Association of Hyponatremia on Mortality in Cryptococcal Meningitis: A Prospective Cohort

Abstract

Background: Sodium abnormalities are frequent in central nervous system infections and may be caused by cerebral salt wasting, syndrome of inappropriate antidiuretic hormone secretion, or medication adverse events. In cryptococcal meningitis (CM), the prevalence of baseline hyponatremia and whether hyponatremia adversely impacts survival is unknown.

Methods: We conducted a secondary analysis of data from 2 randomized trials of human immunodeficiency virus-infected adult Ugandans with CM. We grouped serum sodium into 3 categories: <125, 125-129, and 130-145 mmol/L. We assessed whether baseline sodium abnormalities were associated with clinical characteristics and survival.

Results: Of 816 participants with CM, 741 (91%) had a baseline sodium measurement available: 121 (16%) had grade 3-4 hyponatremia (<125 mmol/L), 194 (26%) had grade 2 hyponatremia (125-129 mmol/L), and 426 (57%) had a baseline sodium of 130-145 mmol/L. Hyponatremia (<125 mmol/L) was associated with higher initial cerebrospinal fluid (CSF) quantitative culture burden (P < .001), higher initial CSF opening pressure (P < .01), lower baseline Glasgow Coma Scale score (P < .01), and a higher percentage of baseline seizures (P = .03). Serum sodium <125 mmol/L was associated with increased 2-week mortality in unadjusted and adjusted survival analyses (adjusted hazard ratio, 1.87 [95% confidence interval, 1.26-2.79]; P < .01) compared to those with sodium 130-145 mmol/L.

Conclusions: Hyponatremia is common in CM and is associated with excess mortality. A standardized management approach to correctly diagnose and correct hyponatremia in CM needs to be developed and tested.

Keywords: cryptococcal meningitis; hyponatremia; mortality; prognostic marker; sodium.

Figure 1.

Thirty-day survival by baseline serum sodium category.

Figure 2.

Pragmatic approach to the evaluation and management of severe hyponatremia in adults with human immunodeficiency virus–associated cryptococcal meningitis (CM). ^aMonitoring of serum sodium (Na+) recommended daily until stable. ^bInitiation of amphotericin-based antifungal therapy requires administration of normal saline prior to and after infusion. Correction of serum Na+ levels is less urgent in the first 48 hours as patients with chronic hyponatremia are at risk of osmotic demyelination syndrome. ^cPersistent serum Na+ <125 mmol/L by day 7 of CM care. ^dExcludes drugs known to enhance activity of arginine vasopressin including carbamazepine. ^ePatients with syndrome of inappropriate antidiuretic hormone secretion may respond to continued treatment of CM. ^fVasopressin receptor antagonist. Abbreviations: CSW, Cerebral salt wasting; GI, Gastrointestinal; ICP, Intracranial pressure; Na+, Sodium; NS, Normal Saline; SIADH, syndrome of inappropriate antidiuretic hormone secretion; V2, vasopressin.