Pediatric Syndrome of Inappropriate Antidiuretic Hormone Secretion 

  • Author: Robert J Ferry Jr, MD; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Apr 29, 2010
 

Background

The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is the most common cause of euvolemic hyponatremia in pediatrics. The syndrome is defined by the hyponatremia and hypo-osmolality that results from inappropriate continued secretion and/or action of antidiuretic hormone (ADH) despite normal or increased plasma volume.

Arginine vasopressin (AVP), the naturally occurring ADH in humans, is an octapeptide similar in structure to oxytocin. AVP is synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus and travels along the supraopticohypophyseal tract into the posterior pituitary, where it is stored in secretory granules in association with a carrier protein, neurophysin. Neurophysins are peptides composed of 2 proteins, each capable of binding 2 molecules of ADH. The neurophysin-vasopressin combination is stored in the posterior pituitary in the terminal dilatations of secretory neurons that rest against blood vessels. ADH is released from the neuron onto the capillary basement membrane in the posterior pituitary and thus directly into the circulation.

Two types of receptors participate in the release of ADH from the posterior pituitary. Osmoreceptors are a group of specialized cells that perceive changes in the extracellular fluid (ECF) osmolality. A 2% increase in the serum osmolality perfusing the supraoptic nuclei can cause release of ADH, whereas a 1.2% decrease in the serum osmolality decreases plasma ADH release. Secretion of ADH is suppressed at plasma osmolalities below 280 mOsm/kg.

Baroreceptors are located in the carotid sinus, aortic arch, and left atrium; these baroreceptors participate in the nonosmolar control of ADH release by responding to a change of plasma volume. An 8-10% reduction in plasma volume significantly increases ADH release. In most physiological states, the volume receptors and osmoreceptors act in concert to increase or decrease ADH release. However, the overriding stimulus for secretion of ADH may be the effective intravascular volume, not the state of extracellular osmolality. ADH is also released in response to several drugs and various stressful stimuli such as pain or anxiety.

The primary role of ADH is to promote the reabsorption of water from the tubular fluid along the course of the distal tubule and collecting duct, the hydroosmotic effect. A second action of ADH is to cause arteriolar vasoconstriction and a rise in arterial blood pressure, the pressor effect. ADH does not exert significant effect on the rate of sodium reabsorption.

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Pathophysiology

The fundamental problem in syndrome of inappropriate antidiuretic hormone secretion is a failure to maximally suppress vasopressin secretion. ADH excess results in water retention and volume expansion, leading to weight gain and natriuresis. Serum osmolality falls below the reference range. Hyponatremia does not develop unless the patient is ingesting or receiving some source of free water. The natriuresis, which occurs in syndrome of inappropriate antidiuretic hormone secretion despite hyponatremia and further contributes to hyponatremia, is produced by a decrease in proximal tubular sodium reabsorption, secondary to the expansion of the extracellular fluid volume.

Hypervolemia suppresses the renin-angiotensin-aldosterone system during the water retention phase, but later, circulating levels of renin and aldosterone rise again, perhaps in response to hyponatremia. The main mediator of the natriuresis in syndrome of inappropriate antidiuretic hormone secretion is probably natriuretic peptides, which may suppress proximal tubular reabsorption of sodium in response to expanded ECF volume. Atrial natriuretic peptide (ANP) is released when hypervolemia distends the cardiac atria. ANP is identical to brain natriuretic peptide (BNP), which is released in response to increased intravascular volume. Central or peripheral mechanisms can be implicated for natriuresis observed in the context of syndrome of inappropriate antidiuretic hormone secretion. Sodium balance is maintained in syndrome of inappropriate antidiuretic hormone secretion, and the sodium output equals the intake.

Four distinct types of osmoregulatory defects have been defined on the basis of plasma AVP determinations during the infusion of hypertonic sodium chloride solution.

In type A (random), observed in approximately 20% of patients, large and unrelated fluctuations in AVP occur unrelated to the rise in plasma osmolality. This pattern usually occurs in association with tumors.

