Standardized electrolyte supplementation and fluid management improves survival during amphotericin therapy for cryptococcal meningitis in resource-limited settings

Abstract

Background: Amphotericin B is the preferred treatment for cryptococcal meningitis, but it has cumulative severe side effects, including nephrotoxicity, hypokalemia, and hypomagnesemia. Amphotericin-induced severe hypokalemia may predispose the patient to cardiac arrhythmias and death, and there is very little data available regarding these toxicities in resource-limited settings. We hypothesized that standardized electrolyte management during amphotericin therapy is essential to minimize toxicity and optimize survival in sub-Saharan Africa.

Methods: Human immunodeficiency virus-infected, antiretroviral therapy naive adults with cryptococcal meningitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphotericin B deoxycholate induction treatment. Intravenous fluid use was intermittent in 2001-2002, and universal in 2006-2012. In 2001-2009, serum potassium (K(+)) was monitored on days 1, 7, and 14 of treatment with replacement (K(+), Mg(2+)) per clinician discretion. In 2011-2012, K(+) was measured on days 1, 5, and approximately every 48 hours thereafter with universal electrolyte (K(+), Mg(2+)) supplementation and standardized replacement. Clinical outcomes were retrospectively compared between fluid and electrolyte management strategies.

Results: With limited intravenous fluids, the 14-day survival was 49% in 2001-2002. With universal intravenous fluids, the 30-day survival improved to 62% in 2006-2010 (P = .003). In 2011-2012, with universal supplementation of fluids and electrolytes, 30-day cumulative survival improved to 78% (P = .021 vs 2006-2010 cohort). The cumulative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011-2012 with universal supplementation (P < .001).

Conclusions: Improved survival was seen in a resource-limited setting with proactive fluid and electrolyte management (K(+), Mg(2+)), as part of comprehensive amphotericin-based cryptococcal therapy.

Keywords: HIV/AIDS; amphotericin; cryptococcal meningitis; potassium; side effect.

Figure 1.

Graphical explanation of cohort timeline. Timeline outlining the division of cohorts by the years over which each cohort took place, antifungal medications given during induction therapy, IV fluid strategy, and electrolyte supplementation and monitoring strategy. Of note, none of the cohorts included patients between 2003 and 2005 because there was no clinical study of patients with cryptococcal meningitis at Mulago hospital during that time period. Abbreviation: IV, intravenous.

Figure 2.

Cumulative incidence of severe hypokalemia (K⁺ <2.5 meq/L) among 3 cohorts. In 2001–2002 (cohort 1), with minimal electrolyte monitoring on day 7 and 14 only, the detected incidence of severe hypokalemia was 1.1% (1 of 92), being only 1.8% (1 of 56) among those surviving to day 7 and zero of 46 who survived to day 14. In cohort 1, K⁺ monitoring did not occur between days 8 and 13. In November 2010–January 2011, among COAT trial participants in cohort 2 who received IV fluids and intensive electrolyte monitoring every 48 hours from day 5, the incidence of severe hypokalemia was 38% (8 of 21). After the implementation of universal supplementation (February 21, 2011) and enhanced attention to weight-based dosing of amphotericin (cohort 3), the incidence of severe hypokalemia declined to 8.5% (12 of 142, P < .001 compared to without supplementation). No persons developed clinically significant hyperkalemia with electrolyte supplementation. The majority of the hypokalemia occurs during the second week of amphotericin therapy, thus with minimal monitoring in cohort 1, the lack of detected hypokalemia does not indicate the absence of hypokalemia. Severe hypokalemia rarely occurs before day 7. Without intensive K⁺ monitoring, absence of hypokalemia at day 14 likely may represent a survival bias. Abbreviation: IV, intravenous.

Figure 3.

Cumulative survival after cryptococcal meningitis by cohort time period. Fourteen-day survival in 2002 (cohort 1) was 49% (95% confidence interval [CI], 39%–59%), including 8 persons who left against medical advice (presumed dead). In 2006–2010 (cohort 2), with universal IV fluids, the 30-day cumulative survival was 62% (95% CI, 55%–69%; P = .003 vs 2001–2002 cohort). In 2011–2012 (cohort 3), with universal IV fluids and electrolyte supplementation, 30-day cumulative survival improved to 78% (95% CI, 70%–85%; P = .021 vs 2006–2010 cohort, P < .001 vs 2001–2002 cohort). Right-hand censoring occurred at time of antiretroviral therapy (ART) initiation (including n = 8 in 2010; n = 49 in 2011–2012 randomized to early ART; n = 3).