The American Journal of Medicine
Volume 120, Issue 11, Supplement 1 , Pages S1-S21 , November 2007

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

  • Joseph G. Verbalis, MD

      Affiliations

    • Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA
    • Corresponding Author InformationRequests for reprints should be addressed to Joseph G. Verbalis, MD, Department of Medicine, 5 PHC, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, District of Columbia 20007.
  • ,
  • Stephen R. Goldsmith, MD

      Affiliations

    • Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
  • ,
  • Arthur Greenberg, MD

      Affiliations

    • Division of Nephrology, Department of Medicine, Duke University, Durham, North Carolina, USA
  • ,
  • Robert W. Schrier, MD

      Affiliations

    • Department of Medicine, University of Colorado, Denver, Colorado, USA
  • ,
  • Richard H. Sterns, MD

      Affiliations

    • Department of Medicine, University of Rochester, Rochester, New York, USA

References 

  1. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119(suppl 1):S30–S35
  2. Verbalis JG. The syndrome of inappropriate antidiuretic hormone secretion and other hypoosmolar disorders. In:  Schrier RW editors. Diseases of the Kidney and Urinary Tract. Philadelphia, Pa: Lippincott Williams & Wilkins; 2007;p. 2214–2248
  3. Sterns RH, Silver SM. Brain volume regulation in response to hypo-osmolality and its correction. Am J Med. 2006;119(suppl 1):S12–S16
  4. Schrier RW. Treatment of hyponatremia. [review] N Engl J Med. 1985;312:1121–1123
  5. Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am J Med. 2006;119(suppl 1):S36–S42
  6. Schrier RW. Water and sodium retention in edematous disorders: role of vasopressin and aldosterone. Am J Med. 2006;119(suppl 1):S47–S53
  7. Weisberg LS. Pseudohyponatremia: a reappraisal. [review] Am J Med. 1989;86:315–318
  8. Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999;106:399–403
  9. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. 2006;17:1820–1832
  10. Beck LH. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1979;301:528–530
  11. Schrier RW. Body fluid volume regulation in health and disease: a unifying hypothesis. Ann Intern Med. 1990;113:155–159
  12. Almond CS, Shin AY, Fortescue EB, et al. Hyponatremia among runners in the Boston Marathon. N Engl J Med. 2005;352:1550–1556
  13. Sonnenblick M, Friedlander Y, Rosin AJ. Diuretic-induced severe hyponatremia (Review and analysis of 129 reported patients). [review] Chest. 1993;103:601–606
  14. Sharabi Y, Illan R, Kamari Y, et al. Diuretic induced hyponatraemia in elderly hypertensive women. J Hum Hypertens. 2002;16:631–635
  15. Chow KM, Szeto CC, Wong TY, Leung CB, Li PK. Risk factors for thiazide-induced hyponatraemia. QJM. 2003;96:911–917
  16. Friedman E, Shadel M, Halkin H, Farfel Z. Thiazide-induced hyponatremia (Reproducibility by single dose rechallenge and an analysis of pathogenesis). Ann Intern Med. 1989;110:24–30
  17. Damaraju SC, Rajshekhar V, Chandy MJ. Validation study of a central venous pressure-based protocol for the management of neurosurgical patients with hyponatremia and natriuresis. Neurosurgery. 1997;40:312–316discussion: 316–317
  18. Palmer BF. Hyponatraemia in a neurosurgical patient: syndrome of inappropriate antidiuretic hormone secretion versus cerebral salt wasting. Nephrol Dial Transplant. 2000;15:262–268
  19. Maesaka JK, Gupta S, Fishbane S. Cerebral salt-wasting syndrome: does it exist?. Nephron. 1999;82:100–109
  20. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967;42:790–806
  21. Michelis MF, Fusco RD, Bragdon RW, Davis BB. Reset of osmoreceptors in association with normovolemic hyponatremia. Am J Med Sci. 1974;267:267–273