In type B (reset osmostat), observed in about 35% of patients, a prompt and parallel rise in AVP and in plasma osmolality occurs, but a significant lowering of the threshold for release is noted. This pattern is consistent with an osmoreceptor reset at a lower-than-normal level.

In type C (leak), observed in approximately 35% of patients, AVP is persistently elevated at low and normal plasma osmolality; however, above the threshold for AVP release, plasma AVP increases normally. This pattern is observed with meningitis or head injuries.

In type D (normal), observed in approximately 10% of patients, plasma AVP is appropriately suppressed under hypotonic conditions and does not rise until plasma osmolality reaches the normal threshold level. Maximal urinary dilution does not occur. This pattern is consistent with an increased renal sensitivity to vasopressin and is observed in patients with bronchogenic carcinoma and diabetes mellitus.

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Epidemiology

Frequency

United States

Syndrome of inappropriate antidiuretic hormone secretion is more common in hospitalized patients. Syndrome of inappropriate antidiuretic hormone secretion is the most common cause of hypotonic, euvolemic hyponatremia in children. Syndrome of inappropriate antidiuretic hormone secretion is rare in the outpatient pediatric population, in whom other causes of hyponatremia are more common. Exact incidence figures are not available.

Mortality/Morbidity

The presence of hyponatremia, its severity, and delay in initiating adequate treatment appear to be the main indicators for both morbidity and mortality.[1]

The mortality rate in patients with hyponatremia is 50-fold higher than in patients who do not develop hyponatremia. Moreover, the mortality rate in patients with serum sodium concentrations less than 120 mmol/L is 25%, or twice that, of patients with mild hyponatremia.

Acute decreases in serum sodium in adults are associated with a cited mortality rate of 5-50%, depending on the severity and rate of development; in children, the mortality rate is only about 8%. Infants probably tolerate cerebral edema with fewer untoward effects because of their expandable cranium.

Symptomatic postoperative hyponatremia can result in high morbidity and mortality rates in children of both sexes, which is due in large part to inadequate brain adaptation and lack of timely treatment.

Sex

Controlled studies in adults have shown that women and men are equally likely to develop hyponatremia and hyponatremic encephalopathy after surgery. Menstruating women who develop hyponatremic encephalopathy are 25 times more likely to die or have permanent brain damage than either men or postmenopausal women.

Age

The syndrome has been described in newborns, children, adults, and elderly people.

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Contributor Information and Disclosures
Author

Robert J Ferry Jr, MD  Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center; Deputy Commander for Clinical Services, Texas Medical Command, Army National Guard

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers Bureau Honoraria Speaking and teaching; Eli Lilly & Co. Grant/research funds Investigator; MacroGenics, Inc. Grant/research funds Investigator; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Investigator

Coauthor(s)

Jose F Pascual-y-Baralt, MD  Chief, Division of Pediatric Nephrology, San Antonio Military Pediatric Center; Clinical Professor, Department of Pediatrics, University of Texas Health Science Campus

Jose F Pascual-y-Baralt, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, American Society of Pediatric Nephrology, Association of Military Surgeons of the US, and International Society of Nephrology

Disclosure: Nothing to disclose.

Specialty Editor Board

Arlan L Rosenbloom, MD  Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lynne Lipton Levitsky, MD  Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research funds PI; NovoNordisk Grant/research funds PI

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

References

  1. Hoorn EJ, van der Lubbe N, Zietse R. SIADH and hyponatraemia: why does it matter?. NDT Plus. Nov 2009;2:iii5-iii11. [Medline].

  2. Kaplan SL, Feigin RD. The syndrome of inappropriate secretion of antidiuretic hormone in children with bacterial meningitis. J Pediatr. May 1978;92(5):758-61. [Medline].

  3. Lim YJ, Park EK, Koh HC, Lee YH. Syndrome of inappropriate secretion of antidiuretic hormone as a leading cause of hyponatremia in children who underwent chemotherapy or stem cell transplantation. Pediatr Blood Cancer. May 2010;54(5):734-7. [Medline].

