INVITED COMMENTARY

ACUTE HOSPITAL-INDUCED HYPONATREMIA IN CHILDREN: A PHYSIOLOGIC APPROACH

MALCOLM A. HOLLIDAY, MD, AARON L. FRIEDMAN, MD, WILLIAM E. SEGAR, MD, RUSSELL CHESNEY, MD, AND LAURENCE FINBERG, MD

hysicians giving children uid therapy today seldom encounter overt dehydration or signs of shock that call for rapid and aggressive extracellular uid (ECF) expansion. Physicians in the era when severe diarrheal dehydration was common rst restored ECF with isotonic saline,a then planned maintenance and replacement therapies, using hypotonic saline. Today, physicians plan uid therapy mostly for children with pneumonia, meningitis, other acute disorders, or for children scheduled for surgery. These children are seldom overtly dehydrated or in shock. Common practice in this setting is to initiate uid therapy with hypotonic saline as maintenance therapy. However, hyponatremia has been a worrisome complication with this practice.1,2,3 In extreme cases, convulsions, brain injury, or death have resulted.4 Two recent articles5,6 have recommended giving maintenance therapy as isotonic saline to avoid this risk. While authors of these articles have done a service in calling attention to the problem of hyponatremia, we believe their remedy has risks of its own. Our analysis of the cases we reviewed suggests a more physiologic approach, using tested principles of uid therapy. In this report, we review maintenance therapy, cite clinical ndings in the cases we surveyed that support subtle hypovolemia as the common cause of hyponatremia, describe the role of rapidly giving isotonic saline to correct hypovolemia, cite risks of using isotonic saline as maintenance therapy, and dene a physiologically based uid therapy protocol that avoids hyponatremia.

Maintenance Therapy
Standard intravenous maintenance therapy7 is designed to replace ongoing physiological water losses when oral intake is suspended. These are net insensible (;35 mL) and urinary (;65 mL) water losses; they are indexed to metabolic rate expressed in 100 kcal/day increments. Consequently, the average allowance for water as maintenance therapy is 100 mL/100 kcal/dayb (Table).8 It is usually met by giving intravenous hypotonic saline in 5% dextrose. Exceptions to the average gure for net insensible loss are uncommon in modern hospital settings. Exceptions to average urinary loss are more common because antidiuretic hormone (ADH) responds to hypovolemia as well as to hyperosmolality.9,10 An uncommon exception is the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In that condition, ADH is elevated in the absence of either hypovolemia or hyperosmolality.11 SIADH is associated with certain brain injuries, drugs, and pain. It is characterized by hyponatremia and oliguria even though circulation is normal. In the rare instance when SIADH is suggested, maintenance therapy should be reduced to half average (not half maintenance) or 50 mL/100 kcal/day (see Table).

Hypovolemia
Hypovolemia is dened as impaired circulation in which organ and tissue perfusion are reduced. Hypovolemia develops with: (1) a contraction of ECF as occurs from net loss of body uid, including diarrhea and vomiting, renal or cerebral salt wasting, (2) extravasation of plasma into tissues as occurs with infection, burns, or trauma (third space loss), or (3) dislocation of blood volume into capacitance vessels as occurs with septic shock or loss of muscle tone. These conditions, acting singly or together, reduce venous return to the heart and elevate plasma ADH, even though plasma sodium is normal or low12 free water excretion is inhibited. Infusing hypotonic saline in that setting leads to free water retention and hyponatremia. Renal salt wasting is associated with renal tubular disease;

