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Standardized Electrolyte Supplementation and Fluid Management Improves Survival During Amphotericin Therapy for Cryptococcal Meningitis in Resource-Limited Settings

Standardized Electrolyte Supplementation and Fluid Management Improves Survival During... MA JO R A R T IC LE Standardized Electrolyte Supplementation and Fluid Management Improves Survival During Amphotericin Therapy for Cryptococcal Meningitis in Resource-Limited Settings 1,2,3 1,2 3 3 1,2,3 1,2,3 Nathan C. Bahr, Melissa A. Rolfes, Abdu Musubire, Henry Nabeta, Darlisha A. Williams, Joshua Rhein, 1,2,3 1,2,3,4 1,2 Andrew Kambugu, David B. Meya, and David R. Boulware 1 2 Division of Infectious Diseases and International Medicine, Department of Medicine, and Center for Infectious Diseases and Microbiology Translational 3 4 Research, University of Minnesota, Minneapolis; Infectious Disease Institute, and School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda 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 hypokale- mia 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 men- ingitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphoter- icin 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 + 2+ + (K ,Mg ) per clinician discretion. In 2011–2012, K was measured on days 1, 5, and approximately every 48 hours + 2+ thereafter with universal electrolyte (K ,Mg ) 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 cumu- lative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011–2012 with uni- versal supplementation (P < .001). Conclusions. Improved survival was seen in a resource-limited setting with proactive fluid and electrolyte man- + 2+ agement (K ,Mg ), as part of comprehensive amphotericin-based cryptococcal therapy. Keywords. amphotericin; cryptococcal meningitis; HIV/AIDS; potassium; side effect. Cryptococcal meningitis is the most common cause of among persons infected with human immunodefi- adult meningitis in sub-Saharan Africa [1–3], and ciency virus (HIV) it accounts for 20%–25% of acquired immune deficiency syndrome-related mortality in Africa [4–7]. Standard treatment is combination thera- py with amphotericin and flucytosine (or with flucona- Received 7 May 2014; accepted 10 July 2014. Correspondence: Nathan C. Bahr, MD, MA, Infectious Diseases Institute, PO Box zole when flucytosine is unavailable) [8, 9]. Although 22418, Mulago Hospital Complex, Kampala, Uganda (bahrx026@umn.edu). amphotericin-based regimens have superior clinical ef- Open Forum Infectious Diseases ficacy over fluconazole monotherapy [10],amphotericin © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Societyof America. This is an Open Access article distributed under the terms has side effects including nonlife-threatening infusion- of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http:// related reactions (eg, rigors, fevers, chills, nausea, and creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work vomiting) as well as more significant cumulative toxic- is not altered or transformed in any way, and that the work is properly cited. For ities such as nephrotoxicity, anemia, hypokalemia, and commercial re-use, please contact journals.permissions@oup.com. DOI: 10.1093/ofid/ofu070 hypomagnesemia [11–13]. + 2+ K Mg Supplementation in Cryptococcus OFID 1 � � In persons receiving amphotericin B deoxycholate for >10 days, hypomagnesemia and hypokalemia are near universal (96% and 100%, respectively) [14]. Yet unlike in high-income + 2+ countries, potassium (K ) and magnesium (Mg ) monitoring and electrolyte replacement are limited in low- and middle- income countries. In many settings, electrolyte monitoring is much more limited or absent, and electrolyte replacement is more sporadic and physician-dependent. Little data exist on how best to optimize management of electrolytes in pat- ients given amphotericin in resource-limited settings. In the second month (January 2011) of the Cryptococcal Optimal Antiretroviral Therapy Timing (COAT) Trial (clinicaltrials. gov NCT01075152), an association was noted between low serum K and in-hospital mortality. A standardized electro- lyte supplementation protocol was thereafter implemented as Figure 1. Graphical explanation of cohort timeline. Timeline outlining the division of cohorts by the years over which each cohort took place, an- a quality improvement initiative. Although electrolyte abnor- tifungal medications given during induction therapy, IV fluid strategy, and malities are a common amphotericin toxicity, before Febru- electrolyte supplementation and monitoring strategy. Of note, none of the ary 2011 electrolyte supplementation had been given only as cohorts included patients between 2003 and 2005 because there was no reactive, physician-dependent ad hoc responses to laboratory clinical study of patients with cryptococcal meningitis at Mulago hospital abnormalities. during that time period. Abbreviation: IV, intravenous. The objective of this project was to retrospectively assess 3 prospective cryptococcal cohorts: (1) intermittent use of intra- venous (IV) fluids and rare ad hoc electrolyte supplementation, (2) standardized IV fluid but rare ad hoc electrolyte supplemen- was obtained. Study protocols were approved by the Institution- tation, and (3) standardized administration of IV fluids and al Review Boards of Makerere University, the University of Min- universal electrolyte supplementation. Mortality was compared nesota, and the Uganda National Council of Science and across cohorts to determine whether an aggressive approach to Technology. fluid and electrolyte management improves short-term (<30 Cryptococcal treatment consisted of standardized induc- days) survival after cryptococcal meningitis in persons receiving tion therapy of 14 days of amphotericin B 0.7–1.0 mg/kg in amphotericin-based therapy to understand how best to safely 500 mL 5% dextrose in water over 4 hours in all cohorts. Patient administer amphotericin in a limited-resource setting. weights were measured in 2001–2002 then estimated until January 2011 when a weighing scale became available again. Lumbar punctures were completed on approximately days 1, METHODS 7, and 14 of amphotericin therapy. During 2010–2012 (this Study Population included patients from the COAT trial in cohorts 2 and 3), ad- Three prospective studies of HIV-infected adults with crypto- junctive oral fluconazole 800 mg/day was also included in the coccal meningitis were conducted at Mulago Hospital, the na- induction regimen [9, 19, 20]. In 2001–2009 (cohorts 1 and 2), tional tertiary referral hospital, in Kampala, Uganda. The first after initial induction therapy, consolidation therapy consisted cohort enrolled from November 2001 through March 2002, of 8 weeks of fluconazole 400 mg/day. During 2010–2012 (pa- before the availability of antiretroviral therapy (ART), as previ- tients from