  22. Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005;352:1884–1890
  23. Decaux G, Vandergheynst F, Bouko Y, Parma J, Vassart G, Vilain C. Nephrogenic syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large pedigree. J Am Soc Nephrol. 2007;18:606–612
  24. Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med. 1980;31:315–327
  25. Ikkos D, Luft R, Olivecrona H. Hypophysectomy in man: effect on water excretion during the first two postoperative months. J Clin Endocrinol Metab. 1955;15:553–567
  26. Diederich S, Franzen NF, Bahr V, Oelkers W. Severe hyponatremia due to hypopituitarism with adrenal insufficiency: report on 28 cases. Eur J Endocrinol. 2003;148:609–617
  27. Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med. 1989;321:492–496
  28. Ishikawa S, Schrier RW. Effect of arginine vasopressin antagonist on renal water excretion in glucocorticoid and mineralocorticoid deficient rats. Kidney Int. 1982;22:587–593
  29. Hanna FW, Scanlon MF. Hyponatraemia, hypothyroidism, and role of arginine-vasopressin. Lancet. 1997;350:755–756
  30. Chinitz A, Turner FL. The association of primary hypothyroidism and inappropriate secretion of the antidiuretic hormone. Arch Intern Med. 1965;116:871–874
  31. Derubertis FR, Michelis MF, Bloom ME, Mintz DH, Field JB, Davis BB. Impaired water excretion in myxedema. Am J Med. 1971;51:41–53
  32. Chen Y-C, Cadnapaphornchai MA, Yang J, et al. Nonosmotic release of vasopressin and renal aquaporins in impaired urinary dilution in hypothyroidism. Am J Physiol Renal Physiol. 2005;289:F672–F678
  33. Irving RA, Noakes TD, Buck R, et al. Evaluation of renal function and fluid homeostasis during recovery from exercise-induced hyponatremia. J Appl Physiol. 1991;70:342–348
  34. Speedy DB, Noakes TD, Rogers IR, et al. Hyponatremia in ultradistance triathletes. Med Sci Sports Exerc. 1999;31:809–815
  35. Noakes T. Fluid replacement during marathon running. Clin J Sport Med. 2003;13:309–318
  36. Hew-Butler T, Almond C, Ayus JC, et al. Consensus statement of the 1st International Exercise-Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa 2005. Clin J Sport Med. 2005;15:208–213
  37. Demanet JC, Bonnyns M, Bleiberg H, Stevens-Rocmans C. Coma due to water intoxication in beer drinkers. Lancet. 1971;2:1115–1117
  38. Thaler SM, Teitelbaum I, Berl T. “Beer potomania” in non-beer drinkers: effect of low dietary solute intake. Am J Kidney Dis. 1998;31:1028–1031
  39. Barlow ED, DeWardener HE. Compulsive water drinking. Q J Med. 1959;28:235–258
  40. Vieweg WV, Robertson GL, Godleski LS, Yank GR. Diurnal variation in water homeostasis among schizophrenic patients subject to water intoxication. Schizophr Res. 1988;1:351–357
  41. de Leon J, Verghese C, Tracy JI, Josiassen RC, Simpson GM. Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature. Biol Psychiatry. 1994;35:408–419
  42. Stuart CA, Neelon FA, Lebovitz HE. Disordered control of thirst in hypothalamic-pituitary sarcoidosis. N Eng J Med. 1980;303:1078–1082
  43. Noakes TD, Wilson G, Gray DA, Lambert MI, Dennis SL. Peak rates of diuresis in healthy humans during oral fluid overload. S Afr Med J. 2001;91:852–857
  44. Cheng JC, Zikos D, Skopicki HA, Peterson DR, Fisher KA. Long-term neurologic outcome in psychogenic water drinkers with severe symptomatic hyponatremia: the effect of rapid correction. Am J Med. 1990;88:561–566
  45. Goldman MB, Luchins DJ, Robertson GL. Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med. 1988;318:397–403
  46. Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation. 1986;73:257–267