ADH ECF

Antidiuretic hormone Extracellular fluid

SIADH

Syndrome inappropriate secretion of antidiuretic hormone

From Department of Pediatrics, University of California, San Francisco, California; Department of Pediatrics, University of Wisconsin, Madison, Wisconsin; Department of Pediatrics, University of Tennessee, Memphis, Tennessee; and Department of Pediatrics, University of California, San Francisco, Stanford University, Stanford, California. Submitted for publication Feb 15, 2004; last revision received May 13, 2004; accepted Jun 29, 2004. Reprint requests: Malcolm A. Holliday, MD, 1515 Oxford St, 1A, Berkeley CA, 94709. E-mail: mah@ itsa.ucsf.edu. a The term normal saline, although widely used, is not permitted in labeling by FDA because it is not a chemically defined normal solution. Isotonic saline is 0.9% saline (154 mEq/ L Na). Hypotonic saline solutions vary between 0.45% and 0.18% saline (77 and 30 mEq/L Na) and deliver between 1/2 and 4/5 of their volume as free water. b Infant: 3-10 kg, 100 kcal/kg. Preschool: 10-20 kg, 1000 1 100 kcals for each 2 kg .10. Older: 20-70 kg, 1500 1100 kcals for each 5 kg .20. J Pediatr 2004;145:584-7. 0022-3476/$ - see front matter Copyright 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.06.077

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Table. Relating body weight (BW) to metabolic rate (MR) and to average and half average maintenance allowances for daily and hourly periods BW MR Maintenance Allowance ML/DA Aver
300 500 700 1000 1100 1300 1500 1700 2000 2500

excrete free water, if plasma ADH is not elevated, it exaggerates hyponatremia when it is elevated. When egregiously excessive amounts of free water have been given, death has resulted.4,19

[see footnote b] kg
3 5 7 10 12 16 20 30 45 70

ML/HR Aver
12 20 24 40 45 50 60 70 80 100

Brain Injury
Brain injury because of hyponatremia is described as water intoxication. It results when retention of free water rapidly decreases serum sodium; brain volume increases because water rapidly equilibrates across cell membranes and solutes do so only slowly. Solutes of both cell and ECF are diluted; both cell and ECF volumes increase. Given the unique anatomic and physiologic features of the brain, these increases in brain volume cause intracranial pressure to rise. If swelling is sufcient, brain ischemia and injury follow. Within hours brain solutes are lost and volume returns toward normal. However in that interval, ischemia may have caused convulsions, brain injury, or death.

kcals
300 500 700 1000 1100 1300 1500 1700 2000 2500

1/2 Aver
150 250 350 500 550 650 750 850 1000 1250

1/2 Aver
6 10 12 20 22 25 30 35 40 50

Refer to footnote b regarding saline solutions

Severe Hypovolemia without Hyponatremia

An extreme example of hypovolemia results in patients with severe burns from extensive extravisation of plasma into interstitial uid, compromising circulation and perfusion. Plasma ADH and other vasoactive agents dramatically rise; urine ow decreases. For example, a 40% skin surface burn results in huge transfers of plasma uid and albumin into both the burn site and normal interstitium. Current treatment is to give 80 mL/kg (2 mL/% skin surface burn) of isotonic saline or Ringers solution in the rst 4 hours.20 That dose or more is repeated in the following 12 to 16 hours until blood pressure and pulse are stable and circulation, perfusion, and urine output become normal. Patients become alert, able to converse, and able to drink water.21 ADH is suppressed22; despite oral water intake, serum sodium remains normal.23 As inammation subsides in the succeeding 24 hours, the extra ECF is recovered into plasma and excreted as urine. Hypovolemia in septic shock results from extreme vasodilation; blood volume is sequestered in capacitance vessels. Levels of plasma ADH and other vasoactive agents rise dramatically.24 A critical component of treatment is massive isotonic saline infusion given rapidly to restore circulation and perfusion.25 Once circulation is restored, the levels of ADH and other agents decrease; the extra ECF is excreted.