the COAT trial in cohorts 2 and 3), enhanced con- ously reported [15]. The second cohort enrolled from June 2006 solidation therapy began with fluconazole (800 mg/day) until through September 2009, after ART availability. During this outpatient clinic registration (∼3 additional weeks) and the time, ART was initiated at a median of 5 weeks [15–17], with 14-day cerebrospinal fluid (CSF) culture was known to be sterile, additional enrollees from November 2010 to January 2011 followed by ∼9 additional weeks of fluconazole (400 mg/day) from individuals screened for enrollment into the COAT trial for a 12-week total consolidation. After consolidation therapy, (clinicaltrials.gov:NCT01075152) [18]. The third cohort con- all cohorts received secondary prophylaxis with fluconazole sisted of individuals screened for enrollment into the COAT (200 mg/day). trial and a follow-on observational cohort that enrolled partic- Cryptococcus meningitis was diagnosed until April 2011 via ipants from February 2011 until November 2012. Figure 1 out- latex agglutination and culture. Qualitative cultures were per- lines the differences in the clinical management of the 3 formed in 2001–2002. Quantitative cultures were performed cohorts. Inclusion and exclusion criteria are listed in the Sup- first witha10 mcLcalibratedloop in 2006–2009 [15], and plementary Material, Appendix S1. Written informed consent then 100 mcL serial 10-fold dilutions in 2010–2012 [21]. 2 OFID Bahr et al � � Fluid and Electrolyte Management 1 week of amphotericin, an additional 16 mEq KCl orally was In 2001–2002 (cohort 1), IV fluids were of limited quantity and added to baseline supplementation. If hypokalemia occurred intermittently available. In 2006–2009 (cohort 2), all participants despite the universal supplementation, the baseline supplemen- received 1 liter of 0.9% NaCl normal saline (NS) before ampho- tation was increased by one 8 mEq tablet twice daily in addition tericin, supported via the Minnesota Medical Foundation. In to one time replacement doses. The KCl replacement dose was + + + + these cohorts, serum electrolyte (Na ,K ) and creatinine moni- standardized at 10 mEq K for each 0.1 mEq/L serum K below toring was performed on days 1, 7, and 14, and electrolyte re- the target goal (K = 4.0 mEq/L). Intravenous replacement was placement was limited in supply. In 2010–2012 (COAT trial via 40 mEq K mixed in 500 mL NS given over 4 hours. patients in cohorts 2 and 3), participants received 2 liters of NS Magnesium supplementation was also addressed in the 2011– 2+ daily, and after provision of informed consent (median day 5), 2012 cohort (cohort 3), although Mg measurement was un- subjects had additional laboratory safety monitoring with available on site. Magnesium is wasted with amphotericin use + + serum electrolyte (Na ,K ,HCO ) and creatinine measurement (as noted above), and hypomagnesemia has numerous deleteri- approximately every 48 hours. In 2010–2012, laboratory results ous effects; however, hypomagnesemia also interferes with the were measured at the Makerere University-Johns Hopkins Uni- patient’s ability to properly replete potassium, thus making mag- versity (MU-JHU) laboratory using a Roche COBAS Integra 400 nesium replacement crucial to adequate potassium replacement. Plus Analyzer. The MU-JHU laboratory is a College of American Universal supplementation was with magnesium trisilicate 2+ Pathologists-accredited laboratory. In 2001–2009, laboratory tests (500 mg, 4 mEq) twice daily, which was the only oral Mg local- were performed at the Mulago Hospital laboratory. ly available, initially. This was later changed to Slow Mag (MgCl) 535 mg (5.33 mEq) tablets for better absorption. In addition, if participants had K levels <3.0 mEq/L for 3 consecutive days de- Electrolyte Supplementation Protocols spite adequate KCl supplementation, participants received 5 g of During the presupplementation period through January 2011 MgSO IV daily until serum K levels normalized; thereafter, (cohorts 1 and 2), electrolyte management was at the treating 2+ baseline oral Mg supplementation was continued. physician’s discretion, and replacement was generally given in response to abnormal electrolyte levels. Replacement was very infrequently completed. Statistical Analysis In February 2011, a routine electrolyte supplementation pro- The primary objective of this analysis was to determine the ef- + 2+ tocol was implemented with K and Mg universally given fect of fluid and electrolyte supplementation on 30-day survival starting on day 1 of amphotericin therapy, data from that in ART naive patients. A 30-day period was chosen to focus on point is termed the supplementation period and corresponds pre-ART mortality as patients started ART at an average of ∼5 with the 2011–2012 cohort (cohort 3). Table 1 summarizes weeks after the diagnosis of cryptococcal meningitis. The 3 co- the management differences. The protocol included baseline horts were organized as follows: cohort 1, intermittent IV fluids K measurement in addition to the measurements on day 5, 7, with no standardized electrolyte management (n = 92 in 2001– 9, 11, and 14 with replacement to goal (K = 4.0 mEq/L) after all 2002); cohort 2, universal IV fluids with no standardized elec- measurements. Potassium supplementation was 32–40 mEq K trolyte management (n = 195, with n = 174 in 2006–2009 and daily (primarily oral KCl 8 mEq tablets in divided doses). After n = 21 in November 2010–January 2011; cohort 3, universal Table 1. Electrolyte Management Strategies During Amphotericin Therapy by Time Period Electrolyte Protocol Presupplementation Component (2001–2010) Universal Supplementation (2011–2012) K monitoring Day 1, 7, 14 Day 1, 5, 7, 9, 11, 14, and as needed (2001–2009) Goal: serum K of 4.0 mEq/L Day 5, 7, 9, 11, 14 (2010) K supplementation In reaction to laboratory � Day 1–6: 32–40 mEq KCl daily abnormalities � Day 7–14: 48–56 mEq KCl daily � Mild hypokalemia (<3.5 mEq/L): � Increase daily routine dose by +16 mEq KCl � Replacement of 10 mEq per 0.1 mEq/L deficit to a target of 4.0 mEq/L with each measurement 2+ Mg monitoring None None 2+ 2+ Mg supplementation At physician discretion Day 1–14: 8 mEq Mg daily MgSO 5g IV, if K levels <3.0 mEq/L for 3 consecutive days despite adequate KCl replacement and continued supplementation until K normalized. + 2+ K Mg Supplementation in Cryptococcus OFID 3 � � a Table 2. Patient Characteristics by Cohort of Persons With Cryptococcal Meningitis in Kampala, Uganda Cohort 1 Cohort 2 Cohort 3 (2001–02) (n = 92) (2006–Jan 2011) (2011–12) (n = 142) Baseline Variables Limited IV Fluids (n = 195) IV Fluids IV Fluids and Electrolytes P Value Male 53% 43% 54% .095 Age in years, mean ± SD 35 ± 7 36 ± 9 35 ± 9 .37 CD4 cells/μL, median (IQR) N/A 20 (7–45) 17 (7–66) .30 HIV viral load, log copies/mL, mean ± SD N/A 5.2 ± 0.6 5.5 ± 0.4 .006 % Glasgow Coma Score <15 7.6% 