosis, hyperpigmentation, exfoliative
dermatitis, and Mees’ lines (trans-
verse white striae of the fingernails);
sensory and motor polyneuritis,
distal weakness. Radiopaque sign on
abdominal x-ray; ECG–QRS broaden-
ing, QT prolongation, ST depression,
T-wave flattening; 24-h urinary
arsenic >67 μmol/d or 50 μg/d; (no
seafood × 24 h); if recent exposure,
serum arsenic >0.9 μmol/L (7 μg/dL).
High arsenic in hair or nails.
With inhalation: pleuritic chest pain,
dyspnea, cyanosis, fever, tachycardia,
nausea, noncardiogenic pulmonary
edema. With ingestion: nausea, vom-
iting, cramps, diarrhea. Bone pain,
fractures with osteomalacia. If recent
exposure, serum cadmium >500
nmol/L (5 μg/dL). Urinary cadmium
>100 nmol/L (10 μg/g creatinine)
and/or urinary β2-microglobulin
>750 μg/g creatinine (but urinary
β2-microglobulin also increased in
other renal diseases such as pyelo-
nephritis).
Abdominal pain, irritability, lethargy,
anorexia, anemia, Fanconi’s syn-
drome, pyuria, azotemia in children
with blood lead level (BPb) >80 μg/
dL; may also see epiphyseal plate
“lead lines” on long bone x-rays.
Convulsions, coma at BPb >120 μg/
dL. Noticeable neurodevelopmental
delays at BPb of 40–80 μg/dL; may
also see symptoms associated with
higher BPb levels. Screening of all
U.S. children when they begin to
crawl (~6 months) is recommended
by the CDC; source identification
and intervention is begun if the
BPb >10 μg/dL. In adults, acute
exposure causes similar symptoms
as in children as well as headaches,
arthralgias, myalgias, depression,
impaired short-term memory, loss
of libido. Physical exam may reveal a
“lead line” at the gingiva-tooth bor-
der, pallor, wrist drop, and cognitive
dysfunction (e.g., declines on the
mini-mental state exam); lab tests
may reveal a normocytic, normo-
chromic anemia, basophilic stippling,
an elevated blood protoporphyrin
level (free erythrocyte or zinc), and
motor delays on nerve conduction.
U.S. OSHA requires regular testing of
lead-exposed workers with removal if
BPb >40 μg/dL. New guidelines have
been proposed recommending that
BPb be maintained at <10 μg/dL,
removal of workers if BPb >20 μg/dL,
and monitoring of cumulative expo-
sure parameters.
Treatment
If acute ingestion, ipecac
to induce vomiting, gastric
lavage, activated charcoal
with a cathartic. Supportive
care in ICU.
Dimercaprol 3–5 mg/kg IM
q4h × 2 days; q6h × 1 day,
then q12h × 10 days; alter-
native: oral succimer.
There is no effective treat-
ment for cadmium poison-
ing (chelation not useful;
dimercaprol can exacerbate
nephrotoxicity).
Avoidance of further expo-
sure, supportive therapy,
vitamin D for osteomalacia.
Identification and correc-
tion of exposure sources is
critical. In some U.S. states,
screening and reporting
to local health boards of
children with BPb >10 μg/
dL and workers with BPb
>40 μg/dL is required. In the
highly exposed individual
with symptoms, chelation
is recommended with oral
DMSA (succimer); if acutely
toxic, hospitalization and IV
or IM chelation with ethyl-
enediamine tetraacetic acid
calcium disodium (CaEDTA)
may be required, with the
addition of dimercaprol
to prevent worsening of
encephalopathy. It is uncer-
tain whether children with
asymptomatic lead exposure
(e.g., BPb 20–40 μg/dL) ben-
efit from chelation; a recent
randomized trial showed
no benefit. Correction of
dietary deficiencies in iron,
calcium, magnesium, and
zinc will lower lead absorp-
tion and may also improve
toxicity. Vitamin C is a weak
but natural chelating agent.
Calcium supplements (1200
mg at bedtime) have been
shown to lower blood lead
levels in pregnant women.
(Continued)
  TABLE 472e-1    Heavy Metals (Continued) 472e-3
Main Sources Metabolism Toxicity Diagnosis Treatment
Mercury
Metallic, mercurous, Elemental mercury (Hg) Acute inhalation of Hg vapor causes Chronic exposure to metallic mer- Treat acute ingestion of
and mercuric mer- is not well absorbed; pneumonitis and noncardiogenic pul- cury vapor produces a characteristic mercuric salts with induced
cury (Hg, Hg+, Hg2+) however, it will volatilize monary edema leading to death, CNS intention tremor and mercurial emesis or gastric lavage and
exposures occur into highly absorb- symptoms, and polyneuropathy. erethism: excitability, memory loss, polythiol resins (to bind mer-
in some chemical, able vapor. Inorganic Chronic high exposure causes CNS insomnia, timidity, and delirium cury in the GI tract). Chelate
metal-processing, mercury is absorbed toxicity (mercurial erethism; see (“mad as a hatter”). On neurobehav- with dimercaprol (up to 24
electrical-equipment, through the gut and Diagnosis); lower exposures impair ioral tests: decreased motor speed, mg/kg per day IM in divided
automotive indus- skin. Organic mercury is renal function, motor speed, memory, visual scanning, verbal and visual doses), DMSA (succimer), or

CHAPTER 472e Heavy Metal Poisoning

tries; they are also in well absorbed through
thermometers, dental inhalation and inges-
amalgams, batteries. tion. Elemental and
Mercury is dispersed organic mercury cross
the blood-brain barrier
by waste incinera-
tion. Environmental and placenta. Mercury
is excreted in urine and
bacteria convert
inorganic to organic feces and has a half-life
mercury, which then in blood of ~60 days;
however, deposits will
bioconcentrates up
the aquatic food chain remain in the kidney
and brain for years.
to contaminate tuna,
swordfish, and other Exposure to mercury
stimulates the kidney
pelagic fish.
to produce metallothio-
nein, which provides
some detoxification
benefit. Mercury binds
sulfhydryl groups and
interferes with a wide
variety of critical enzy-
matic processes.
Abbreviations: ATPase, adenosine triphosphatase; BPb, blood lead; CDC, Centers for Disease Control and Prevention; CNS, central nervous system; DMSA, dimercaptosuccinic acid;
ECG, electrocardiogram; GI, gastrointestinal; ICU, intensive care unit; IQ, intelligence quotient; LFT, liver function tests; OSHA, Occupational Safety and Health Administration; RBC, red
blood cell.
coordination.
Acute ingestion of inorganic mercury
causes gastroenteritis, the nephritic
syndrome, or acute renal failure,
hypertension, tachycardia, and cardio-
vascular collapse, with death at a dose
of 10–42 mg/kg.
Ingestion of organic mercury causes
gastroenteritis, arrhythmias, and
lesions in the basal ganglia, gray
matter, and cerebellum at doses
>1.7 mg/kg.
High exposure during pregnancy
causes derangement of fetal neuronal
migration resulting in severe mental
retardation.
Mild exposures during pregnancy
(from fish consumption) are associ-
ated with declines in neurobehavioral
performance in offspring.
Dimethylmercury, a compound
only found in research labs, is
“supertoxic”—a few drops of exposure
via skin absorption or inhaled vapor
can cause severe cerebellar degenera-
tion and death.
memory, visuomotor coordination. penicillamine, with 5-day
Children exposed to mercury in any courses separated by several
days of rest. If renal failure
form may develop acrodynia (“pink
disease”): flushing, itching, swelling, occurs, treat with peritoneal
dialysis, hemodialysis, or
tachycardia, hypertension, excessive
salivation or perspiration, irritability, extracorporeal regional com-
plexing hemodialysis and
weakness, morbilliform rashes, des-
quamation of palms and soles. succimer.
Chronic inorganic mercury
Toxicity from elemental or inorganic
mercury exposure begins when poisoning is best treated
with N-acetyl penicillamine.
blood levels >180 nmol/L (3.6 μg/dL)
and urine levels >0.7 μmol/L
(15 μg/dL). Exposures that ended
years ago may result in a >20-μg
increase in 24-h urine after a 2-g
dose of succimer.
Organic mercury exposure is best
measured by levels in blood (if
recent) or hair (if chronic); CNS toxic-
ity in children may derive from fetal
exposures associated with maternal
hair Hg >30 nmol/g (6 μg/g).

residents in parts of Bangladesh and Western India. Contamination
was formerly considered only a problem with deep wells; however, the
geology of this region allows most residents only a few alternatives for
potable drinking water. The combustion of leaded gasoline with result-
ing contamination of air and soil with lead oxide remains a problem in
some countries of Central Asia, Southeast Asia, Africa, and the Middle
East. Populations living in the Arctic have been shown to have particu-
larly high exposures to mercury due to long-range transport patterns
that concentrate mercury in the polar regions, as well as the traditional
dependence of Arctic peoples on the consumption of fish and other
wildlife that bioconcentrate methylmercury.
A few additional metals deserve brief mention but are not covered
in Table 472e-1 because of the relative rarity of their being clinically
encountered or the uncertainty regarding their potential toxicities.
Aluminum contributes to the encephalopathy in patients with severe
renal disease, who are undergoing dialysis (Chap. 424). High levels
of aluminum are found in the neurofibrillary tangles in the cerebral
cortex and hippocampus of patients with Alzheimer’s disease, as well
as in the drinking water and soil of areas with an unusually high inci-
dence of Alzheimer’s. The experimental and epidemiologic evidence
for the aluminum–Alzheimer’s disease link remains relatively weak,
however, and it cannot be concluded that aluminum is a causal agent
or a contributing factor in neurodegenerative disease. Hexavalent
chromium is corrosive and sensitizing. Workers in the chromate and
chrome pigment production industries have consistently had a greater
risk of lung cancer. The introduction of cobalt chloride as a fortifier in
beer led to outbreaks of fatal cardiomyopathy among heavy consum-
ers. Occupational exposure (e.g., of miners, dry-battery manufacturers,
and arc welders) to manganese can cause a parkinsonian syndrome
within 1–2 years, including gait disorders; postural instability; a
masked, expressionless face; tremor; and psychiatric symptoms. With
the introduction of methylcyclopentadienyl manganese tricarbonyl
(MMT) as a gasoline additive, there is concern for the toxic potential
of environmental manganese exposure. For example, a recent study
found a high prevalence of parkinsonian disorders in a community
with risks proportionate to estimated manganese exposures emitted by
local ferroalloy industries. Epidemiologic studies have also suggested
that manganese may interfere with early childhood neurodevelopment
in ways similar to that of lead. Nickel exposure induces an allergic
response, and inhalation of nickel compounds with low aqueous
solubility (e.g., nickel subsulfide and nickel oxide) in occupational set-
tings is associated with an increased risk of lung cancer. Overexposure
to selenium may cause local irritation of the respiratory system and
eyes, gastrointestinal irritation, liver inflammation, loss of hair, depig-
mentation, and peripheral nerve damage. Workers exposed to certain
organic forms of tin (particularly trimethyl and triethyl derivatives)
have developed psychomotor disturbances, including tremor, convul-
sions, hallucinations, and psychotic behavior.
Thallium, which is a component of some insecticides, metal alloys,
and fireworks, is absorbed through the skin as well as by ingestion and
inhalation. Severe poisoning follows a single ingested dose of >1 g or
>8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis
precede confusion, psychosis, organic brain syndrome, and coma.
Thallium is radiopaque. Induced emesis or gastric lavage is indicated
within 4–6 h of acute ingestion; Prussian blue prevents absorption
and is given orally at 250 mg/kg in divided doses. Unlike other types
of metal poisoning, thallium poisoning may be less severe when acti-
vated charcoal is used to interrupt its enterohepatic circulation. Other
measures include forced diuresis, treatment with potassium chloride
(which promotes renal excretion of thallium), and peritoneal dialysis.

473e Poisoning and Drug Overdose
Mark B. Mycyk
Poisoning refers to the development of dose-related adverse effects
following exposure to chemicals, drugs, or other xenobiotics. To para-
phrase Paracelsus, the dose makes the poison. In excessive amounts,
substances that are usually innocuous, such as oxygen and water,
can cause toxicity. Conversely, in small doses, substances commonly
regarded as poisons, such as arsenic and cyanide, can be consumed
without ill effect. Although most poisons have predictable dose-
related effects, individual responses to a given dose may vary because
of genetic polymorphism, enzymatic induction or inhibition in the
presence of other xenobiotics, or acquired tolerance. Poisoning may
be local (e.g., skin, eyes, or lungs) or systemic depending on the route
of exposure, the chemical and physical properties of the poison, and
its mechanism of action. The severity and reversibility of poisoning
also depend on the functional reserve of the individual or target organ,
which is influenced by age and preexisting disease.
EPIDEMIOLOGY
More than 5 million poison exposures occur in the United States
each year. Most are acute, are accidental (unintentional), involve a
single agent, occur in the home, result in minor or no toxicity, and
involve children <6 years of age. Pharmaceuticals are involved in 47%
of exposures and in 84% of serious or fatal poisonings. Unintentional
exposures can result from the improper use of chemicals at work or
play; label misreading; product mislabeling; mistaken identification
of unlabeled chemicals; uninformed self-medication; and dosing
errors by nurses, pharmacists, physicians, parents, and the elderly.
Excluding the recreational use of ethanol, attempted suicide (deliber-
ate self-harm) is the most common reported reason for intentional
poisoning. Recreational use of prescribed and over-the-counter drugs
for psychotropic or euphoric effects (abuse) or excessive self-dosing
(misuse) is increasingly common and may also result in unintentional
self-poisoning.
About 20–25% of exposures require bedside health-professional
evaluation, and 5% of all exposures require hospitalization. Poisonings
account for 5–10% of all ambulance transports, emergency depart-
ment visits, and intensive care unit admissions. Up to 30% of psychi-
atric admissions are prompted by attempted suicide via overdosage.
Overall, the mortality rate is low: <1% of all exposures. It is much
higher (1–2%) among hospitalized patients with intentional (sui-
cidal) overdose, who account for the majority of serious poisonings.
Acetaminophen is the pharmaceutical agent most often implicated in
fatal poisoning. Overall, carbon monoxide is the leading cause of death
from poisoning, but this prominence is not reflected in hospital or poi-
son center statistics because patients with such poisoning are typically
dead when discovered and are referred directly to medical examiners.
DIAGNOSIS
Although poisoning can mimic other illnesses, the correct diagnosis
can usually be established by the history, physical examination, rou-
tine and toxicologic laboratory evaluations, and characteristic clinical
course.
HISTORY
The history should include the time, route, duration, and circum-
stances (location, surrounding events, and intent) of exposure; the
name and amount of each drug, chemical, or ingredient involved; the
time of onset, nature, and severity of symptoms; the time and type of
first-aid measures provided; and the medical and psychiatric history.
In many cases the patient is confused, comatose, unaware of an
exposure, or unable or unwilling to admit to one. Suspicious circum-
stances include unexplained sudden illness in a previously healthy
person or a group of healthy people; a history of psychiatric problems
(particularly depression); recent changes in health, economic status,
or social relationships; and onset of illness during work with chemicals 473e-1
or after ingestion of food, drink (especially ethanol), or medications.
When patients become ill soon after arriving from a foreign country
or being arrested for criminal activity, “body packing” or “body stuff-
ing” (ingesting or concealing illicit drugs in a body cavity) should
be suspected. Relevant information may be available from family,
friends, paramedics, police, pharmacists, physicians, and employers,
who should be questioned regarding the patient’s habits, hobbies,
behavioral changes, available medications, and antecedent events.
A search of clothes, belongings, and place of discovery may reveal a
suicide note or a container of drugs or chemicals. The imprint code
CHAPTER 473e Poisoning and Drug Overdose
on pills and the label on chemical products may be used to identify the
ingredients and potential toxicity of a suspected poison by consult-
ing a reference text, a computerized database, the manufacturer, or
a regional poison information center (800-222-1222). Occupational
exposures require review of any available material safety data sheet
(MSDS) from the worksite. Because of increasing globalization, unfa-
miliar poisonings may result in local emergency department evalua-
tion. Pharmaceuticals, industrial chemicals, or drugs of abuse from
foreign countries may be identified with the assistance of a regional
poison center or via the World Wide Web.
PHYSICAL EXAMINATION AND CLINICAL COURSE
The physical examination should focus initially on vital signs, the car-
diopulmonary system, and neurologic status. The neurologic examina-
tion should include documentation of neuromuscular abnormalities
such as dyskinesia, dystonia, fasciculations, myoclonus, rigidity, and
tremors. The patient should also be examined for evidence of trauma
and underlying illnesses. Focal neurologic findings are uncommon in
poisoning, and their presence should prompt evaluation for a struc-
tural central nervous system (CNS) lesion. Examination of the eyes
(for nystagmus and pupil size and reactivity), abdomen (for bowel
activity and bladder size), and skin (for burns, bullae, color, warmth,
moisture, pressure sores, and puncture marks) may reveal findings of
diagnostic value. When the history is unclear, all orifices should be
examined for the presence of chemical burns and drug packets. The
odor of breath or vomitus and the color of nails, skin, or urine may
provide important diagnostic clues.
The diagnosis of poisoning in cases of unknown etiology primarily
relies on pattern recognition. The first step is to assess the pulse, blood
pressure, respiratory rate, temperature, and neurologic status and to
characterize the overall physiologic state as stimulated, depressed,
discordant, or normal (Table 473e-1). Obtaining a complete set of
vital signs and reassessing them frequently are critical. Measuring core
temperature is especially important, even in difficult or combative
patients, since temperature elevation is the most reliable prognos-
ticator of poor outcome in poisoning or drug withdrawal. The next
step is to consider the underlying causes of the physiologic state and
to attempt to identify a pathophysiologic pattern or toxic syndrome
(toxidrome) based on the observed findings. Assessing the severity of
physiologic derangements (Table 473e-2) is useful in this regard and
also for monitoring the clinical course and response to treatment. The
final step is to attempt to identify the particular agent involved by
looking for unique or relatively poison-specific physical or ancillary
test abnormalities. Distinguishing among toxidromes on the basis of
the physiologic state is summarized next.
The Stimulated Physiologic State  Increased pulse, blood pressure, respi-
ratory rate, temperature, and neuromuscular activity characterize the
stimulated physiologic state, which can reflect sympathetic, antimusca-
rinic (anticholinergic), or hallucinogen poisoning or drug withdrawal
(Table 473e-1). Other features are noted in (Table 473e-2). Mydriasis,
a characteristic feature of all stimulants, is most marked in antimus-
carinic (anticholinergic) poisoning since pupillary reactivity relies on
muscarinic control. In sympathetic poisoning (e.g., due to cocaine),
pupils are also enlarged, but some reactivity to light remains. The
antimuscarinic (anticholinergic) toxidrome is also distinguished by
hot, dry, flushed skin; decreased bowel sounds; and urinary reten-
tion. Other stimulant syndromes increase sympathetic activity and
cause diaphoresis, pallor, and increased bowel activity with varying
 473e-2   Table 473e-1    Differential Diagnosis of Poisoning Based on Physiologic State
Stimulated Depressed Discordant Normal
Sympathetics Sympatholytics Asphyxiants Nontoxic exposure
Sympathomimetics α1-Adrenergic antagonists Cytochrome oxidase inhibitors Psychogenic illness
Ergot alkaloids α2-Adrenergic agonists Inert gases “Toxic time-bombs”
Methylxanthines ACE inhibitors Irritant gases Slow absorption
Monoamine oxidase inhibitors Angiotensin receptor blockers Methemoglobin inducers Anticholinergics
Thyroid hormones Antipsychotics Oxidative phosphorylation inhibitors Carbamazepine
Anticholinergics β-Adrenergic blockers AGMA inducers Concretion formers
Antihistamines Calcium channel blockers Alcohol (ketoacidosis) Extended-release phenytoin sodium
Antiparkinsonian agents Cardiac glycosides Ethylene glycol capsules (Dilantin Kapseals)
PART 18

Antipsychotics Cyclic antidepressants Iron Drug packets

Antispasmodics Cholinergics Methanol Enteric-coated pills
Belladonna alkaloids Acetylcholinesterase inhibitors Salicylate Diphenoxylate-atropine (Lomotil)
Cyclic antidepressants Muscarinic agonists Toluene Opioids
Mushrooms and plants Nicotinic agonists CNS syndromes Salicylates
Sustained-release pills
Poisoning, Drug Overdose, and Envenomation

Hallucinogens Opioids Extrapyramidal reactions

Cannabinoids (marijuana) Analgesics Hydrocarbon inhalation Valproate
LSD and analogues GI antispasmodics Isoniazid Slow distribution
Mescaline and analogues Heroin Lithium Cardiac glycosides
Mushrooms Sedative-hypnotics Neuroleptic malignant syndrome Lithium
Phencyclidine and analogues Alcohols Serotonin syndrome Metals
Withdrawal syndromes Anticonvulsants Strychnine Salicylate
Barbiturates Barbiturates Membrane-active agents Valproate
Benzodiazepines Benzodiazepines Amantadine Toxic metabolite
Ethanol GABA precursors Antiarrhythmics Acetaminophen
Opioids Muscle relaxants Antihistamines Carbon tetrachloride
Sedative-hypnotics Other agents Antipsychotics Cyanogenic glycosides
Sympatholytics GHB products Carbamazepine Ethylene glycol
Cyclic antidepressants Methanol
Local anesthetics Methemoglobin inducers
Opioids (some) Mushroom toxins
Orphenadrine Organophosphate insecticides
Quinoline antimalarials Paraquat
Metabolism disruptors
Antineoplastic agents
Antiviral agents
Colchicine
Hypoglycemic agents
Immunosuppressive agents
MAO inhibitors
Metals
Salicylate
Warfarin
Abbreviations: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic acidosis; CNS, central nervous system; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyrate; GI, gastro-
intestinal; LSD, lysergic acid diethylamide; MAO, monoamine oxidase.