  47. Lee DS, Austin PC, Rouleau JL, Liu PP, Haimark D, Tu JV. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA. 2003;290:2581–2587
  48. Zucker IH, Share L, Gilmore JP. Renal effects of left atrial distension in dogs with chronic congestive heart failure. Am J Physiol. 1979;236:H554–H560
  49. Zucker IH, Gorman AJ, Cornish KG, Lang M. Impaired atrial receptor modulation or renal nerve activity in dogs with chronic volume overload. Cardiovasc Res. 1985;19:411–418
  50. Abraham WT, Lowes BD, Ferguson DA, et al. Systemic hemodynamic, neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients with hemodynamically decompensated heart failure. J Card Fail. 1998;4:37–44
  51. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med. 1999;341:577–585
  52. Berl T, Henrich WL, Erickson AL, Schrier RW. Prostaglandins in the beta-adrenergic and baroreceptor-mediated secretion of renin. Am J Physiol. 1979;236:F472–F477
  53. Schrier RW. Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (1). [review] N Engl J Med. 1988;319:1065–1072[published correction appears in N Engl J Med. 1989;320:676]
  54. Schrier RW. Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (2). [review] N Engl J Med. 1988;319:1127–1134[published correction appears in N Engl J Med. 1989;320:676]
  55. Myers BD, Deen WM, Brenner BM. Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafiltration and proximal tubule fluid reabsorption in the rat. Circ Res. 1975;37:101–110
  56. Ruf AE, Kremers WK, Chavez LL, Descalzi VI, Podesta LG, Villamil FG. Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transpl. 2005;11:336–343
  57. Porcel A, Diaz F, Rendon P, Macías M, Martín-Herrara L, Girón-González JA. Dilutional hyponatremia in patients with cirrhosis and ascites. Arch Intern Med. 2002;162:323–328
  58. Schrier RW, Niederberger M, Weigert A, Gines P. Peripheral arterial vasodilatation: determinant of functional spectrum of cirrhosis. [review] Semin Liver Dis. 1994;14:14–22
  59. Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med. 1998;339:533–541
  60. Gerbes AL, Gulberg V, Gines P, et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist (A randomized double-blind multicenter trial). Gastroenterology. 2003;124:933–939
  61. McManus ML, Churchwell KB, Strange K. Regulation of cell volume in health and disease. N Engl J Med. 1995;333:1260–1266
  62. Pasantes-Morales H, Lezama RA, Ramos-Mandujano G, Tuz KL. Mechanisms of cell volume regulation in hypo-osmolality. Am J Med. 2006;119(suppl 1):S4–S11
  63. Sjoblom E, Hojer J, Ludwigs U, Pirskanen R. Fatal hyponatraemic brain oedema due to common gastroenteritis with accidental water intoxication. Intensive Care Med. 1997;23:348–350
  64. Sterns RH. Severe symptomatic hyponatremia: treatment and outcome (A study of 64 cases). Ann Intern Med. 1987;107:656–664
  65. Helwig FC, Schutz CB, Kuhn HP. Water intoxication: moribund patient cured by administration of hypertonic salt solution. JAMA. 1938;110:644–645
  66. Battison C, Andrews PJ, Graham C, Petty T. Randomized, controlled trial on the effect of a 20% mannitol solution and a 7.5% saline/6% dextran solution on increased intracranial pressure after brain injury. Crit Care Med. 2005;33:196–202
  67. Sterns RH, Riggs JE, Schochet SS. Osmotic demyelination syndrome following correction of hyponatremia. N Eng J Med. 1986;314:1535–1542
  68. Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol. 1994;4:1522–1530
  69. Brunner JE, Redmond JM, Haggar AM, Elias SB. Central pontine myelinolysis and pontine lesions after rapid correction of hyponatremia: a prospective magnetic resonance imaging study. Ann Neurol. 1990;27:61–66
