Abstract
Hyponatremia is common in neurocritical care patients and is associated with significant morbidity and mortality. Despite decades of research into the syndrome of inappropriate antidiuretic hormone (SIADH) and cerebral salt wasting (CSW), their underlying pathophysiological mechanisms are still not fully understood. This paper reviews the history behind our understanding of hyponatremia in patients with neurologic injury, including the first reports of CSW and SIADH, and current and future challenges to diagnosis and management in this setting. Such challenges include distinguishing CSW, SIADH, and hypovolemic hyponatremia due to a normal pressure natriuresis from the administration of large volumes of fluids, and hyponatremia due to certain medications used in the neurocritical care population. Potential treatments for hyponatremia include mineralocorticoids and vasopressin 2 receptor antagonists, but further work is required to validate their usage. Ultimately, a greater understanding of the pathophysiological mechanisms underlining hyponatremia in neurocritical care patients remains our biggest obstacle to optimizing patient outcomes in this challenging population.
Similar content being viewed by others
References
Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Eff Resour Alloc. 2006;4:10.
Tisdall M, Crocker M, Watkiss J, Smith M. Disturbances of sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol. 2006;18(1):57–63.
Rabinstein AA, Wijdicks EF. Hyponatremia in critically ill neurological patients. Neurologist. 2003;9:290–300.
DeVita MV, Gardenswartz MH, Konecky A, Zabetakis PM. Incidence and etiology of hyponatremia in an intensive care unit. Clin Nephrol. 1990;34(4):163–6.
Bennani SL, Abouqal R, Zeggwagh AA, et al. Incidence, causes and prognostic factors of hyponatremia in intensive care. Rev Med Interne. 2003;24(4):224–9.
Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol Dial Transplant. 2006;21(1):70–6.
Zada G, Liu CY, Fishback D, Singer PA, Weiss MH. Recognition and management of delayed hyponatremia following transsphenoidal pituitary surgery. J Neurosurg. 2007;106(1):66–71.
Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119(7 Suppl 1):S30–5.
Sherlock M, O’Sullivan E, Agha A, et al. The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clin Endocrinol (Oxf). 2006;64(3):250–4.
Sata A, Hizuka N, Kawamata T, Hori T, Takano K. Hyponatremia after transsphenoidal surgery for hypothalamo-pituitary tumors. Neuroendocrinology. 2006;83(2):117–22.
Peruzzi WT, Shapiro BA, Meyer PR Jr, Krumlovsky F, Seo BW. Hyponatremia in acute spinal cord injury. Crit Care Med. 1994;22(2):252–8.
Kurokawa Y, Uede T, Ishiguro M, et al. Pathogenesis of hyponatremia following subarachnoid hemorrhage due to ruptured cerebral aneurysm. Surg Neurol. 1996;46(5):500–7; discussion 507–8.
Callewart CC, Minchew JT, Kanim LE, et al. Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion in adult spinal surgery. Spine (Phila Pa 1976) 1994;19(15):1674–9.
Diringer MN, Zazulia AR. Hyponatremia in neurologic patients: consequences and approaches to treatment. Neurologist. 2006;12:117–26.
Adrogue HJ. Consequences of inadequate management of hyponatremia. Am J Nephrol. 2005;25:240–9.
Dellabarca C, Servilla KS, Hart B, Murata GH, Tzamaloukas AH. Osmotic myelinolysis following chronic hyponatremia corrected at an overall rate consistent with current recommendations. Int Urol Nephrol. 2005;37:171–3.
Cushny AR. The secretion of the urine. London: Longman’s Green & Co; 1926.
Jungmann J, Meyer E. Experimentelle Untersuchungen ueber die Abhaengigkeit der Nierenfunktion vom Nervensystem. Archiv f Exp Path und Pharm. 1913;73:49.
Peters JP, Welt LG, Sims EA, Orloff J, Needham J. A salt-wasting syndrome associated with cerebral disease. Trans Assoc Am Physicians. 1950;63:57–64.
Welt LG, Seldin DW, Nelson WP, German WJ, Peters JP. Role of the central nervous system in metabolism of electrolytes and water. AMA Arch Intern Med. 1952;90(3):355–78.
Kaplan SA, Rapoport S. Urinary excretion of sodium and chloride after splanchnicotomy; effect on the proximal tubule. Am J Physiol. 1951;164(1):175–81.
Cort JH. Cerebral salt wasting. Lancet. 1954;266(6815):752–4.
Schwartz WB, Bennett W, Curelop S, Bartter FC. Syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med. 1957;23:529–42.