28% 31% <.001 CSF opening pressure, cm H O, mean ± SD 35 ± 14 32 ± 16 29 ± 14 .11 Creatinine at screening, mean ± SD 1.2 ± 0.5 N/A 1.0 ± 0.5 .29 CSF cryptococcal antigen by latex 1:1600 1:2700 1:2900 .069 agglutination, geometric mean Headache duration prior to diagnosis (%) .88 <7 days 34% 30% 31% 7–14 days 23% 33% 24% >14 days 43% 37% 45% Potassium at screening, mEq/L, mean ± SD 4.2 ± 0.8 N/A 3.8 ± 0.6 .010 Potassium at day 7, mEq/L, mean ± SD 4.0 ± 0.7 3.5 ± 1.0 4.0 ± 0.8 .88 Potassium at day 14, mEq/L, mean ± SD 3.0 ± 0.9 3.0 ± 0.9 3.6 ± 0.8 .161 Abbreviations: CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; IQR, interquartile range; IV, intravenous; N/A, data not available; SD, standard deviation. Baseline participant characteristics were compared between the cohorts using analysis of variance or 2-sample t tests to compare means and the Fisher exact χ test to compare frequencies. Available complete data on 100 patients in the 2006–2009 and 21 in 2010–January 2011 cohort 2. CRAG latex agglutination titer available on 50 patients from 2011–2012 cohort. 2010–January 2011 only, n = 16 for day 7, n = 13 for day 14. IV fluids and universal electrolyte supplementation (n = 142, RESULTS February 2011–November 2012). Patient Characteristics Baseline participant characteristics were compared between Ninety-two subjects were included in cohort 1, 195 in cohort 2 the cohorts using analysis of variance or 2-sample t tests to (174 in 2006–2009 and 21 in November 2010–January 2011), compare means and the Fisher exact test to compare frequen- and 142 in cohort 3. Table 2 displays baseline demographics. cies. Serial serum K levels were evaluated using a repeated mea- Demographics were similar, except for the following: propor- sures model with levels at days 1, 7, and 14 of amphotericin tion of persons with altered mental status with a Glasgow therapy. The occurrence of severe hypokalemia (K 2.0–2.4 Coma Scale(GCS) < 15was less in cohort 1thancohorts 2 mEq/L) or mild hypokalemia (K 2.5–3.4 mEq/L) was com- and 3 (7.6%, 28%, 31%, P < .001); the mean HIV viral load pared with the Fisher exact test. Cox proportional hazard re- was slightly higher in cohort 3 than cohort 2 (5.5 vs 5.2 log gression compared survival between cohorts with adjustment, 10 copies/mL, P = .006); and viral load and CD4 counts were not when possible, for different baseline characteristics. The surviv- available for cohort 1. Time from hospital admission to defini- al analysis was restricted to the pre-ART time period only. Par- tive diagnosis also improved over time (median 3 to ≤1 days), ticipants contributed time from cryptococcal meningitis yet demographics were overall similar. diagnosis to one of the following: 30-day survival, death, or ART initiation. COAT trial participants randomized to early ART were right-hand censored for the survival analysis at Incidence of Severe Hypokalemia COAT trial randomization (n =8 in 2010, n =49 in 2011– Figure 2 displays the time to severe or life-threatening (Grade 2012). Thus, no persons received ART in the 30-day survival ≥3) hypokalemia (K < 2.5 mEq/L) by cohort. The incidence analysis, to make all 3 cohorts comparable. For determination of severe electrolyte abnormalities in cohort 1 during 2001– of cumulative incidence of hypokalemia, all participants were 2002 was negligible. Among those surviving to day 7, only included. Statistical analysis was conducted using SPSS version 1.8% (1 of 56) had severe hypokalemia, and zero of 46 who sur- 21 (IBM Corporation, Armonk, NY) and evaluated against type vived to day 14 had severe hypokalemia. Electrolyte data were I error α < 0.05. not prospectively recorded for cohort 2 between 2006 and 4 OFID Bahr et al � � + Figure 2. Cumulative incidence of severe hypokalemia (K <2.5 meq/L) among 3 cohorts. In 2001–2002 (cohort 1), with minimal electrolyte mon- itoring 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 sup- Figure 3. Cumulative survival after cryptococcal meningitis by cohort plementation (February 21, 2011) and enhanced attention to weight-based time period. Fourteen-day survival in 2002 (cohort 1) was 49% (95% con- dosing of amphotericin (cohort 3), the incidence of severe hypokalemia fidence interval [CI], 39%–59%), including 8 persons who left against med- declined to 8.5% (12 of 142, P < .001 compared to without supplementa- ical advice ( presumed dead). In 2006–2010 (cohort 2), with universal IV tion). No persons developed clinically significant hyperkalemia with elec- fluids, the 30-day cumulative survival was 62% (95% CI, 55%–69%; trolyte supplementation. The majority of the hypokalemia occurs during the P = .003 vs 2001–2002 cohort). In 2011–2012 (cohort 3), with universal second week of amphotericin therapy, thus with minimal monitoring in co- IV fluids and electrolyte supplementation, 30-day cumulative survival im- hort 1, the lack of detected hypokalemia does not indicate the absence of proved to 78% (95% CI, 70%–85%; P = .021 vs 2006–2010 cohort, hypokalemia. Severe hypokalemia rarely occurs before day 7. Without in- P < .001 vs 2001–2002 cohort). Right-hand censoring occurred at time of tensive K monitoring, absence of hypokalemia at day 14 likely may repre- antiretroviral therapy (ART) initiation (including n = 8 in 2010; n =49 in sent a survival bias. Abbreviation: IV, intravenous. 2011–2012 randomized to early ART; n = 3). administered by study nurses and monitored by study 2009, but similarly negligible incidence of severe hypokalemia physicians. at day 7 and day 14 was recalled (D. B. M., A. M.). However, in the 2010 period of cohort 2 when electrolytes were measured Survival starting at day 5 approximately every 48 hours, the cumulative When limited IV fluids were available and intermittent shortages incidence of severe hypokalemia (K < 2.5 mEq/L) was 38% (8 occurred, the 14-day survival was 49% (45 of 92) in 2001–2002. of 21), with 19 severe hypokalemic events occurring in 8 partic- With universal provision of IV fluids in 2006–2010, the 30-day ipants in the first 14 days of amphotericin. Severe hypokalemia cumulative survival was 62% (log rank P =.003 vs 2001–2002 co- was evenly distributed between the trial’s randomization arms. hort). In 2011–2012, with universal supplementation of fluids After the standardized electrolyte protocol was implemented in and electrolytes, the 30-day cumulative survival improved to February 2011, 15 severe hypokalemic events occurred among 78% (log rank P =.021 vs 2006–2010 cohort) (Figure 3). Cox re- 12 participants for a cumulative incidence of 8.5% (12 of 142) gression models were also used to adjust for baseline GCS, creat- (relative risk = 4.5; 95% CI, 2.1–9.7; P < .001). Thus, a lack of se- inine, opening pressure, and potassium: none of these analyses vere hypokalemia observed in 2001–2009 likely reflects unrec- altered the significance of the survival differences. With fluid