  70. Lien YH. Role of organic osmolytes in myelinolysis: a topographic study in rats after rapid correction of hyponatremia. J Clin Invest. 1995;95:1579–1586
  71. Soupart A, Silver S, Schrooeder B, Sterns R, DeCaux G. Rapid (24-hour) reaccumulation of brain organic osmolytes (particularly myo-inositol) in azotemic rats after correction of chronic hyponatremia. J Am Soc Nephrol. 2002;13:1433–1441
  72. Ellis SJ. Severe hyponatraemia: complications and treatment. QJM. 1995;88:905–909
  73. Tanneau RS, Henry A, Rouhart F, et al. High incidence of neurologic complications following rapid correction of severe hyponatremia in polydipsic patients. J Clin Psychiatry. 1994;55:349–354
  74. Cluitmans FH, Meinders AE. Management of severe hyponatremia: rapid or slow correction [review]?. [See comments.] Am J Med. 1990;88:161–166
  75. Karp BI, Laureno R. Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia. Medicine. 1993;72:359–373
  76. Ayus JC, Krothapalli RK, Arieff AI. Treatment of symptomatic hyponatremia and its relation to brain damage: a prospective study. N Engl J Med. 1987;317:1190–1195
  77. Nzerue CM, Baffoe-Bonnie H, You W, Falana B, Dai S. Predictors of outcome in hospitalized patients with severe hyponatremia. J Natl Med Assoc. 2003;95:335–343
  78. Ayus JC, Arieff AI. Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. [See comments.] JAMA. 1999;281:2299–2304
  79. Verbalis JG. Hyponatremia: endocrinologic causes and consequences of therapy. Trends Endocrinol Metab. 1992;3:1–7
  80. Lin SH, Chau T, Wu CC, Yang SS. Osmotic demyelination syndrome after correction of chronic hyponatremia with normal saline. Am J Med Sci. 2002;323:259–262
  81. Ashraf N, Locksley R, Arieff AI. Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med. 1981;70:1163–1168
  82. Ayus JC, Krothapalli RK, Arieff AI. Changing concepts in treatment of severe symptomatic hyponatremia: rapid correction and possible relation to central pontine myelinolysis. Am J Med. 1985;78:897–902
  83. Robertson GL. Posterior pituitary. In:  Felig P,  Baxter J,  Broadus A,  Frohman L editor. Endocrinology and Metabolism. New York, NY: McGraw-Hill; 1986;p. 338–385
  84. List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA, Johnson DH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol. 1986;4:1191–1198
  85. Cherrill DA, Stote RM, Birge JR, Singer I. Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion. Ann Intern Med. 1975;83:654–656
  86. Dousa TP, Wilson DM. Effect of demethylchlorotetracycline on cellular action of antidiuretic hormone in vitro. Kidney Int. 1974;5:279–284
  87. Miller PD, Linas SL, Schrier RW. Plasma demeclocycline levels and nephrotoxicity: correlation in hyponatremic cirrhotic patients. JAMA. 1980;243:2513–2515
  88. Forrest JN, Cox M, Hong C, Morrison G, Bia M, Singer I. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1978;298:173–177
  89. Decaux G, Mols P, Cauchi P, Delwiche F. Use of urea for treatment of water retention in hyponatraemic cirrhosis with ascites resistant to diuretics. BMJ. 1985;290:1782–1783
  90. Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of osmoregulation. Am J Med. 1982;72:339–353
  91. Bosch-Marce M, Poo JL, Jimenez W, et al. Comparison of two aquaretic drugs (niravoline and OPC-31260) in cirrhotic rats with ascites and water retention. J Pharmacol Exp Ther. 1999;289:194–201
  92. Gadano A, Moreau R, Pessione F, et al. Aquaretic effects of niravoline, a kappa-opioid agonist, in patients with cirrhosis. J Hepatol. 2000;32:38–42
  93. Huang EA, Feldman BJ, Schwartz ID, Geller DH, Rosenthal SM, Gitelman SE. Oral urea for the treatment of chronic syndrome of inappropriate antidiuresis in children. J Pediatr. 2006;148:128–131
