Background

1. The Impact of Routine Electrolyte Supplementation During Amphotericin Induction Therapy in Resource-limited Settings Nathan Bahr,1 Melissa AR Rolfes,1 Abdu Musubire,2 Henry Nabeta,2 Melanie W Lo,1 David B Meya,1,2 David R Boulware 1,2 1 Department of Medicine, University of Minnesota, Minneapolis, MN; 2 Infectious Disease Institute, Makerere University, Kampala, Uganda Abstract Background / Methods Results • Background • Amphotericin (AmB) is the preferred treatment for Cryptococcal meningitis (CM); however AmB has severe side effects, including nephrotoxicity, anemia, hypokalemia, and hypomagnesemia. During the initial phases of a multisite randomized strategy trial on when to initiate antiretroviral therapy (ART), an association was noted between low serum potassium (K+) and 2-week mortality. In the absence of routine universal electrolyte supplementation and EKG monitoring, the question of interest was whether more aggressive, proactive electrolyte management during AmB therapy impacts short term CM-survival. • Methods • HIV-infected, ART-naïve adults with CM were prospectively enrolled at Mulago Hospital in Kampala, Uganda and received induction therapy with AmB 0.7-1.0 mg/kg/day and fluconazole 800 mg/day for 2 weeks, followed by consolidation therapy and secondary prophylaxis with fluconazole. Subjects were followed up for clinical and laboratory evaluations (Table 1). • Serum electrolytes were compared between subjects under two electrolyte management protocols: • Pre-supplementation protocol: electrolytes were given at clinician discretion in reaction to laboratory abnormalities • Routine universal supplementation protocol : • 32-40 mEq/day of K+ was given orally or IV daily for the first week of AmB therapy with an additional 16 K+ mEq/day during the second week, with increases in supplementation as needed; • 1000mg of magnesium trisilicate given daily (8 mEq/day) during AmB therapy; • Daily monitoring of K+ levels when <3.5 mEq/L; • Aggressive replacement of K+to obtain a target serum K+ level of 4.0 mEq/L. • MgSO4 5g IV given when K+ <3 mEq/L on two consecutive measurements. • Results • Sixteen subjects were observed during the pre-supplementation period and 16 subjects were observed during the universal supplementation period. Participants in each protocol period were similar with regards to CD4 count, viral load, prevalence of altered mental status, and age; there were slightly more men in the universal supplementation period (Table 2). • During the pre-supplementation period, 8 of 16 subjects died (50% mortality, 95% CI: 25% to 75%) whereas the universal supplementation period had only 19% mortality (95% CI: 4% to 46%). • Serum K+ was significantly higher 9, 11, and 14 days after starting AmB in participants who received the universal supplementation protocol (Table 3, Figure 1). Severe hypokalemia was eliminated with universal supplementation. Finally, there was a trend towards longer survival with universal electrolyte supplementation (Figure 2). TABLE 3: Participant characteristics TABLE 4: Serum potassium & adverse events • Amphotericin B plus fluconazole is the preferred treatment for Cryptococcosis in resource-limited settings • Severe AmB side effects are common and can include: nephrotoxicity, anemia, K+,  Mg2+ • Anecdotal evidence indicated a possible association between K+ and 2-week mortality • This analysis evaluates a more aggressive, routine supplementation of electrolytes during AmB to reduce toxicity due to AmB and possibly avert early mortality in CM patients • Methods: • We evaluated baseline characteristics, serum potassium (K+), and 3-week mortality in 16 subjects before and 16 subjects after implementation of routine, universal electrolyte supplementation. • Serum K+, CD4+ T cell counts, and HIV RNA viral load were measured onsite at the Makerere University - Johns Hopkins University (MU-JHU) laboratory, a CAP-certified laboratory • Survival was compared using Kaplan-Meier curves and log-rank statistics • Incidence of hypokalemia was compared using the χ2 statistic • Median K+ levels were compared using Kruskal-Wallis non-parametric test FIGURE 2: Kaplan-Meier survival curves Log rank p-value = 0.133 Electrolyte Supplementation Protocols TABLE 2: Protocols for electrolyte supplementation • Participant demographics were similar, with slightly more men after universal supplementation (Table 3) • Effect on Serum K+ • Serum K+ trends were similar during each period, though noticeably higher at each evaluation with universal supplementation (Figure 1) • Median serum K+ was significantly higher by day 9, 11, and 14 after starting AmB with universal supplementation (Table 4) • No participants receiving universal supplementation experienced a grade >3 adverse event from hypokalemia (serum K+ <2.5 mEq/L) • Universal supplementation decreased overall hypokalemia (serum K+ <3.5 mEq/L) compared to the pre-supplementation period (Table 4) • Effect on Survival • Mortality was 19% with universal supplementation , decreasing from 50% (OR = 0.23, 95% CI: 0.05 to 1.14) • Universal supplementation did not significantly increase the survival probability through 3 weeks after CM presentation (p-value = 0.133) • However, a clear divergence of the survival curves indicates that survival may be improved beyond 3 weeks with universal electrolyte supplementation (Figure 2) Conclusions FIGURE 1: Median serum K+ • Routine electrolyte supplementation resulted in a higher level of serum K+ during AmB induction therapy and through 3 weeks of observation with statistically significantly higher median serum K+ levels during the second week of AmB. • Grade >3 adverse events were eliminated with universal supplementation, compared to the pre-supplementation period where 31% (5/16) of participants had severe hypokalemia (<2.5 mEq/L) during the second week of AmB therapy. • Mortality was reduced with universal supplementation (19% vs. 50%), though not statistically significant with the current sample size. • International Guidelines for cryptococcal meningitis treatment should emphasize in resource limited areas: • Importance of electrolyte management in reducing early mortality • Routine electrolyte supplementation • Potentially shorter courses of 5, 7, or 10 days of amphotericin as the risk/benefit of 2 weeks may not be favorable • Clinical Trials are needed to assess the early fungicidal activity of short course amphotericin in combination with high dose fluconazole TABLE 1: Cryptococcal Meningitis Treatment and Timing of Laboratory Evaluations Acknowledgements We wish to thanks support from the NIH NIAID (U01 AI089244) and support and input from Drs. Tihana Bicanic, Graeme Meintjes, Thomas Harrison, Andrew Kambugu, Yuka Manabe, Ali ElBireer, and the MU-JHU laboratory staff.