ognized severe hypokalemia because of lack of testing between and electrolyte support, 14-day survival improved by 30% despite day 8 and 13 as well as a survival bias, namely those who sur- similar amphotericin-based treatment (0.7–1.0 mg/kg per day) vived to 14 days were more likely the patients without severe hy- regimens and frequency of lumbar punctures (median n =3 in pokalemia during amphotericin therapy. Unintentional missed 2001–2002 and in 2011–2012). There was no association between doses of amphotericin are unlikely because the medication was week 1 deaths and hyperkalemia in any cohort. + 2+ K Mg Supplementation in Cryptococcus OFID 5 � � DISCUSSION fungicidal activity) compared to 14 days of amphotericin (1.0 mg/kg per day) but without electrolyte abnormalities. In that Implementation of a comprehensive electrolyte management study, routine potassium (40 mEq/day) supplementation was protocol was associated with reduced severe hypokalemia and given. Similar high levels of efficacy without toxicity were also improved survival when added to standard amphotericin treat- reported in a similar 7-day randomized trial of amphotericin ment and IV fluids for HIV-associated cryptococcal meningitis (1.0 mg/kg per day) with fluconazole (1200 mg/day) in Malawi in a resource-limited setting. Current Infectious Diseases Soci- [28].An unresolved clinical question, raised by Thomas Harrison ety of America guidelines for cryptococcal treatment mention and colleagues, St. George’s University, London [27, 28], is the that if facilities do not have sufficiently rapid or reliable K ideal length of amphotericin induction, and this question is cur- monitoring, amphotericin use may not be safe [8]. However, rently being tested in a phase III trial (ISRCTN45035509). further guidance is not provided, and magnesium is not men- Finally, in resource-limited settings without access to KCl tioned [8, 22]. pharmaceutical preparations, foods rich in potassium may be In the high-income countries, electrolytes are checked fre- readily available and could provide suitable potassium replace- quently and replaced rapidly in hospitalized patients; however, ment while on amphotericin. For example, the average US avo- in the many resource-limited settings, unique barriers exist for cado has ∼6.5 mEq of potassium per 100 g, whereas a banana the close monitoring of electrolytes. Laboratory facilities may has approximately two thirds of that amount [29]. In a patient not be reliably available or not able to return results rapidly able to tolerate food or nasogastric feeding, this may be a rea- enough to be acted upon in a clinically useful fashion. Electro- sonable alternative method of potassium supplementation. lyte replacements themselves may be unavailable in many Defaulting to fluconazole monotherapy to avoid amphoteri- settings, and cost, although low relative to many other medica- cin toxicity is a poor strategy. The survival with fluconazole tions, can be a barrier. Thus, although a comprehensive electro- monotherapy is ∼30% worse than with amphotericin, in cross- lyte management strategy would be ideal, this may not be cohort comparisons [10]. Although the lure of less toxicity in realistic in all settings. Yet, amphotericin-induced electrolyte fluconazole monotherapy may be appealing, as we have demon- wasting is a universal expectation, and so the issue must be ad- strated here, the electrolyte toxicity of amphotericin is manage- dressed. In many illnesses, this may be inconsequential; howev- able, and acute kidney injury is relatively infrequent (∼8%) with er, for any illness treated with electrolyte wasting medications, IV fluid prehydration [11]. As mentioned above, in 2001–2002 + 2+ such as amphotericin, K and Mg replacement becomes ex- (cohort 1), IV fluids were of limited quantity and intermittently tremely important [23–25]. Stakeholders who influence health available. In 2006–2009 (cohort 2), all participants received 1 policy in low- and middle-income countries should view elec- liter of 0.9% NaCl NS before amphotericin. In 2010–2012 trolyte management as part of the package of care for proper (COAT trial patients in cohorts 2 and 3), participants received cryptococcal treatment. 2 liters of NS daily according to trial standard operating proce- Multiple alternatives to the comprehensive electrolyte re- dures. Persistent significant chronic kidney injury is rare: in the placement strategy detailed above are possible. Amphotericin 2006–2009 Kampala cohort [17], 95% of survivors had a serum predictably depletes potassium and magnesium [14, 26]. Thus, creatinine <2 mg/dL at 5 weeks after cryptococcal meningitis di- scheduled supplementation only without additional measure- agnosis, with 80% <1.5 mg/dL. In 2010–2012, 99% of survivors ment or replacement doses would be feasible. Although there had creatinine <2 mg/dL at 5 weeks. is some risk of hyperkalemia due to replacement, the predict- Cost is often considered as a barrier to therapeutic interven- able nature of electrolyte wasting allows for scheduled replace- tions. As an example of the costs of these medications; 1 non- ment without significant fear of hyperkalemia. Furthermore, profit medical wholesaler in Kampala, Uganda supplies the because amphotericin’s effect on electrolyte wasting is known following prices of 1 vial of 10 mEq IV KCl for $1.04 and oral to be cumulative and dose dependent [11, 14, 26], increasing 8 mEq KCl for $3.30 per 100 tablets [30]. Magnesium prices are the potassium supplementation during the second week should similar [30]. Although these purchases would require some re- be well tolerated. This strategy would reduce overall hypokale- sources, the cost is quite affordable when one considers the im- mia but likely leave some small percentage of patients (∼10%) mediate 30-day survival benefit. Supporting local industry and severely hypokalemic; moreover, routine replacement would local avocado or banana farmers may be a wiser investment have an acceptable, potential risk of hyperkalemia should than importing supplies. even routine monitoring be difficult to obtain. The main limitation is the historical comparison of 3 cohorts A second strategy would be to use shorter 1-week courses of over time. Although fluid and electrolyte management was the amphotericin. In a prospective study in Uganda by Muzoora major change, other unseen bias influencing mortality may et al [27], 5 days of amphotericin (1.0 mg/kg per day) with ad- exist. Severity of illness was similar among cohorts and, if any- junctive fluconazole (1200 mg/days) was well tolerated with ap- thing, increased over time with higher proportions with altered proximately 75% of the rate of microbiologic clearance (ie, early mental status and higher CRAG titers during 2006–2012. 