  4. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. May 1967;DA - 19670701(5):790-806. [Medline].

  5. Rianthavorn P, Cain JP, Turman MA. Use of conivaptan to allow aggressive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH. Pediatr Nephrol. Apr 24 2008;[Medline].

  6. Al-Mufti H, Arieff AI. Hyponatremia due to cerebral salt-wasting syndrome. Combined cerebral and distal tubular lesion. Am J Med. Oct 1984;77(4):740-6. [Medline].

  7. Arieff AI. Central nervous system manifestations of disordered sodium metabolism. Clin Endocrinol Metab. Jul 1984;13(2):269-94. [Medline].

  8. Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med. Jun 12 1986;314(24):1529-35. [Medline].

  9. Arieff AI, Ayus JC, Fraser CL. Hyponatremia and death or permanent brain damage in healthy children. BMJ. May 9 1992;304(6836):1218-22. [Medline].

  10. Ayus JC, Wheeler JM, Arieff AI. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med. Dec 1 1992;117(11):891-7. [Medline].

  11. Beck LH. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1979;301:528-30. [Medline].

  12. Benson H, Akbarian M, Adler LN. Hemodynamic effects of pneumonia. I. Normal and hypodynamic responses. J Clin Invest. Apr 1970;49(4):791-8. [Medline].

  13. Braden GL, Geheb MA, Shook A. Demeclocycline-induced natriuresis and renal insufficiency: in vivo and in vitro studies. Am J Kidney Dis. May 1985;5(5):270-7. [Medline].

  14. Brewerton TD, Jackson CW. Prophylaxis of carbamazepine-induced hyponatremia by demeclocycline in six patients. J Clin Psychiatry. 1994;55:249-51. [Medline].

  15. Burrows FA, Shutack JG, Crone RK. Inappropriate secretion of antidiuretic hormone in a postsurgical pediatric population. Crit Care Med. Jul 1983;11(7):527-31. [Medline].

  16. Cogan E, Debieve MF, Pepersack T. Natriuresis and atrial natriuretic factor secretion during inappropriate antidiuresis. Am J Med. Mar 1988;84(3 Pt 1):409-18. [Medline].

  17. David R, Ellis D, Gartner JC. Water intoxication in normal infants: role of antidiuretic hormone in pathogenesis. Pediatrics. Sep 1981;68(3):349-53. [Medline].

  18. De Troyer A, Demanet JC. Correction of antidiuresis by demeclocycline. N Engl J Med. Oct 30 1975;293(18):915-8. [Medline].

  19. Decaux G, Musch W. Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Clin J Am Soc Nephrol. Apr 23 2008;[Medline].

  20. Decaux G, Waterlot Y, Genette F. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide. N Engl J Med. Feb 5 1981;304(6):329-30. [Medline].

  21. Dubovsky SL, Grabon S, Berl T. Syndrome of inappropriate secretion of antidiuretic hormone with exacerbated psychosis. Ann Intern Med. Oct 1973;79(4):551-4. [Medline].

  22. Feigin RD. Interaction of nutrition and infection: plans for future research. Am J Clin Nutr. Sep 1977;30(9):1553-63. [Medline].

  23. Ferry RJ Jr, Kesavulu V, Kelly A, Levitt Katz LE, Moshang T Jr. Hyponatremia and polyuria in children with central diabetes insipidus: challenges in diagnosis and management. J Pediatr. 2001;138:744-7. [Medline].

  24. Friedman AL, Segar WE. Antidiuretic hormone excess. J Pediatr. 1979;94:521-526. [Medline].

  25. Ganong CA, Kappy MS. Cerebral salt wasting in children. The need for recognition and treatment [published erratum appears in Am J Dis Child 1993 Apr;147(4):369]. Am J Dis Child. Feb 1993;147(2):167-9. [Medline].

  26. Glassock RJ, Cohen AH, Danovitch G. Human immunodeficiency virus (HIV) infection and the kidney [published erratum appears in Ann Intern Med 1990 Mar 15;112(6):476]. Ann Intern Med. Jan 1 1990;112(1):35-49. [Medline].