Schwartz WB, Tassel D, Bartter FC. Further observations on hyponatremia and renal sodium loss probably resulting from inappropriate secretion of antidiuretic hormone. N Engl J Med. 1960;262:743–8.
Leaf A, Bartter FC, Santos RF, Wrong O. Evidence in man that urinary electrolyte loss induced by pitressin is function of water retention. J Clin Invest. 1953;32:868–78.
Epstein FH, Levitin H. “Cerebral salt-wasting”: example of sustained inappropriate release of antidiuretic horone. J Clin Invest. 1959;38:1001.
Carter NW, Rector FC Jr, Seldin DW. Pathogenesis of persistent hyponatremia with water retention in cerebral disease. Clin Res. 1959;7:273.
Carter NW, Rector FC Jr, Seldin DW. Hyponatremia in cerebral disease resulting from the inappropriate secretion of antidiuretic hormone. N Engl J Med. 1961;264:67–72.
Nelson PB, Seif SM, Maroon JC, Robinson AG. Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Neurosurg. 1981;55(6):938–41.
Oh MS, Carroll HJ. Cerebral salt-wasting syndrome. We need better proof of its existence. Nephron. 1999;82(2):110–4.
Betjes MG. Hyponatremia in acute brain disease: the cerebral salt wasting syndrome. Eur J Intern Med. 2002;13(1):9–14.
Wijdicks EF, Vermeulen M, ten Haaf JA, et al. Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm. Ann Neurol. 1985;18(2):211–6.
Sivakumar V, Rajshekhar V, Chandy MJ. Management of neurosurgical patients with hyponatremia and natriuresis. Neurosurgery. 1994;34(2):269–74.
Audibert G, Steinmann G, de Talance N, et al. Endocrine response after severe subarachnoid hemorrhage related to sodium and blood volume regulation. Anesth Analg. 2009;108(6):1922–8.
Doczi T, Bende J, Huszka E, Kiss J. Syndrome of inappropriate secretion of antidiuretic hormone after subarachnoid hemorrhage. Neurosurgery. 1981;9(4):394–7.
Sherlock M, O’Sullivan E, Agha A, et al. Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgrad Med J. 2009;85:171–5.
Brimioulle S, Orellana-Jimenez C, Aminian A, Vincent JL. Hyponatremia in neurological patients: cerebral salt wasting versus inappropriate antidiuretic hormone secretion. Intensive Care Med. 2008;34(1):125–31.
Rahman M, Friedman WA. Hyponatremia in neurosurgical patients: clinical guidelines development. Neurosurgery. 2009;65:925–36.
Singh S, Bohn D, Carlotti AP, et al. Cerebral salt wasting: truths, fallacies, theories, and challenges. Crit Care Med. 2002;30(11):2575–9.
Shamiss A, Peleg E, Rosenthal T, Ezra D. The role of atrial natriuretic peptide in the diuretic effect of Ca2+ entry blockers. Eur J Pharmacol. 1993;233(1):113–7.
Fiad TM, Cunningham SK, Hayes FJ, McKenna TJ. Effects of nifedipine treatment on the renin-angiotensin-aldosterone axis. J Clin Endocrinol Metab. 1997;82(2):457–60.
Kosaka H, Hirayama K, Yoda N, et al. The L-, N-, and T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family. Eur J Pharmacol. 2010;635(1–3):49–55.
Sterns RH, Silver SM. Cerebral salt wasting versus SIADH: what difference? J Am Soc Nephrol. 2008;19(2):194–6.
Taplin CE, Cowell CT, Silink M, Ambler GR. Fludrocortisone therapy in cerebral salt wasting. Pediatrics. 2006;118(6):e1904–8.
Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med. 1987;83(5):905–8.
Verbalis JG. Vasopressin V2 receptor antagonists. J Mol Endocrinol. 2002;29(1):1–9.
Schrier RW. Body fluid volume regulation in health and disease: a unifying hypothesis. Ann Intern Med. 1990;113(2):155–9.
Harrigan MR. Cerebral salt wasting syndrome: a review. Neurosurgery. 1996;38(1):152–60.
Maesaka JK, Gupta S, Fishbane S. Cerebral salt-wasting syndrome: does it exist? Nephron. 1999;82(2):100–9.
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(2):312–6; discussion 316–7.
Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. 2008;134(1):172–8.
Sakka SG, Reuter DA, Perel A. The transpulmonary thermodilution technique. J Clin Monit Comput. 2012;26(5):347–53.
Bennington S, Ferris P, Nirmalan M. Emerging trends in minimally invasive haemodynamic monitoring and optimization of fluid therapy. Eur J Anaesthesiol. 2009;26(11):893–905.