6 OFID Bahr et al � � Quantitative cultures were performed in cohorts 2 and 3; how- survival with amphotericin B deoxycholate therapy. Second, ever, the method was different, and so direct comparison would routine, proactive potassium and magnesium supplementation not be accurate. One of the major improvements in clinical care is superior to a reactive approach of replacing electrolytes once a during the trial of cohort 2 and 3 was improved safety monitor- life-threatening deficiency has been identified. Third, more op- ing with more frequent detection of laboratory abnormalities. In erational research is needed to determine whether potentially 2001–2002, K monitoring at day 1, 7, and 14 only detected 2% shorter courses of 5, 7, or 10 days of amphotericin have a with hypokalemia at day 7. Yet lack of monitoring did not more favorable risk/benefit in resource-limited regions com- equate to absence of hypokalemia during the second week of pared to 2 weeks of amphotericin [33]. Using initial quantitative amphotericin, based on a 38% incidence of hypokalemia in CSF culture burden to guide therapy duration may be more ra- 2010 with more frequent monitoring. Likewise, monitoring tional than giving all persons 14 days of amphotericin [33]. In alone without action did not decrease mortality or hypokalemia conclusion, in comparing 3 cohorts of patients with cryptococ- in 2010. One might also argue that caregiver or institutional expe- cal meningitis treated with amphotericin in Kampala, Uganda, rience may have been gained over time, which explained the sur- survival significantly improved with a comprehensive electro- vival benefit. However, we believe this explanation is also unlikely lyte monitoring and replacement strategy. given that the medical officers and nurses caring for the patients directly changedwitheachstudy (A.K.; D. B. M./A.M.; H. N.). Supplementary Material Other specific changes were made. First, the cryptococcal Supplementary material is available online at Open Forum Infectious Dis- antigen lateral flow assay (Immy, Norman, Oklahoma) was im- eases (http://OpenForumInfectiousDiseases.oxfordjournals.org/). plemented in April 2011 as a point-of-care test to decrease time-to-diagnosis. Although exceedingly helpful, the severity Acknowledgments of illness and demographics remained similar. Second, concom- itant fluconazole 800 mg/day was given starting in 2010 during We thank support and input from Drs. Thomas Harrison, Tihana Bicanic, Graeme Meintjes, Yukari Manabe, Radha Rajasingham, Paul Boh- induction therapy and as enhanced consolidation until the CSF janen, and Melanie Lo, as well as Ali El Bireer, and the MU-JHU laboratory was known to be sterile. This fluconazole regimen was in place staff. We thank Dr. Meagan O′Brien for clinical care in 2001–2002, and during the initial 2 months of the COAT trial when the inves- Dr. Merle Sande for mentorship. We also thank the Accordia Global Health Foundation for support of the Infectious Disease Institute. tigators detected an association between hypokalemia and mor- Financial support. This work was supported by the National Institute tality. Based on a 2013 trial, the addition of fluconazole to of Allergy and Infectious Diseases and Fogarty International Center at the amphotericin did not have a statistical survival benefitover4 National Institutes of Health (K23AI073192, U01AI089244, R25TW009345, T32AI055433) and the University of Minnesota Foundation. weeks of amphotericin alone [31]. The higher dose fluconazole (800 mg/day) “enhanced” consolidation therapy was used in References 2010–2012, but this is of unproven significance in terms of any potential benefit. Although fluconazole adjunctive therapy with 1. Jarvis JN, Meintjes G, Williams A, et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. amphotericin leads to more rapid clearance of Cryptococcus BMC Infect Dis 2010; 10:67. from the CSF [15, 18], this alone is unlikely to explain the im- 2. Durski KN, Kuntz KM, Yasukawa K, et al. Cost-effective diagnostic proved survival in the third cohort [31]. The 16% magnitude of checklists for meningitis in resource-limited settings. J Acquir Immune Defic Syndr 2013; 63:e101–8. 30-day survival difference between cohorts 2 and 3 was beyond 3. Cohen DB, Zijlstra EE, Mukaka M, et al. Diagnosis of cryptococcal and the expected effect of added fluconazole (5% better 14-day sur- tuberculous meningitis in a resource-limited African setting. Trop Med vival) [31]. A further limitation is the lack of recording of elec- Int Health 2010; 15:910–7. 4. Castelnuovo B, Manabe YC, Kiragga A, et al. Cause-specific mortality trolyte and creatinine data during 2006–2009, although the and the contribution of immune reconstitution inflammatory syndrome values would be expected to be similar to 2001–2002 or 2010. in the first 3 years after antiretroviral therapy initiation in an urban African cohort. Clin Infect Dis 2009; 49:965–72. 5. Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the cur- CONCLUSIONS rent global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009; 23:525–30. In summary, survival was substantially improved with IV fluids 6. French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of coupled with universal electrolyte supplementation of K and HIV-1-infected Ugandan adults. AIDS 2002; 16:1031–8. 2+ 7. Liechty CA, Solberg P, Were W, et al. Asymptomatic serum cryptococ- Mg , electrolyte monitoring, and standardized electrolyte re- cal antigenemia and early mortality during antiretroviral therapy in placement. WHO Rapid Advice for cryptococcosis treatment rural Uganda. Trop Med Int Health 2007; 12:929–35. published in December 2011 recommended intense monitoring 8. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infec- and supplementation based on our earlier data [9, 32]. We be- tious Diseases Society of America. Clin Infect Dis 2010; 50:291–322. lieve that the data presented herein should cause stakeholders to 9. World Health Organization. Rapid advice: Diagnosis, prevention and emphasize 3 important issues unique to cryptococcal treatment. management of cryptococcal disease in HIV-infected adults, adoles- First, electrolyte management is important for improving cents and children. Geneva: World Health Organization, 2011. + 2+ K Mg Supplementation in Cryptococcus OFID 7 � � 10. Rajasingham R, Rolfes MA, Birkenkamp KE, et al. Cryptococcal 22. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and meningitis treatment strategies in resource-limited settings: a cost- treatment of opportunistic infections in HIV-infected adults and ado- effectiveness analysis. PLoS Med 2012; 9:e1001316. lescents: recommendations from CDC, the National Institutes of 11. Girmenia C, Gentile G, Micozzi A, et al. Nephrotoxicity of amphoteri- Health, and the HIV Medicine Association of the Infectious Diseases cin B desoxycholate. Clin Infect Dis 2001; 33:915–6. Society of America. MMWR Recomm Rep 2009; 58:1–207. 12. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical 23. Bamba AV, Jadhav MP, Prabhu R, et al. Refractory hypokalemia due to experience. Rev Infect Dis 1990; 12:308–29. conventional amphotericin B in patients with leukemia. Indian J Cancer 13. Imhof A, Walter RB, Schaffner A. Continuous infusion of escalated 2009; 46:76–7. doses of amphotericin B deoxycholate: an open-label observational 24. White MH, Bowden RA, Sandler ES, et al. Randomized, double-blind study. Clin Infect Dis 2003; 36:943–51. clinical trial of amphotericin B colloidal dispersion vs. amphotericin 14. Mayer J, Doubek M, Vorlicek J. Must we really fear toxicity of conven- B in the empirical treatment of fever and neutropenia. Clin Infect Dis tional amphotericin B in oncological patients? 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Clinical features and J Infect 2012; 64:76–81. serum biomarkers in HIV immune reconstitution inflammatory syn- 28. Jackson AT, Nussbaum JC, Phulusa J, et al. A phase II randomized con- drome after cryptococcal meningitis: a prospective cohort study. PLoS trolled trial adding oral flucytosine to high-dose fluconazole, with short- Med 2010; 7:e1000384. course amphotericin B, for cryptococcal meningitis. AIDS 2012; 18. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral ther- 26:1363–70. apy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 29. Pennington JAT, Youngt B. Sodium, potassium, calcium, phosphorus, 370:2487–98. and magnesium in foods from the United States total diet study. J 19. Loyse A, Wilson D, Meintjes G, et al. Comparison of the early fungicidal Food Compost Anal 1990; 3:145–65. activity of high-dose fluconazole, voriconazole, and flucytosine as 30. Joint Medical Store. Potassium chloride slow-release 600mg tablet second-line drugs given in combination with amphotericin B for the (Product catalog). Available at: http://www.jms.co.ug/resources.Ac- treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis cessed 1 September 2013. 2012; 54:121–8. 31. Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for 20. Pappas PG, Chetchotisakd P, Larsen RA, et al. A phase II randomized cryptococcal meningitis. PLoS Med 2013; 368:1291–302. trial of amphotericin B alone or combined with fluconazole in the treat- 32. Bahr N, Rolfes MAR, Musubire A, et al. The impact of routine elec- ment of HIV-associated cryptococcal meningitis. Clin Infect Dis 2009; trolyte supplementation during amphotericin induction therapy in 48:1775–83. resource-limited settings. In: 8th International Conference on Crypto- 21. Bicanic T, Meintjes G, Wood R, et al. Fungal burden, early fungicidal coccus and Cryptococcosis. Charleston, SC, 2011. activity, and outcome in cryptococcal meningitis in antiretroviral- 33. Rhein J, Boulware DR. Prognosis and management of cryptococcal naive or antiretroviral-experienced patients treated with amphotericin meningitis in patients with human immunodeficiency virus infection. Bor fluconazole. Clin Infect Dis 2007; 45:76–80. Neurobehavioral HIV Med 2012; 4:45–61. 8 OFID Bahr et al � � http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Standardized Electrolyte Supplementation and Fluid Management Improves Survival During Amphotericin Therapy for Cryptococcal Meningitis in Resource-Limited Settings

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Abstract

MA JO R A R T IC LE Standardized Electrolyte Supplementation and Fluid Management Improves Survival During Amphotericin Therapy for Cryptococcal Meningitis in Resource-Limited Settings 1,2,3 1,2 3 3 1,2,3 1,2,3 Nathan C. Bahr, Melissa A. Rolfes, Abdu Musubire, Henry Nabeta, Darlisha A. Williams, Joshua Rhein, 1,2,3 1,2,3,4 1,2 Andrew Kambugu, David B. Meya, and David R. Boulware 1 2 Division of Infectious Diseases and International Medicine, Department of Medicine, and Center for Infectious Diseases and Microbiology Translational 3 4 Research, University of Minnesota, Minneapolis; Infectious Disease Institute, and School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda 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 hypokale- mia 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 men- ingitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphoter- icin 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 + 2+ + (K ,Mg ) per clinician discretion. In 2011–2012, K was measured on days 1, 5, and approximately every 48 hours + 2+ thereafter with universal electrolyte (K ,Mg ) 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 cumu- lative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011–2012 with uni- versal supplementation (P < .001). Conclusions. Improved survival was seen in a resource-limited setting with proactive fluid and electrolyte man- + 2+ agement (K ,Mg ), as part of comprehensive amphotericin-based cryptococcal therapy. Keywords. amphotericin; cryptococcal meningitis; HIV/AIDS; potassium; side effect. Cryptococcal meningitis is the most common cause of among persons infected with human immunodefi- adult meningitis in sub-Saharan Africa [1–3], and ciency virus (HIV) it accounts for 20%–25% of acquired immune deficiency syndrome-related mortality in Africa [4–7]. Standard treatment is combination thera- py with amphotericin and flucytosine (or with flucona- Received 7 May 2014; accepted 10 July 2014. Correspondence: Nathan C. Bahr, MD, MA, Infectious Diseases Institute, PO Box zole when flucytosine is unavailable) [8, 9]. Although 22418, Mulago Hospital Complex, Kampala, Uganda (bahrx026@umn.edu). amphotericin-based regimens have superior clinical ef- Open Forum Infectious Diseases ficacy over fluconazole monotherapy [10],amphotericin © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Societyof America. This is an Open Access article distributed under the terms has side effects including nonlife-threatening infusion- of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http:// related reactions (eg, rigors, fevers, chills, nausea, and creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work vomiting) as well as more significant cumulative toxic- is not altered or transformed in any way, and that the work is properly cited. For ities such as nephrotoxicity, anemia, hypokalemia, and commercial re-use, please contact journals.permissions@oup.com. DOI: 10.1093/ofid/ofu070 hypomagnesemia [11–13]. + 2+ K Mg Supplementation in Cryptococcus OFID 1 � � In persons receiving amphotericin B deoxycholate for >10 days, hypomagnesemia and hypokalemia are near universal (96% and 100%, respectively) [14]. Yet unlike in high-income + 2+ countries, potassium (K ) and magnesium (Mg ) monitoring and electrolyte replacement are limited in low- and middle- income countries. In many settings, electrolyte monitoring is much more limited or absent, and electrolyte replacement is more sporadic and physician-dependent. Little data exist on how best to optimize management of electrolytes in pat- ients given amphotericin in resource-limited settings. In the second month (January 2011) of the Cryptococcal Optimal Antiretroviral Therapy Timing (COAT) Trial (clinicaltrials. gov NCT01075152), an association was noted between low serum K and in-hospital mortality. A standardized electro- lyte supplementation protocol was thereafter implemented as Figure 1. Graphical explanation of cohort timeline. Timeline outlining the division of cohorts by the years over which each cohort took place, an- a quality improvement initiative. Although electrolyte abnor- tifungal medications given during induction therapy, IV fluid strategy, and malities are a common amphotericin toxicity, before Febru- electrolyte supplementation and monitoring strategy. Of note, none of the ary 2011 electrolyte supplementation had been given only as cohorts included patients between 2003 and 2005 because there was no reactive, physician-dependent ad hoc responses to laboratory clinical study of patients with cryptococcal meningitis at Mulago hospital abnormalities. during that time period. Abbreviation: IV, intravenous. The objective of this project was to retrospectively assess 3 prospective cryptococcal cohorts: (1) intermittent use of intra- venous (IV) fluids and rare ad hoc electrolyte supplementation, (2) standardized IV fluid but rare ad hoc electrolyte supplemen- was obtained. Study protocols were approved by the Institution- tation, and (3) standardized administration of IV fluids and al Review Boards of Makerere University, the University of Min- universal electrolyte supplementation. Mortality was compared nesota, and the Uganda National Council of Science and across cohorts to determine whether an aggressive approach to Technology. fluid and electrolyte management improves short-term (<30 Cryptococcal treatment consisted of standardized induc- days) survival after cryptococcal meningitis in persons receiving tion therapy of 14 days of amphotericin B 0.7–1.0 mg/kg in amphotericin-based therapy to understand how best to safely 500 mL 5% dextrose in water over 4 hours in all cohorts. Patient administer amphotericin in a limited-resource setting. weights were measured in 2001–2002 then estimated until January 2011 when a weighing scale became available again. Lumbar punctures were completed on approximately days 1, METHODS 7, and 14 of amphotericin therapy. During 2010–2012 (this Study Population included patients from the COAT trial in cohorts 2 and 3), ad- Three prospective studies of HIV-infected adults with crypto- junctive oral fluconazole 800 mg/day was also included in the coccal meningitis were conducted at Mulago Hospital, the na- induction regimen [9, 19, 20]. In 2001–2009 (cohorts 1 and 2), tional tertiary referral hospital, in Kampala, Uganda. The first after initial induction therapy, consolidation therapy consisted cohort enrolled from November 2001 through March 2002, of 8 weeks of fluconazole 400 mg/day. During 2010–2012 (pa- before the availability of antiretroviral therapy (ART), as previ- tients from the COAT trial in cohorts 2 and 3), enhanced con- ously reported [15]. The second cohort enrolled from June 2006 solidation therapy began with fluconazole (800 mg/day) until through September 2009, after ART availability. During this outpatient clinic registration (∼3 additional weeks) and the time, ART was initiated at a median of 5 weeks [15–17], with 14-day cerebrospinal fluid (CSF) culture was known to be sterile, additional enrollees from November 2010 to January 2011 followed by ∼9 additional weeks of fluconazole (400 mg/day) from individuals screened for enrollment into the COAT trial for a 12-week total consolidation. After consolidation therapy, (clinicaltrials.gov:NCT01075152) [18]. The third cohort con- all cohorts received secondary prophylaxis with fluconazole sisted of individuals screened for enrollment into the COAT (200 mg/day). trial and a follow-on observational cohort that enrolled partic- Cryptococcus meningitis was diagnosed until April 2011 via ipants from February 2011 until November 2012. Figure 1 out- latex agglutination and culture. Qualitative cultures were per- lines the differences in the clinical management of the 3 formed in 2001–2002. Quantitative cultures were performed cohorts. Inclusion and exclusion criteria are listed in the Sup- first witha10 mcLcalibratedloop in 2006–2009 [15], and plementary Material, Appendix S1. Written informed consent then 100 mcL serial 10-fold dilutions in 2010–2012 [21]. 2 OFID Bahr et al � � Fluid and Electrolyte Management 1 week of amphotericin, an additional 16 mEq KCl orally was In 2001–2002 (cohort 1), IV fluids were of limited quantity and added to baseline supplementation. If hypokalemia occurred intermittently available. In 2006–2009 (cohort 2), all participants despite the universal supplementation, the baseline supplemen- received 1 liter of 0.9% NaCl normal saline (NS) before ampho- tation was increased by one 8 mEq tablet twice daily in addition tericin, supported via the Minnesota Medical Foundation. In to one time replacement doses. The KCl replacement dose was + + + + these cohorts, serum electrolyte (Na ,K ) and creatinine moni- standardized at 10 mEq K for each 0.1 mEq/L serum K below toring was performed on days 1, 7, and 14, and electrolyte re- the target goal (K = 4.0 mEq/L). Intravenous replacement was placement was limited in supply. In 2010–2012 (COAT trial via 40 mEq K mixed in 500 mL NS given over 4 hours. patients in cohorts 2 and 3), participants received 2 liters of NS Magnesium supplementation was also addressed in the 2011– 2+ daily, and after provision of informed consent (median day 5), 2012 cohort (cohort 3), although Mg measurement was un- subjects had additional laboratory safety monitoring with available on site. Magnesium is wasted with amphotericin use + + serum electrolyte (Na ,K ,HCO ) and creatinine measurement (as noted above), and hypomagnesemia has numerous deleteri- approximately every 48 hours. In 2010–2012, laboratory results ous effects; however, hypomagnesemia also interferes with the were measured at the Makerere University-Johns Hopkins Uni- patient’s ability to properly replete potassium, thus making mag- versity (MU-JHU) laboratory using a Roche COBAS Integra 400 nesium replacement crucial to adequate potassium replacement. Plus Analyzer. The MU-JHU laboratory is a College of American Universal supplementation was with magnesium trisilicate 2+ Pathologists-accredited laboratory. In 2001–2009, laboratory tests (500 mg, 4 mEq) twice daily, which was the only oral Mg local- were performed at the Mulago Hospital laboratory. ly available, initially. This was later changed to Slow Mag (MgCl) 535 mg (5.33 mEq) tablets for better absorption. In addition, if participants had K levels <3.0 mEq/L for 3 consecutive days de- Electrolyte Supplementation Protocols spite adequate KCl supplementation, participants received 5 g of During the presupplementation period through January 