  Table 473e-2    Severity of Physiologic Stimulation and Depression in Poisoning and Drug Withdrawal
Physiologic Stimulation
Grade 1 Anxious, irritable, tremulous; vital signs normal; diaphoresis, flushing or pallor, mydriasis, and hyperreflexia sometimes present
Grade 2 Agitated; may have confusion or hallucinations but can converse and follow commands; vital signs mildly to moderately increased
Grade 3 Delirious; unintelligible speech, uncontrollable motor hyperactivity; moderately to markedly increased vital signs; tachyarrhythmias possible
Grade 4 Coma, seizures, cardiovascular collapse
Physiologic Depression
Grade 1 Awake, lethargic, or sleeping but arousable by voice or tactile stimulation; able to converse and follow commands; may be confused
Grade 2 Responds to pain but not voice; can vocalize but not converse; spontaneous motor activity present; brainstem reflexes intact
Grade 3 Unresponsive to pain; spontaneous motor activity absent; brainstem reflexes depressed; motor tone, respirations, and temperature decreased
Grade 4 Unresponsive to pain; flaccid paralysis; brainstem reflexes and respirations absent; cardiovascular vital signs decreased
degrees of nausea, vomiting, abnormal distress, and occasionally
diarrhea. The absolute and relative degree of vital-sign changes and
neuromuscular hyperactivity can help distinguish among stimulant
toxidromes. Since sympathetics stimulate the peripheral nervous sys-
tem more directly than do hallucinogens or drug withdrawal, mark-
edly increased vital signs and organ ischemia suggest sympathetic
poisoning. Findings helpful in suggesting the particular drug or class
causing physiologic stimulation include reflex bradycardia from selec-
tive α-adrenergic stimulants (e.g., decongestants), hypotension from
selective β-adrenergic stimulants (e.g., asthma therapeutics), limb
ischemia from ergot alkaloids, rotatory nystagmus from phencyclidine
and ketamine (the only physiologic stimulants that cause this finding),
and delayed cardiac conduction from high doses of cocaine and some
anticholinergic agents (e.g., antihistamines, cyclic antidepressants, and
antipsychotics). Seizures suggest a sympathetic etiology, an anticho-
linergic agent with membrane-active properties (e.g., cyclic antide-
pressants, orphenadrine, phenothiazines), or a withdrawal syndrome.
Close attention to core temperature is critical in patients with grade
4 physiologic stimulation (Table 473e-2).
The Depressed Physiologic State  Decreased pulse, blood pressure, respi-
ratory rate, temperature, and neuromuscular activity are indicative of
the depressed physiologic state caused by “functional” sympatholytics
(agents that decrease cardiac function and vascular tone as well as sym-
pathetic activity), cholinergic (muscarinic and nicotinic) agents, opi-
oids, and sedative-hypnotic γ-aminobutyric acid (GABA)-ergic agents
(Table 473e-1 and 473e-2). Miosis is also common and is most pro-
nounced in opioid and cholinergic poisoning. Miosis is distinguished
from other depressant syndromes by muscarinic and nicotinic signs
and symptoms (Table 473e-1). Pronounced cardiovascular depres-
sion in the absence of significant CNS depression suggests a direct or
peripherally acting sympatholytic. In contrast, in opioid and sedative-
hypnotic poisoning, vital-sign changes are secondary to depression of
CNS cardiovascular and respiratory centers (or consequent hypox-
emia), and significant abnormalities in these parameters do not occur
until there is a marked decrease in the level of consciousness (grade 3
or 4 physiologic depression; [Table 473e-2]). Other clues that suggest
the cause of physiologic depression include cardiac arrhythmias and
conduction disturbances (due to antiarrhythmics, β-adrenergic antag-
onists, calcium channel blockers, digitalis glycosides, propoxyphene,
and cyclic antidepressants), mydriasis (due to tricyclic antidepres-
sants, some antiarrhythmics, meperidine, and diphenoxylate-atropine
[Lomotil]), nystagmus (due to sedative-hypnotics), and seizures (due
to cholinergic agents, propoxyphene, and cyclic antidepressants).
The Discordant Physiologic State  The discordant physiologic state is
characterized by mixed vital-sign and neuromuscular abnormalities,
as observed in poisoning by asphyxiants, CNS syndromes, membrane-
active agents, and anion-gap metabolic acidosis (AGMA) inducers
(Table 473e-1). In these conditions, manifestations of physiologic
stimulation and physiologic depression occur together or at different
times during the clinical course. For example, membrane-active agents
can cause simultaneous coma, seizures, hypotension, and tachyar-
rhythmias. Alternatively, vital signs may be normal while the patient
has an altered mental status or is obviously sick or clearly symptom-
atic. Early, pronounced vital-sign and mental-status changes suggest
asphyxiant or membrane-active agent poisoning; the lack of such
abnormalities suggests an AGMA inducer; and marked neuromuscu-
lar dysfunction without significant vital-sign abnormalities suggests a
CNS syndrome.
The Normal Physiologic State  A normal physiologic status and physical
examination may be due to a nontoxic exposure, psychogenic illness,
or poisoning by “toxic time-bombs”: agents that are slowly absorbed,
are slowly distributed to their sites of action, require metabolic activa-
tion, or disrupt metabolic processes (Table 473e-1). Because so many
medications have now been reformulated into a once-a-day prepara-
tions for the patient’s convenience and adherence, toxic time-bombs
are increasingly common. Diagnosing a nontoxic exposure requires
that the identity of the exposure agent be known or that a toxic
time-bomb exposure be excluded and the time since exposure exceed 473e-3
the longest known or predicted interval between exposure and peak
toxicity. Psychogenic illness (fear of being poisoned, mass hysteria)
may also follow a nontoxic exposure and should be considered when
symptoms are inconsistent with exposure history. Anxiety reactions
resulting from a nontoxic exposure can cause mild physiologic stimu-
lation (Table 473e-2) and be indistinguishable from toxicologic causes
without ancillary testing or a suitable period of observation.
LABORATORY ASSESSMENT
Laboratory assessment may be helpful in the differential diagnosis.
CHAPTER 473e Poisoning and Drug Overdose
Increased AGMA is most common in advanced methanol, ethylene
glycol, and salicylate intoxication but can occur with any poisoning
that results in hepatic, renal, or respiratory failure; seizures; or shock.
The serum lactate concentration is more commonly low (less than
the anion gap) in the former and high (nearly equal to the anion gap)
in the latter. An abnormally low anion gap can be due to elevated
blood levels of bromide, calcium, iodine, lithium, or magnesium. An
increased osmolal gap—a difference of >10 mmol/L between serum
osmolality (measured by freezing-point depression) and osmolality cal-
culated from serum sodium, glucose, and blood urea nitrogen levels—
suggests the presence of a low-molecular-weight solute such as
acetone; an alcohol (benzyl, ethanol, isopropanol, methanol); a glycol
(diethylene, ethylene, propylene); ether (ethyl, glycol); or an “unmea-
sured” cation (calcium, magnesium) or sugar (glycerol, mannitol, sor-
bitol). Ketosis suggests acetone, isopropyl alcohol, salicylate poisoning,
or alcoholic ketoacidosis. Hypoglycemia may be due to poisoning with
β-adrenergic blockers, ethanol, insulin, oral hypoglycemic agents, qui-
nine, and salicylates, whereas hyperglycemia can occur in poisoning
with acetone, β-adrenergic agonists, caffeine, calcium channel block-
ers, iron, theophylline, or N-3-pyridylmethyl-N′-p-nitrophenylurea
(PNU [Vacor]). Hypokalemia can be caused by barium, β-adrenergic
agonists, caffeine, diuretics, theophylline, or toluene; hyperkalemia
suggests poisoning with an α-adrenergic agonist, a β-adrenergic
blocker, cardiac glycosides, or fluoride. Hypocalcemia may be seen in
ethylene glycol, fluoride, and oxalate poisoning.
The electrocardiogram (ECG) can be useful for rapid diagnostic pur-
poses. Bradycardia and atrioventricular block may occur in patients
poisoned by α-adrenergic agonists, antiarrhythmic agents, beta block-
ers, calcium channel blockers, cholinergic agents (carbamate and
organophosphate insecticides), cardiac glycosides, lithium, or tricyclic
antidepressants. QRS- and QT-interval prolongation may be caused
by hyperkalemia, various antidepressants, and other membrane-active
drugs (Table 473e-1). Ventricular tachyarrhythmias may be seen in
poisoning with cardiac glycosides, fluorides, membrane-active drugs,
methylxanthines, sympathomimetics, antidepressants, and agents that
cause hyperkalemia or potentiate the effects of endogenous catechol-
amines (e.g., chloral hydrate, aliphatic and halogenated hydrocarbons).
Radiologic studies may occasionally be useful. Pulmonary edema
(adult respiratory distress syndrome (ARDS) can be caused by poison-
ing with carbon monoxide, cyanide, an opioid, paraquat, phencycli-
dine, a sedative-hypnotic, or salicylate; by inhalation of irritant gases,
fumes, or vapors (acids and alkali, ammonia, aldehydes, chlorine,
hydrogen sulfide, isocyanates, metal oxides, mercury, phosgene, poly-
mers); or by prolonged anoxia, hyperthermia, or shock. Aspiration
pneumonia is common in patients with coma, seizures, and petroleum
distillate aspiration. The presence of radiopaque densities on abdomi-
nal x-rays suggests the ingestion of calcium salts, chloral hydrate,
chlorinated hydrocarbons, heavy metals, illicit drug packets, iodinated
compounds, potassium salts, enteric-coated tablets, or salicylates.
Toxicologic analysis of urine and blood (and occasionally of gas-
tric contents and chemical samples) can sometimes confirm or rule
out suspected poisoning. Interpretation of laboratory data requires
knowledge of the qualitative and quantitative tests used for screening
and confirmation (enzyme-multiplied, fluorescence polarization, and
radio-immunoassays; colorimetric and fluorometric assays; thin-layer,
gas-liquid, or high-performance liquid chromatography; gas chro-
matography; mass spectrometry), their sensitivity (limit of detection)
and specificity, the preferred biologic specimen for analysis, and the
 473e-4 optimal time of specimen sampling. Personal communication with
the hospital laboratory is essential to an understanding of institutional
testing capabilities and limitations.
Rapid qualitative hospital-based urine tests for drugs of abuse
are only screening tests that cannot confirm the exact identity of the
detected substance and should not be considered diagnostic or used
for forensic purposes: False-positive and false-negative results are com-
mon. A positive screen may result from other pharmaceuticals that
interfere with laboratory analysis (e.g., fluoroquinolones commonly
cause “false-positive” opiate screens). Confirmatory testing with gas
chromatography/mass spectrometry can be requested, but it often
takes weeks to obtain a reported result. A negative screening result may
mean that the responsible substance is not detectable by the test used or
PART 18
that its concentration is too low for detection at the time of sampling.
For instance, recent new drugs of abuse that often result in emergency
department evaluation for unexpected complications, such as synthetic
cannabinoids (spice), cathinones (bath salts), and opiate substitutes
(kratom), are not detectable by hospital-based tests. In cases where
a drug concentration is too low to be detected early during clinical
Poisoning, Drug Overdose, and Envenomation
evaluation, repeating the test at a later time may yield a positive result.
Patients symptomatic from drugs of abuse often require immediate
management based on the history, physical examination, and observed
toxidrome without laboratory confirmation (e.g., apnea from opioid
intoxication). When the patient is asymptomatic or when the clinical
picture is consistent with the reported history, qualitative screening
is neither clinically useful nor cost-effective. Thus, qualitative drug
screens are of greatest value for the evaluation of patients with severe or
unexplained toxicities, such as coma, seizures, cardiovascular instabil-
ity, metabolic or respiratory acidosis, and nonsinus cardiac rhythms.
In contrast to qualitative drug screens, quantitative serum tests are
useful for evaluation of patients poisoned with acetaminophen (Chap.
361), alcohols (including ethylene glycol and methanol), anticonvul-
sants, barbiturates, digoxin, heavy metals, iron, lithium, salicylate, and
theophylline as well as for the presence of carboxyhemoglobin and
methemoglobin. The serum concentration in these cases guides clinical
management, and results are often available within an hour.
The response to antidotes is sometimes useful for diagnostic pur-
poses. Resolution of altered mental status and abnormal vital signs
within minutes of IV administration of dextrose, naloxone, or fluma-
zenil is virtually diagnostic of hypoglycemia, opioid poisoning, and
benzodiazepine intoxication, respectively. The prompt reversal of
dystonic (extrapyramidal) signs and symptoms following an IV dose of
benztropine or diphenhydramine confirms a drug etiology. Although
complete reversal of both central and peripheral manifestations of
anticholinergic poisoning by physostigmine is diagnostic of this con-
dition, physostigmine may cause some arousal in patients with CNS
depression of any etiology.
TREATMENT Poisoning and Drug Overdose
GENERAL PRINCIPLES
Treatment goals include support of vital signs, prevention of fur-
ther poison absorption (decontamination), enhancement of poison
elimination, administration of specific antidotes, and prevention
of reexposure (Table 473e-3). Specific treatment depends on the
identity of the poison, the route and amount of exposure, the time
of presentation relative to the time of exposure, and the severity of
poisoning. Knowledge of the offending agents’ pharmacokinetics
and pharmacodynamics is essential.
During the pretoxic phase, prior to the onset of poisoning, decon-
tamination is the highest priority, and treatment is based solely on
the history. The maximal potential toxicity based on the greatest
possible exposure should be assumed. Since decontamination is
more effective when accomplished soon after exposure and when
the patient is asymptomatic, the initial history and physical exami-
nation should be focused and brief. It is also advisable to establish IV
access and initiate cardiac monitoring, particularly in patients with
potentially serious ingestions or unclear histories.
  Table 473e-3    Fundamentals of Poisoning Management
Supportive Care
Airway protection Treatment of seizures
Oxygenation/ventilation Correction of temperature abnormalities
Treatment of arrhythmias Correction of metabolic derangements
Hemodynamic support Prevention of secondary complications
Prevention of Further Poison Absorption
Gastrointestinal decontamination Decontamination of other sites
Gastric lavage Eye decontamination
Activated charcoal Skin decontamination
Whole-bowel irrigation Body cavity evacuation
Dilution
Endoscopic/surgical removal
Enhancement of Poison Elimination
Multiple-dose activated charcoal Extracorporeal removal
administration Hemodialysis
Alteration of urinary pH
Hemoperfusion
Chelation Hemofiltration
Plasmapheresis
Exchange transfusion
Hyperbaric oxygenation
Administration of Antidotes
Neutralization by antibodies Metabolic antagonism
Neutralization by chemical binding Physiologic antagonism
Prevention of Reexposure
Adult education Notification of regulatory agencies
Child-proofing Psychiatric referral
When an accurate history is not obtainable and a poison causing
delayed toxicity (i.e., a toxic time-bomb) or irreversible damage is
suspected, blood and urine should be sent for appropriate toxico-
logic screening and quantitative analysis. During poison absorption
and distribution, blood levels may be greater than those in tissue
and may not correlate with toxicity. However, high blood levels
of agents whose metabolites are more toxic than the parent com-
pound (acetaminophen, ethylene glycol, or methanol) may indicate
the need for additional interventions (antidotes, dialysis). Most
patients who remain asymptomatic or who become asymptomatic
6 h after ingestion are unlikely to develop subsequent toxicity and
can be discharged safely. Longer observation will be necessary for
patients who have ingested toxic time-bombs.
During the toxic phase—the interval between the onset of poi-
soning and its peak effects—management is based primarily on
clinical and laboratory findings. Effects after an overdose usually
begin sooner, peak later, and last longer than they do after a thera-
peutic dose. A drug’s published pharmacokinetic profile in standard
references such as the Physician’s Desk Reference (PDR) is usually
different from its toxicokinetic profile in overdose. Resuscitation
and stabilization are the first priority. Symptomatic patients should
have an IV line placed and should undergo oxygen saturation deter-
mination, cardiac monitoring, and continuous observation. Baseline
laboratory, ECG, and x-ray evaluation may also be appropriate.
Intravenous glucose (unless the serum level is documented to be
normal), naloxone, and thiamine should be considered in patients
with altered mental status, particularly those with coma or seizures.
Decontamination should also be considered, but it is less likely to be
effective during this phase than during the pretoxic phase.
Measures that enhance poison elimination may shorten the
duration and severity of the toxic phase. However, they are not
without risk, which must be weighed against the potential benefit.
Diagnostic certainty (usually via laboratory confirmation) is gener-
ally a prerequisite. Intestinal (gut) dialysis with repetitive doses of
activated charcoal (see “Multiple-Dose Activated Charcoal,” later)
can enhance the elimination of selected poisons such as theophyl-
line or carbamazepine. Urinary alkalinization may enhance the elimi-
nation of salicylates and a few other poisons. Chelation therapy can
enhance the elimination of selected metals. Extracorporeal elimina-
tion methods are effective for many poisons, but their expense and
risk make their use reasonable only in patients who would otherwise
have an unfavorable outcome.
During the resolution phase of poisoning, supportive care and
monitoring should continue until clinical, laboratory, and ECG
abnormalities have resolved. Since chemicals are eliminated sooner
from the blood than from tissues, blood levels are usually lower than
tissue levels during this phase and again may not correlate with
toxicity. This discrepancy applies particularly when extracorporeal
elimination procedures are used. Redistribution from tissues may
cause a rebound increase in the blood level after termination of
these procedures. When a metabolite is responsible for toxic effects,
continued treatment may be necessary in the absence of clinical
toxicity or abnormal laboratory studies.
SUPPORTIVE CARE
The goal of supportive therapy is to maintain physiologic homeo-
stasis until detoxification is accomplished and to prevent and treat
secondary complications such as aspiration, bedsores, cerebral and
pulmonary edema, pneumonia, rhabdomyolysis, renal failure, sep-
sis, thromboembolic disease, coagulopathy, and generalized organ
dysfunction due to hypoxemia or shock.
Admission to an intensive care unit is indicated for the following:
patients with severe poisoning (coma, respiratory depression, hypo-
tension, cardiac conduction abnormalities, cardiac arrhythmias,
hypothermia or hyperthermia, seizures); those needing close moni-
toring, antidotes, or enhanced elimination therapy; those showing
progressive clinical deterioration; and those with significant under-
lying medical problems. Patients with mild to moderate toxicity can
be managed on a general medical service, on an intermediate care
unit, or in an emergency department observation area, depend-
ing on the anticipated duration and level of monitoring needed
(intermittent clinical observation versus continuous clinical, cardiac,
and respiratory monitoring). Patients who have attempted suicide
require continuous observation and measures to prevent self-injury
until they are no longer suicidal.
Respiratory Care  Endotracheal intubation for protection against the
aspiration of gastrointestinal contents is of paramount importance
in patients with CNS depression or seizures as this complication can
increase morbidity and mortality rates. Mechanical ventilation may
be necessary for patients with respiratory depression or hypoxemia
and for facilitation of therapeutic sedation or paralysis of patients
in order to prevent or treat hyperthermia, acidosis, and rhabdomy-
olysis associated with neuromuscular hyperactivity. Since clinical
assessment of respiratory function can be inaccurate, the need
for oxygenation and ventilation is best determined by continuous
pulse oximetry or arterial blood-gas analysis. The gag reflex is not
a reliable indicator of the need for intubation. A patient with CNS
depression may maintain airway patency while being stimulated
but not if left alone. Drug-induced pulmonary edema is usually
noncardiac rather than cardiac in origin, although profound CNS
depression and cardiac conduction abnormalities suggest the latter.
Measurement of pulmonary artery pressure may be necessary to
establish the cause and direct appropriate therapy. Extracorporeal
measures (membrane oxygenation, venoarterial perfusion, cardio-
pulmonary bypass) and partial liquid (perfluorocarbon) ventilation
may be appropriate for severe but reversible respiratory failure.
Cardiovascular Therapy  Maintenance of normal tissue perfusion is criti-
cal for complete recovery to occur once the offending agent has been
eliminated. If hypotension is unresponsive to volume expansion,
treatment with norepinephrine, epinephrine, or high-dose dopamine
may be necessary. Intraaortic balloon pump counterpulsation and
venoarterial or cardiopulmonary perfusion techniques should be
considered for severe but reversible cardiac failure. For patients with
a return of spontaneous circulation after resuscitative treatment for 473e-5
cardiopulmonary arrest secondary to poisoning, therapeutic hypo-
thermia should be used according to protocol. Bradyarrhythmias
associated with hypotension generally should be treated as described
in Chaps. 274 and 275. Glucagon, calcium, and high-dose insulin
with dextrose may be effective in beta blocker and calcium channel
blocker poisoning. Antibody therapy may be indicated for cardiac
glycoside poisoning.
Supraventricular tachycardia associated with hypertension and
CNS excitation is almost always due to agents that cause general-
ized physiologic excitation (Table 473e–1). Most cases are mild or
CHAPTER 473e Poisoning and Drug Overdose
moderate in severity and require only observation or nonspecific
sedation with a benzodiazepine. In severe cases or those associ-
ated with hemodynamic instability, chest pain, or ECG evidence
of ischemia, specific therapy is indicated. When the etiology is
sympathetic hyperactivity, treatment with a benzodiazepine should
be prioritized. Further treatment with a combined alpha and
beta blocker (labetalol), a calcium channel blocker (verapamil or
diltiazem), or a combination of a beta blocker and a vasodilator
(esmolol and nitroprusside) may be considered for cases refractory
to high doses of benzodiazepines. Treatment with an α-adrenergic
antagonist (phentolamine) alone may sometimes be appropriate.
If the cause is anticholinergic poisoning, physostigmine alone can
be effective. Supraventricular tachycardia without hypertension is
generally secondary to vasodilation or hypovolemia and responds
to fluid administration.
For ventricular tachyarrhythmias due to tricyclic antidepres-
sants and other membrane-active agents (Table 473e-1), sodium
bicarbonate is indicated, whereas class IA, IC, and III antiarrhythmic
agents are contraindicated because of similar electrophysiologic
effects. Although lidocaine and phenytoin are historically safe for
ventricular tachyarrhythmias of any etiology, sodium bicarbonate
should be considered first for any ventricular arrhythmia suspected
to have a toxicologic etiology. Intravenous emulsion therapy has
shown benefit for treatment of arrhythmias and hemodynamic
instability from various membrane-active agents. Beta blockers can
be hazardous if the arrhythmia is due to sympathetic hyperactiv-
ity. Magnesium sulfate and overdrive pacing (by isoproterenol or a
pacemaker) may be useful in patients with torsades des pointes and
prolonged QT intervals. Magnesium and anti-digoxin antibodies
should be considered in patients with severe cardiac glycoside poi-
soning. Invasive (esophageal or intracardiac) ECG recording may be
necessary to determine the origin (ventricular or supraventricular)
of wide-complex tachycardias (Chaps. 276 and 277). If the patient
is hemodynamically stable, however, it is reasonable to simply
observe him or her rather than to administer another potentially
proarrhythmic agent. Arrhythmias may be resistant to drug therapy
until underlying acid-base, electrolyte, oxygenation, and tempera-
ture derangements are corrected.
Central Nervous System Therapies  Neuromuscular hyperactivity and
seizures can lead to hyperthermia, lactic acidosis, and rhabdomyoly-
sis and should be treated aggressively. Seizures caused by excessive
stimulation of catecholamine receptors (sympathomimetic or hal-
lucinogen poisoning and drug withdrawal) or decreased activity of
GABA (isoniazid poisoning) or glycine (strychnine poisoning) recep-
tors are best treated with agents that enhance GABA activity, such as
benzodiazepine or barbiturates. Since benzodiazepines and barbitu-
rates act by slightly different mechanisms (the former increases the
frequency and the latter increases the duration of chloride channel
opening in response to GABA), therapy with both may be effective
when neither is effective alone. Seizures caused by isoniazid, which
inhibits the synthesis of GABA at several steps by interfering with the
cofactor pyridoxine (vitamin B6), may require high doses of supple-
mental pyridoxine. Seizures resulting from membrane destabiliza-
tion (beta blocker or cyclic antidepressant poisoning) require GABA
enhancers (benzodiazepines first, barbiturates second). Phenytoin
is contraindicated in toxicologic seizures: Animal and human data
demonstrate worse outcomes after phenytoin loading, especially
 473e-6 in theophylline overdose. For poisons with central dopaminergic
effects (methamphetamine, phencyclidine) manifested by psychotic
behavior, a dopamine receptor antagonist, such as haloperidol, may
be useful. In anticholinergic and cyanide poisoning, specific antidotal
therapy may be necessary. The treatment of seizures secondary to
cerebral ischemia or edema or to metabolic abnormalities should
include correction of the underlying cause. Neuromuscular paralysis
is indicated in refractory cases. Electroencephalographic monitoring
and continuing treatment of seizures are necessary to prevent per-
manent neurologic damage. Serotonergic receptor overstimulation
in serotonin syndrome may be treated with cyproheptadine.
Other Measures  Temperature extremes, metabolic abnormalities,
PART 18
hepatic and renal dysfunction, and secondary complications should
be treated by standard therapies.
PREVENTION OF POISON ABSORPTION
Gastrointestinal Decontamination  Whether or not to perform gastro-
intestinal decontamination and which procedure to use depends
on the time since ingestion; the existing and predicted toxicity of
Poisoning, Drug Overdose, and Envenomation
the ingestant; the availability, efficacy, and contraindications of the
procedure; and the nature, severity, and risk of complications. The
efficacy of all decontamination procedures decreases with time,
and data are insufficient to support or exclude a beneficial effect
when they are used >1 h after ingestion. The average time from
ingestion to presentation for treatment is >1 h for children and >3 h
for adults. Most patients will recover from poisoning uneventfully
with good supportive care alone, but complications of gastroin-
testinal decontamination, particularly aspiration, can prolong this
process. Hence, gastrointestinal decontamination should be per-
formed selectively, not routinely, in the management of overdose
patients. It is clearly unnecessary when predicted toxicity is minimal
or the time of expected maximal toxicity has passed without sig-
nificant effect.
Activated charcoal has comparable or greater efficacy; has fewer
contraindications and complications; and is less aversive and inva-
sive than ipecac or gastric lavage. Thus it is the preferred method
of gastrointestinal decontamination in most situations. Activated
charcoal suspension (in water) is given orally via a cup, straw, or
small-bore nasogastric tube. The generally recommended dose is
1 g/kg body weight because of its dosing convenience, although in
vitro and in vivo studies have demonstrated that charcoal adsorbs
≥90% of most substances when given in an amount equal to
10 times the weight of the substance. Palatability may be increased
by adding a sweetener (sorbitol) or a flavoring agent (cherry, choco-
late, or cola syrup) to the suspension. Charcoal adsorbs ingested poi-
sons within the gut lumen, allowing the charcoal-toxin complex to
be evacuated with stool. Charged (ionized) chemicals such as min-
eral acids, alkalis, and highly dissociated salts of cyanide, fluoride,
iron, lithium, and other inorganic compounds are not well adsorbed
by charcoal. In studies with animals and human volunteers, charcoal
decreases the absorption of ingestants by an average of 73% when
given within 5 min of ingestant administration, 51% when given at
30 min, and 36% when given at 60 min. For this reason, charcoal
given before hospital arrival increases the potential clinical benefit.
Side effects of charcoal include nausea, vomiting, and diarrhea or
constipation. Charcoal may also prevent the absorption of orally
administered therapeutic agents. Complications include mechanical
obstruction of the airway, aspiration, vomiting, and bowel obstruc-
tion and infarction caused by inspissated charcoal. Charcoal is not
recommended for patients who have ingested corrosives because
it obscures endoscopy.
Gastric lavage should be considered for life-threatening poisons
that cannot be treated effectively with other decontamination,
elimination, or antidotal therapies (e.g., colchicine). Gastric lavage
is performed by sequentially administering and aspirating ~5 mL
of fluid per kilogram of body weight through a no. 40 French oro-
gastric tube (no. 28 French tube for children). Except in infants,
for whom normal saline is recommended, tap water is acceptable.
The patient should be placed in Trendelenburg and left lateral
decubitus positions to prevent aspiration (even if an endotracheal
tube is in place). Lavage decreases ingestant absorption by an
average of 52% if performed within 5 min of ingestion administra-
tion, 26% if performed at 30 min, and 16% if performed at 60 min.
Significant amounts of ingested drug are recovered from <10% of
patients. Aspiration is a common complication (occurring in up to
10% of patients), especially when lavage is performed improperly.
Serious complications (esophageal and gastric perforation, tube
misplacement in the trachea) occur in ~1% of patients. For this
reason, the physician should personally insert the lavage tube and
confirm its placement, and the patient must be cooperative dur-
ing the procedure. Gastric lavage is contraindicated in corrosive
or petroleum distillate ingestions because of the respective risks
of gastroesophageal perforation and aspiration pneumonitis. It is
also contraindicated in patients with a compromised unprotected
airway and those at risk for hemorrhage or perforation due to
esophageal or gastric pathology or recent surgery. Finally, gastric
lavage is absolutely contraindicated in combative patients or those
who refuse, as most published complications involve patient resis-
tance to the procedure.
Syrup of ipecac, an emetogenic agent that was once the sub-
stance most commonly used for decontamination, no longer has
a role in poisoning management. Even the American Academy of
Pediatrics—traditionally the strongest proponent of ipecac—issued
a policy statement in 2003 recommending that ipecac should no lon-
ger be used in poisoning treatment. Chronic ipecac use (by patients
with anorexia nervosa or bulimia) has been reported to cause elec-
trolyte and fluid abnormalities, cardiac toxicity, and myopathy.
Whole-bowel irrigation is performed by administering a bowel-
cleansing solution containing electrolytes and polyethylene glycol
(Golytely, Colyte) orally or by gastric tube at a rate of 2 L/h (0.5 L/h in
children) until rectal effluent is clear. The patient must be in a sitting
position. Although data are limited, whole-bowel irrigation appears
to be as effective as other decontamination procedures in volunteer
studies. It is most appropriate for those who have ingested foreign
bodies, packets of illicit drugs, and agents that are poorly adsorbed
by charcoal (e.g., heavy metals). This procedure is contraindicated
in patients with bowel obstruction, ileus, hemodynamic instability,
and compromised unprotected airways.
Cathartics are salts (disodium phosphate, magnesium citrate
and sulfate, sodium sulfate) or saccharides (mannitol, sorbitol) that
historically have been given with activated charcoal to promote the
rectal evacuation of gastrointestinal contents. However, no animal,
volunteer, or clinical data have ever demonstrated any decon-
tamination benefit from cathartics. Abdominal cramps, nausea, and
occasional vomiting are side effects. Complications of repeated dos-
ing include severe electrolyte disturbances and excessive diarrhea.
Cathartics are contraindicated in patients who have ingested corro-
sives and in those with preexisting diarrhea. Magnesium-containing
cathartics should not be used in patients with renal failure.
Dilution (i.e., drinking water, another clear liquid, or milk at a
volume of 5 mL/kg of body weight) is recommended only after the
ingestion of corrosives (acids, alkali). It may increase the dissolution
rate (and hence absorption) of capsules, tablets, and other solid
ingestants and should not be used in these circumstances.
Endoscopic or surgical removal of poisons may be useful in rare
situations, such as ingestion of a potentially toxic foreign body that
fails to transit the gastrointestinal tract, a potentially lethal amount
of a heavy metal (arsenic, iron, mercury, thallium), or agents that
have coalesced into gastric concretions or bezoars (heavy metals,
lithium, salicylates, sustained-release preparations). Patients who
become toxic from cocaine due to its leakage from ingested drug
packets require immediate surgical intervention.
Decontamination of Other Sites  Immediate, copious flushing with
water, saline, or another available clear, drinkable liquid is the initial
treatment for topical exposures (exceptions include alkali metals, cal-
cium oxide, phosphorus). Saline is preferred for eye irrigation. A triple
wash (water, soap, water) may be best for dermal decontamination.
Inhalational exposures should be treated initially with fresh air or oxy-
gen. The removal of liquids from body cavities such as the vagina or
rectum is best accomplished by irrigation. Solids (drug packets, pills)
should be removed manually, preferably under direct visualization.
ENHANCEMENT OF POISON ELIMINATION
Although the elimination of most poisons can be accelerated by
therapeutic interventions, the pharmacokinetic efficacy (removal of
drug at a rate greater than that accomplished by intrinsic elimina-
tion) and clinical benefit (shortened duration of toxicity or improved
outcome) of such interventions are often more theoretical than
proven. Accordingly, the decision to use such measures should be
based on the actual or predicted toxicity and the potential efficacy,
cost, and risks of therapy.
Multiple-Dose Activated Charcoal  Repetitive oral dosing with charcoal
can enhance the elimination of previously absorbed substances by
binding them within the gut as they are excreted in the bile, are
secreted by gastrointestinal cells, or passively diffuse into the gut
lumen (reverse absorption or enterocapillary exsorption). Doses of
0.5–1 g/kg of body weight every 2–4 h, adjusted downward to avoid
regurgitation in patients with decreased gastrointestinal motility,
are generally recommended. Pharmacokinetic efficacy approaches
that of hemodialysis for some agents (e.g., phenobarbital, theophyl-
line). Multiple-dose therapy should be considered only for selected
agents (theophylline, phenobarbital, carbamazepine, dapsone,
quinine). Complications include intestinal obstruction, pseudo-
obstruction, and nonocclusive intestinal infarction in patients with
decreased gut motility. Because of electrolyte and fluid shifts,
sorbitol and other cathartics are absolutely contraindicated when
multiple doses of activated charcoal are administered.
Urinary Alkalinization  Ion trapping via alteration of urine pH may
prevent the renal reabsorption of poisons that undergo excre-
tion by glomerular filtration and active tubular secretion. Since
membranes are more permeable to non-ionized molecules than to
their ionized counterparts, acidic (low-pKa) poisons are ionized and
trapped in alkaline urine, whereas basic ones become ionized and
trapped in acid urine. Urinary alkalinization (producing a urine pH
≥7.5 and a urine output of 3–6 mL/kg of body weight per hour by
the addition of sodium bicarbonate to an IV solution) enhances the
excretion of chlorophenoxyacetic acid herbicides, chlorpropamide,
diflunisal, fluoride, methotrexate, phenobarbital, sulfonamides, and
salicylates. Contraindications include congestive heart failure, renal
failure, and cerebral edema. Acid-base, fluid, and electrolyte param-
eters should be monitored carefully. Although acid diuresis may
make theoretical sense for some overdoses (amphetamines), it is
never indicated and is potentially harmful.
Extracorporeal Removal  Hemodialysis, charcoal or resin hemoperfu-
sion, hemofiltration, plasmapheresis, and exchange transfusion are
capable of removing any toxin from the bloodstream. Agents most
amenable to enhanced elimination by dialysis have low molecular
mass (<500 Da), high water solubility, low protein binding, small
volumes of distribution (<1 L/kg of body weight), prolonged elimi-
nation (long half-life), and high dialysis clearance relative to total-
body clearance. Molecular weight, water solubility, and protein
binding do not limit the efficacy of the other forms of extracorporeal
removal.
Dialysis should be considered in cases of severe poisoning due to
carbamazepine, ethylene glycol, isopropyl alcohol, lithium, metha-
nol, theophylline, salicylates, and valproate. Although hemoperfu-
sion may be more effective in removing some of these poisons, it
does not correct associated acid-base and electrolyte abnormali-
ties, and most hospitals no longer have hemoperfusion cartridges
readily available. Fortunately, recent advances in hemodialysis
technology make it as effective as hemoperfusion for removing
poisons such as caffeine, carbamazepine, and theophylline. Both
techniques require central venous access and systemic antico-
agulation and may result in transient hypotension. Hemoperfusion
may also cause hemolysis, hypocalcemia, and thrombocytopenia.
Peritoneal dialysis and exchange transfusion are less effective but 473e-7
may be used when other procedures are unavailable, contraindi-
cated, or technically difficult (e.g., in infants). Exchange transfusion
may be indicated in the treatment of severe arsine- or sodium
chlorate–induced hemolysis, methemoglobinemia, and sulfhemo-
globinemia. Although hemofiltration can enhance elimination of
aminoglycosides, vancomycin, and metal-chelate complexes, the
roles of hemofiltration and plasmapheresis in the treatment of poi-
soning are not yet defined.
Candidates for extracorporeal removal therapies include patients
with severe toxicity whose condition deteriorates despite aggres-
CHAPTER 473e Poisoning and Drug Overdose
sive supportive therapy; those with potentially prolonged, irrevers-
ible, or fatal toxicity; those with dangerous blood levels of toxins;
those who lack the capacity for self-detoxification because of liver or
renal failure; and those with a serious underlying illness or complica-
tion that will adversely affect recovery.
Other Techniques  The elimination of heavy metals can be enhanced
by chelation, and the removal of carbon monoxide can be acceler-
ated by hyperbaric oxygenation.
ADMINISTRATION OF ANTIDOTES
Antidotes counteract the effects of poisons by neutralizing them
(e.g., antibody-antigen reactions, chelation, chemical binding) or by
antagonizing their physiologic effects (e.g., activation of opposing
nervous system activity, provision of a competitive metabolic or
receptor substrate). Poisons or conditions with specific antidotes
include acetaminophen, anticholinergic agents, anticoagulants,
benzodiazepines, beta blockers, calcium channel blockers, car-
bon monoxide, cardiac glycosides, cholinergic agents, cyanide,
drug-induced dystonic reactions, ethylene glycol, fluoride, heavy
metals, hypoglycemic agents, isoniazid, membrane-active agents,
methemoglobinemia, opioids, sympathomimetics, and a variety of
envenomations. Intravenous lipid emulsion has been shown to be
a successful antidote for poisoning from various anesthetics and
membrane-active agents (e.g., cyclic antidepressants), but the exact
mechanism of benefit is still under investigation. Antidotes can sig-
nificantly reduce morbidity and mortality rates but are potentially
toxic if used for inappropriate reasons. Since their safe use requires
correct identification of a specific poisoning or syndrome, details of
antidotal therapy are discussed with the conditions for which they
are indicated (Table 473e-4).
PREVENTION OF REEXPOSURE
Poisoning is a preventable illness. Unfortunately, some adults
and children are poison-prone, and recurrences are common.
Unintentional polypharmacy poisoning has become especially
common among adults with developmental delays, among the
growing population of geriatric patients who are prescribed a large
number of medications, and among adolescents and young adults
experimenting with pharmaceuticals for recreational euphoria.
Adults with unintentional exposures should be instructed regard-
ing the safe use of medications and chemicals (according to
labeling instructions). Confused patients may need assistance
with the administration of their medications. Errors in dosing by
health care providers may require educational efforts. Patients
should be advised to avoid circumstances that result in chemical
exposure or poisoning. Appropriate agencies and health depart-
ments should be notified in cases of environmental or workplace
exposure. The best approach to young children and patients with
intentional overdose (deliberate self-harm or attempted suicide)
is to limit their access to poisons. In households where children
live or visit, alcoholic beverages, medications, household products
(automotive, cleaning, fuel, pet-care, and toiletry products), ined-
ible plants, and vitamins should be kept out of reach or in locked
or child-proof cabinets. Depressed or psychotic patients should
undergo psychiatric assessment, disposition, and follow-up. They
should be given prescriptions for a limited supply of drugs with a
limited number of refills and should be monitored for compliance
and response to therapy.
 473e-8   Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings
Physiologic
Condition, Causes Examples
Stimulated
Sympatheticsa
Sympathomimetics α1-Adrenergic agonists
(decongestants): phenyleph-
rine, phenylpropanolamine
β2-Adrenergic agonists
(bronchodilators): albuterol,
terbutaline
Nonspecific adrenergic ago-
PART 18
nists: amphetamines, cocaine,
ephedrine
Poisoning, Drug Overdose, and Envenomation
Ergot alkaloids Ergotamine, methysergide,
bromocriptine, pergolide
Methylxanthines Caffeine, theophylline
Monoamine oxidase Phenelzine, tranylcypromine,
inhibitors selegiline
Anticholinergics
Antihistamines Diphenhydramine, doxyl-
amine, pyrilamine
Antipsychotics Chlorpromazine, olanzapine,
quetiapine, thioridazine
Belladonna alkaloids Atropine, hyoscyamine, sco-
polamine
Mechanism of Action
Stimulation of central and
peripheral sympathetic
receptors directly or indirectly
(by promoting release or
inhibiting reuptake of
norepinephrine and
sometimes dopamine)
Stimulation and inhibition of
serotonergic and α-adrenergic (Table 473e-2); formication;
receptors; stimulation of
dopamine receptors
Inhibition of adenosine syn-
thesis and adenosine receptor (Table 473e-2); pronounced
antagonism; stimulation of
epinephrine and norepineph- and β agonist effects (see
rine release; inhibition of
phosphodiesterase resulting
in increased intracellular cyclic poisoning than in acute
adenosine and guanosine
monophosphate
Inhibition of monoamine
oxidase resulting in impaired physiologic stimulation
metabolism of endogenous
catecholamines and exog-
enous sympathomimetic
agents
Inhibition of central and post-
ganglionic parasympathetic
muscarinic cholinergic recep-
tors. At high doses, aman-
tadine, diphenhydramine,
orphenadrine, phenothiazines,
and tricyclic antidepressants
have additional nonanticho-
linergic activity (see below).
Inhibition of α-adrenergic,
dopaminergic, histaminergic,
muscarinic, and serotonergic
receptors. Some agents also
inhibit sodium, potassium,
and calcium channels.
Inhibition of central and
postganglionic
parasympathetic muscarinic
cholinergic receptors
Clinical Features Specific Treatments
Physiologic stimulation Phentolamine, a nonselective
(Table 473e-2). Reflex brady-α1-adrenergic receptor antagonist,
cardia can occur with selec- for severe hypertension due to
tive α1 agonists; β agonists α1-adrenergic agonists; propranolol, a
can cause hypotension and nonselective β blocker, for hypoten-
hypokalemia. sion and tachycardia due to β2 ago-
nists; either labetalol, a β blocker with
α-blocking activity, or phentolamine
with esmolol, metoprolol, or another
cardioselective β blocker for hyper-
tension with tachycardia due to non-
selective agents (β blockers, if used
alone, can exacerbate hypertension
and vasospasm due to unopposed
α stimulation.); benzodiazepines;
propofol
Physiologic stimulation Nitroprusside or nitroglycerine for
severe vasospasm; prazosin (an
vasospasm with limb (isolated α1 blocker), captopril, nifedipine, and
or generalized), myocardial, cyproheptadine (a serotonin recep-
and cerebral ischemia tor antagonist) for mild-to-moderate
progressing to gangrene limb ischemia; dopamine receptor
or infarction. Hypotension, antagonists (antipsychotics) for hallu-
bradycardia, and involuntary cinations and movement disorders
movements can also occur.
Physiologic stimulation Propranolol, a nonselective β blocker,
for tachycardia with hypotension;
gastrointestinal symptoms any β blocker for supraventricular
or ventricular tachycardia without
above). Toxicity occurs at hypotension; elimination enhanced
lower drug levels in chronic by multiple-dose charcoal, hemoper-
fusion, and hemodialysis. Indications
poisoning. for hemoperfusion or hemodialysis
include unstable vital signs, seizures,
and a theophylline level of 80–100
μg/mL after an acute overdose and
40–60 μg/mL with chronic exposure.
Delayed or slowly progressive Short-acting agents (e.g., nitroprus-
side, esmolol) for severe hypertension
(Table 473e-2); terminal and tachycardia; direct-acting sym-
hypotension and bradycardia pathomimetics (e.g., norepinephrine,
in severe cases epinephrine) for hypotension and
bradycardia
Physiologic stimulation Physostigmine, an acetylcholinesterase
(Table 473e-2); dry skin inhibitor (see below), for delirium,
and mucous membranes, hallucinations, and neuromuscular
decreased bowel sounds, hyperactivity. Contraindications
flushing, and urinary retention; include asthma and non-
myoclonus and picking anticholinergic cardiovascular
activity. Central effects may toxicity (e.g., cardiac conduction
occur without significant abnormalities, hypotension, and
autonomic dysfunction. ventricular arrhythmias).
Physiologic depression Sodium bicarbonate for ventricular
(Table 473e-2), miosis, tachydysrhythmias associated with
anticholinergic effects (see QRS prolongation; magnesium,
above), extrapyramidal isoproterenol, and overdrive pacing
reactions (see below), for torsades des pointes. Avoid class
tachycardia IA, IC, and III antiarrhythmics.
Physiologic stimulation Physostigmine, an acetylcholinesterase
(Table 473e-2); dry skin inhibitor (see below), for delirium,
and mucous membranes, hallucinations, and neuromuscular
decreased bowel sounds, hyperactivity. Contraindications
flushing, and urinary retention; include asthma and non-
myoclonus and picking anticholinergic cardiovascular
activity. Central effects may toxicity (e.g., cardiac conduction
occur without significant abnormalities, hypotension, and
autonomic dysfunction. ventricular arrhythmias).
(Continued )
  Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued)
Physiologic
Condition, Causes Examples
 Cyclic antidepres- Amitriptyline, doxepin,
sants imipramine
 Mushrooms and Amanita muscaria and
plants A. pantherina, henbane,
jimson weed, nightshade
Depressed
Sympatholytics
α2-Adrenergic Clonidine, guanabenz,
agonists tetrahydrozoline and other
imidazoline decongestants,
tizanidine and other
imidazoline muscle relaxants
Antipsychotics Chlorpromazine, clozapine,
haloperidol, risperidone,
thioridazine
β-Adrenergic Cardioselective (β1) blockers: Inhibition of β-adrenergic
blockers atenolol, esmolol, metoprolol receptors (class II antiarrhythmic 473e-2), atrioventricular block,
Nonselective (β1 and β2)
blockers: nadolol, propranolol, activity at additional receptors seizures. Partial agonists can
timolol
Partial β agonists: acebutolol, (see below).
pindolol
α1 Antagonists: carvedilol,
labetalol
Membrane-active agents: ace-
butolol, propranolol, sotalol
Calcium channel Diltiazem, nifedipine and
blockers other dihydropyridine deriva- cardiovascular calcium
tives, verapamil
Cardiac glycosides Digoxin, endogenous cardio- Inhibition of cardiac Na+,
active steroids, foxglove and
other plants, toad skin secre-
tions (Bufonidae spp.)
Mechanism of Action
Inhibition of α-adrenergic,
dopaminergic, GABA-ergic,
histaminergic, muscarinic, and
serotonergic receptors; inhibi-
tion of sodium channels (see
membrane-active agents);
inhibition of norepinephrine
and serotonin reuptake
Inhibition of central and
postganglionic parasympa-
thetic muscarinic cholinergic
receptors
Stimulation of α2-adrenergic
receptors leading to inhibition
of CNS sympathetic outflow.
Activity at nonadrenergic
imidazoline binding sites also
contributes to CNS effects.
Inhibition of α-adrenergic,
dopaminergic, histaminergic,
muscarinic, and serotonergic
receptors. Some agents also
inhibit sodium, potassium,
and calcium channels.
effect). Some agents have
or have membrane effects
Inhibition of slow (type L)
channels (class IV
antiarrhythmic effect)
K+-ATPase membrane pump
Clinical Features
Physiologic depression (Table
473e-2), seizures, tachycardia,
cardiac conduction delays
(increased PR, QRS, JT, and QT
intervals; terminal QRS right-
axis deviation) with aberrancy
and ventricular tachydys-
rhythmias; anticholinergic
toxidrome (see above)
Physiologic stimulation (Table
473e-2); dry skin and mucous
membranes, decreased bowel
sounds, flushing, and urinary
retention; myoclonus and
picking activity. Central effects
may occur without significant
autonomic dysfunction.
Physiologic depression (Table Dopamine and norepinephrine for
473e-2), miosis. Transient ini- hypotension; atropine for symptom-
tial hypertension may be seen. atic bradycardia; naloxone for CNS
depression (inconsistently effective)
Physiologic depression (Table
473e-2), miosis, anticholinergic
effects (see above), extrapyra-
midal reactions (see below),
tachycardia. Cardiac conduc-
tion delays (increased PR,
QRS, JT, and QT intervals) with
ventricular tachydysrhythmias,
including torsades des pointes,
can sometimes develop.
Physiologic depression (Table
hypoglycemia, hyperkalemia,
cause hypertension and
tachycardia. Sotalol can cause
increased QT interval and
ventricular tachydysrhythmias.
Onset may be delayed after
sotalol and sustained-release
formulation overdose.
Physiologic depression
(Table 473e-2), atrioventricular
block, organ ischemia and
infarction, hyperglycemia,
seizures. Hypotension is
usually due to decreased
vascular resistance rather than
to decreased cardiac output.
Onset may be delayed for
≥12 h after overdose of
sustained-release formulations.
Physiologic depression (Table
473e-2); gastrointestinal, psy-
chiatric, and visual symptoms;
atrioventricular block with or
without concomitant supra-
ventricular tachyarrhythmia;
ventricular tachyarrhythmias;
hyperkalemia in acute poison-
ing. Toxicity occurs at lower
drug levels in chronic poison-
ing than in acute poisoning.
473e-9
Specific Treatments
Hypertonic sodium bicarbonate (or
hypertonic saline) for ventricular
tachydysrhythmias associated with
QRS prolongation. Use of phenytoin is
controversial. Avoid class IA, IC, and III
antiarrhythmics. IV emulsion therapy
may be beneficial in some cases.
CHAPTER 473e Poisoning and Drug Overdose
Physostigmine, an acetylcholinester-
ase inhibitor (see below), for delirium,
hallucinations, and neuromuscular
hyperactivity. Contraindications
include asthma and nonanticholin-
ergic cardiovascular toxicity (e.g., car-
diac conduction abnormalities, hypo-
tension, and ventricular arrhythmias).
Sodium bicarbonate for ventricular
tachydysrhythmias associated with
QRS prolongation; magnesium, iso-
proterenol, and overdrive pacing for
torsades des pointes. Avoid class IA,
IC, and III antiarrhythmics.
Glucagon for hypotension and symp-
tomatic bradycardia. Atropine, iso-
proterenol, dopamine, dobutamine,
epinephrine, and norepinephrine
may sometimes be effective. High-
dose insulin (with glucose and potas-
sium to maintain euglycemia and
normokalemia), electrical pacing, and
mechanical cardiovascular support
for refractory cases
Calcium and glucagon for hypoten-
sion and symptomatic bradycardia.
Dopamine, epinephrine, norepineph-
rine, atropine, and isoproterenol are
less often effective but can be used
adjunctively. High-dose insulin (with
glucose and potassium to maintain
euglycemia and normokalemia), IV
lipid emulsion therapy, electrical pac-
ing, and mechanical cardiovascular
support for refractory cases
Digoxin-specific antibody fragments
for hemodynamically compromising
dysrhythmias, Mobitz II or third-
degree atrioventricular block, hyper-
kalemia (>5.5 meq/L; in acute poi-
soning only). Temporizing measures
include atropine, dopamine, epineph-
rine, and external cardiac pacing for
bradydysrhythmias and magnesium,
lidocaine, or phenytoin, for ventricular
tachydysrhythmias. Internal cardiac
pacing and cardioversion can increase
ventricular irritability and should be
reserved for refractory cases.
(Continued )
 473e-10   Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued)
Physiologic
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
Cyclic antidepres- Amitriptyline, doxepin, Inhibition of α-adrenergic, Physiologic depression (Table Hypertonic sodium bicarbonate (or
sants imipramine dopaminergic, GABA-ergic, 473e-2), seizures, tachycardia, hypertonic saline) for ventricular
histaminergic, muscarinic, and cardiac conduction delays tachydysrhythmias associated with
serotonergic receptors; inhibi- (increased PR, QRS, JT, and QT QRS prolongation. Use of phenytoin is
tion of sodium channels (see intervals; terminal QRS right- controversial. Avoid class IA, IC, and III
membrane-active agents); axis deviation) with aberrancy antiarrhythmics. IV emulsion therapy
inhibition of norepinephrine and ventricular tachydys- may be beneficial in some cases.
and serotonin reuptake rhythmias; anticholinergic
toxidrome (see above)
Cholinergics
PART 18