  94. Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med. 2000;132:711–714
  95. Davis TM, Singh B, Sheridan G. Parasitic procrastination: late-presenting ovale malaria and schistosomiasis. Med J Aust. 2001;175:146–148
  96. Robertson GL. Abnormalities of thirst regulation. Kidney Int. 1984;25:460–469
  97. Canuso CM, Goldman MB. Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome. J Neuropsychiatry Clin Neurosci. 1999;11:86–90
  98. Kawai N, Baba A, Suzuki T. Risperidone failed to improve polydipsia-hyponatremia of the schizophrenic patients. Psychiatry Clin Neurosci. 2002;56:107–110
  99. Decaux G. Is asymptomatic hyponatremia really asymptomatic?. Am J Med. 2006;119(suppl 1):S79–S82
  100. Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol. 2005;46:1785–1791
  101. Licata G, Di Pasquale P, Parrinello G, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: long-term effects. Am Heart J. 2003;145:459–466
  102. Choudhury J, Sanyal AJ. Treatment of ascites. Curr Treat Options Gastroenterol. 2003;6:481–491
  103. Thibonnier M, Conarty DM, Preston JA, Wilkins PL, Berti-Mattera LN, Mattera R. Molecular pharmacology of human vasopressin receptors. Adv Exp Med Biol. 1998;449:251–276
  104. Knepper MA. Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin. Am J Physiol. 1997;272(pt 2):F3–F12
  105. Kinter LB, Ileson BE, Caltabinol S, et al. Antidiuretic hormone antagonism in humans: are there predictors?. In:  Jard S,  Jamison R editor. Vasopressin. Paris: John Libbey Eurotext; 1991;p. 321–329
  106. Ohnishi A, Orita Y, Okahara R, et al. Potent aquaretic agent: a novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men. J Clin Invest. 1993;92:2653–2659
  107. Macion-Dazard R, Callahan N, Xu Z, Wu N, Thibonnier M, Shoham M. Mapping the binding site of six nonpeptide antagonists to the human V2-renal vasopressin receptor. J Pharmacol Exp Ther. 2006;316:564–571
  108. Lee CR, Watkins ML, Patterson JH, et al. Vasopressin: a new target for the treatment of heart failure. Am Heart J. 2003;146:9–18
  109. Ghali JK, Koren MJ, Taylor JR, et al. Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab. 2006;91:2145–2152
  110. Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int. 2006;69:2124–2130
  111. Palm C, Pistrosch F, Herbrig K, Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Am J Med. 2006;119(suppl 1):S87–S92
  112. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355:2099–2112
  113. Gheorghiade M, Niazi I, Ouyang J, et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation. 2003;107:2690–2696
  114. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342:1581–1589
  115. Goldsmith SR. Vasopressin receptor antagonists: mechanisms of action and potential effects in heart failure. Cleve Clin J Med. 2006;73(suppl 2):S20–S23
  116. Gheorghiade M, Gattis WA, O’Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA. 2004;291:1963–1971
  117. Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297:1319–1331
  118. Singh A, Blackwell J, Neher J. Clinical inquiries: does furosemide decrease morbidity or mortality for patients with diastolic or systolic dysfunction?. J Fam Pract. 2005;54:370–372
  119. Goldsmith SR. Is there a cardiovascular rationale for the use of combined vasopressin V1a/V2 receptor antagonists?. Am J Med. 2006;119(suppl 1):S93–S96
  120. Renneboog B, Musch W, Vandemergel X, Manto MU, DeCaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119:71;e1–e8

 Statement of author disclosure: Please see the Author Disclosure section at the end of this article.

PII: S0002-9343(07)00845-5

doi: 10.1016/j.amjmed.2007.09.001

The American Journal of Medicine
Volume 120, Issue 11, Supplement 1 , Pages S1-S21 , November 2007