cerebral salt wasting results from brain disease, notably meningitis. Both cause salt loss and hypovolemia, distinguishing them from SIADH.13 We derived evidence for hypovolemia in children with hospital-induced hyponatremia from several reports. In one, 25 of 27 acutely ill children with hyponatremia had elevated plasma ADH levels.14 In another, children with hyponatremia as a result of gastroenteritis and dehydration had elevated plasma ADH levels.15 More children with diarrheal dehydration and elevated ADH levels who were given 0.45% saline [77 mEq/L] became hyponatremic than did those who were given isotonic saline [154 mEq/L].16 In a prospective study, children with meningitis and elevated ADH either were given isotonic saline plus maintenance or maintenance alone; those given isotonic saline then maintenance lowered ADH, while those given maintenance alone did not.17 In another prospective study, children who were given isotonic saline during surgery had lower plasma ADH levels postoperatively than those given no uids, although plasma sodium was the same for both groups.18 In general, patients who had elevated ADH and were given hypotonic saline did not lower ADH and often remained hyponatremic; those who had elevated ADH and were given isotonic saline did lower ADH and generally were normonatremic. In these same articles, maintenance therapy was often ordered in excess of that recommended. In one report,2 physicians gave >150% recommended maintenance uid to 16 of 23 patients. Commonly, orders were written for one and a half maintenance without evidence of increased losses. In other instances, maintenance uids were indexed to body weight at a rate of 100 mL/kg/day, not per 100 kcal/day, increasing intake for older children by as much as three times recommended (see Table). While giving maintenance uid in excess of recommended rarely exceeds a patients capacity to
Acute Hospital-Induced Hyponatremia in Children: A Physiologic Approach

Gravity and Hypovolemia

Gravity contributes to dislocation of blood volume. Normal young men standing upright with muscles fully relaxed develop syncope and hypotension within 15 minutes. Blood is sequestered in the lower limbs; plasma ADH increases dramatically. When the men lie down, eliminating the gravity effect, these signs abate.26 Children lying supine for extended periods lose muscle tone; this has a comparable effect, pooling blood dorsally. Anesthesia and sedation exaggerate this effect. Rapid ECF expansion with isotonic
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saline counters it. Early active mobilization, where practical, is also effective.

The rst author wishes to thank Robert Holliday for valuable editorial input.