Acetylcholin- Carbamate insecticides (aldi- Inhibition of acetylcholinester-

esterase inhibitors carb, carbaryl, propoxur) and
medicinals (neostigmine,
physostigmine, tacrine); nerve
gases (sarin, soman, tabun,
VX); organophosphate insec-
ticides (diazinon, chlorpyrifos-
Poisoning, Drug Overdose, and Envenomation
Physiologic depression (Table
ase leading to increased syn- 473e-2). Muscarinic signs and
aptic acetylcholine at musca- symptoms: seizures, exces-
rinic and nicotinic cholinergic
sive secretions (lacrimation,
receptor sites salivation, bronchorrhea and
wheezing, diaphoresis), and
increased bowel and bladder
Atropine for muscarinic signs and
symptoms; 2-PAM, a cholinesterase
reactivator, for nicotinic signs and
symptoms due to organophosphates,
nerve gases, or an unknown anticho-
linesterase

ethyl, malathion) activity with nausea, vomiting,

Muscarinic agonists Bethanechol, mushrooms
(Boletus, Clitocybe, Inocybe
spp.), pilocarpine
Nicotinic agonists Lobeline, nicotine (tobacco)
Sedative-hypnoticsb
Anticonvulsants Carbamazepine, ethosuxi-
mide, felbamate, gabapentin,
lamotrigine, levetiracetam,
oxcarbazepine, phenytoin,
tiagabine, topiramate, valpro-
ate, zonisamide
Barbiturates Short-acting: butabarbital,
pentobarbital, secobarbital
Long-acting: phenobarbital,
primidone
Benzodiazepines Ultrashort-acting: estazolam,
midazolam, temazepam,
triazolam
Short-acting: alprazolam,
flunitrazepam, lorazepam,
oxazepam
Long-acting: chlordiazepox-
ide, clonazepam, diazepam,
flurazepam
Pharmacologically related
agents: zaleplon, zolpidem
GABA precursors γ-Hydroxybutyrate
(sodium oxybate; GHB),
γ-butyrolactone (GBL),
1,4-butanediol
Muscle relaxants Baclofen, carisoprodol,
cyclobenzaprine, etomidate,
metaxalone, methocarbamol,
orphenadrine, propofol, tiza-
nidine and other imidazoline
muscle relaxants
Stimulation of CNS and post- diarrhea, abdominal cramps,
ganglionic parasympathetic and incontinence of feces
cholinergic (muscarinic) and urine. Nicotinic signs and
receptors symptoms: hypertension,
tachycardia, muscle cramps,
Stimulation of preganglionic fasciculations, weakness, and
sympathetic and parasym- paralysis. Death is usually
pathetic and striated muscle due to respiratory failure.
(neuromuscular junction) cho- Cholinesterase activity in
linergic (nicotine) receptors plasma and red cells is <50%
of normal in acetylcholinester-
ase inhibitor poisoning.
Potentiation of the inhibitory Physiologic depression (Table Benzodiazepines, barbiturates, or pro-
effects of GABA by binding 473e-2), nystagmus. pofol for seizures.
to the neuronal GABA–A Delayed absorption can occur
chloride channel receptor with carbamazepine, phe-
complex and increasing nytoin, and valproate.
the frequency or duration
of chloride channel open- Myoclonus, seizures, hyper-
ing in response to GABA tension, and tachyarrhythmias
stimulation. Baclofen and, to can occur with baclofen,
some extent, GHB act at the carbamazepine, and orphen-
GABA–B receptor complex. adrine.
Meprobamate, its metabolite Hemodialysis and hemoperfu-
carisoprodol, felbamate, and sion may be indicated for severe
orphenadrine antagonize poisoning by some agents (see
NDMA excitatory receptors. “Extracorporeal Removal,” in text).
Ethosuximide, valproate,
and zonisamide decrease
conduction through T-type
calcium channels. Valproate Tachyarrhythmias can also See above and below for treatment
decreases GABA degradation, occur with chloral hydrate. of anticholinergic and sodium chan-
and tiagabine blocks GABA AGMA, hypernatremia, nel (membrane)–blocking effects.
reuptake. Carbamazepine, hyperosmolality, hyperam-
lamotrigine, oxcarbazepine, monemia, chemical hepatitis,
phenytoin, topiramate, valpro- and hypoglycemia can be
ate, and zonisamide slow the seen in valproate poisoning.
Carbamazepine and oxcar-
rate of recovery of inactivated
sodium channels. Some bazepine may produce hypo-
natremia from SIADH.
agents also have α2 agonist,
anticholinergic, and sodium
channel–blocking activity (see
above and below).
Some agents can cause
anticholinergic and sodium
channel (membrane) blocking
effects (see above and below).