Sayama T, Inamura T, Matsushima T, et al. High incidence of hyponatremia in patients with ruptured anterior communicating artery aneurysms. Neurol Res. 2000;22(2):151–5.
Qureshi AI, Suri MF, Sung GY, et al. Prognostic significance of hypernatremia and hyponatremia among patients with aneurysmal subarachnoid hemorrhage. Neurosurgery. 2002;50(4):749–55; discussion 755–6.
Hasan D, Wijdicks EF, Vermeulen M. Hyponatremia is associated with cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage. Ann Neurol. 1990;27(1):106–8.
Wijdicks EF, Vermeulen M, Hijdra A, van Gijn J. Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysms: is fluid restriction harmful? Ann Neurol. 1985;17(2):137–40.
Isotani E, Suzuki R, Tomita K, et al. Alterations in plasma concentrations of natriuretic peptides and antidiuretic hormone after subarachnoid hemorrhage. Stroke. 1994;25(11):2198–203.
Wijdicks EF, Ropper AH, Hunnicutt EJ, Richardson GS, Nathanson JA. Atrial natriuretic factor and salt wasting after aneurysmal subarachnoid hemorrhage. Stroke. 1991;22(12):1519–24.
Wijdicks EF, Schievink WI, Burnett JC Jr. Natriuretic peptide system and endothelin in aneurysmal subarachnoid hemorrhage. J Neurosurg. 1997;87(2):275–80.
Espiner EA, Leikis R, Ferch RD, et al. The neuro-cardio-endocrine response to acute subarachnoid haemorrhage. Clin Endocrinol (Oxf). 2002;56(5):629–35.
Diringer M, Ladenson PW, Stern BJ, Schleimer J, Hanley DF. Plasma atrial natriuretic factor and subarachnoid hemorrhage. Stroke. 1988;19(9):1119–24.
Nakagawa I, Kurokawa S, Nakase H. Hyponatremia is predictable in patients with aneurysmal subarachnoid hemorrhage—clinical significance of serum atrial natriuretic peptide. Acta Neurochir (Wien). 2010;152(12):2147–52.
Berendes E, Walter M, Cullen P, et al. Secretion of brain natriuretic peptide in patients with aneurysmal subarachnoid haemorrhage. Lancet. 1997;349(9047):245–9.
Tomida M, Muraki M, Uemura K, Yamasaki K. Plasma concentrations of brain natriuretic peptide in patients with subarachnoid hemorrhage. Stroke. 1998;29(8):1584–7.
Sviri GE, Feinsod M, Soustiel JF. Brain natriuretic peptide and cerebral vasospasm in subarachnoid hemorrhage. Clinical and TCD correlations. Stroke. 2000;31(1):118–22.
McGirt MJ, Blessing R, Nimjee SM, et al. Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage. Neurosurgery. 2004;54(6):1369–73; discussion 1373–4.
Tung PP, Olmsted E, Kopelnik A, et al. Plasma B-type natriuretic peptide levels are associated with early cardiac dysfunction after subarachnoid haemorrhage. Stroke. 2005;36(7):1567–9.
Inoha S, Inamura T, Nakamizo A, et al. Fluid loading in rats increases serum brain natriuretic peptide concentration. Neurol Res. 2001;23(1):93–5.
Powner DJ, Hergenroeder GW, Awili M, Atik MA, Robertson C. Hyponatremia and comparison of NT-pro-BNP concentrations in blood samples from jugular bulb and arterial sites after traumatic brain injury in adults: a pilot study. Neurocrit Care. 2007;7(2):119–23.
Juul R, Edvinsson L, Ekman R, et al. Atrial natriuretic peptide-LI following subarachnoid haemorrhage in man. Acta Neurochir (Wien). 1990;106(1–2):18–23.
Oropello JM, Weiner L, Benjamin E. Hypertensive, hypervolemic, hemodilutional therapy for aneurysmal subarachnoid hemorrhage. Is it efficacious? No. Crit Care Clin. 1996;12(3):709–30.
Clifton GL, Ziegler MG, Grossman RG. Circulating catecholamines and sympathetic activity after head injury. Neurosurgery. 1981;8(1):10–4.
Israel A, Torres M, Cierco M, Barbella Y. Further evidence for a dopaminergic involvement in the renal action of centrally administered atrial natriuretic peptide in rats. Brain Res Bull. 1991;27(5):739–42.
Aperia AC. Renal dopamine system and salt balance. Am J Kidney Dis. 1998; 31:xlii–v.