REFERENCES
Protocol for Avoiding Hypovolemia
The rst priority in planning uid therapy for acutely ill children is to determine if hypovolemia is likely. If so, rapid rehydration/restoration therapy is indicated. If hypovolemia is marginal to moderate, 20 to 40 mL/kg of isotonic saline or Ringers solution, given in 2-4 hours, should sufce. If hypovolemia is more severe, 40 to 80 mL/kg may be needed. Therapy is indexed to body weight, not to metabolic rate, because blood and ECF vary with body weight. Surgical patients are subject to hypovolemia when uids are withheld, from operative trauma and from extended bed rest. These patients benet from isotonic saline given rapidly to restore circulation. It is standard practice to continue an isotonic saline infusion during surgery and throughout time in the recovery room. For patients who do not tolerate oral intake after 6 to 12 hours, intravenous maintenance uid therapy using hypotonic saline should be initiated.
1. Shann F, Germer S. Hyponatremia associated with pneumonia or bacterial meningitis. Arch Dis Child 1985;60:963-6. 2. Halberthal M, Halperin ML, Bohn D. Acute hyponatremia in children admitted to hospital: retrospective analysis of factors contributing to its development and evolution. BMJ 2001;322:780-2. 3. Judd BA, Haycock GB, Dalton N, Chantler C. Hyponatremia in premature babies and following surgery in older children. Acta Pediatr Scand 1987;76:385-93. 4. Arief AL, Ayus JC, Frazier JC. Hyponatremia and death or permanent brain damage in healthy children. BMJ 1992;304:1218-22. 5. Moritz ML, Ayus JC. Prevention of hospital acquired hyponatremia: a case for using isotonic saline in maintenance uid therapy. Pediatrics 2003; 111:227-30. 6. Duke T, Molyneux EM. Intravenous uids for seriously ill children: time to reconsider. Lancet 2003;362:1320-3. 7. Friedman AL. Fluid and electrolyte therapy. In: Berhman RE, Kliegman RM, eds. Nelsons Essential Pediatrics. 4th ed. Philadelphia: WB Saunders; 2002:671-709. 8. Holliday MA, Segar WE. The maintenance need for water in parenteral uid therapy. Pediatrics 1957;19:823-32. 9. Friedman AL, Segar WE. Antidiuretic hormone excess. J Pediatr 1979; 94:521-6. 10. Holliday MA. Extracellular uid and its proteins: dehydration, shock, and recovery. Pediatr Nephrol 1999;13:989-95. 11. Albanese A, Hindmarsh P, Stanhope R. Management of hyponatremia in patients with acute cerebral insults. Arch Dis Child 2001;85:246-51. 12. Segar WE, Moore WW. The regulation of antidiuretic hormone in man. J Clin Invest 1968;47:2143-51. 13. Ganong CA, Kappy MS. Cerebral salt wasting in children. Amer J Dis Child 1993;147:167-9. 14. Gerigk M, Gnehm HE, Rascher W. Arginine vasopressin and renin in acutely ill children: implications for uid therapy. Acta Pediatr 1996;85: 550-3. 15. Neville KA, OMeara M, Verge CF, Walker JL. Hyponatremia in gastroenteritis may be associated with antidiuretc hormone (ADH) dysregulation. Presented as poster #865 at the Pediatric Academic Societys annual meeting, Seattle, Wash 2003. 16. Neville KA, OMeara M, Verge CF, Walker JL. Normal saline is better than half normal saline for rehydration of children with gastroenteritis. Presented as poster #866 at the Pediatric Academic Societys annual meeting, Seattle, Wash 2003. 17. Powell KR, Sugarman LI, Eskenazi AE, Woodin KA, Kays MA, McCormick KL, et al. Normalization of plasma arginine vasopressin concentrations when children with meningitis are given maintenace plus replacement uid therapy. J Pediatr 1991;118:996-8. 18. Judd BA, Haycock GB, Dalton RN, Chantler C. Antidiuretic hormone following surgery in children. Acta Pediatr Scand 1990;79:461-6. 19. Jackson J, Bolte RG. Risks of administration of hypotonic uids for pediatric patients in ED and prehospital settings. Am J Emerg Med 2000;18: 269-70. 20. Pufnbarger NK, Tuggle DI, Smith EI. Rapid isotonic uid resuscitation in pediatric thermal injury. J Pediat Surg 1994;29:339-41. 21. Moyers CA, Margraf HW, Monafo WW. Burn shock and extravascular sodium deciency-treatment with Ringers solution with lactate. Arch Surg 1965;90:799-811. 22. McIntosh N, Michaelis L, Barclay C, Muir M, Stephen R, Sedowoa K. Dissociation of osmoregulation from plasma arginine vasopressin levels following thermal injury in childhood. Burns 2000;26:543-7. 23. Carvajal HF. Fluid resuscitation of pediatric burn victims: a critical appraisal. Pediatric Nephrol 1994;8:357-66. 24. Hollenberg SM, Cunnion RE. Endothelial and vascular smooth muscle function in sepsis. J Crit Care 1994;9:262-80. 25. Carcillo JA, Davis AL, Zaritsky A. Role of early uid resuscitation in pediatric septic shock. JAMA 1991;266:1242-5.

Risks of Using Isotonic Saline for Maintenance Therapy

The two proposals5,6 to use isotonic saline as maintenance therapy, in some cases for extended periods, was recommended without describing any clinical experience. This, we believe, incurs unwarranted risks.27,28 It is comparable to the use of hypotonic saline as initial or replacement therapy without clinical trials. Several potential problems can be anticipated. Giving isotonic saline at maintenance rates to hypovolemic patients unnecessarily delays the correcting of hypovolemia; hypovolemia should always be rapidly corrected. Giving isotonic saline for periods >6 to 12 hours to children with cardiopulmonary or renal disease imposes a hazardous sodium load. Even in normal patients, prolonged infusion of isotonic saline may have unanticipated consequences. In one study, women who had had elective surgery received a postoperative infusion for 24 hours of isotonic saline at rates approximating those of maintenance therapy. This led to excess sodium excretion and a decrease in serum sodium; that is, more sodium, but not more water, was excreted than was given.29