(Continued )
  Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued) 473e-11
Physiologic
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
Other agents Chloral hydrate, ethchlorvynol,
glutethimide, meprobamate,
methaqualone, methyprylon
Discordant
Asphyxiants
Cytochrome oxidase Cyanide, hydrogen sulfide Inhibition of mitochondrial Signs and symptoms of High-dose oxygen; IV hydroxocobala-
inhibitors cytochrome oxidase, with hypoxemia with initial physi- min or IV sodium nitrite and sodium
consequent blockage of elec- ologic stimulation and sub- thiosulfate (Lilly cyanide antidote kit)

CHAPTER 473e Poisoning and Drug Overdose

tron transport and oxidative sequent depression (Table for coma, metabolic acidosis, and
metabolism. Carbon monox- 473e-2); lactic acidosis; normal cardiovascular dysfunction in cyanide
ide also binds to hemoglobin Po2 and calculated oxygen poisoning
and myoglobin and prevents saturation but decreased
oxygen binding, transport, oxygen saturation by co-
and tissue uptake. (Binding to oximetry. (That measured by
hemoglobin shifts the oxygen pulse oximetry is falsely ele-
dissociation curve to the left.) vated but is less than normal
and less than the calculated
value.) Headache and nausea
are common with carbon
monoxide. Sudden collapse
may occur with cyanide and
hydrogen sulfide exposure.
A bitter almond breath odor
may be noted with cyanide
ingestion, and hydrogen sul-
fide smells like rotten eggs.
Methemoglobin Aniline derivatives, dapsone, Oxidation of hemoglobin iron Signs and symptoms of High-dose oxygen; IV methylene blue
inducers local anesthetics, nitrates, from ferrous (Fe2+) to ferric hypoxemia with initial physi- for methemoglobin fraction >30%,
nitrites, nitrogen oxides, nitro- (Fe3+) state prevents oxygen ologic stimulation and sub- symptomatic hypoxemia, or ischemia
and nitrosohydrocarbons, binding, transport, and tissue sequent depression (Table (contraindicated in G6PD deficiency);
phenazopyridine, primaquine- uptake. (Methemoglobinemia 473e-2), gray-brown cyanosis exchange transfusion and hyperbaric
type antimalarials, sulfon- shifts oxygen dissociation unresponsive to oxygen at oxygen for severe or refractory cases
amides curve to the left.) Oxidation of methemoglobin fractions
hemoglobin protein causes >15–20%, headache, lactic
hemoglobin precipitation and acidosis (at methemoglobin
hemolytic anemia (manifest- fractions >45%), normal Po2
ing as Heinz bodies and "bite and calculated oxygen satura-
cells" on peripheral-blood tion but decreased oxygen
smear). saturation and increased
methemoglobin fraction by
co-oximetry (Oxygen satura-
tion by pulse oximetry may be
falsely increased or decreased
but is less than normal and
less than the calculated value.)
AGMA inducers Ethylene glycol Ethylene glycol causes CNS Initial ethanol-like intoxication, Sodium bicarbonate to correct
depression and increased nausea, vomiting, increased acidemia; thiamine, folinic acid, mag-
serum osmolality. Metabolites osmolar gap, calcium oxylate nesium, and high-dose pyridoxine
(primarily glycolic acid) cause crystalluria; delayed AGMA, to facilitate metabolism; ethanol
AGMA, CNS depression, and back pain, renal failure; coma, or fomepizole for AGMA, crystal-
renal failure. Precipitation of seizures, hypotension, ARDS in luria or renal dysfunction, ethylene
oxalic acid metabolite as cal- severe cases glycol level >3 mmol/L (20 mg/
cium salt in tissues and urine dL), and ethanol-like intoxication or
results in hypocalcemia, tissue increased osmolal gap if level not
edema, and crystalluria. readily obtainable; hemodialysis
for persistent AGMA, lack of clinical
improvement, and renal dysfunction;
hemodialysis also useful for enhanc-
ing ethylene glycol elimination and
shortening duration of treatment
when ethylene glycol level is
>8 mmol/L (50 mg/dL)
AGMA inducers Iron Hydration of ferric (Fe3+) ion Initial nausea, vomiting, Whole-bowel irrigation for large
generates H+. Non-transferrin- abdominal pain, diarrhea; ingestions; endoscopy and gastros-
bound iron catalyzes forma- AGMA, cardiovascular and tomy if clinical toxicity and large
tion of free radicals that cause CNS depression, hepatitis, number of tablets are still visible on
mitochondrial injury, lipid coagulopathy, and seizures x-ray; IV hydration; sodium bicarbon-
peroxidation, increased capil- in severe cases. Radiopaque ate for acidemia; IV deferoxamine
lary permeability, vasodilation, iron tablets may be seen on for systemic toxicity, iron level >90
and organ toxicity. abdominal x-ray. μmol/L (500 μg/dL)

(Continued )
 473e-12   Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued)
Physiologic
Condition, Causes Examples Mechanism of Action
Methanol Methanol causes ethanol-like
CNS depression and increased
serum osmolality. Formic acid
metabolite causes AGMA and
retinal toxicity.
PART 18
Salicylate Increased sensitivity of CNS
respiratory center to changes
Poisoning, Drug Overdose, and Envenomation
in and stimulates respira-
tion. Uncoupling of oxidative
phosphorylation, inhibition
of Krebs cycle enzymes, and
stimulation of carbohydrate
and lipid metabolism gener-
ate unmeasured endogenous
anions and cause AGMA.
CNS syndromes
Extrapyramidal Antipsychotics (see above), Decreased CNS dopaminergic
reactions some cyclic antidepressants activity with relative excess of
and antihistamines cholinergic activity
Isoniazid Interference with activation
and supply of pyridoxal-
5-phosphate, a cofactor for
glutamic acid decarboxylase,
which converts glutamic acid
to GABA, results in decreased
levels of this inhibitory CNS
neurotransmitter; complex-
ation with and depletion of
pyridoxine itself; inhibition of
nicotine adenine dinucleotide–
dependent lactate and
hydroxybutyrate dehydroge-
nases, resulting in substrate
accumulation
Lithium Interference with cell mem-
brane ion transport, adenylate
cyclase and Na+, K+-ATPase
activity, and neurotransmitter
release
Clinical Features
Initial ethanol-like intoxication,
nausea, vomiting, increased
osmolar gap; delayed AGMA,
visual (clouding, spots, blind-
ness) and retinal (edema,
hyperemia) abnormalities;
coma, seizures, cardiovascular
depression in severe cases;
possible pancreatitis
Initial nausea, vomiting,
hyperventilation, alkalemia,
alkaluria; subsequent alka-
lemia with both respiratory
alkalosis and AGMA and
paradoxical aciduria; late aci-
demia with CNS and respira-
tory depression; cerebral and
pulmonary edema in severe
cases. Hypoglycemia, hypo-
calcemia, hypokalemia, and
seizures can occur.
Akathisia, dystonia, parkin-
sonism
Nausea, vomiting, agitation,
confusion; coma, respiratory
depression, seizures, lactic and seizures; diazepam or barbiturates for
ketoacidosis in severe cases
Nausea, vomiting, diarrhea,
ataxia, choreoathetosis,
encephalopathy, hyperre-
flexia, myoclonus, nystagmus,
nephrogenic diabetes insipi-
dus, falsely elevated serum
chloride with low anion gap,
tachycardia; coma, seizures,
arrhythmias, hyperthermia,
and prolonged or permanent
encephalopathy and move-
ment disorders in severe
cases; delayed onset after
acute overdose, particularly
with delayed-release formula-
tions. Toxicity occurs at lower
drug levels in chronic poison-
ing than in acute poisoning.
Specific Treatments
Gastric aspiration for recent ingestion;
sodium bicarbonate to correct
acidemia; high-dose folinic acid or
folate to facilitate metabolism;
ethanol or fomepizole for AGMA,
visual symptoms, methanol level
>6 mmol/L (20 mg/dL), and ethanol-
like intoxication or increased osmolal
gap if level not readily obtainable;
hemodialysis for persistent AGMA,
lack of clinical improvement, and
renal dysfunction; hemodialysis
also useful for enhancing methanol
elimination and shortening duration
of treatment when methanol level is
>15 mmol/L (50 mg/dL)
IV hydration and supplemental
glucose; sodium bicarbonate to cor-
rect acidemia; urinary alkalinization
for systemic toxicity; hemodialysis
for coma, cerebral edema, seizures,
pulmonary edema, renal failure,
progressive acid-base disturbances
or clinical toxicity, salicylate level >7
mmol/L (100 mg/dL) following acute
overdose
Oral or parenteral anticholinergic
agent such as benztropine or diphen-
hydramine
High-dose IV pyridoxine (vitamin B6)
for agitation, confusion, coma, and
seizures
Whole-bowel irrigation for large
ingestions; IV hydration; hemodialysis
for coma, seizures, encephalopathy or
neuromuscular dysfunction (severe,
progressive, or persistent), peak lith-
ium level >4 meq/L following acute
overdose
(Continued )
  Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued)
Physiologic
Condition, Causes Examples
Serotonin syndrome Amphetamines, cocaine, dex-
tromethorphan, meperidine,
MAO inhibitors, selective sero-
tonin (5-HT) reuptake inhibi-
tors, tricyclic antidepressants,
tramadol, triptans, tryptophan
Mechanism of Action
Promotion of serotonin
release, inhibition of serotonin
reuptake, or direct stimula-
tion of CNS and peripheral
serotonin receptors (primarily
5-HT-1a and 5-HT-2), alone or
in combination
473e-13
Clinical Features Specific Treatments
Altered mental status (agita- Discontinue the offending agent(s);
tion, confusion, mutism, the serotonin receptor antagonist
coma, seizures), neuromuscu- cyproheptadine may be helpful in
lar hyperactivity (hyperreflexia, severe cases.
myoclonus, rigidity, tremors),
and autonomic dysfunction
(abdominal pain, diarrhea,
diaphoresis, fever, flushing,
labile hypertension, mydriasis,

CHAPTER 473e Poisoning and Drug Overdose

Membrane-active Amantadine, anti-arrhythmics
agents (class I and III agents; some
beta blockers), antipsychotics
(see above), antihistamines
(particularly diphenhydr-
amine), carbamazepine,
local anesthetics (including
cocaine), opioids (meperidine,
propoxyphene), orphenadrine,
quinoline antimalarials (chlo-
roquine, hydroxychloroquine,
quinine), cyclic antidepres-
sants (see above)
See above and Chap. 469e. bSee above and Chap. 468e.
a
Blockade of fast sodium
membrane channels prolongs
phase 0 (depolarization) of
the cardiac action potential,
which prolongs QRS dura-
tion and promotes reentrant
(monomorphic) ventricular
tachycardia. Class Ia, Ic, and
III antiarrhythmics also block
potassium channels during
phases 2 and 3 (repolariza-
tion) of the action potential,
prolonging the JT interval and
promoting early after-depolar-
izations and polymorphic (tor-
sades des pointes) ventricular
tachycardia. Similar effects on
neuronal membrane channels
cause CNS dysfunction. Some
agents also block α-adrenergic
and cholinergic receptors or
have opioid effects (see above
and Chap. 468e).
tearing, salivation, tachycar-
dia). Complications include
hyperthermia, lactic acidosis,
rhabdomyolysis, and multisys-
tem organ failure.
QRS and JT prolongation
(or both) with hypotension,
ventricular tachyarrhythmias,
CNS depression, seizures;
anticholinergic effects with
amantadine, antihistamines,
carbamazepine, disopyramide,
antipsychotics, and cyclic
antidepressants (see above);
opioid effects with meperi-
dine and propoxyphene (see
Chap. 468e); cinchonism
(hearing loss, tinnitus, nau-
sea, vomiting, vertigo, ataxia,
headache, flushing, diapho-
resis) and blindness with
quinoline
antimalarials
Hypertonic sodium bicarbonate (or
hypertonic saline) for cardiac con-
duction delays and monomorphic
ventricular tachycardia; lidocaine
for monomorphic ventricular tachy-
cardia (except when due to class Ib
antiarrhythmics); magnesium, iso-
proterenol, and overdrive pacing for
polymorphic ventricular tachycardia;
physostigmine for anticholinergic
effects (see above); naloxone for opi-
oid effects (see Chap. 468e); extra-
corporeal removal for some agents
(see text).

Abbreviations: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; CNS, central nervous system; GABA, γ-aminobutyric acid; GBL, γ-butyrolactone; GHB,
γ-hydroxybutyrate; G6PD, glucose-6-phosphate dehydrogenase; MAO, monoamine oxidase; NDMA, N-methyl-d-aspartate; 2-PAM, pralidoxime; SIADH, syndrome of inappropirate antidi-
uretic hormone secretion.

SPECIFIC TOXIC SYNDROMES AND POISONINGS
Table 473e-4 summarizes the pathophysiology, clinical features, and
treatment of toxidromes and poisonings that are common, produce
life-threatening toxicity, or require unique therapeutic interventions.
In all cases, treatment should include attention to the general prin-
ciples discussed above and, in particular, supportive care. Poisonings
not covered in this chapter are discussed in specialized texts.
Alcohol, cocaine, hallucinogen, and opioid poisoning and
alcohol and opioid withdrawal are discussed in Chaps. 467–469e;
nicotine addiction is discussed in Chap. 470; acetaminophen
poisoning is discussed in Chap. 361; the neuroleptic malignant
syndrome is discussed in Chap. 449; and heavy metal poisoning is
discussed in Chap. 472e.
Acknowledgment
The author acknowledges the contributions of Christopher H. Linden
and Michael J. Burns to this chapter in previous editions of this text.
 Part 18: Poisoning, Drug Overdose, and Envenomation 2733

474 Disorders Caused by Venomous

Snakebites and Marine Animal
Exposures
Charles Lei, Natalie J. Badowski, Paul S. Auerbach,
Robert L. Norris

CHAPTER 474
This chapter outlines general principles for the evaluation and man-
agement of victims of envenomation and poisoning by venomous
snakes and marine animals. Because the incidence of serious bites and
stings is relatively low in developed nations, there is a paucity of rel-
evant clinical research; as a result, therapeutic decision making often is
based on anecdotal information.

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

VENOMOUS SNAKEBITE
EPIDEMIOLOGY
The venomous snakes of the world belong to the families Viperidae
(subfamily Viperinae: Old World vipers; subfamily Crotalinae: New
World and Asian pit vipers), Elapidae (including cobras, coral snakes,
sea snakes, kraits, and all Australian venomous snakes), Lamprophiidae
(subfamily Atractaspidinae: burrowing asps), and Colubridae (a large
family in which most species are nonvenomous and only a few are
dangerously toxic to humans). Most snakebites occur in developing
countries with temperate and tropical climates in which populations
subsist on agriculture and fishing. Recent estimates indicate that some-
where between 1.2 million and 5.5 million snakebites occur worldwide
each year, with 421,000–1,841,000 envenomations and 20,000–94,000
deaths. Such wide-ranging estimates reflect the challenges of collecting
accurate data in the regions most affected by venomous snakes; many
victims do not seek hospital treatment, and reporting and record keep-
ing are generally poor.

SNAKE ANATOMY/IDENTIFICATION
The typical snake venom delivery apparatus consists of bilateral venom
glands situated below and behind the eyes and connected by ducts to
hollow anterior maxillary fangs. In viperids (vipers and pit vipers),
these fangs are long and highly mobile; they are retracted against the
roof of the mouth when the snake is at rest and brought to an upright
position for a strike. In elapids, the fangs are smaller and are relatively
fixed in an erect position. Approximately 20% of pit viper bites and
higher percentages of other snakebites (up to 75% for sea snakes) are
“dry” bites, meaning no venom is released. Significant envenomation
probably occurs in ~50% of all venomous snakebites.
Differentiation of venomous from nonvenomous snake species
can be difficult. Viperids are characterized by somewhat triangular
heads (a feature shared with many harmless snakes), elliptical pupils
(also seen in some nonvenomous snakes, such as boas and pythons),
enlarged maxillary fangs, and, in pit vipers, heat-sensing pits (foveal
organs) on each side of the head that assist with locating prey and aim-
ing strikes. The New World rattlesnakes possess a series of interlock-
ing keratin plates (the rattle) on the tip of the tail that emits a buzzing
sound when the snake rapidly vibrates its tail; this sound serves as a
warning signal to perceived threats. Identifying venomous snakes by
color pattern is notoriously misleading, as many harmless snakes have
color patterns that closely mimic those of venomous snakes found in
the same region.

VENOMS AND CLINICAL MANIFESTATIONS

Snake venoms are highly variable and complex mixtures of enzymes,
low-molecular-weight polypeptides, glycoproteins, and other con-
stituents. Among the deleterious components are hemorrhagins that
promote vascular leakage and cause both local and systemic bleeding.

HPIM19_Part18_p2733-p2752.indd 2733 2/9/15 4:40 PM

 2734 Proteolytic enzymes cause local tissue necrosis, affect the coagulation
pathway at various steps, and impair organ function. Hyaluronidases
promote the spread of venom through connective tissue. Myocardial
depressant factors reduce cardiac output, and bradykinins cause
vasodilation and hypotension. Neurotoxins act either pre- or postsyn-
aptically to block transmission at the neuromuscular junction, causing
muscle paralysis. Most snake venoms have multisystem effects on their
victims.
After a venomous snakebite, the time to symptom onset and clinical
presentation can be quite variable and depend on the species involved,
the anatomic location of the bite, and the amount of venom injected.
Envenomations by most viperids and some elapids with necrotizing
venoms cause progressive local pain, swelling, ecchymosis (Fig. 474-1),
PART 18

and (over a period of hours to days) hemorrhagic or serum-filled

vesicles and bullae. In serious bites, tissue loss can be significant
(Figs. 474-2 and 474-3). Systemic findings are extremely variable
and can include tachycardia or bradycardia, hypotension, generalized
weakness, changes in taste, mouth numbness, muscle fasciculations,
pulmonary edema, renal dysfunction, and spontaneous hemorrhage
Poisoning, Drug Overdose, and Envenomation

(from essentially any anatomic site). Envenomations by neurotoxic

elapids such as kraits (Bungarus species), many Australian elapids
(e.g., death adders [Acanthophis species] and tiger snakes [Notechis
species]), some cobras (Naja species), and some viperids (e.g., the
South American rattlesnake [Crotalus durissus] and some Indian
Russell’s vipers [Daboia russelii]) cause neurologic dysfunction. Early
findings may consist of nausea and vomiting, headache, paresthesias
or numbness, and altered mental status. Victims may develop cranial
nerve abnormalities (e.g., ptosis, difficulty swallowing) followed by Figure 474-2  Early stages of severe, full-thickness necrosis
peripheral motor weakness. Severe envenomation may result in muscle 5 days after a Russell’s viper (Daboia russelii) bite in southwestern
paralysis, including the muscles of respiration, and lead to death from India.
respiratory failure and aspiration. Sea snake envenomation results in
local pain (variable), generalized myalgias, trismus, rhabdomyolysis,
and progressive flaccid paralysis; these manifestations can be delayed
for several hours.

TREATMENT  V enomous Snakebite

FIELD MANAGEMENT
The most important aspect of prehospital care of a person bitten by
a venomous snake is rapid transport to a medical facility equipped
to provide supportive care (airway, breathing, and circulation) and
antivenom therapy. Most of the first-aid measures recommended
in the past are of little benefit, and some actually worsen outcome.
It is reasonable to apply a splint to the bitten extremity to lessen
bleeding and discomfort and, if possible, to keep the extremity at
approximately heart level. In developing countries, indigenous peo-
ple should be encouraged to seek immediate care at a health care
A

B
Figure 474-1  Northern Pacific rattlesnake (Crotalus oreganus ore-
ganus) envenomations. A. Moderately severe envenomation. Note
edema and early ecchymosis 2 h after a bite to the finger. B. Severe
envenomation. Note extensive ecchymosis 5 days after a bite to the Figure 474-3  Severe necrosis 10 days after a pit viper bite in a
ankle. young child in Colombia. (Courtesy of Jay R. Stanka; with permission.)

HPIM19_Part18_p2733-p2752.indd 2734 2/9/15 4:40 PM

 facility equipped with antivenom instead of consulting traditional
healers and thus incurring significant delays in reaching appropriate
care. Attempting to capture and transport the offending snake, alive
or dead, is not advised; instead, digital photographs of the snake
taken from a safe distance may assist with snake identification and
treatment decisions.
Incising and/or applying suction to the bite site should be
avoided, as these measures are ineffective and exacerbate local
tissue damage. Similarly ineffective and potentially harmful are
the application of poultices, ice, and electric shock. Techniques or
devices used in an effort to limit venom spread (e.g., lymphooc-
clusive bandages or tourniquets) are ineffective and may result in
greater local tissue damage by restricting the spread of potentially
necrotizing venom. Tourniquet use can result in loss of function and
amputation even in the absence of envenomation.
Elapid venoms that are primarily neurotoxic and have no signifi-
cant effects on local tissue may be localized by pressure-immobili-
zation, a technique in which the entire limb is wrapped immediately
with a bandage (e.g., crepe or elastic) and then immobilized. For
this technique to be effective, the wrap pressure must be precise
(40–70 mmHg in upper-extremity application and 55–70 mmHg in
lower-extremity application) and the victim must be carried out of
the field because walking generates muscle-pumping activity that—
regardless of the anatomic site of the bite—will disperse venom into
the systemic circulation. Pressure-immobilization should be used
only in cases in which the offending snake is reliably identified and
known to be primarily neurotoxic, the rescuer is skilled in pressure-
wrap application, the necessary supplies are readily available, and
the victim can be fully immobilized and carried to medical care—an
uncommon combination of conditions, particularly in the regions of
the world where such bites are most common.
HOSPITAL MANAGEMENT
In the hospital, the victim should be closely monitored (vital signs,
cardiac rhythm, oxygen saturation, urine output) while a history
is quickly obtained and a rapid, thorough physical examination is
performed. To objectively evaluate the progression of local enven-
omation, the level of swelling in the bitten extremity should be
marked and limb circumference should be measured every 15 min
until the swelling has stabilized. During this period of observation,
the extremity should be positioned at approximately heart level.
Measures applied in the field (such as bandages or wraps) should be
removed once IV access has been obtained, with cognizance that
the release of such ligatures may result in hypotension or dysrhyth-
mias when stagnant acidotic blood containing venom is released
into the systemic circulation. Two large-bore IV lines should be
established in unaffected extremities. Because of the potential for
coagulopathy, venipuncture attempts should be minimized, and
noncompressible sites (e.g., a subclavian vein) should be avoided.
Early hypotension is due to pooling of blood in the pulmonary and
splanchnic vascular beds. Later, systemic bleeding, hemolysis, and
loss of intravascular volume into the soft tissues may play important
roles. Fluid resuscitation with isotonic saline (20–40 mL/kg IV) should
be initiated if there is any evidence of hemodynamic instability, and
a trial of 5% albumin (10–20 mL/kg IV) may be given if the response
to saline infusion is inadequate. Only after aggressive volume
resuscitation and antivenom administration (see below) are accom-
plished should vasopressors (e.g., dopamine) be added. Invasive
hemodynamic monitoring (central venous and/or continuous arte-
rial pressures) can be helpful in such cases, although obtaining cen-
tral vascular access is risky if coagulopathy has developed. Victims of
neurotoxic envenomation should be watched carefully for evidence
of cranial nerve dysfunction (e.g., ptosis) that may precede the onset
of difficulty swallowing or respiratory insufficiency that necessitates
definitive airway protection by endotracheal intubation.
Blood should be drawn for typing and cross-matching and for
laboratory evaluation as soon as possible. Important studies include
a complete blood count to determine the degree of hemorrhage
or hemolysis and to identify thrombocytopenia; studies of renal
HPIM19_Part18_p2733-p2752.indd 2735
and hepatic function; coagulation studies to diagnose consumptive 2735
coagulopathy; creatine kinase for suspected rhabdomyolysis; and
testing of urine for blood or myoglobin. In developing regions, the
20-min whole-blood clotting test can be used to reliably diagnose
coagulopathy. A few milliliters of fresh blood are placed in a new,
clean, plain glass receptacle (e.g., a test tube) and left undisturbed
for 20 min. The tube is then tipped once to 45° to determine whether
a clot has formed. If it has not, coagulopathy is diagnosed. Arterial
blood gas studies, electrocardiography, and chest radiography may
be helpful in severe envenomations or when there is significant
comorbidity. Any arterial puncture in the setting of coagulopathy
CHAPTER 474
requires great caution and must be performed at an anatomic site
amenable to direct-pressure tamponade. After antivenom therapy
(see below), laboratory values should be rechecked every 6 h until
clinical stability is achieved. If initial laboratory values are normal,
the complete blood count and coagulation studies should be
repeated every hour until it is clear that no systemic envenomation
has occurred.
The mainstay of treatment of a venomous snakebite resulting
Disorders Caused by Venomous Snakebites and Marine Animal Exposures
in significant envenomation is prompt administration of specific
antivenom. Antivenoms are produced by injecting animals (gener-
ally horses or sheep) with venoms from medically important snakes.
Once the stock animals develop antibodies to the venoms, their
serum is harvested and the antibodies are isolated for antivenom
preparation, which may involve varying degrees of digestion and
purification of the IgG molecules. The goal of antivenom adminis-
tration is to allow antibodies (or antibody fragments) to bind and
deactivate circulating venom components before they can attach
to target tissues and cause deleterious effects. Antivenoms may be
monospecific (directed against a particular snake species) or poly-
specific (covering several medically important species in the region)
but rarely offer cross-protection against snake species other than
those used in their production unless the species are known to have
homologous venoms. Thus, antivenom selection must be specific
for the offending snake; if the antivenom chosen does not contain
antibodies to that snake’s venom components, it will provide no
benefit and may lead to unnecessary complications (see below). In
the United States, assistance in finding appropriate antivenom can
be obtained from regional poison control centers.
For victims of bites by viperids or cytotoxic elapids, indications
for antivenom administration include significant progressive local
findings (e.g., soft tissue swelling crossing a joint or involving more
than half the bitten limb) and any evidence of systemic enven-
omation (systemic symptoms or signs, laboratory abnormalities).
Caution must be used in determining the significance of isolated
soft tissue swelling after the bite of an unidentified snake because
the saliva of some relatively harmless species can cause mild edema
at the bite site; in such bites, antivenoms are useless and potentially
harmful. Antivenoms have limited efficacy in preventing tissue dam-
age caused by necrotizing venoms, as venom components bind to
local tissues very quickly, before antivenom administration can be
initiated. Nevertheless, antivenom should be administered as soon
as the need for it is identified to limit further tissue damage and
systemic effects. Antivenom administration after bites by neurotoxic
elapids is indicated at the first sign of any evidence of neurotoxicity
(e.g., cranial nerve dysfunction, peripheral neuropathy). In general,
antivenom is effective only in reversing active venom toxicity; it is
of no benefit in reversing effects that already have been established
(e.g., renal failure, established paralysis) and that will improve only
with time and other supportive therapies.
Specific comments related to the management of venomous
snakebites in the United States and Canada appear in Table 474-1.
The package insert for the selected antivenom can be consulted
regarding species covered, method of administration, starting dose,
and need (if any) for re-dosing. The information in antivenom pack-
age inserts, however, is not always accurate and reliable. Whenever
possible, it is advisable for treating physicians to seek advice from
experts in snakebite management regarding indications for and
dosing of antivenom.
2/9/15 4:40 PM
 2736   TABLE 474-1    Management of Venomous Snakebite in the United States and Canadaa
Pit viper bites (rattlesnakes [Crotalus and Sistrurus spp.], cottonmouth water moccasins [Agkistrodon piscivorus], and copperheads [Agkistrodon
contortrix])
•  Stabilize airway, breathing, and circulation.
•  Institute monitoring (vital signs, cardiac rhythm, and oxygen saturation).
•  Establish two large-bore IV lines.
•  If the patient is hypotensive, administer a normal saline bolus (20–40 mL/kg IV).
•  If hypotension persists, consider 5% albumin (10–20 mL/kg IV).
•  Take rapid history and perform thorough physical examination.
•  Identify offending snake if possible.
•  Measure and record circumference of bitten extremity every 15 min until swelling has stabilized.
PART 18