Egge A, Waterloo K, Sjoholm H, et al. Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery. 2001;49(3):605–6.
Muench E, Horn P, Bauhuf C, et al. Effects of hypervolemia and hypertension on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation after subarachnoid hemorrhage. Crit Care Med. 2007;35(8):1844–51.
Diringer MN, Bleck TP, Claude Hemphill J 3rd, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15(2):211–40.
Cole CD, Gottfried ON, Liu JK, Couldwell WT. Hyponatremia in the neurosurgical patient: diagnosis and management. Neurosurg Focus. 2004;16(4):E9.
Mount DB. Fluid and Electrolyte Disturbances. In: Longo DL et al., editors. Harrison’s Principles of Internal Medicine, 18th ed. Boston: McGraw-Hill Medical; 2011. p. 341–359.
Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064–72.
Mori T, Katayama Y, Kawamata T, Hirayama T. Improved efficiency of hypervolemic therapy with inhibition of natriuresis by fludrocortisone in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 1999;91(6):947–52.
Wijdicks EF, Vermeulen M, van Brummelen P, van Gijn J. The effect of fludrocortisone acetate on plasma volume and natriuresis in patients with aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg. 1988;90(3):209–14.
Woo MH, Kale-Pradhan PB. Fludrocortisone in the treatment of subarachnoid hemorrhage-induced hyponatremia. Ann Pharmacother. 1997;31(5):637–9.
Katayama Y, Haraoka J, Hirabayashi H, et al. A randomized controlled trial of hydrocortisone against hyponatremia in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38(8):2373–5.
Moro N, Katayama Y, Kojima J, Mori T, Kawamata T. Prophylactic management of excessive natriuresis with hydrocortisone for efficient hypervolemic therapy after subarachnoid hemorrhage. Stroke. 2003;34(12):2807–11.
Ogden AT, Mayer SA, Connolly ES Jr. Hyperosmolar agents in neurosurgical practice: the evolving role of hypertonic saline. Neurosurgery. 2005;57(2):207–15.
Steele A, Gowrishankar M, Abrahamson S, et al. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Ann Intern Med. 1997;126(1):20–5.
Robertson GL. Vaptans for the treatment of hyponatremia. Nat Rev Endocrinol. 2011;7:151–61.
Porzio P, Halberthal M, Bohn D, Halperin ML. Treatment of acute hyponatremia: ensuring the excretion of a predictable amount of electrolyte-free water. Crit Care Med. 2000;28(6):1905–10.
Pokaharel M, Block CA. Dysnatremia in the ICU. Curr Opin Crit Care. 2011;17(6):581–93.
Torres AC, Wickham EP, Biskobing DM. Tolvaptan for the management of syndrome of inappropriate antidiuretic hormone secretion: lessons learned in titration of dose. Endocr Pract. 2011;17(4):e97–100.
Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010;21(4):705–12.
Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099–112.
Graziani G, Cucchiari D, Aroldi A, et al. Syndrome of inappropriate secretion of antidiuretic hormone in traumatic brain injury: when tolvaptan becomes a life saving drug. J Neurol Neurosurg Psychiatry. 2012;83(5):510–2.
Potts MB, DeGiacomo AF, Deragopian L, Blevins LS Jr. Use of Intravenous conivaptan in neurosurgical patients with hyponatremia from syndrome of inappropriate antidiuretic hormone secretion. Neurosurgery. 2011;69:268–73.
Schrier RW, Masoumi A, Elhassan E. Role of vasopressin and vasopressin receptor antagonists in type I cardiorenal syndrome. Blood Purif. 2009;27(1):28–32.
Fraser JF, Stieg PE. Hyponatremia in the neurosurgical patient: epidemiology, pathophysiology, diagnosis, and management. Neurosurgery. 2006;59(2):222–9; discussion 222–9.
Braley LM, Adler GK, Mortensen RM, et al. Dose effect of adrenocorticotropin on aldosterone and cortisol biosynthesis in cultured bovine adrenal glomerulosa cells: in vitro correlate of hyperreninemic hypoaldosteronism. Endocrinology. 1992;131(1):187–94.
Zhang Y, Mircheff AK, Hensley CB, et al. Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis. Am J Physiol. 1996;270(6 Pt 2):F1004–14.
Conflict of interest
No authors have any conflicts of interest or financial disclosures.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kirkman, M.A., Albert, A.F., Ibrahim, A. et al. Hyponatremia and Brain Injury: Historical and Contemporary Perspectives. Neurocrit Care 18, 406–416 (2013). https://doi.org/10.1007/s12028-012-9805-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12028-012-9805-y