SUMMARY
Children admitted with acute disease or for surgery incur a signicant risk of hyponatremia if even subtle hypovolemia is present and is not corrected before they are given hypotonic saline as maintenance therapy. The risk is exaggerated if maintenance therapy is given in excess of recommendations. This risk is greatly reduced (1) by initially giving children with even subtle hypovolemia, 20 to 40 mL/kg of isotonic saline in 2-4 hours and (2) by correctly calculating maintenance therapy, indexing it to metabolic rate (see Table) and clinical state.
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26. Bjerkhoel P, Lindgren P, Lundvall J. Protein loss and capillary protein permeability in dependent regions upon quiet standing. Acta Physiol Scand 1995;154:311-20. 27. Holliday MA, Segar WE, Friedman A. Reducing errors in uid therapy management. Pediatr 2003;111:424-5.

28. Holliday MA, Segar WE, Friedman A, Chesney R, Finberg L. Intravenous uids for seriously ill children [letter]. Lancet 2004;363:241. 29. Steele A, Gowrishankar M, Abrahamson S, Mazer D, Feldman RD, Halperin ML. Postoperative hyponatremia despite near isotonic saline infusion: a phenomenon of desalination. Ann Intern Med 1997;126:823-32.

50 Years Ago in The Journal of Pediatrics

ACUTE FAMILIAL INFANTILE HEREDODEGENERATIVE DISORDER OF THE CENTRAL NERVOUS SYSTEM
Palinsky M, Kozinn PJ, Zahtz H. J Pediatr 1954;45:538-45 This case report of a family with a recessive neurodegenerative disorder illustrates the myriad of changes that have occurred in the practice of what we now refer to as neurogenetics, in 50 years. It shows as well the progress made in the diagnosis of this family of conditions. It is doubtful that anyone would perform and report the history and physical examination as meticulously as in this paper, and it is possible that modern pediatric neurologists could not do so. Pathology has taken a back seat to enzymatic and DNA studies with the consequent benet of far faster and far less invasive diagnostic methods. If a geneticist were involved, the patient might not even have had imaging studies. No one would write, in such detail, of each of the possible disorders, since we now appreciate the overlap between their manifestations, interindividual variations for identical mutations, and of course, the redenition of diseases, initially by their enzyme decits, and more recently by their mutations. More mild mutations result in later onset and often in different clinical manifestations despite involvement of the same gene. One can even argue that clinical eponyms (perhaps anachronistic for all disorders) should be limited to the clinical manifestations regardless of the genetic cause, creating a dissociation between historical and modern visions of these diseases. While we celebrate our modern sophistication, are all of these modern views salutary? Disease is caused ultimately by anatomical and physiological changes in the cells and tissues, and they cannot be treated without appreciating these changes, neither of which is addressed directly by enzymology and genetics. Appreciation of the pathological anatomy and physiological changes permits rational thought about palliative treatments, whereas genetics and enzymology focus singlemindedly on cure through gene therapy, or palliation by one mean alone, that of enzyme enhancement or infusion. It is premature and inappropriate to throw out the new, but it is not too early to advocate the return and strengthening of the old, such as pathology. We need to return to visit the autopsy room and the histology laboratory and let the pathologists know that their observations matter for the future treatment of these conditions. Stephen Cederbaum, MD Departments of Psychiatry, Pediatrics and Human Genetics David Geffen School of Medicine at UCLA Los Angeles, CA 90095 YMPD1138
10.1016/j.jpeds.2004.08.019

Acute Hospital-Induced Hyponatremia in Children: A Physiologic Approach

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