•  Send laboratory studies (CBC, metabolic panel, PT/INR/PTT, fibrinogen level, FDP, blood type and cross-matching, urinalysis).
•  If normal, repeat CBC and coagulation studies every hour until it is clear that no systemic envenomation has occurred.
•  If abnormal, repeat 6 h after antivenom administration (see below).
•  Determine severity of envenomation.
•  None: fang marks only (“dry” bite)
•  Mild: local findings only (e.g., pain, ecchymosis, nonprogressive swelling)
Poisoning, Drug Overdose, and Envenomation

•  Moderate: swelling that is clearly progressing, systemic symptoms or signs, and/or laboratory abnormalities
•  Severe: neurologic dysfunction, respiratory distress, and/or cardiovascular instability/shock
•  Contact regional poison control center.
•  Locate and administer antivenom as indicated: Crotalidae Polyvalent Immune Fab (CroFab) (Ovine) (BTG International Inc., West Conshohocken, PA).
•  Starting dose
•  Based on severity of envenomation
•  None or mild: none
•  Moderate: 4–6 vials
•  Severe: 6 vials
•  Dilute reconstituted vials in 250 mL of normal saline.
•  No pretesting for potential hypersensitivity; no pretreatment
•  Infuse IV over 1 h (with physician in close attendance).
•  If acute reaction to antivenom:
•  Stop infusion.
•  Treat with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV).
•  When reaction is controlled, restart antivenom as soon as possible (may further dilute in larger volume of normal saline).
•  Monitor clinical status over 1 h.
•  Stabilized or improved: Admit to hospital.
•  Progressing or unimproved: Repeat starting dose (and continue this pattern until patient’s condition is stable or improved).
•  Blood products are rarely needed; if required, they should be given only after antivenom administration.
•  Update tetanus immunization as needed.
•  Prophylactic antibiotics are unnecessary unless prehospital care included incision or mouth suction.
•  Pain management: acetaminophen and/or narcotics as needed; avoidance of salicylates and nonsteroidal anti-inflammatory agents
•  Admit to hospital. (If no evidence of envenomation, monitor for 8 h before discharge.)
•  Give additional CroFab (2 vials every 6 h for 3 additional doses, with close monitoring).
•  Monitor for evidence of rising intracompartmental pressures (see text).
•  Provide wound care (see text).
•  Start physical therapy (see text).
•  At discharge, warn patient of possible recurrent coagulopathy and symptoms/signs of delayed serum sickness.
Coral snakebites (Micrurus spp. and Micruroides euryxanthus)
•  Stabilize airway, breathing, and circulation.
•  Institute monitoring (vital signs, cardiac rhythm, and oxygen saturation).
•  Establish one large-bore IV line and initiate normal saline infusion.
•  Take rapid history and perform thorough physical examination.
•  Identify offending snake if possible.
•  Laboratory studies are unlikely to be helpful.
•  Contact regional poison control center.
•  Locate and administer antivenom as indicated: Antivenin (Micrurus fulvius) (equine) (commonly referred to as North American Coral Snake Antivenin; Wyeth
Pharmaceuticals, New York, NY).b
•  Refer to antivenom package insert.
•  Dilute 3–5 reconstituted vials of antivenom in 250 mL of normal saline.
•  Infuse IV over 1 h (with physician in close attendance).
•  If signs of envenomation progress despite initial antivenom, repeat the starting dose (up to 10 vials total may be required).
(Continued )

HPIM19_Part18_p2733-p2752.indd 2736 2/9/15 4:40 PM

   TABLE 474-1    Management of Venomous Snakebite in the United States and Canadaa (CONTINUED) 2737
•  If acute adverse reaction to antivenom:
•  Stop infusion.
•  Treat with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV).
•  When reaction is controlled, restart antivenom as soon as possible (may further dilute in larger volume of normal saline).
•  If any evidence of neurologic dysfunction (e.g., any cranial nerve abnormalities such as ptosis):
•  Trial of acetylcholinesterase inhibitors (see Table 474-2)
•  With any evidence of difficulty swallowing or breathing, proceed with endotracheal intubation and ventilatory support (may be required for days or weeks).
•  Update tetanus immunization as needed.
•  Prophylactic antibiotics are unnecessary unless prehospital care included incision or mouth suction.

CHAPTER 474
•  Admit to hospital (intensive care unit) even if there is no evidence of envenomation; monitor for at least 24 h.
These recommendations are specific to the care of victims of venomous snakebites in the United States and Canada and should not be applied to bites in other regions of the
a

world.  bAt the time of publication, a single lot of antivenom remains, with an extended expiration date of April 30, 2015.
Abbreviations: CBC, complete blood count; FDP, fibrin degradation products; PT/INR/PTT, prothrombin time/international normalized ratio/partial thromboplastin time.

Antivenom should be administered only by the IV route, and the administration and may present as fever, chills, urticaria, myalgias,

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

infusion should be started slowly, with the physician at the bed-
side ready to intervene immediately at the first signs of an acute
adverse reaction. In the absence of an adverse reaction, the rate of
infusion can be increased gradually until the full starting dose has
been administered (over a total period of ~1 h). Further antivenom
may be necessary if the patient’s acute clinical condition worsens
or fails to stabilize or if venom effects that were initially controlled
recur. The decision to administer further antivenom to a stabilized
patient should be based on clinical evidence of persistent circula-
tion of unbound venom components. For viperid bites, antivenom
administration generally should be continued until the victim
shows definite improvement (e.g., stabilized vital signs, reduced
pain, restored coagulation). Neurotoxicity from elapid bites may
be more difficult to reverse with antivenom. Once neurotoxicity is
established and endotracheal intubation is required, further doses
of antivenom are unlikely to be beneficial. In such cases, the victim
must be maintained on mechanical ventilation until recovery, which
may take days or weeks.
Adverse reactions to antivenom administration include imme-
diate (nonallergic and, less commonly, allergic anaphylaxis) and
delayed-type hypersensitivity reactions (serum sickness). Clinical
manifestations of immediate hypersensitivity include urticaria,
laryngeal edema, bronchospasm, and hypotension. Skin testing
for potential hypersensitivity, although recommended by some
antivenom manufacturers, is insensitive and nonspecific and should
be omitted. Worldwide, the quality of antivenoms is highly vari-
able. Rates of acute nonallergic anaphylactic reactions to some of
these products exceed 50%. For this reason, some authorities have
recommended pretreatment with IV antihistamines (e.g., diphen-
hydramine, 1 mg/kg to a maximum of 100 mg; and cimetidine, 5–10
mg/kg to a maximum of 300 mg) or even a prophylactic SC or IM
dose of epinephrine (0.01 mg/kg, up to 0.3 mg). Further research is
necessary, however, to determine whether any pretreatment mea-
sures are truly beneficial. Modest expansion of the patient’s intra-
vascular volume with crystalloids may blunt acute adverse blood
pressure decline. Epinephrine and airway equipment should always
be immediately available during antivenom infusion. An acute ana-
phylactic reaction may be heralded by a single hive or mild itching
or may present as bronchospasm or acute cardiovascular collapse.
If the patient develops an acute reaction to antivenom, the infu-
sion should be temporarily stopped and the reaction immediately
treated with IM epinephrine and IV antihistamines and glucocorti-
coids. Once the reaction has been controlled, if the severity of the
envenomation warrants additional antivenom, the dose should be
diluted further in isotonic saline and restarted as soon as possible.
Rarely, in cases of recalcitrant hypotension, a concomitant IV infu-
sion of epinephrine may be initiated and titrated to clinical effect
while antivenom is administered. The patient must be monitored
very closely during such therapy, preferably in an intensive care set-
ting. Serum sickness typically develops 1–2 weeks after antivenom
arthralgias, lymphadenopathy, and renal or neurologic dysfunction.
Treatment of serum sickness consists of systemic glucocorticoids
(e.g., oral prednisone, 1–2 mg/kg daily) until all symptoms have
resolved, followed by a taper over 1–2 weeks. Oral antihistamines
and analgesics may provide additional relief of symptoms.
Blood products are rarely necessary in the management of an
envenomed patient. The venoms of many snake species can deplete
coagulation factors and cause a decrease in platelet count or hema-
tocrit. Nevertheless, these components usually rebound within
hours after administration of adequate antivenom. If the need for
blood products is thought to be great (e.g., a dangerously low
platelet count in a hemorrhaging patient), these products should be
given only after adequate antivenom administration to avoid fuel-
ing ongoing consumptive coagulopathy.
Rhabdomyolysis and hemolysis should be managed in standard
fashion. Victims who develop acute renal failure should be evaluated
by a nephrologist and referred for hemodialysis or peritoneal dialysis
as needed. Such renal failure, which usually is due to acute tubular
necrosis, is frequently reversible. If bilateral cortical necrosis occurs,
however, the prognosis for renal recovery is less favorable, and long-
term dialysis with possible renal transplantation may be necessary.
Acetylcholinesterase inhibitors (e.g., edrophonium and neostig-
mine) may promote neurologic improvement in patients bitten by
snakes with postsynaptic neurotoxins. Snakebite victims with objec-
tive evidence of neurologic dysfunction should receive a test dose
of acetylcholinesterase inhibitors, as outlined in Table 474-2. If they
exhibit improvement, additional doses of long-acting neostigmine
can be administered as needed. Close monitoring is required to
prevent aspiration if repetitive dosing of neostigmine is used in an
  TABLE 474-2    Use of Acetylcholinesterase Inhibitors in Neurotoxic
Snake Envenomation
1.  Patients with clear, objective evidence of neurotoxicity (e.g., ptosis or
inability to maintain upward gaze) should receive a test dose of edropho-
nium (if available) or neostigmine.
a.  Pretreat with atropine: 0.6 mg IV (children, 0.02 mg/kg with a minimum
of 0.1 mg)
b.  Treat with:
Edrophonium: 10 mg IV (children, 0.25 mg/kg)
or
Neostigmine: 1.5–2.0 mg IM (children, 0.025–0.08 mg/kg)
2.  If objective improvement is evident after 5 min, treat with:
a.  Neostigmine: 0.5 mg IV or SC (children, 0.01 mg/kg) every 30 min as
needed
b.  Atropine: 0.6 mg IV continuous infusion over 8 h (children, 0.02 mg/kg
over 8 h)
3.  Closely monitor the airway and perform endotracheal intubation as
needed.

HPIM19_Part18_p2733-p2752.indd 2737 2/9/15 4:40 PM

 2738 attempt to obviate endotracheal intubation. Acetylcholinesterase
inhibitors are not a substitute for administration of an appropriate
antivenom when available.
Care of the bite wound includes simple cleansing with soap and
water; application of a dry, sterile dressing; and splinting of the
affected extremity with padding between the digits. Once antive-
nom therapy has been initiated, the extremity should be elevated
above heart level to reduce swelling. Tetanus immunization should
be updated as appropriate. Prophylactic antibiotics are generally
unnecessary after bites by North American snakes, as the incidence
of secondary infection is low. In some regions, secondary bacterial
infection is more common and the consequences are dire; in these
regions, prophylactic antibiotics (e.g., cephalosporins) are used
PART 18
commonly. Antibiotics may also be considered if misguided first aid
efforts have included incision or mouth suction of the bite site. Pain
control should be achieved with acetaminophen or narcotic analge-
sics. Salicylates and nonsteroidal anti-inflammatory agents should
be avoided because of their effects on blood clotting.
Most snake envenomations involve SC deposition of venom. On
Poisoning, Drug Overdose, and Envenomation
occasion, however, venom can be injected more deeply into muscle
compartments, particularly if the offending snake was large and
the bite occurred on the lower leg, forearm, or hand. Intramuscular
swelling of the affected extremity may be accompanied by severe
pain, decreased strength, altered sensation, cyanosis, and apparent
pulselessness—signs suggesting a muscle compartment syndrome.
If there is clinical concern that subfascial muscle edema may be
impeding tissue perfusion, intracompartmental pressures should
be measured by a minimally invasive technique (e.g., wick catheter
or digital readout device). If the intracompartmental pressure is
high (>30–40 mmHg), the extremity should be kept elevated while
antivenom is administered. A dose of IV mannitol (1 g/kg) can be
given in an effort to reduce muscle edema if the patient is hemo-
dynamically stable. If the intracompartmental pressure remains
elevated after 1 h of such therapy, a surgical consultation should be
obtained for possible fasciotomy. Although evidence from animal
studies suggests that fasciotomy may actually worsen myonecrosis,
compartmental decompression is still necessary to preserve nerve
function. Fortunately, the incidence of compartment syndrome is
very low after a snakebite, with fasciotomies required in <1% of
cases. Nevertheless, vigilance is essential. If a fasciotomy is deemed
necessary, it should be undertaken with the patient’s informed con-
sent whenever possible.
Wound care in the days after the bite should include careful asep-
tic debridement of clearly necrotic tissue once coagulation has been
restored. Intact serum-filled vesicles or hemorrhagic blebs should be
left undisturbed. If ruptured, they should be debrided with sterile
technique. Any debridement of damaged muscle should be conser-
vative because there is evidence that such muscle may recover to a
significant degree after antivenom therapy.
Physical therapy should be started as soon as possible so that the
victim can return to a functional state. The incidence of long-term
loss of function (e.g., reduced range of motion, impaired sensory
function) is unclear but is probably quite high (>30%), particularly
after viperid bites.
Any patient with signs of envenomation should be observed in
the hospital for at least 24 h. In North America, a patient with an
apparently “dry” viperid bite should be watched for at least 8 h
before discharge, as significant toxicity occasionally develops after
a delay of several hours. The onset of systemic symptoms com-
monly is delayed for a number of hours after bites by several of the
elapids (including coral snakes, Micrurus species), some non–North
American viperids (e.g., the hump-nosed pit viper [Hypnale hyp-
nale]), and sea snakes. Patients bitten by these snakes should be
observed in the hospital for at least 24 h. Patients whose condition
is not stable should be admitted to an intensive care setting.
At hospital discharge, victims of venomous snakebites should be
warned about symptoms and signs of wound infection, antivenom-
related serum sickness, and potential long-term sequelae, such as pitu-
itary insufficiency from Russell’s viper (D. russelii) bites. If coagulopathy
HPIM19_Part18_p2733-p2752.indd 2738
developed in the acute stages of envenomation, it can recur during
the first 2–3 weeks after the bite. In such cases, victims should be
warned to avoid elective surgery or activities posing a high risk of
trauma during this period. Outpatient analgesic treatment, wound
management, and physical therapy should be provided.
MORBIDITY AND MORTALITY
The overall mortality rates for victims of venomous snakebites are low
in regions with rapid access to medical care and appropriate antiven-
oms. In the United States, for example, the mortality rate is <1% for
victims who receive antivenom. Eastern and western diamondback
rattlesnakes (Crotalus adamanteus and Crotalus atrox, respectively) are
responsible for the majority of snakebite deaths in the United States.
Snakes responsible for large numbers of deaths in other countries
include cobras (Naja spp.), carpet and saw-scaled vipers (Echis spp.),
Russell’s vipers (D. russelii), large African vipers (Bitis spp.), lancehead
pit vipers (Bothrops spp.), and tropical rattlesnakes (C. durissus).
The incidence of morbidity—defined as permanent functional
loss in a bitten extremity—is difficult to estimate but is substantial.
Morbidity may be due to muscle, nerve, or vascular injury or to scar
contracture. Such morbidity can have devastating consequences for
victims in the developing world when they lose the ability to work and
provide for their families. In the United States, functional loss tends to
be more common and severe after rattlesnake bites than after bites by
copperheads (Agkistrodon contortrix) or water moccasins (Agkistrodon
piscivorus).
GLOBAL CONSIDERATIONS
In many developing countries where snakebites are common,
scarce access to medical care and antivenom resources con-
tributes to high rates of morbidity and mortality. In many
countries, the available antivenoms are inappropriate and ineffective
against the venoms of medically important indigenous snakes. In those
regions, further research is necessary to determine the actual impact of
venomous snakebites and the specific antivenom needs in terms of
both quantity and spectrum of coverage. Without accurate statistics, it
is difficult to persuade antivenom manufacturers to begin and sustain
production of appropriate antisera in developing nations. There is
evidence that antivenoms can be produced in much more cost-effec-
tive ways than those currently being used. Just as important as getting
the correct antivenoms into underserved regions is the need to educate
populations about snakebite prevention and to train medical care pro-
viders in proper management approaches. Local protocols written with
significant input from experienced providers in the region of concern
should be developed and distributed. Appropriate antivenoms must be
available at the likely first point of medical contact for patients (e.g.,
primary health centers) in order to minimize the common practice of
referring victims to more distant, higher levels of care for the initiation
of antivenom therapy. Those who care for snakebite victims in these
often-remote clinics must have the skills and confidence required to
begin antivenom treatment (and to treat possible reactions) as soon as
possible when needed.
MARINE ENVENOMATIONS
Much of the management of envenomation by marine creatures is
supportive in nature. A specific marine antivenom can be used when
appropriate.
INVERTEBRATES
Cnidarians  The Golgi apparatus of the cnidoblast cells within cnidar-
ians, such as hydroids, fire coral, jellyfish, Portuguese men-of-war,
and sea anemones, secretes specialized living stinging organelles called
cnidae (also referred to as cnidocysts, a term that encompasses nema-
tocysts, ptychocysts, and spirocysts). Within each organelle resides
a stinging mechanism (“thread tube”) and venom. In the stinging
process, cnidocysts are released and discharged upon mechanosen-
sory stimulation. The venoms from these organisms contain bioac-
tive substances such as tetramine, 5-hydroxytryptamine, histamine,
2/9/15 4:40 PM
 serotonin, and high-molecular-weight toxins, all of which can, among
other effects, change the permeability of cells to ions. Victims usu-
ally report immediate prickling or burning, pruritus, paresthesias,
and painful throbbing with radiation. The skin becomes reddened,
darkened, edematous, and blistered and may show signs of super-
ficial necrosis. A legion of neurologic, cardiovascular, respiratory,
rheumatologic, gastrointestinal, renal, and ocular symptoms has been
described, especially following stings from anemones, Physalia species,
and scyphozoans. Anaphylaxis is possible. Hundreds of deaths have
been reported, many of them caused by Chironex fleckeri, Stomolophus
nomurai, Physalia physalis, and Chiropsalmus quadrumanus. Irukandji
syndrome, associated with the Australian jellyfish Carukia barnesi and
successfully against a number of marine stingers, and may prevent or 2739
diminish the effects of coelenterate stings. Whenever possible, a dive
skin or wet suit should be worn when entering ocean waters.
Sea Sponges  Many sponges produce crinotoxins that are present on
their surface or in their internal secretions. As a result, touching a sea
sponge may result in dermatitis or “sponge diver’s disease,” a necrotic
skin reaction. Irritant dermatitis may result if small spicules of silica
or calcium carbonate penetrate the skin. It is impossible to distinguish
between the allergic and spicule reactions, so the treatment is the same
for both. Afflicted skin should be gently dried and adhesive tape used

other species, is a potentially fatal condition that most commonly is
characterized by hypertension; severe back, chest, and abdominal pain;
nausea and vomiting; headache; sweating; and, in the most serious
cases, myocardial troponin leak, pulmonary edema, and ultimately
hypotension. This syndrome is thought to be mediated, at least in part,
by the release of endogenous catecholamines followed by cytokines
and nitric oxide.
CHAPTER 474
to remove embedded spicules. Vinegar should be applied immediately
and then for 10–30 min three or four times a day. Rubbing alcohol may
be used if vinegar is unavailable. After spicule removal and skin decon-
tamination, glucocorticoid or antihistamine cream may be applied to
the skin. Severe vesiculation should be treated with a 2-week tapering
course of systemic glucocorticoids. Mild reactions subside in 3–7 days,
while involvement of large areas of the skin may result in systemic
symptoms of fever, dizziness, nausea, muscle cramps, and formication.

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

Rescuers should note that envenomations by different cnidar-
ians (typified by jellyfish) may respond differently to similar topical Annelid Worms  Annelid worms (bristleworms) possess rows of soft,
therapies; thus, the recommendations in this chapter must be tailored cactus-like spines capable of inflicting painful stings. Contact results
to local species and clinical practices. During stabilization, the skin in symptoms similar to those of nematocyst envenomation. Without
should be decontaminated immediately with a generous application treatment, pain usually subsides over several hours, but inflammation
of lidocaine (up to 4%), an all-purpose agent that appears to be use- may persist for up to a week (Fig. 474-4). Victims should resist the
ful for relieving pain caused by a large number of species. Vinegar urge to scratch because scratching may fracture retrievable spines.
(5% acetic acid), rubbing alcohol (40–70% isopropyl alcohol), baking Visible bristles should be removed with forceps and adhesive tape or
soda (sodium bicarbonate, especially for sea nettle stings), papain a commercial facial peel; alternatively, a thin layer of rubber cement
(unseasoned meat tenderizer), fresh lemon or lime juice, olive oil, or can be used to entrap and then peel away the spines. Use of vinegar or
sugar may be effective, depending on the species of stinging creature. rubbing alcohol or a brief application of lidocaine or unseasoned meat
Household ammonia may in and of itself cause skin irritation. tenderizer (papain) may provide additional relief. Local inflammation
The pressure-immobilization technique is no longer recommended should be treated with topical or systemic glucocorticoids.
for venom containment in the setting of any jellyfish sting. For the
Sea Urchins  Venomous sea urchins possess either hollow, venom-
sting of the venomous box jellyfish (C. fleckeri), vinegar should be
filled calcified spines or triple-jawed, globiferous pedicellariae with
used. Local application of heat (up to 45°C/113°F), commonly by
venom glands. Venom may also be found within the integumentary
immersion in hot water, may be as effective. A baking soda slurry
sheath on the external spine surface of certain species. The venom
(50% baking soda, 50% water) has been recommended for Cyanea and
contains toxic components, including steroid glycosides, hemolysins,
Chrysaora species. Commercial (chemical) cold packs or real ice packs
proteases, serotonin, and cholinergic substances. Contact with either
applied over a thin dry cloth or a plastic membrane have been shown
venom apparatus produces immediate and intensely painful stings.
to be effective in alleviating mild or moderate Physalia utriculus (blue-
One or more spines entering a joint can cause synovitis that may, over
bottle jellyfish) stings but may be less effective than application of heat.
time, progress to arthritis if the spine(s) remain in or near the joint. If
Perfume, aftershave lotion, and high-proof ethanol are not efficacious
multiple spines penetrate the skin, the patient may develop systemic
and may be detrimental; formalin, ether, gasoline, and other organic
symptoms, including nausea, vomiting, numbness, muscular paralysis,
solvents should not be used. Shaving the skin helps remove remaining
and respiratory distress. A delayed hypersensitivity reaction 7–10 days
nematocysts. Freshwater irrigation and rubbing lead to further sting-
after resolution of primary symptoms has been described.
ing by adherent nematocysts and should be avoided.
The affected part should be immersed immediately in hot water
After decontamination, topical application of an anesthetic oint-
to tolerance (up to 45°C/113°F). Pedicellariae should be removed by
ment (lidocaine, benzocaine), an antihistamine (diphenhydramine),
shaving so that envenomation cannot continue. Accessible embedded
or a glucocorticoid (hydrocortisone) may be helpful. Persistent severe
spines should be removed but may break off and remain lodged in
pain after decontamination may be treated with morphine, meperidine,
fentanyl, or another narcotic analgesic. Muscle spasms may respond
to diazepam (2–5 mg, titrated upward as necessary) or 10% calcium
gluconate (5–10 mL) given IV. An ovine-derived IgG antivenom is
available from Commonwealth Serum Laboratories (see “Sources of
Antivenoms and Other Assistance,” below) for stings from the box jel-
lyfish found in Australian and Indo-Pacific waters. However, despite
its reported clinical efficacy, one school of thought holds that perhaps
the antivenom is unable to bind the venom rapidly enough to account
for its effects. Until further notice, current recommendations for its
use apply. Treatment for Irukandji syndrome may require administra-
tion of opioid analgesics and MgSO4 as well as aggressive treatment
(phentolamine, 5 mg IV) of hypertension. All victims with systemic
reactions should be observed for at least 6–8 h for rebound from any
therapy, and all elderly adults should be checked for cardiac arrhyth-
mias. Patients may suffer postinflammatory hyperpigmentation and
persistent cutaneous hypersensitivity in areas of skin contact.
Safe Sea, a “jellyfish-safe” sunblock (www.nidaria.com) applied to
the skin before an individual enters the water, inactivates the recog- Figure 474-4  Rash on the hand of a diver from the spines of a
nition and discharge mechanisms of nematocysts, has been tested bristleworm. (Courtesy of Paul Auerbach, with permission.)