  27. Hantman D, Rossier B, Zohlman R. Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. An alternative treatment to hypertonic saline. Ann Intern Med. Jun 1973;78(6):870-5. [Medline].

  28. Harrigan MR. Cerebral salt wasting syndrome: a review. Neurosurgery. Jan 1996;38:152-60. [Medline].

  29. Haycock GB. The syndrome of inappropriate secretion of antidiuretic hormone. Pediatr Nephrol. Jun 1995;9:375-81. [Medline].

  30. Huang EA, Feldman BJ, Schwartz ID, et al. Oral urea for the treatment of chronic syndrome of inappropriate antidiuresis in children. J Pediatr. Jan 2006;148(1):128-31. [Medline].

  31. Ishikawa S, Schrier RW. Effect of arginine vasopressin antagonist on renal water excretion in glucocorticoid and mineralocorticoid deficient rats. Kidney Int. Dec 1982;22(6):587-93. [Medline].

  32. Janss AJ, Heller G, Grimberg A, Ferry RJ Jr. Neuro-oncology-endocrinology interface: a patient who earned her salt. Med Pediatr Oncol. Oct 1999;33(4):413-7. [Medline].

  33. Kamoi K, Ebe T, Kobayashi O. Atrial natriuretic peptide in patients with the syndrome of inappropriate antidiuretic hormone secretion and with diabetes insipidus. J Clin Endocrinol Metab. May 1990;70(5):1385-90. [Medline].

  34. Laureno R. Central pontine myelinolysis following rapid correction of hyponatremia. Ann Neurol. 1983;13:232-234. [Medline].

  35. Linas SL, Berl T, Robertson GL. Role of vasopressin in the impaired water excretion of glucocorticoid deficiency. Kidney Int. Jul 1980;18(1):58-67. [Medline].

  36. Liskin B, Walsh BT, Roose SP. Imipramine-induced inappropriate ADH secretion. J Clin Psychopharmacol. Jun 1984;4(3):146-7. [Medline].

  37. Lowance DC, Garfinkel HB, Mattern WD. The effect of chronic hypotonic volume expansion on the renal regulation of acid-base equilibrium. J Clin Invest. Nov 1972;51(11):2928-40. [Medline].

  38. Manoogian C, Pandian M, Ehrlich L. Plasma atrial natriuretic hormone levels in patients with the syndrome of inappropriate antidiuretic hormone secretion. J Clin Endocrinol Metab. Sep 1988;67(3):571-5. [Medline].

  39. Maramattom BV. Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures. Neurology. Mar 14 2006;66(5):773-4. [Medline].

  40. McDade G. Disorders of sodium balance: hyponatraemia and drug use (and abuse). BMJ. Apr 8 2006;332(7545):853. [Medline].

  41. Mendoza SA. Syndrome of inappropriate antidiuretic hormone secretion (SIADH). Pediatr Clin North Am. Nov 1976;DA - 19770125(4):681-90. [Medline].

  42. Mor J, Ben-Galim E, Abrahamov A. Inappropriate antidiuretic hormone secretion in an infant with severe pneumonia. Am J Dis Child. Jan 1975;129(1):133-5. [Medline].

  43. Moylan FM, Herrin JT, Krishnamoorthy K. Inappropriate antidiuretic hormone secretion in premature infants with cerebral injury. Am J Dis Child. Apr 1978;132(4):399-402. [Medline].

  44. Neville KA, Verge CF, O'Meara MW, Walker JL. High antidiuretic hormone levels and hyponatremia in children with gastroenteritis. Pediatrics. Dec 2005;116(6):1401-7. [Medline].

  45. Nolph KD, Schrier RW. Sodium, potassium and water metabolism in the syndrome of inappropriate antidiuretic hormone secretion. Am J Med. Oct 1970;49(4):534-45. [Medline].