HPIM19_Part18_p2733-p2752.indd 2739 2/9/15 4:40 PM

 2740 the victim. Residual dye from the surface of a spine remaining after
the spine’s removal may mimic a retained spine but is otherwise of no
consequence. Soft tissue radiography or MRI can confirm the presence
of retained spines, which may warrant referral for attempted surgical
removal if the spines are near vital structures (e.g., joints, neurovascu-
lar bundles). Retained spines may cause the formation of granulomas
that are amenable to excision or to intralesional injection with triam-
cinolone hexacetonide (5 mg/mL). Chronic granulomatous arthritis of
the proximal interphalangeal joints has been treated with synovectomy
and removal of granulation tissue. Erbium-YAG laser ablation has
been deployed to destroy multiple sea urchin spines embedded in the
foot and identified visually at the surface level without causing thermal
necrosis of the adjacent tissues. Eosinophilic pneumonia and local and
PART 18
diffuse neuropathies have been observed separately after penetration
by multiple spines of the black sea urchin (presumed Diadema species).
The pathophysiologies of these phenomena have not been determined.
Starfish  The crown-of-thorns Acanthaster planci produces venom
in glandular tissue underneath the epidermis, which is released via its
spiny surfaces (Fig. 474-5). Skin puncture causes pain, bleeding, and
Poisoning, Drug Overdose, and Envenomation
local edema, usually with remission over 30–180 min. Multiple punc-
tures may result in reactions such as local muscle paralysis; retained
fragments may cause granulomatous lesions and synovitis. There has
also been a case report of elevated liver enzymes after A. planci enven-
omation. Envenomed persons benefit from acute immersion therapy
in hot water, local anesthesia, wound cleansing, and possible explora-
tion to remove foreign material.
Sea Cucumbers  Sea cucumbers produce holothurin (a cantharin-like
liquid toxin) in their body walls. This toxin is concentrated in the
tentacular organs that are projected when the animal is threatened.
Underwater, holothurin induces minimal contact dermatitis in the
skin but can cause significant corneal and conjunctival irritation. A
severe reaction can lead to blindness. Skin should be detoxified with
5% acetic acid (vinegar), papain, or isopropyl alcohol. The eye should
be anesthetized with one or two drops of 0.5% proparacaine and irri-
gated with 100–250 mL of normal saline, with subsequent slit-lamp
examination to identify corneal defects.
Cone Snails  Cone snails use a detachable dartlike tooth to inject cono-
toxins into prey, inducing tetanus followed by paralysis. In an unknow-
ing handler, stings result in small, burning punctate wounds followed
by local ischemia, cyanosis, and numbness. Dysphagia, syncope, dysar-
thria, ptosis, blurred vision, and pruritus have also been documented.
Some envenomations induce paralysis leading to respiratory failure,
coma, and death. There is no antivenom. Pressure-immobilization
(see “Octopuses,” below), hot-water soaks, and local anesthetics have
been used empirically with success. The wound should be inspected for
a foreign body. Edrophonium has been recommended as therapy for
paralysis if a Tensilon test is positive.
Octopuses  Serious envenomations and deaths have followed bites of
Australian blue-ringed octopuses (Octopus maculosus and Octopus
Figure 474-5  Spines on the crown-of-thorns sea star (Acanthaster
planci). (Courtesy of Paul Auerbach, with permission.)
HPIM19_Part18_p2733-p2752.indd 2740
lunulata). Although these animals rarely exceed 20 cm in length,
their salivary venom contains a potent neurotoxin (maculotoxin) that
inhibits peripheral nerve transmission by blocking sodium conduc-
tance. Oral numbness and facial numbness develop within several
minutes of a serious envenomation and rapidly progress to total flaccid
paralysis, including failure of respiratory muscles. Immediately after
envenomation, a circumferential pressure-immobilization dressing
15 cm wide should be applied over a gauze pad (~7 × 7 × 2 cm) that
has been placed directly over the sting. The dressing should be applied
at venous-lymphatic pressure, with the preservation of distal arterial
pulses. The limb should then be splinted. Once the victim has been
transported to the nearest medical facility, the bandage can be released.
Because there is no antidote and passive immunotherapy (rabbit IgG
antibody) has been proven effective only against tetrodotoxin in mice,
treatment is supportive. Patients with respiratory failure may need
to be mechanically ventilated. If respirations are assisted, the victim
may remain awake although completely paralyzed. Even with serious
envenomations, significant recovery often takes place within 4–10
h, although complete recovery may require 2–4 days. Sequelae are
uncommon unless related to hypoxia.
VERTEBRATES
As for all penetrating injuries, first-aid care should be undertaken. In
addition, consideration must be given to local wound infection by marine
Vibrio species and freshwater Aeromonas hydrophila as well as other
“aquatic bacteria,” particularly if spines and needles remain embedded.
Stingrays  A stingray injury is both an envenomation and a traumatic
wound. Thoracic and cardiac penetration, major vessel laceration, and
compartment syndrome have all been observed. The venom, which
contains serotonin, 5′-nucleotidase, and phosphodiesterase, causes
immediate, intense pain that may last up to 48 h. The wound is very
painful (with the pain peaking at 30–60 min and lasting up to 48 h),
often becomes ischemic in appearance, and heals poorly, with adjacent
soft tissue swelling and prolonged disability. Systemic effects include
weakness, diaphoresis, nausea, vomiting, diarrhea, dysrhythmias,
syncope, hypotension, muscle cramps, fasciculations, paralysis, and
(in rare cases) death. Because of differences in the toxins present on
the tissues covering the stingers, freshwater stingrays may cause more
severe injuries than marine stingrays.
Scorpionfish  The designation scorpionfish encompasses members of
the family Scorpaenidae and includes not only scorpionfish but also
lionfish and stonefish. A complex venom with neuromuscular toxic-
ity is delivered through 12 or 13 dorsal, 2 pelvic, and 3 anal spines.
In general, the sting of a stonefish is regarded as the most serious
(severe to life-threatening); that of the scorpionfish is of intermediate
seriousness; and that of the lionfish is the least serious. Like that of a
stingray, the sting of a scorpionfish is immediately and intensely pain-
ful. Pain from a stonefish envenomation may last for days. Systemic
manifestations of scorpionfish stings are similar to those of stingray
envenomations but may be more pronounced, particularly in the case
of a stonefish sting, which may cause severe local tissue necrosis in
addition to vital organ failure. The rare deaths that follow stonefish
envenomation usually occur within 6–8 h. There is a commercially
available stonefish antivenom.
Other Fish  Three species of marine catfish—Plotosus lineatus (oriental
catfish), Bagre marinus (sail catfish), and Galeichthys felis (common
sea catfish)—as well as several species of freshwater catfish are capable
of stinging humans. Venom is delivered through a single dorsal spine
and two pectoral spines. Clinically, a catfish sting is comparable to that
of a stingray, although marine catfish envenomations are generally
more severe than those of their freshwater counterparts. Surgeonfish
(doctorfish, tang), weeverfish, ratfish, and horned venomous sharks
have also envenomed humans.
Platypus  The platypus is a venomous mammal. The male has a kera-
tinous spur on each hind limb; the spur is connected to a venom gland
within the upper thigh. Skin puncture causes soft tissue edema and
2/9/15 4:40 PM
 pain that may last for days or weeks. Care is supportive, and hot-water 2741
therapy does not appear to benefit the victim.

TREATMENT  Marine Vertebrate Stings

The stings of all marine vertebrates are treated in a similar fashion.
Except for stonefish and serious scorpionfish envenomations (see
below), no antivenom is available. The affected part should be
immersed immediately in nonscalding hot water (45°C/113°F) for
30–90 min or until there is significant relief from pain. Recurrent

CHAPTER 474
pain may respond to repeated hot-water treatment. Cryotherapy
is contraindicated, and no data support the use of antihistamines
or steroids. Opiates will help alleviate the pain, as will local wound
infiltration or regional nerve block with 1% lidocaine, 0.5% bupiva-
caine, and sodium bicarbonate mixed in a 5:5:1 ratio. After soaking
and anesthetic administration, the wound must be explored and
debrided. Radiography (in particular, MRI) may be helpful in iden-
tification of foreign bodies. After exploration and debridement,

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

the wound should be irrigated vigorously with warm sterile water,
saline, or 1% povidone-iodine in solution. Bleeding usually can be
controlled by sustained local pressure for 10–15 min. In general,
wounds should be left open to heal by secondary intention or
treated by delayed primary closure. Tetanus immunization should
be updated. Antibiotic treatment should be considered for serious
wounds and for envenomation in immunocompromised hosts. The
initial antibiotics should cover Staphylococcus and Streptococcus
species. If the victim is immunocompromised, if a wound is primar-
ily repaired and is more than minor, or if an infection develops,
antibiotic coverage should be broadened to include Vibrio species.
Infection with Aeromonas species is of similar concern for wounds
associated with natural freshwater.

APPROACH TO THE PATIENT:

Marine Envenomations
Figure 474-6  Spiny sea urchins. (Courtesy of Dr. Paul Auerbach, with
It is useful to be familiar with the local marine fauna and to recog- permission.)
nize patterns of injury.
A large puncture wound or jagged laceration (particularly on the
Divers Alert Network, a nonprofit organization designed to assist
lower extremity) that is more painful than one would expect from the
in the care of injured divers, also may help with the treatment of
size and configuration of the wound is likely to be a stingray enven-
marine injuries. The network can be reached on the Internet at www
omation. Smaller punctures, as described above, represent the activ-
.diversalertnetwork.org or by telephone 24 h a day at (919) 684-9111.
ity of a sea urchin (Fig. 474-6) or starfish. Stony corals cause rough
An antivenom for the box jellyfish (C. fleckeri) and another for stonefish
abrasions and, in rare instances, lacerations or puncture wounds.
Coelenterate (marine invertebrate) stings sometimes create
diagnostic skin patterns. A diffuse urticarial rash on exposed skin
is often indicative of exposure to fragmented hydroids or larval
anemones. A linear, whiplike print pattern appears where a jelly-
fish tentacle has contacted the skin. In the case of the dreaded box
jellyfish, a cross-hatched appearance, followed by development of
dark purple coloration within a few hours of the sting, heralds skin
necrosis. A frosted appearance may be created by aluminum salt–
based remedies applied to the wound. An encounter with fire coral
causes immediate pain and swollen red skin irritation in the pattern
of contact, similar to but more severe than the imprint left by expo-
sure to an intact feather hydroid. Seabather’s eruption, caused by
thimble jellyfishes and larval anemones, may produce a diffuse rash
that consists of clusters of erythematous macules or raised papules
and is accompanied by intense itching (Fig. 474-7). Toxic sponges
create a burning and painful red rash on exposed skin, which may
blister and later desquamate. Because virtually all marine stingers
invoke the sequelae of inflammation, local erythema, swelling, and
adenopathy are fairly nonspecific.

SOURCES OF ANTIVENOMS AND OTHER ASSISTANCE

The best way to locate a specific antivenom in the United States Figure 474-7  Erythematous, papular rash typical of seabather’s
is to call a regional poison control center and ask for assistance. eruption caused by thimble jellyfish and larval anemones.

HPIM19_Part18_p2733-p2752.indd 2741 2/9/15 4:40 PM

 2742 (and severe scorpionfish) envenomation are made in Australia by the
Commonwealth Serum Laboratories (CSL; 45 Poplar Road, Parkville,
Victoria, Australia 3052; www.csl.com.au; 61-3-9389-1911). When
administering the box jellyfish antivenom, time is of the essence.
For cardiac or respiratory decompensation, give a minimum of one
ampoule and up to six ampoules consecutively IV, preferably in a 1:10
dilution with normal saline. For stonefish (or severe scorpionfish)
envenomation, give one ampoule of specific antivenom IM for every
one or two punctures, to a maximum of three ampoules.
MARINE POISONINGS
CIGUATERA
PART 18
Epidemiology and Pathogenesis  Ciguatera poisoning is the most com-
mon nonbacterial food poisoning associated with fish in the United
States; most U.S. cases occur in Florida and Hawaii, although, with
transportation of imported fish nationwide, all clinicians need to be
aware of ciguatera. The poisoning almost exclusively involves tropical
and semitropical marine coral reef fish common in the Indian Ocean,
the South Pacific, and the Caribbean Sea. Global estimates predict
Poisoning, Drug Overdose, and Envenomation
that 20,000–50,000 people may be affected by this poisoning each
year. More than 400 different fish have been associated with ciguatera
toxicity, but 75% of poisonings involve the reef-dwelling barracuda,
snapper, jack, or grouper. Ciguatera toxin is created by warm-water
ocean reef microalgae of the genus Gambierdiscus toxicus, whose con-
sumption by grazing fish allows the toxin to bioaccumulate in the food
chain. Three major ciguatoxins are found in the flesh and viscera of
ciguateric fish: CTX-1, -2, and -3. Recent research suggests that CTX-1
activates astrocytes and astroglia. In addition, TRPV1, a nonselective
cation channel expressed in nociceptive neurons, may play a role in
the neurologic disturbances unique to ciguatera poisoning. Most, if not
all, ciguatoxins are unaffected by freeze-drying, heat, cold, and gastric
acid. None of the toxins affects the odor, color, or taste of fish. Cooking
methods may alter the relative concentrations of the various toxins.
Clinical Manifestations  The onset of symptoms may come within 15–30
min of ingestion and typically takes place within 2–6 h. Symptoms
increase in severity over the ensuing 4–6 h. Most victims develop
symptoms within 12 h of ingestion, and virtually all are afflicted
within 24 h. The more than 150 signs and symptoms reported include
those shown in Table 474-3. Diarrhea, vomiting, and abdominal pain
usually develop 3–6 h after ingestion of a ciguatoxic fish. Symptoms
may persist for 48 h and then generally resolve (even without treat-
ment). A pathognomonic symptom is the reversal of hot and cold
tactile perception, which develops in some persons after 3–5 days and
may last for months. More severe reactions tend to occur in persons
previously stricken with the disease. Persons who have ingested par-
rotfish (scaritoxin) may develop classic ciguatera poisoning as well as
a “second-phase” syndrome (after 5–10 days’ delay) of disequilibrium
  TABLE 474-3    Representative Signs and Symptoms of Ciguatera
Poisoning
System Signs/Symptoms
Gastrointestinal Abdominal pain, nausea, vomiting, diarrhea
Neurologic Paresthesias, pruritus, tongue and throat numbness or
burning, sensation of  “carbonation” during swallowing,
odontalgia or dental dysesthesias, dysphagia, tremor, fas-
ciculations, athetosis, meningismus, aphonia, ataxia, ver-
tigo, pain and weakness in the lower extremities, visual
blurring, transient blindness, hyporeflexia, seizures, coma
Dermatologic Conjunctivitis, maculopapular rash, skin vesiculations,
dermatographism
Cardiovascular Bradycardia, heart block, hypotension, central respiratory
failurea
Other Chills, dysuria, dyspnea, dyspareunia, weakness, fatigue,
nasal congestion and dryness, insomnia, sialorrhea, dia-
phoresis, headache, arthralgias, myalgias
a
Tachycardia and hypertension may occur after potentially severe transient bradycardia
and hypotension. Death is rare.
HPIM19_Part18_p2733-p2752.indd 2742
with locomotor ataxia, dysmetria, and resting or kinetic tremor. This
syndrome may persist for 2–6 weeks.
Diagnosis  The differential diagnosis of ciguatera includes paralytic
shellfish poisoning, eosinophilic meningitis, type E botulism, organo-
phosphate insecticide poisoning, tetrodotoxin poisoning, and psycho-
genic hyperventilation. At present, the diagnosis of ciguatera poisoning
is made on clinical grounds because no routinely used laboratory test
detects ciguatoxin in human blood. Liquid chromatography–mass
spectrometry is available for ciguatoxins but is of limited clinical
value because most health care institutions do not have the equipment
needed to perform the test. A ciguatoxin enzyme immunoassay or
radioimmunoassay may be used to test small portions of the suspected
fish, but even these tests may not detect the very small amount of toxin
(0.1 ppb) necessary to render fish flesh toxic. A newer neuroblastoma
assay may be sufficiently sensitive to detect small amounts of toxin but
is not readily available for clinical use.
TREATMENT Ciguatera Poisoning
Therapy is supportive and based on symptoms. Nausea and vom-
iting may be controlled with an antiemetic such as ondansetron
(4–8 mg IV). Syrup of ipecac and activated charcoal are not recom-
mended for ciguatera poisoning. Hypotension may require the
administration of IV crystalloid and, in rare cases, a pressor drug.
Bradyarrhythmias that lead to cardiac insufficiency and hypoten-
sion generally respond well to atropine (0.5 mg IV, up to 2 mg).
Goal-directed combination cardiovascular fluid and pressor therapy
may be required. Cool showers or the administration of hydroxyzine
(25 mg PO every 6–8 h) may relieve pruritus. Amitriptyline (25 mg
PO twice a day) reportedly alleviates pruritus and dysesthesias. In
three cases unresponsive to amitriptyline, tocainide has appeared
to be efficacious. Nifedipine has been used to treat headache and
poor circulation in order to prevent hypotension, but only after
the initial acute phase of the poisoning has passed. IV infusion of
mannitol may be beneficial in moderate or severe cases in fluid-
repleted patients, particularly for the relief of distressing neurologic
or cardiovascular symptoms, although the efficacy of this therapy
has been challenged and has not been definitively proved. The infu-
sion is rendered initially as 1 g/kg per day over 45–60 min during
the acute phase (days 1–5). If symptoms improve, a second dose
may be given within 3–4 h and a third dose may be administered
the next day. Care must be taken to avoid dehydration in a treated
patient. The mechanism of the benefit against ciguatera intoxica-
tion is perhaps hyperosmotic water-drawing action, which reverses
ciguatoxin-induced Schwann cell edema. Mannitol may also act in
some fashion as a “hydroxyl scavenger” or may competitively inhibit
ciguatoxin at the cell membrane.
During recovery from ciguatera poisoning, the victim should
exclude the following from the diet for 6 months: fish (fresh or pre-
served), fish sauces, shellfish, shellfish sauces, alcoholic beverages,
nuts, and nut oils. Consumption of fish in ciguatera-endemic regions
should be avoided. All oversized fish of any predacious reef species
should be suspected of harboring ciguatoxin. Neither moray eels
nor the viscera of tropical marine fish should ever be eaten.
DIARRHETIC SHELLFISH POISONING
Diarrhetic shellfish poisoning occurs with consumption of shell-
fish producing diarrheal illness. The first suspected incident, which
occurred in the Netherlands in 1961, was followed by outbreaks in
Japan, the United Kingdom, and (most recently) China. The causative
agents are the lipophilic compound okadaic acid and the dinophysis-
toxins, which inhibit serine and threonine protein phosphatases, with
consequent protein accumulation and continued secretion of fluid in
intestinal cells leading to diarrhea. Shellfish acquire these toxins by
feeding on dinoflagellates, particularly of the genera Dinophysis and
Prorocentrum.
Symptoms include diarrhea, nausea, vomiting, abdominal pain, and
chills. Onset occurs within 30 min to 12 h. The illness is usually
2/9/15 4:40 PM
 self-limited; most patients recover in 3 or 4 days, and only a few
require hospitalization. Treatment is supportive and focused on hydra-
tion. Toxins can be detected in food samples by a mouse bioassay, an
immunoassay, and high-performance liquid chromatography with
fluorometric detection (HPLC-FLD).
PARALYTIC SHELLFISH POISONING
Paralytic shellfish poisoning is induced by ingestion of any of a variety
of feral or aquacultured filter-feeding organisms, including clams,
oysters, scallops, mussels, chitons, limpets, starfish, and sand crabs.
The origin of their toxicity is the chemical toxin they accumulate and
concentrate by feeding on various planktonic dinoflagellates (e.g.,
Protogonyaulax, Ptychodiscus, and Gymnodinium) and protozoan
organisms. The unicellular phytoplanktonic organisms form the foun-
dation of the food chain, and in warm summer months these organisms
“bloom” in nutrient-rich coastal temperate and semitropical waters. In
the United States, paralytic shellfish poisoning is acquired primarily
from seafood harvested in the Northeast, the Pacific Northwest, and
Alaska. These planktonic species can release massive amounts of toxic
metabolites into the water and cause mortality in bird and marine
populations. The paralytic shellfish toxins are water soluble as well as
heat and acid stable; they cannot be destroyed by ordinary cooking
or freezing. Contaminated seafood looks, smells, and tastes normal.
The best-characterized, most potent, and most frequently identified
paralytic shellfish toxin is saxitoxin, which takes its name from the
Alaska butter clam Saxidomus giganteus. Saxitoxin appears to block
sodium conductance, inhibiting neuromuscular transmission at the
axonal and muscle membrane levels. A toxin concentration of >75
µg/100 g of foodstuff is considered hazardous to humans. In the 1972
New England “red tide,” the concentration of saxitoxin in blue mussels
exceeded 9000 µg/100 g of foodstuff.
The onset of intraoral and perioral paresthesias (notably of the lips,
tongue, and gums) comes within minutes to a few hours after ingestion
of contaminated shellfish, and these paresthesias progress rapidly to
involve the neck and distal extremities. The tingling or burning sensa-
tion later changes to numbness. Other symptoms rapidly develop and
include light-headedness, disequilibrium, incoordination, weakness,
hyperreflexia, incoherence, dysarthria, sialorrhea, dysphagia, thirst,
diarrhea, abdominal pain, nausea, vomiting, nystagmus, dysmetria,
headache, diaphoresis, loss of vision, chest pain, and tachycardia.
Flaccid paralysis and respiratory insufficiency may follow 2–12 h after
ingestion. In the absence of hypoxia, the victim often remains alert but
paralyzed. Up to 12% of patients die.
TREATMENT Paralytic Shellfish Poisoning
Treatment is supportive and based on symptoms. If the victim
comes to medical attention within the first few hours after poison
ingestion, the stomach should be emptied by gastric lavage and
then irrigated with 2 L (in 200-mL aliquots) of a solution of 2%
sodium bicarbonate; this intervention has not been proved to be of
benefit but is based on the notion that gastric acidity may enhance
the potency of saxitoxin. Because breathing difficulty can be rapid
in onset, induction of emesis is not advised. The administration of
activated charcoal (50–100 g) and a cathartic (sorbitol, 20–50 g)
makes empirical sense because these shellfish toxins are believed to
bind well to charcoal. Some authors advise against administration
of magnesium-based solutions (e.g., certain cathartics), cautioning
that hypermagnesemia may contribute to suppression of nerve
conduction.
The most serious problem is respiratory paralysis. The victim
should be closely observed for respiratory distress for at least 24 h
in a hospital. With prompt recognition of ventilatory failure, endo-
tracheal intubation, and assisted ventilation, anoxic myocardial and
brain injury may be prevented. If the patient survives for 18 h, the
prognosis is good for a complete recovery.
A direct human serum assay to identify the toxin responsible for
paralytic shellfish poisoning is not yet clinically available; the mouse
bioassay in widespread use may be replaced by an automated
HPIM19_Part18_p2733-p2752.indd 2743
tissue-culture bioassay. A polyclonal enzyme-linked immunosor- 2743
bent assay (ELISA) to measure specific toxins is under development,
as is HPLC-FLD. In addition, an inhibition immunoassay that may be
able to simultaneously detect paralytic shellfish, diarrhetic shellfish,
and amnesic shellfish toxins is being investigated.
DOMOIC ACID INTOXICATION (AMNESTIC SHELLFISH POISONING)
In late 1987 in eastern Canada, an outbreak of gastrointestinal and
neurologic symptoms (amnestic shellfish poisoning) was documented
in persons who had consumed mussels found to be contaminated with
domoic acid. In this outbreak, the source of the toxin was Nitzschia
CHAPTER 474
pungens, a diatom ingested by the mussels. Since the Canadian out-
break, the toxin has been found in shellfish from the United States, the
United Kingdom, and Spain. In 1991, an epidemic of domoic acid poi-
soning in the state of Washington was attributed to the consumption
of razor clams. A water-soluble, heat-stable neuroexcitatory amino
acid with biochemical analogues of kainic acid and glutamic acid,
domoic acid binds to the kainate type of glutamate receptor with three
Disorders Caused by Venomous Snakebites and Marine Animal Exposures
times the affinity of kainic acid and is 20 times as powerful a toxin.
Shellfish can be tested for domoic acid by mouse bioassay and HPLC.
The regulatory limit for domoic acid in shellfish is 20 parts per million.
The abnormalities noted within 24 h of ingesting contaminated
mussels (Mytilus edulis) include arousal, confusion, disorientation,
and memory loss. The median time of onset is 5.5 h. Other prominent
signs and symptoms include severe headache, nausea, vomiting, diar-
rhea, abdominal cramps, hiccups, arrhythmias, hypotension, seizures,
ophthalmoplegia, pupillary dilation, piloerection, hemiparesis, mut-
ism, grimacing, agitation, emotional lability, coma, copious bronchial
secretions, and pulmonary edema. Histologic study of brain tissue
taken at autopsy has shown neuronal necrosis or cell loss and astro-
cytosis, most prominently in the hippocampus and the amygdaloid
nucleus—findings similar to those in animals poisoned with kainic
acid. Several months after the primary intoxication, victims still dis-
play chronic residual memory deficits and motor neuronopathy or
axonopathy. Nonneurologic illness does not persist.
TREATMENT Domoic Acid Intoxication
Therapy is supportive and based on symptoms. Because kainic acid
neuropathology seems to be nearly entirely seizure mediated, the
emphasis should be on anticonvulsive therapy, for which diazepam
appears to be as effective as any other drug.
SCOMBROID POISONING
Scombroid fish poisoning may be the most common type of seafood
poisoning worldwide. It follows consumption of scombroid (mackerel-
like) fish, which include albacore, bluefin, and yellowfin tuna; mackerel;
saury; needlefish; wahoo; skipjack; and bonito, as well as nonscombroid
fish, such as dolphinfish (Hawaiian mahimahi, Coryphaena hippurus),
kahawai, sardine, black marlin, pilchard, anchovy, herring, amberjack,
and Australian ocean salmon. In the northeastern and mid-Atlantic
United States, bluefish (Pomatomus saltatrix) has been linked to
scombroid poisoning. Because greater numbers of nonscombroid fish
are being recognized as scombrotoxic, the syndrome may more appro-
priately be called pseudoallergic fish poisoning.
Under conditions of inadequate preservation or refrigeration, the
musculature of these dark- or red-fleshed fish undergoes decomposi-
tion by Proteus morganii and Klebsiella pneumoniae bacteria, with con-
sequent decarboxylation of the amino acid l-histidine to histamine,
histamine phosphate, and histamine hydrochloride. Histamine levels
of 20–50 mg/100 g are noted in toxic fish, with levels >400 mg/100 g
on occasion. However, it is possible that some other compound may
be responsible for this intoxication, because large doses of oral hista-
mine do not reproduce the affliction. It is proposed that this unknown
agent works by inhibiting the metabolism of histamine, promoting
degranulation of mast cells to release endogenous histamine, or acting
as a histamine receptor agonist. Whatever toxin or toxins are involved
2/9/15 4:40 PM
 2744 are heat stable and are not destroyed by domestic or commercial cook-
ing. Affected fish typically have a sharply metallic or peppery taste;
however, they may be normal in appearance, color, and flavor. Not all
persons who eat a contaminated fish necessarily become ill, perhaps
because of uneven distribution of decay within the fish.
Symptoms develop within 15–90 min of ingestion. Most cases are
mild, with tingling of lips and mouth, mild abdominal discomfort,
and nausea. The more severe and commonly described presentation
includes flushing (sharply demarcated; exacerbated by ultraviolet
exposure; particularly pronounced on the face, neck, and upper trunk),
a sensation of warmth without elevated core temperature, conjunc-
tival hyperemia, pruritus, urticaria, and angioneurotic edema. This
syndrome may progress to bronchospasm, nausea, vomiting, diar-
PART 18
rhea, epigastric pain, abdominal cramps, dysphagia, headache, thirst,
pharyngitis, gingival burning, palpitations, tachycardia, dizziness,
and hypotension. Without treatment, the symptoms generally resolve
within 8–12 h. Because of blockade of gastrointestinal tract histami-
nase, the reaction may be more severe in a person who is concurrently
ingesting isoniazid.
Poisoning, Drug Overdose, and Envenomation
TREATMENT Scombroid Poisoning
Therapy is directed at reversing the histamine effect with antihis-
tamines, either H-1 or H-2. If bronchospasm is severe, an inhaled
bronchodilator—or in rare, extremely severe circumstances,
injected epinephrine—may be used. Glucocorticoids are of no
proven benefit. Protracted nausea and vomiting, which may empty
the stomach of toxin, may be controlled with a specific antiemetic,
such as ondansetron or prochlorperazine. The persistent headache
of scombroid poisoning may respond to cimetidine or a similar anti-
histamine if standard analgesics are not effective.
475
Ectoparasite Infestations and
Arthropod Injuries
Richard J. Pollack, Scott A. Norton
Ectoparasites include arthropods and creatures from other phyla that
infest the skin or hair of animals; the host animals provide them with
sustenance and shelter. The ectoparasites may penetrate within or
beneath the surface of the host or may attach by mouthparts and spe-
cialized claws. These organisms may inflict direct mechanical injury,
consume blood or nutrients, induce hypersensitivity reactions, inocu-
late toxins, transmit pathogens, and incite fear or disgust. Humans are
the sole or obligate hosts for many kinds of ectoparasites and serve as
facultative or paratenic (accidental) hosts for many others.
Arthropods that are ectoparasitic or otherwise cause injury include
insects (such as lice, fleas, bedbugs, wasps, ants, bees, and flies), arach-
nids (spiders, scorpions, mites, and ticks), millipedes, and centipedes.
Certain nematodes (helminths), such as the hookworms (Chap. 256),
are ectoparasitic in that they penetrate and migrate through the skin.
Infrequently encountered ectoparasites in other phyla include the pen-
tastomes (tongue worms) and leeches.
Arthropods may also cause injury when they attempt to take a blood
meal or as they defend themselves by biting, stinging, or exuding ven-
oms. Various arachnids (spiders and scorpions), insects (bees, hornets,
wasps, ants, flies, true bugs, caterpillars, and beetles), millipedes, and
centipedes produce ill effects during these behaviors. Similarly, certain
ectoparasites (e.g., ticks, biting mites, and fleas) that typically infest
nonhuman animals can be medically significant. In the United States,
lesions caused by arthropod bites and stings are so diverse and vari-
able that it is rarely possible to identify the precise causative organism
without a bona fide specimen and taxonomic expertise.
HPIM19_Part18_p2733-p2752.indd 2744
SCABIES
The human itch mite, Sarcoptes scabiei var. hominis, is a common
cause of itching dermatosis, infesting ~300 million persons worldwide
at any one time. Gravid female mites (~0.3 mm in length) burrow
superficially within the stratum corneum, depositing three or fewer
eggs per day. Six-legged larvae mature to eight-legged nymphs and
then to adults. Gravid adult females emerge to the surface of the skin
about 8 days later and then (re)invade the skin of the same or another
host. Newly fertilized female mites are transferred from person to
person mainly by direct skin-to-skin contact; transfer is facilitated by
crowding, poor hygiene, and sex with multiple partners. Generally,
these mites die within a day or so in the absence of host contact.
Transmission via sharing of contaminated bedding or clothing occurs
far less frequently than is often thought. In the United States, scabies
may account for up to 5% of visits to dermatologists. Outbreaks
occur in preschools, hospitals, nursing homes, and other residential
institutions.
The itching and rash associated with scabies derive from a sensitiza-
tion reaction to the mites and their secretions/excretions. A person’s
initial infestation remains asymptomatic for up to 6 weeks before the
onset of intense pruritus, but a reinfestation produces a hypersensitiv-
ity reaction without delay. Burrows become surrounded by inflamma-
tory infiltrates composed of eosinophils, lymphocytes, and histiocytes,
and a generalized hypersensitivity rash later develops in remote sites.
Immunity and associated scratching limit most infestations to <15
mites per person. Hyperinfestation with thousands of mites, a condi-
tion known as crusted scabies (formerly termed Norwegian scabies),
may result from glucocorticoid use, immunodeficiency, and neu-
rologic or psychiatric illnesses that limit the itch and/or the scratch
response.
Pruritus typically intensifies at night and after hot showers. Classic
burrows are often difficult to find because they are few in number and
may be obscured by excoriations. Burrows appear as dark wavy lines
in the upper epidermis and are 3–15 mm long. Scabetic lesions are
most common on the volar wrists and along the digital web spaces.
In males, the penis and scrotum become involved. Small papules and
vesicles, often accompanied by eczematous plaques, pustules, or nod-
ules, appear symmetrically at those sites; within intertriginous areas;
around the navel and belt line; in the axillae; and on the buttocks and
upper thighs. Except in infants, the face, scalp, neck, palms, and soles
are usually spared. Crusted scabies often resembles psoriasis: both are
characterized by widespread thick keratotic crusts, scaly plaques, and
dystrophic nails. Characteristic burrows are not seen in crusted sca-
bies, and patients usually do not itch, although their infestations are
highly contagious and have been responsible for outbreaks of classic
scabies in hospitals.
Scabies should be considered in patients with pruritus and symmet-
ric superficial, excoriated, papulovesicular skin lesions in characteristic
locations, particularly if there is a history of household contact with
an infested person. Burrows should be sought and unroofed with a
sterile needle or scalpel blade, and the scrapings should be examined
microscopically for mites, eggs, and fecal pellets. Examination of skin
biopsies (including superficial cyanoacrylate biopsy) or scrapings,
dermatoscopic imaging of papulovesicular lesions, and microscopic
inspection of clear cellophane tape lifted from lesions also may be
diagnostic. In the absence of identifiable mites or eggs, the diagnosis
is based on a history of pruritus, a clinical examination, and an epide-
miologic link. Diverse kinds of dermatitis from other causes frequently
are misdiagnosed as scabies, particularly in presumed “outbreak” situ-
ations. Scabies mites of other animals may cause transient irritation,
but they do not reside or reproduce in human hosts.
TREATMENT Scabies
Permethrin cream (5%) is less toxic than 1% lindane preparations
and is effective against lindane-tolerant infestations. Scabicides are
applied thinly but thoroughly behind the ears and from the neck
down after bathing—with careful application to interdigital spaces
and the umbilicus and under the fingernails—and are removed
2/9/15 4:40 PM
 8–14 h later with soap and water. Successful treatment of crusted
scabies requires preapplication of a keratolytic agent such as 6%
salicylic acid and then of scabicides to the scalp, face, and ears.
Repeated treatments or the sequential use of several agents may
be necessary. Ivermectin has not been approved by the U.S. Food
and Drug Administration (FDA) for treatment of any form of scabies,
but a single oral dose (200 μg/kg) is effective in otherwise healthy
persons; patients with crusted scabies may require two doses sepa-
rated by an interval of 1–2 weeks. All FDA-approved scabicides are
available solely by prescription.
Within 1 day of effective treatment, scabies infestations become
noncommunicable, but the pruritic hypersensitivity dermatitis
induced by the now-dead mites and their remnant products fre-
quently persists for weeks. Unnecessary re-treatment with topical
agents may provoke contact dermatitis. Antihistamines, salicylates,
and calamine lotion relieve itching during treatment, and topical
glucocorticoids are useful for pruritus that lingers after effective
treatment. To prevent reinfestations, bedding and clothing should
be washed and dried on high heat or heat-pressed. Close con-
tacts of confirmed cases, even if asymptomatic, should be treated
simultaneously.
CHIGGERS AND OTHER BITING MITES
Chiggers are the larvae of trombiculid (harvest) mites that normally
feed on mice in grassy or brush-covered sites in tropical, subtropi-
cal, and (less frequently) temperate areas during warm months. They
reside on low vegetation and attach themselves to passing mammalian
hosts. While feeding, larvae secrete saliva with proteolytic enzymes
to create a tube-like invagination in the host’s skin; this stylostome
allows the mite to imbibe tissue fluids. The stylostomal saliva is highly
antigenic and causes exceptionally pruritic papular, papulovesicular,
or papulourticarial lesions (≤2 cm in diameter). In people previously
sensitized to salivary antigens, the papules develop within hours of
attachment. While attached, mites appear as tiny red vesicles on the
skin. Generally, lesions vesicate and develop a hemorrhagic base.
Scratching, however, invariably destroys the body of a mite. Itching
and burning often persist for weeks. The rash is common on the ankles
and areas where clothing obstructs the further wanderings of the mites.
Repellents are useful for preventing chigger bites.
Many kinds of mites that are associated with peridomestic birds and
rodents are particularly bothersome when they invade homes and bite
people. In North America, the northern fowl mite, chicken mite, tropi-
cal rat mite, and house mouse mite normally feed on poultry, various
songbirds, and small mammals and are abundant in and around their
hosts’ nests. After their natural hosts die or leave the nest, these mites
frequently invade human habitations. Although the mites are rarely
seen because of their small size, their bites can be painful and pruritic.
Once confirmed as the cause of irritation, rodent- and bird-associated
mites are best eliminated by excluding their hosts, removing the nests,
and cleaning and treating the nesting area with appropriate acaricides.
Pyemotes and other mites that infest grain, straw, cheese, hay, or other
products occasionally produce similar episodes of rash and discom-
fort and may produce a unique dermatologic “comet sign” lesion—a
paisley-shaped urticarial plaque.
Diagnosis of mite-induced dermatitides (including those caused by
chiggers) relies on confirmation of the mite’s identity or elicitation of a
history of exposure to the mite’s source. Oral antihistamines or topical
steroids may suppress mite-induced pruritus temporarily but do not
eliminate the mites.
TICK BITES AND TICK PARALYSIS
Ticks attach superficially to skin and feed painlessly; blood is their
only food. Their salivary secretions are biologically active and can pro-
duce local reactions, induce fevers, and cause paralysis in addition to
transmitting diverse pathogens. The two main families of ticks are the
hard (ixodid) and soft (argasid) ticks. Generally, soft ticks attach for
<1 h, leaving red macules after they drop off. Some species in Africa,
the western United States, and Mexico produce painful hemorrhagic
HPIM19_Part18_p2733-p2752.indd 2745
lesions. Hard ticks are much more common and transmit most of the 2745
tick-borne infections that are familiar to physicians and patients. Hard
ticks attach to the host and feed for several days or sometimes for >1
week. At the site of hard-tick bites, small areas of induration, often
purpuric, develop and may be surrounded by an erythematous rim.
A necrotic eschar, called a tâche noire, occasionally develops. Chronic
nodules (persistent tick-bite granulomas) can be several centimeters
in diameter and may linger for months after the feeding tick has been
removed. These granulomas can be treated with injected intralesional
glucocorticoids or by surgical excision. Tick-induced fever, unas-
sociated with transmission of any pathogen, is often accompanied by
headache, nausea, and malaise but usually resolves ≤36 h after the tick
CHAPTER 475
is removed.
Tick paralysis, an acute ascending flaccid paralysis that resembles
Guillain-Barré syndrome, is believed to be caused by one or more
toxins in tick saliva that block neuromuscular transmission and
decrease nerve conduction. This rare complication has followed the
bites of more than 60 kinds of ticks, although in the United States dog
and wood ticks (Dermacentor species) are most commonly involved.
Ectoparasite Infestations and Arthropod Injuries
Weakness begins symmetrically in the lower extremities ≤6 days after
the tick’s attachment, ascends symmetrically during several days, and
may culminate in complete paralysis of the extremities and cranial
nerves. Deep tendon reflexes are diminished or absent, but sensory
examination and findings on lumbar puncture are typically normal.
Removal of the tick generally leads to rapid improvement within a few
hours and complete recovery after several days, although the patient’s
condition may continue to deteriorate for a full day. Failure to remove
the tick may lead to dysarthria, dysphagia, and ultimately death from
aspiration or respiratory paralysis. Diagnosis depends on finding the
tick, which is often hidden beneath scalp hair. An antiserum to the
saliva of Ixodes holocyclus, the usual cause of tick paralysis in Australia,
effectively reverses paralysis caused by these ticks.
Removal of hard ticks during the first 36 h of attachment nearly
always prevents transmission of the agents of Lyme disease, babesiosis,
anaplasmosis, and ehrlichiosis, although several tick-borne viruses
may be transmitted more quickly. Ticks should be removed by traction
with fine-tipped forceps placed firmly around the tick’s mouthparts.
Careful handling (to avoid rupture of ticks) and use of gloves may avert
accidental contamination with pathogens contained in tick fluids. Use
of occlusive dressings, heat, or other substances (in an attempt to induce
the tick to detach) merely delay tick removal. Afterward, the site of
attachment should be disinfected. Tick mouthparts sometimes remain
in the skin but generally are shed spontaneously within days without
excision. Although somewhat controversial, current guidelines from the
Centers for Disease Control and Prevention suggest that, rather than
awaiting the onset of erythema migrans, the results of tick testing, or
seroconversion to antigens diagnostic for Lyme disease, administering
prophylaxis with a single oral dose of doxycycline (200 mg) within 72 h
of tick removal is appropriate in adult patients with bites thought to be
associated with deer ticks (Fig. 475-1) in Lyme disease–endemic areas
from Maryland to Maine and in Wisconsin and Minnesota.
LOUSE INFESTATION (PEDICULIASIS AND PTHIRIASIS)
Nymphs and adults of all three kinds of human lice feed at least once
a day, ingesting human blood exclusively. Head lice (Pediculus capitis)
infest mainly the hair of the scalp, body lice (Pediculus humanus) the
clothing, and crab or pubic lice (Pthirus pubis) mainly the hair of the
pubis. The saliva of lice produces a pruritic morbilliform or urticarial
rash in some sensitized persons. Female head and pubic lice cement
their eggs (nits) firmly to hair, whereas female body lice cement their
eggs to clothing, particularly to threads along clothing seams. After
~10 days of development within the egg, a nymph hatches. Empty eggs
may remain affixed for months thereafter.
In North America, head lice infest ~1% of elementary school-age
children. Head lice are transmitted mainly by direct head-to-head
contact rather than by fomites such as shared headgear, bed linens,
hairbrushes, and other grooming implements. Chronic infestations by
head lice tend to be asymptomatic. Pruritus, due mainly to hypersen-
sitivity to the louse’s saliva, generally is transient and mild. Head lice
2/9/15 4:40 PM
 2746
PART 18
Figure 475-1  Deer ticks (Ixodes scapularis, black-legged ticks) on
a U.S. penny: larva (below ear), nymph (right), adult male (above), and
Poisoning, Drug Overdose, and Envenomation
adult female (left).
removed from a person succumb to desiccation and starvation within
~1 day. Head lice are not known to serve as a natural vector for any
pathogens.
Body lice remain on clothing except when feeding and generally
succumb in ≤2 days if separated from their host. In most Western
countries, body lice are generally found on a small proportion of indi-
gent persons but may become increasingly prevalent after upheaval
associated with natural or human-caused disasters, when homeless
victims are in close contact with infested individuals with whom they
share accommodations. Body lice are acquired by direct contact or by
sharing of infested clothing and bedding. These lice are vectors for
the agents of louse-borne (epidemic) typhus (Chap. 211), louse-borne
relapsing fever (Chap. 209), and trench fever (Chap. 197). Pruritic
lesions from their bites are particularly common around the neckline.
Chronic infestations result in a postinflammatory hyperpigmentation
and thickening of skin known as vagabond’s disease.
The crab or pubic louse is transmitted mainly by sexual contact.
These lice occur predominantly on pubic hair and less frequently on
axillary or facial hair, including the eyelashes. Children and adults may
acquire pubic lice by sexual or close nonsexual contact. Intensely pru-
ritic, bluish macules ~3 mm in diameter (maculae ceruleae) develop
at the site of bites. Blepharitis commonly accompanies infestations of
the eyelashes.
Pediculiasis is often suspected upon the detection of nits firmly
cemented to hairs or in clothing. Many bona fide nits, however, are
dead or hatched relics of prior infestation, and pseudo-nits are fre-
quently misconstrued to be signs of a louse infestation. Confirmation of
a louse infestation, therefore, best relies on the discovery of a live louse.
TREATMENT Louse Infestation
Generally, treatment is warranted only if live lice are discovered.
The presence of nits alone is evidence of a former—not necessarily
current—infestation. Mechanical removal of lice and their eggs
with a fine-toothed louse or nit comb (Fig. 475-2) often fails to
eliminate infestations. Treatment of newly identified active infes-
tations generally relies on a 10-min topical application of ~1%
permethrin or pyrethrins, with a second application ~10 days later.
Lice persisting after this treatment may be resistant to pyrethroids.
Chronic infestations may be treated for ≤12 h with 0.5% malathion.
Lindane is applied for just 4 min but seems less effective and may
pose a greater risk of adverse reactions, particularly when misused.
Resistance of head lice to permethrin, malathion, and lindane has
been reported. Newer FDA-approved topical pediculicides contain
benzyl alcohol, dimethicone, spinosad, and ivermectin. Although
children infested by head lice—or those who simply have remnant
nits from a prior infestation—are frequently isolated or excluded
HPIM19_Part18_p2733-p2752.indd 2746
Figure 475-2  Adult female human head louse (Pediculus capitis) on
a nit (louse-egg) comb.
from school, this practice increasingly is seen as unjustified and
ineffective.
Body lice usually are eliminated by bathing and by changing
to laundered clothes. Application of topical pediculicides from head
to foot may be necessary for hirsute patients. Clothes and bedding
are effectively deloused by heating in a clothes dryer at ≥55°C