  46. Norlela S, Azmi KN, Khalid BA. Syndrome of inappropriate antidiuretic hormone caused by continuous lumbar spinal fluid drainage after transphenoidal surgery. Singapore Med J. Jan 2006;47(1):75-6. [Medline].

  47. Passamonte PM. Hypouricemia, inappropriate secretion of antidiuretic hormone, and small cell carcinoma of the lung. Arch Intern Med. Aug 1984;144(8):1569-70. [Medline].

  48. Paxson CL Jr, Stoerner JW, Denson SE. Syndrome of inappropriate antidiuretic hormone secretion in neonates with pneumothorax or atelectasis. J Pediatr. Sep 1977;91(3):459-63. [Medline].

  49. Powell KR, Sugarman LI, Eskenazi AE. Normalization of plasma arginine vasopressin concentrations when children with meningitis are given maintenance plus replacement fluid therapy. J Pediatr. Oct 1990;117(4):515-22. [Medline].

  50. Rascher W, Tulassay T, Lang RE. Atrial natriuretic peptide in plasma of volume-overloaded children with chronic renal failure. Lancet. Aug 10 1985;2(8450):303-5. [Medline].

  51. Raskind M, Barnes F. Water metabolism in psychiatric disorders. Sem Nephrol. 1984;4:316.

  52. Robertson GL. Physiology of ADH secretion. Kidney Int Suppl. Aug 1987;21:S20-6. [Medline].

  53. Robertson GL, Shelton RL, Athar S. The osmoregulation of vasopressin. Kidney Int. 1976;10:25-37. [Medline].

  54. Rose BD. New approach to disturbances in the plasma sodium concentration. Am J Med. Dec 1986;81(6):1033-40. [Medline].

  55. Schrier RW, Bichet DG. Osmotic and nonosmotic control of vasopressin release and the pathogenesis of impaired water excretion in adrenal, thyroid, and edematous disorders. J Lab Clin Med. Jul 1981;DA - 19810915(1):1-15. [Medline].

  56. Schwartz WB, Bennett W, Curelop S. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med. 1957;23:529-42.

  57. Sklar C, Fertig A, David R. Chronic syndrome of inappropriate secretion of antidiuretic hormone in childhood. Am J Dis Child. Jul 1985;139(7):733-5. [Medline].

  58. Sordillo P, Sagransky DM, Mercado RM. Carbamazepine-induced syndrome of inappropriate antidiuretic hormone secretion. Reversal by concomitant phenytoin therapy. Arch Intern Med. Feb 1978;138(2):299-301. [Medline].

  59. Streefkerk JO, van Zwieten PA. Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents. Auton Autacoid Pharmacol. Apr 2006;26(2):141-8. [Medline].

  60. Tho LM, Ferry DR. Is the paraneoplastic syndrome of inappropriate antidiuretic hormone secretion in lung cancer always attributable to the small cell variety?. Postgrad Med J. Nov 2005;81(961):e17. [Medline].

  61. Ting S, Eshaghpour E. Inappropriate secretion of antidiuretic hormone after open heart surgery. Am J Dis Child. 1980;134:873-4. [Medline].

  62. Tisdall M, Crocker M, Watkiss J, Smith M. Disturbances of sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol. Jan 2006;18(1):57-63. [Medline].

  63. Verbalis JG. An experimental model of syndrome of inappropriate antidiuretic hormone secretion in the rat. Am J Physiol. Oct 1984;247(4 Pt 1):E540-53. [Medline].

  64. Weinberg MS, Donohue JF. Hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: Rapid correction with osmotic agents. South Med J. 1984;78:348-351. [Medline].

  65. Weizman Z, Goitein K, Amit Y, et al. Combined treatment of severe hyponatremia due to inappropriate antidiuretic hormone secretion. Pediatrics. May 1982;69(5):610-2. [Medline].

  66. Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med. 1980;31:315-27. [Medline].

 
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Disorders associated with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
Drugs that impair water excretion.
Cerebral salt-wasting syndrome (CSWS) versus syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
 
 
 
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