(≥131°F) for 30 min or by heat-pressing. Emergency mass delous-
ing of persons and clothing may be warranted during periods of
civil strife and after natural disasters to reduce the risk of pathogen
transmission by body lice.
Pubic louse infestations are treated with topical pediculicides,
except for eyelid infestations (pthiriasis palpebrum), which generally
respond to a coating of petrolatum applied for 3–4 days.
MYIASIS (FLY INFESTATION)
Myiasis refers to infestations by several kinds of fly larvae (maggots)
that invade living or necrotic tissues or body cavities and produce
different clinical syndromes, depending on the species of fly.
In forested parts of Central and South America, larvae of the human
botfly (Dermatobia hominis) produce furuncular (boil-like) papules or
subcutaneous nodules ≤3 cm in diameter. A gravid adult female bot-
fly captures a mosquito or another bloodsucking insect and deposits
her eggs on its abdomen. When the carrier insect attacks a human or
bovine host several days later, the warmth and moisture of the host’s
skin stimulate the eggs to hatch. The emerging larvae promptly pen-
etrate intact skin. After 6–12 weeks of development, mature larvae
emerge from the skin and drop to the ground to pupate and then
become adults.
The African tumbu fly (Cordylobia anthropophaga) deposits its
eggs on damp sand or leaf litter or on drying laundry, particularly that
contaminated by urine or sweat. Larvae hatch from eggs upon contact
with a host’s body and penetrate the skin, producing boil-like lesions
from which mature larvae emerge ~9 days later. Furuncular myiasis is
suggested by uncomfortable lesions with a central breathing pore that
emits bubbles when submerged in water. A sensation of movement
under the patient’s skin may cause severe emotional distress.
Larvae that cause furuncular myiasis may be induced to emerge if
the air pore is coated with petrolatum or another occlusive substance.
Removal may be facilitated by injection of a local anesthetic into
the surrounding tissue, but surgical excision is sometimes necessary
because upward-pointing spines of some species hold the larvae firmly
in place.
Other fly larvae cause nonfuruncular myiasis. For example, lar-
vae of the horse botfly (Gasterophilus intestinalis) emerge from eggs
deposited on the horse’s flanks and may come into contact with and
infest human beings. After penetrating human skin, these larvae rarely
mature but instead may migrate for weeks in the dermis. The resulting
pruritic and serpiginous eruption resembles cutaneous larva migrans
caused by canine or feline hookworms (Chap. 256). Larvae of rabbit
and rodent botflies (Cuterebra species) occasionally cause dermal or
tracheopulmonary myiasis.
2/9/15 4:40 PM
 Certain flies are attracted to blood and pus, laying their eggs on open
or draining sores. Newly hatched larvae enter wounds or diseased skin.
Larvae of several types of green bottle flies (Lucilia/Phaenicia species)
usually remain superficial and confined to necrotic tissue. Specially
raised, sterile “surgical maggots” are sometimes used intentionally for
wound debridement. Larvae of screwworm flies, Cochliomyia, and the
flesh fly invade viable tissues more deeply and produce large suppu-
rating lesions. Larvae that infest wounds also may enter body cavities
such as the mouth, nose, ears, sinuses, anus, vagina, and lower urinary
tract, particularly in unconscious or otherwise debilitated patients. The
consequences range from harmless colonization to destruction of the
nose, meningitis, and deafness. Treatment involves removal of mag-
gots and debridement of tissue.
The maggots responsible for furuncular and wound myiasis also
may cause ophthalmomyiasis. Sequelae include nodules in the eyelid,
retinal detachment, and destruction of the globe. Most instances in
which maggots are found in human feces result from deposition of
eggs or larvae by flies on recently passed stools, not from an intestinal
maggot infestation.
PENTASTOMIASIS
Pentastomids (tongue worms) inhabit the respiratory passages of
reptiles and carnivorous mammals. Human infestation by Linguatula
serrata is common in the Middle East and results from the consump-
tion of encysted larval stages in raw liver or lymph nodes of sheep
and goats, which are true intermediate hosts for the tongue worms.
Larvae migrate to the nasopharynx and produce an acute self-limiting
syndrome—known as halzoun or marrara—characterized by pain and
itching of the throat and ears, coughing, hoarseness, dysphagia, and
dyspnea. Severe edema may cause obstruction that requires trache-
ostomy. In addition, ocular invasion has been described. Diagnostic
larvae measuring ≤10 mm in length appear in copious nasal discharge
or vomitus. Individuals become infected with another type of tongue
worm, Armillifer armillatus, by consuming its eggs in contaminated
food or drink or after handling the definitive host, the African
python. Larvae encyst in various organs but rarely cause symptoms.
Cysts may require surgical removal as they enlarge during molting,
but they usually are encountered as an incidental finding at autopsy.
Parasite-induced lesions may be misinterpreted as a malignancy, with
the correct diagnosis confirmed histopathologically. Cutaneous larva
migrans–type syndromes of other pentastomes have been reported
from Southeast Asia and Central America.
LEECH INFESTATIONS
Medically important leeches are annelid worms that attach to their
hosts with chitinous cutting jaws and draw blood through muscular
suckers. The medicinal leech (Hirudo medicinalis) is still used occa-
sionally for medical purposes to reduce venous congestion in surgical
flaps or replanted body parts. This practice has been complicated by
intractable bleeding, wound infections, myonecrosis, and sepsis due
to Aeromonas hydrophila, which colonizes the gullets of commercially
available leeches.
Ubiquitous aquatic leeches that parasitize fish, frogs, and turtles
readily attach to the skin of human beings and avidly suck blood. More
notorious are arboreal land leeches that live among moist vegetation
of tropical rain forests. Attachment is usually painless, and the leeches
will detach themselves when satiated with a blood meal. Hirudin, a
powerful anticoagulant secreted by the leech, causes continued bleed-
ing after the leech has detached. Healing of a leech-bite wound is slow,
and bacterial infections are not uncommon. Several kinds of aquatic
leeches in Africa, Asia, and southern Europe can enter the mouth,
nose, and genitourinary tract and attach to mucosal surfaces at sites
as deep as the esophagus and trachea. Externally attached leeches
generally drop off after they have engorged, but removal is hastened
by gentle scraping aside of the anterior and posterior suckers the leech
uses for attachment and feeding. Some authorities dispute the wisdom
of removing leeches with alcohol, salt, vinegar, insect repellent, a flame
or heated instrument, or applications of other noxious substances.
HPIM19_Part18_p2733-p2752.indd 2747
Internally attached leeches may detach on exposure to gargled saline 2747
or may be removed by forceps.
SPIDER BITES
Of the more than 30,000 recognized species of spiders, only ~100
defend themselves aggressively and have fangs sufficiently long to
penetrate human skin. The venom that some spiders use to immo-
bilize and digest their prey can cause necrosis of skin and systemic
toxicity. Whereas the bites of most spiders are painful but not harmful,
envenomations by recluse or fiddleback spiders (Loxosceles species)
and widow spiders (Latrodectus species) may be life-threatening.
Identification of the offending spider is important because specific
CHAPTER 475
treatments exist for bites of widow spiders and because injuries attrib-
uted to spiders are frequently due to other causes. Except in cases
where the patient actually observes a spider immediately associated
with the bite or fleeing from the site, lesions reported as spider-bite
reactions are most often due to other injuries or to infections with
bacteria such as methicillin-resistant Staphylococcus aureus (MRSA).
Recluse Spider Bites and Necrotic Arachnidism  Brown recluse spiders
Ectoparasite Infestations and Arthropod Injuries
live mainly in the south-central United States and have close relatives
in Central and South America, Africa, and the Middle East. Bites by
brown recluse spiders usually cause only minor injuries, with edema
and erythema. Envenomation, however, occasionally causes severe
necrosis of skin and subcutaneous tissue and more rarely causes sys-
temic hemolysis. These spiders are not aggressive toward humans and
will bite only if threatened or pressed against the skin. They hide under
rocks and logs or in caves and animal burrows. They invade homes and
seek dark and undisturbed hiding spots in closets, in folds of clothing,
or under furniture and rubbish in storage rooms, garages, and attics.
Despite their impressive abundance in some homes, these spiders
rarely bite humans. Bites tend to occur while the victim is dressing and
are sustained primarily on the hands, arms, neck, and lower abdomen.
Initially, the bite is painless or may produce a stinging sensation.
Within the next few hours, the site becomes painful and pruritic, with
central induration surrounded by a pale ischemic zone that itself is
encircled by a zone of erythema. In most cases, the lesion resolves
without treatment in just a few days. In severe cases, the erythema
spreads, and the center of the lesion becomes hemorrhagic or necrotic
with an overlying bulla. A black eschar forms and sloughs several
weeks later, leaving an ulcer that eventually may create a depressed
scar. Healing usually takes place in ≤6 months but may take as long as
3 years if adipose tissue is involved. Local complications include injury
to nerves and secondary bacterial infection. Fever, chills, weakness,
headache, nausea, vomiting, myalgia, arthralgia, maculopapular rash,
and leukocytosis may develop ≤72 h after the bite. Reports of deaths
attributed to bites of North American brown recluse spiders have not
been verified.
TREATMENT Recluse Spider Bites
Initial management includes RICE (rest, ice, compression, elevation).
Analgesics, antihistamines, antibiotics, and tetanus prophylaxis
should be administered if indicated. Early debridement or surgical
excision of the wound without closure delays healing. Routine use
of antibiotics or dapsone is unnecessary. Patients should be moni-
tored closely for signs of hemolysis, renal failure, and other systemic
complications.
Widow Spider Bites  The black widow spider, common in the south-
eastern United States, measures ≤1 cm in body length and 5 cm in leg
span and is shiny black with a red hourglass marking on the ventral
abdomen. Other dangerous Latrodectus species occur elsewhere in
temperate and subtropical parts of the world. The bites of the female
widow spiders are notorious for their potent neurotoxins.
Widow spiders spin their webs under stones, logs, plants, or rock
piles and in dark spaces in barns, garages, and outhouses. Bites are
most common in the summer and early autumn and occur when a
web is disturbed or a spider is trapped or provoked. The initial bite
2/9/15 4:40 PM
 2748 is perceived as a sharp pinprick or may go unnoticed. Fang-puncture
marks are uncommon. The venom that is injected does not produce
local necrosis, and some persons experience no other symptoms.
α-Latrotoxin, the most active component of the venom, binds irrevers-
ibly to presynaptic nerve terminals and causes release and eventual
depletion of acetylcholine, norepinephrine, and other neurotrans-
mitters from those terminals. Painful cramps may spread within 60
min from the bite site to large muscles of the extremities and trunk.
Extreme rigidity of the abdominal muscles and excruciating pain
may suggest peritonitis, but the abdomen is not tender on palpation
and surgery is not warranted. The pain begins to subside during the
first 12 h but may recur during several days or weeks before resolving
spontaneously. A wide range of other neurologic sequelae may include
PART 18
salivation, diaphoresis, vomiting, hypertension, tachycardia, labored
breathing, anxiety, headache, weakness, fasciculations, paresthesia,
hyperreflexia, urinary retention, uterine contractions, and premature
labor. Rhabdomyolysis and renal failure have been reported, and respi-
ratory arrest, cerebral hemorrhage, or cardiac failure may end fatally,
especially in very young, elderly, or debilitated persons.
Poisoning, Drug Overdose, and Envenomation
TREATMENT Widow Spider Bites
Treatment consists of RICE and tetanus prophylaxis. Hypertension
that does not respond to analgesics and antispasmodics (e.g., ben-
zodiazepines or methocarbamol) requires specific antihypertensive
medication. The efficacy and safety of antivenoms for black widow
and redback spiders are controversial because of concerns about
potential anaphylaxis or serum sickness.
Tarantulas and Other Spiders  Tarantulas are hairy spiders of which
30 species are found in the United States, mainly in the Southwest.
The tarantulas that have become popular household pets are usually
imported from Central or South America. Tarantulas bite only when
threatened and usually cause no more harm than a bee sting, but on
occasion the venom causes deep pain and swelling. Several species of
tarantulas are covered with urticating hairs that are brushed off in
the thousands when a threatened spider rubs its hind legs across its
dorsal abdomen. These hairs can penetrate human skin and produce
pruritic papules that may persist for weeks. Failure to wear gloves or
to wash the hands after handling the Chilean Rose tarantula, a popular
pet spider, has resulted in transfer of hairs to the eye with subsequent
devastating ocular inflammation. Treatment of bites includes local
washing and elevation of the bitten area, tetanus prophylaxis, and
analgesic administration. Antihistamines and topical or systemic glu-
cocorticoids are given for exposure to urticating hairs.
Atrax robustus, a funnel-web spider of Australia, and Phoneutria
species, the South American banana spiders, are among the most
dangerous spiders in the world because of their aggressive behavior
and potent neurotoxins. Envenomation by A. robustus causes a rapidly
progressive neuromotor syndrome that can be fatal within 2 h. The
bite of a banana spider causes severe local pain followed by profound
systemic symptoms and respiratory paralysis that can lead to death
within 2–6 h. Specific antivenoms for use after bites by each of these
spiders are available. Yellow sac spiders (Cheiracanthium species) are
common in homes worldwide. Their bites, though painful, generally
lead to only minor erythema, edema, and pruritus.
SCORPION STINGS
Scorpions are arachnids that feed on ground-dwelling arthropods
and small lizards. They paralyze their prey and defend themselves
by injecting venom from a stinger on the tip of the tail. Painful but
relatively harmless scorpion stings need to be distinguished from
the potentially lethal envenomations that are produced by ~30 of the
~1000 known species and that cause more than 5000 deaths worldwide
each year. Scorpions are nocturnal and remain hidden during the
day in crevices or burrows or under wood, loose bark, or rocks. They
occasionally enter houses and tents and may hide in shoes, clothing, or
bedding. Scorpions sting humans only when threatened.
HPIM19_Part18_p2733-p2752.indd 2748
Of the 40 or so scorpion species in the United States, only bark
scorpions—e.g., Centruroides sculpturatus (C. exilicauda) in the
Southwest—produce venom that is potentially lethal to humans. This
venom contains neurotoxins that cause sodium channels to remain
open. Such envenomations usually are associated with little swelling, but
prominent pain, paresthesia, and hyperesthesia can be accentuated by
tapping on the affected area (the tap test). These symptoms soon spread
to other locations; dysfunction of cranial nerves and hyperexcitability
of skeletal muscles develop within hours. Patients present with restless-
ness, blurred vision, abnormal eye movements, profuse salivation, lac-
rimation, rhinorrhea, slurred speech, difficulty in handling secretions,
diaphoresis, nausea, and vomiting. Muscle twitching, jerking, and shak-
ing may be mistaken for a seizure. Complications include tachycardia,
arrhythmias, hypertension, hyperthermia, rhabdomyolysis, and acido-
sis. Symptoms progress to maximal severity in ~5 h and subside within a
day or two, although pain and paresthesia can last for weeks. Fatal respi-
ratory arrest is most common among young children and the elderly.
Envenomations by Leiurus quinquestriatus in the Middle East
and North Africa, by Mesobuthus tamulus in India, by Androctonus
species along the Mediterranean littoral and in North Africa and the
Middle East, and by Tityus serrulatus in Brazil cause massive release
of endogenous catecholamines with hypertensive crises, arrhythmias,
pulmonary edema, and myocardial damage. Acute pancreatitis occurs
with stings of Tityus trinitatis in Trinidad, and central nervous toxic-
ity complicates stings of Parabuthus and Buthotus scorpions of South
Africa. Tissue necrosis and hemolysis may follow stings of the Iranian
Hemiscorpius lepturus.
Stings of most other species cause immediate sharp local pain
followed by edema, ecchymosis, and a burning sensation. Symptoms
typically resolve within a few hours, and skin does not slough. Allergic
reactions to the venom sometimes develop.
TREATMENT Scorpion Stings
Identification of the offending scorpion helps to determine the
course of treatment. Stings of nonlethal species require at most
ice packs, analgesics, or antihistamines. Because most victims
­experience only local discomfort, they can be managed at home
with instructions to return to the emergency department if signs
of cranial-nerve or neuromuscular dysfunction develop. Aggressive
supportive care and judicious use of antivenom can reduce or elimi-
nate deaths from more severe envenomations. Keeping the patient
calm and applying pressure dressings and cold packs to the sting
site are measures that decrease the absorption of venom. A con-
tinuous IV infusion of midazolam controls the agitation, flailing, and
involuntary muscle movements produced by scorpion stings. Close
monitoring during treatment with this drug and other sedatives or
narcotics is necessary for persons with neuromuscular symptoms
because of the risk of respiratory arrest. Hypertension and pul-
monary edema respond to nifedipine, nitroprusside, hydralazine,
or prazosin. Dangerous bradyarrhythmias can be controlled with
atropine.
Commercially prepared antivenoms are available in several coun-
tries for some of the most dangerous species. An FDA-approved
C. sculpturatus antivenom in horse serum is now available. IV admin-
istration of antivenom rapidly reverses cranial-nerve dysfunction
and muscular symptoms. Although effective, cost analyses s­ uggest
that antivenoms should be reserved for only the most severe
­envenomations.
HYMENOPTERA STINGS
Insects that sting in defense or to subdue their prey belong to the order
Hymenoptera, which includes bees, wasps, hornets, yellow jackets,
and ants. Their venoms contain a wide array of amines, peptides, and
enzymes that cause local and systemic reactions. Although the toxic
effect of multiple stings can be fatal to a human, nearly all of the ≥100
deaths due to hymenopteran stings in the United States each year
result from allergic reactions.
2/9/15 4:40 PM
 Bee and Wasp Stings  The stinger of the honeybee (Apis mellifera) is
unique in being barbed. When a bee stings a foe, its stinging apparatus
and attached venom sac tear loose from its body. Muscular contrac-
tion of the venom sac continues to inject venom into the skin. Other
kinds of bees, ants, and wasps have smooth stinging mechanisms and
can sting numerous times in succession. Honeybees, bumblebees,
and social wasps generally attack only when a colony is disturbed.
Africanized honeybees (now present in South and Central America
and the southern and western United States) respond to minimal
intrusions more aggressively. Whereas the sting of an Africanized bee
contains less venom than that of its non-Africanized relatives, victims
tend to sustain far more stings and therefore to receive a far greater
overall volume of venom. Most patients who report having sustained
a “bee sting,” however, are more likely to have encountered stinging
wasps instead.
The venoms of different species of hymenopterans are biochemi-
cally and immunologically distinct. Direct toxic effects are mediated
by mixtures of low-molecular-weight compounds such as serotonin,
­histamine, acetylcholine, and several kinins. Polypeptide toxins in hon-
eybee venom include mellitin that damages cell membranes, mast cell–
degranulating protein that causes histamine release, the neurotoxin
apamin, and the anti-inflammatory compound adolapin. Enzymes in
venom include hyaluronidase and phospholipases. There appears to be
little cross-sensitization between the venoms of honeybees and wasps.
Uncomplicated hymenopteran stings cause immediate pain, a
wheal-and-flare reaction, and local edema, all of which usually subside
in a few hours. Multiple stings can lead to vomiting, diarrhea, general-
ized edema, dyspnea, hypotension, and non-anaphylactic circulatory
collapse. Rhabdomyolysis and intravascular hemolysis may cause
renal failure. Death from the direct (nonallergic) effects of venom has
followed stings of several hundred honeybees. Stings to the tongue or
mouth may induce life-threatening edema of the upper airways.
Large local reactions accompanied by erythema, edema, warmth,
and tenderness that spread ≥10 cm around the sting site over 1–2 days
are not uncommon. These reactions may resemble bacterial cellulitis
but are caused by hypersensitivity rather than by secondary infection.
Such reactions tend to recur on subsequent exposure but are sel-
dom accompanied by anaphylaxis and are not prevented by venom
immunotherapy.
An estimated 0.4–4.0% of the U.S. population exhibits clinical
immediate-type hypersensitivity to hymenopteran stings, and 15%
may have asymptomatic sensitization manifested by positive skin
tests. Persons who experience severe allergic reactions are likely to
have similar reactions after subsequent stings by the same or closely
related species. Occasionally, persons who have had mild reactions
earlier in life will experience more serious reactions to subsequent
stings. Mild anaphylactic reactions from insect stings, as from other
causes, consist of nausea, abdominal cramping, generalized urticaria,
flushing, and angioedema. Serious reactions, including upper airway
edema, bronchospasm, hypotension, and shock, may be rapidly fatal.
Severe reactions usually begin within 10 min of the sting and only
rarely develop after 5 h.
TREATMENT Bee and Wasp Stings
Honeybee stingers embedded in the skin should be removed as
soon as possible to limit the quantity of venom delivered. The
stinger and venom sac may be scraped off with a blade, the edge
of a credit card, or a fingernail or may be removed with forceps. The
site should be cleansed and disinfected and ice packs applied to
slow the spread of venom. Elevation of the affected site and admin-
istration of analgesics, oral antihistamines, and topical calamine
lotion help relieve symptoms. Large local reactions may require
a short course of oral therapy with glucocorticoids. Patients with
numerous stings should be monitored for 24 h for evidence of renal
failure or coagulopathy.
Anaphylaxis is treated with SC injection of 0.3–0.5 mL of epi-
nephrine hydrochloride in a 1:1000 dilution; treatment is repeated
every 20–30 min as necessary. IV epinephrine (2–5 mL of a 1:10,000
HPIM19_Part18_p2733-p2752.indd 2749
solution administered by slow push) is indicated for profound shock. 2749
A tourniquet may slow the spread of venom. Parenteral antihista-
mines, fluid resuscitation, bronchodilators, supplemental oxygen,
intubation, and vasopressors may be required. Patients should be
observed for 24 h for recurrent anaphylaxis.
Persons with a history of allergy to insect stings should carry an
anaphylaxis kit with a preloaded syringe containing epinephrine for
self-administration. These patients should seek medical attention
immediately after using the kit.
Repeated injections of purified venom produce a blocking IgG
antibody response to venom and reduce the incidence of recurrent
CHAPTER 475
anaphylaxis. Honeybee, wasp, and yellow jacket venoms are com-
mercially available for desensitization and for skin testing. Results of
skin tests and venom-specific radioallergosorbent tests (RASTs) aid
in the selection of patients for immunotherapy and guide the design
of such treatment.
Stinging Ants
Ectoparasite Infestations and Arthropod Injuries
Stinging fire ants are an important medical problem in the United
States. Imported fire ants (Solenopsis species) infest southern states
from Texas to North Carolina, with colonies now established in
California, New Mexico, Arizona, and Virginia. Slight disturbances of
their mound nests have provoked massive outpourings of ants and as
many as 10,000 stings on a single person. Elderly and immobile per-
sons are at high risk for attacks when fire ants invade dwellings.
Fire ants attach to skin with powerful mandibles and rotate their
bodies while repeatedly injecting venom with posteriorly situated
stingers. The alkaloid venom consists of cytotoxic and hemolytic
piperidines and several proteins with enzymatic activity. The initial
wheal-and-flare reaction, burning, and itching resolve in ~30 min,
and a sterile pustule develops within 24 h. The pustule ulcerates over
the next 48 h and then heals in ≥1 week. Large areas of erythema and
edema lasting several days are not uncommon and in extreme cases
may compress nerves and blood vessels. Anaphylaxis occurs in fewer
than 2% of victims; seizures and mononeuritis have been reported.
Stings are treated with ice packs, topical glucocorticoids, and oral
antihistamines. Pustules should be cleansed and then covered with
bandages and antibiotic ointment to prevent bacterial infection.
Epinephrine administration and supportive measures are indicated
for anaphylactic reactions. Fire ant whole-body extracts are available
for skin testing and immunotherapy, which appears to lower the rate
of anaphylactic reactions.
European fire (red) ants (Myrmica rubra) have recently become
public health pests in the northeastern United States and south-
ern Canada. The western United States is home to harvester ants
(Pogonomyrmex species). The painful local reaction that follows
harvester ant stings often extends to lymph nodes and may be accom-
panied by anaphylaxis. The bullet or conga ant (Paraponera clavata)
of South America is known locally as hormiga veinticuatro (“24-hour
ant”), a designation that refers to the 24 h of throbbing, excruciating
pain following a sting that delivers the potent paralyzing neurotoxin
poneratoxin.
DIPTERAN (FLY AND MOSQUITO) BITES
In the process of feeding on vertebrate blood and tissue fluids, adults
of certain flies inflict painful bites, produce local allergic reactions, and
may transmit pathogenic agents. Bites of mosquitoes, tiny “no-see-
um” (ceratopogonid) midges, and phlebotomine sand flies typically
produce a wheal and a pruritic papule. Small humpbacked black flies
(simuliids) lacerate skin, resulting in a lesion with serosanguineous
discharge that is often painful and pruritic. Regional lymphadenopa-
thy, fever, or anaphylaxis occasionally ensues. The widely distributed
deerflies and horseflies as well as the tsetse flies of Africa are stout flies
measuring ≤25 mm in length that attack during the day and produce
large and painful bleeding punctures. Houseflies (Musca domestica) do
not consume blood but use rasping mouthparts to scarify skin and feed
upon tissue fluids and salt. Beyond direct injury from bites of any kind
2/9/15 4:40 PM
 2750 of fly, risks include transmission of diverse pathogens and secondary
infection of the lesion.
TREATMENT Fly and Mosquito Bites
Treatment of fly bites is symptom based. Topical application of
antipruritic agents, glucocorticoids, or antiseptic lotions may relieve
itching and pain. Allergic reactions may require oral antihistamines.
Antibiotics may be necessary for the treatment of large bite wounds
that become secondarily infected.
PART 18
FLEA BITES
Common human-biting fleas include the dog and cat fleas
(Ctenocephalides species) and the rat flea (Xenopsylla cheopis), which
infest their respective hosts and the hosts’ nests and resting sites.
Sensitized persons develop erythematous pruritic papules (papular
urticaria) and occasionally vesicles and bacterial superinfection at the
site of the bite. Symptom-based treatment consists of antihistamines,
Poisoning, Drug Overdose, and Envenomation
topical glucocorticoids, and topical antipruritic agents.
Flea infestations are eliminated by removal and treatment of animal
nests, frequent cleaning of pet bedding, and application of contact and
systemic insecticides to pets and the dwelling. Flea infestations in the
home may be abated or prevented if pets are regularly treated with
veterinary antiparasitic agents and insect growth regulators.
Tunga penetrans, like other fleas, is a wingless, laterally flattened
insect that feeds on blood. Also known as the chigoe flea, sand flea,
or jigger (not to be confused with the chigger), it occurs in tropical
regions of Africa and the Americas. Adult female chigoes live in sandy
soil and burrow under the skin, usually between toes, under nails, or
on the soles of bare feet. Gravid chigoes engorge on the host’s blood
and grow from pinpoint to pea size during a 2-week interval. They
produce lesions that resemble a white pustule with a central black
depression and that may be pruritic or painful. Occasional complica-
tions include tetanus, bacterial infections, and autoamputation of toes
(ainhum). Tungiasis is treated by removal of the intact flea with a
sterile needle or scalpel, tetanus vaccination, and topical application
of antibiotics.
HEMIPTERAN (TRUE BUG) BITES
Several true bugs of the family Reduviidae inflict bites that produce
allergic reactions and are sometimes painful. The cone-nose bugs,
so called because of their elongated heads, include the assassin and
wheel bugs, which feed on other insects and bite vertebrates only
in self-defense, and the kissing bugs, which routinely feed on verte-
brate blood. The bites of the night-feeding kissing bugs are painless.
Reactions to such bites depend on prior sensitization and include
tender and pruritic papules, vesicular or bullous lesions, extensive urti-
caria, fever, lymphadenopathy, and (rarely) anaphylaxis. Bug bites are
treated with topical antipruritics or oral antihistamines. Persons with
anaphylactic reactions to reduviid bites should keep an epinephrine
kit available. Some reduviids transmit Trypanosoma cruzi, the agent of
New World trypanosomiasis (also called Chagas disease) (Chap. 252).
The cosmopolitan bedbugs (Cimex species) hide in crevices of mat-
tresses, bed frames and other furniture, walls, and picture frames and
under loose wallpaper. Bedbug populations have resurged, recently
attaining levels and spreading to an extent not encountered since the
mid-twentieth century. These bugs are now a common pest in homes,
dormitories, and hotels; on cruise ships; and even in medical facilities.
Generally, the bugs hide during the day and take blood meals at night.
Their bite is painless, but minutes to days later, sensitized persons
develop erythema, itching, and wheals around a central hemorrhagic
punctum. Bedbugs are not known to transmit pathogens.
CENTIPEDE BITES AND MILLIPEDE DERMATITIS
The fangs of centipedes of the genus Scolopendra can penetrate human
skin and deliver a venom that produces intense burning pain, swell-
ing, erythema, and sterile lymphangitis. Dizziness, nausea, and anxiety
are described occasionally, and rhabdomyolysis and renal failure have
HPIM19_Part18_p2733-p2752.indd 2750
been reported. Treatment includes washing of the site, application of
cold dressings, oral analgesic administration or local lidocaine infiltra-
tion, and tetanus prophylaxis.
Millipedes are docile and do not bite, but some secrete defensive flu-
ids that may burn and discolor human skin. Affected skin turns brown
overnight and may blister and exfoliate. Secretions in the eye cause
intense pain and inflammation that can result in corneal ulcers and
even blindness. Management includes irrigation with copious amounts
of water or saline, use of analgesics, and local care of denuded skin.
CATERPILLAR STINGS AND DERMATITIS
Caterpillars of several moth species are covered with hairs or spines
that produce mechanical irritation and may contain or be coated
with venom. Contact with these caterpillars or their hairs may lead
to lepidopterism or caterpillar envenomation. The response typically
consists of an immediate burning sensation followed by local swelling
and erythema and occasionally by regional lymphadenopathy, nausea,
vomiting, and headache. A rare reaction to a South American caterpil-
lar, Lonomia obliqua, can cause disseminated coagulopathy and fatal
hemorrhagic shock. In the United States, dermatitis is most often
associated with caterpillars of the io, puss, saddleback, and brown-tail
moths. Even contact with detached hairs of other caterpillars, such as
gypsy moth larvae, can later produce a pruritic urticarial or papular
rash called erucism. Spines may be deposited on tree trunks or drying
laundry or may be airborne and cause irritation of the eyes and upper
airways. Treatment of caterpillar stings consists of repeated application
of adhesive or cellophane tape to remove the hairs, which can then be
identified microscopically. Local ice packs, topical glucocorticoids, and
oral antihistamines relieve symptoms.
BEETLE VESICATION AND DERMITITIS
Several families of beetles have independently developed the ability
to produce chemically unrelated vesicating toxins. When disturbed,
blister beetles (family Meloidae) extrude cantharidin, a low-molecular-
weight toxin that produces thin-walled blisters (≤5 cm in diameter)
2–5 h after contact. The blisters are not painful or pruritic unless
broken and resolve without treatment in ≤10 days. Nephritis may fol-
low unusually heavy cantharidin exposure. Contact occurs when indi-
viduals sit on the ground, work in the garden, or deliberately handle
the beetles. The hemolymph of certain rove beetles (Staphylinidae)
contains pederin, a potent vesicant. When these beetles are crushed or
brushed against the skin, the released fluid causes painful, red, flaccid
bullae. These beetles occur worldwide but are most numerous and
problematic in parts of Africa (where they are called “Nairobi fly”) and
southwestern Asia. Ocular lesions may develop after impact with flying
beetles at night or unintentional transfer of the vesicant on the fingers.
Treatment is rarely necessary, although ruptured blisters should be
kept clean and bandaged.
Larvae of common carpet beetles are adorned with dense arrays
of ornate hairs called hastisetae. Contact with these larvae or their
setae results in delayed dermal reactions in sensitized individuals. The
lesions are commonly mistaken as bites of bedbugs.
DELUSIONAL INFESTATIONS
The groundless conviction that one is infested with arthropods or
other parasites (Ekbom’s syndrome, delusory parasitosis, delusions
of parasitosis, and perhaps Morgellons syndrome) is extremely dif-
ficult to treat and, unfortunately, is not uncommon. Patients describe
uncomfortable sensations of something moving in or on their skin.
Excoriations and self-induced ulcerations typically accompany the
pruritus, dysesthesias, and imaginary insect bites. Patients often
believe that some invisible or as yet undescribed creatures are infest-
ing their skin, clothing, homes, or environment in general. Frequently,
patients submit as evidence of infestation specimens that consist of
plant-feeding and nonbiting peridomestic arthropods, pieces of skin,
vegetable matter, lint, and other inanimate detritus. When evaluating a
patient with possible delusional parasitosis, it is imperative to rule out true
infestations and bites by arthropods, endocrinopathies, sensory disorders
due to neuropathies, opiate and other drug use, environmental irritants
2/9/15 4:40 PM
 (e.g., fiberglass threads), and other causes of tingling or prickling
sensations. Frequently, such patients repeatedly seek medical consulta-
tions, resist alternative explanations for their symptoms, and exacer-
bate their discomfort by self-treatment. Long-term pharmacotherapy
with pimozide or other psychotropic agents has been more helpful
than psychotherapy in treating this disorder. Patients with delusional
parasitosis often develop the unshakeable conviction that they are
HPIM19_Part18_p2733-p2752.indd 2751
infested by a previously unknown pathogen, while their personal lives, 2751
family support, and employment collapse around them.
Acknowledgment
The substantial contributions of Andrew Spielman and James H.
Maguire to this chapter in previous editions are gratefully acknowledged.
CHAPTER 475
Ectoparasite Infestations and Arthropod Injuries
2/9/15 4:40 PM
This page intentionally left blank