2011 MgSO IV daily until serum K levels normalized; thereafter, (cohorts 1 and 2), electrolyte management was at the treating 2+ baseline oral Mg supplementation was continued. physician’s discretion, and replacement was generally given in response to abnormal electrolyte levels. Replacement was very infrequently completed. Statistical Analysis In February 2011, a routine electrolyte supplementation pro- The primary objective of this analysis was to determine the ef- + 2+ tocol was implemented with K and Mg universally given fect of fluid and electrolyte supplementation on 30-day survival starting on day 1 of amphotericin therapy, data from that in ART naive patients. A 30-day period was chosen to focus on point is termed the supplementation period and corresponds pre-ART mortality as patients started ART at an average of ∼5 with the 2011–2012 cohort (cohort 3). Table 1 summarizes weeks after the diagnosis of cryptococcal meningitis. The 3 co- the management differences. The protocol included baseline horts were organized as follows: cohort 1, intermittent IV fluids K measurement in addition to the measurements on day 5, 7, with no standardized electrolyte management (n = 92 in 2001– 9, 11, and 14 with replacement to goal (K = 4.0 mEq/L) after all 2002); cohort 2, universal IV fluids with no standardized elec- measurements. Potassium supplementation was 32–40 mEq K trolyte management (n = 195, with n = 174 in 2006–2009 and daily (primarily oral KCl 8 mEq tablets in divided doses). After n = 21 in November 2010–January 2011; cohort 3, universal Table 1. Electrolyte Management Strategies During Amphotericin Therapy by Time Period Electrolyte Protocol Presupplementation Component (2001–2010) Universal Supplementation (2011–2012) K monitoring Day 1, 7, 14 Day 1, 5, 7, 9, 11, 14, and as needed (2001–2009) Goal: serum K of 4.0 mEq/L Day 5, 7, 9, 11, 14 (2010) K supplementation In reaction to laboratory � Day 1–6: 32–40 mEq KCl daily abnormalities � Day 7–14: 48–56 mEq KCl daily � Mild hypokalemia (<3.5 mEq/L): � Increase daily routine dose by +16 mEq KCl � Replacement of 10 mEq per 0.1 mEq/L deficit to a target of 4.0 mEq/L with each measurement 2+ Mg monitoring None None 2+ 2+ Mg supplementation At physician discretion Day 1–14: 8 mEq Mg daily MgSO 5g IV, if K levels <3.0 mEq/L for 3 consecutive days despite adequate KCl replacement and continued supplementation until K normalized. + 2+ K Mg Supplementation in Cryptococcus OFID 3 � � a Table 2. Patient Characteristics by Cohort of Persons With Cryptococcal Meningitis in Kampala, Uganda Cohort 1 Cohort 2 Cohort 3 (2001–02) (n = 92) (2006–Jan 2011) (2011–12) (n = 142) Baseline Variables Limited IV Fluids (n = 195) IV Fluids IV Fluids and Electrolytes P Value Male 53% 43% 54% .095 Age in years, mean ± SD 35 ± 7 36 ± 9 35 ± 9 .37 CD4 cells/μL, median (IQR) N/A 20 (7–45) 17 (7–66) .30 HIV viral load, log copies/mL, mean ± SD N/A 5.2 ± 0.6 5.5 ± 0.4 .006 % Glasgow Coma Score <15 7.6% 28% 31% <.001 CSF opening pressure, cm H O, mean ± SD 35 ± 14 32 ± 16 29 ± 14 .11 Creatinine at screening, mean ± SD 1.2 ± 0.5 N/A 1.0 ± 0.5 .29 CSF cryptococcal antigen by latex 1:1600 1:2700 1:2900 .069 agglutination, geometric mean Headache duration prior to diagnosis (%) .88 <7 days 34% 30% 31% 7–14 days 23% 33% 24% >14 days 43% 37% 45% Potassium at screening, mEq/L, mean ± SD 4.2 ± 0.8 N/A 3.8 ± 0.6 .010 Potassium at day 7, mEq/L, mean ± SD 4.0 ± 0.7 3.5 ± 1.0 4.0 ± 0.8 .88 Potassium at day 14, mEq/L, mean ± SD 3.0 ± 0.9 3.0 ± 0.9 3.6 ± 0.8 .161 Abbreviations: CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; IQR, interquartile range; IV, intravenous; N/A, data not available; SD, standard deviation. Baseline participant characteristics were compared between the cohorts using analysis of variance or 2-sample t tests to compare means and the Fisher exact χ test to compare frequencies. Available complete data on 100 patients in the 2006–2009 and 21 in 2010–January 2011 cohort 2. CRAG latex agglutination titer available on 50 patients from 2011–2012 cohort. 2010–January 2011 only, n = 16 for day 7, n = 13 for day 14. IV fluids and universal electrolyte supplementation (n = 142, RESULTS February 2011–November 2012). Patient Characteristics Baseline participant characteristics were compared between Ninety-two subjects were included in cohort 1, 195 in cohort 2 the cohorts using analysis of variance or 2-sample t tests to (174 in 2006–2009 and 21 in November 2010–January 2011), compare means and the Fisher exact test to compare frequen- and 142 in cohort 3. Table 2 displays baseline demographics. cies. Serial serum K levels were evaluated using a repeated mea- Demographics were similar, except for the following: propor- sures model with levels at days 1, 7, and 14 of amphotericin tion of persons with altered mental status with a Glasgow therapy. The occurrence of severe hypokalemia (K 2.0–2.4 Coma Scale(GCS) < 15was less in cohort 1thancohorts 2 mEq/L) or mild hypokalemia (K 2.5–3.4 mEq/L) was com- and 3 (7.6%, 28%, 31%, P < .001); the mean HIV viral load pared with the Fisher exact test. Cox proportional hazard re- was slightly higher in cohort 3 than cohort 2 (5.5 vs 5.2 log gression compared survival between cohorts with adjustment, 10 copies/mL, P = .006); and viral load and CD4 counts were not when possible, for different baseline characteristics. The surviv- available for cohort 1. Time from hospital admission to defini- al analysis was restricted to the pre-ART time period only. Par- tive diagnosis also improved over time (median 3 to ≤1 days), ticipants contributed time from cryptococcal meningitis yet demographics were overall similar. diagnosis to one of the following: 30-day survival, death, or ART initiation. COAT trial participants randomized to early ART were right-hand censored for the survival analysis at Incidence of Severe Hypokalemia COAT trial randomization (n =8 in 2010, n =49 in 2011– Figure 2 displays the time to severe or life-threatening (Grade 2012). Thus, no persons received ART in the 30-day survival ≥3) hypokalemia (K < 2.5 mEq/L) by cohort. The incidence analysis, to make all 3 cohorts comparable. For determination of severe electrolyte abnormalities in cohort 1 during 2001– of cumulative incidence of hypokalemia, all participants were 2002 was negligible. Among those surviving to day 7, only included. Statistical analysis was conducted using SPSS version 1.8% (1 of 56) had severe hypokalemia, and zero of 46 who sur- 21 (IBM Corporation, Armonk, NY) and evaluated against type vived to day 14 had severe hypokalemia. Electrolyte data were I error α < 0.05. not prospectively recorded for cohort 2 between 2006 and 4 OFID Bahr et al � � + Figure 2. Cumulative incidence of severe hypokalemia (K <2.5 meq/L) among 3 cohorts. In 2001–2002 (cohort 1), with minimal electrolyte mon- itoring 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 sup- Figure 3. Cumulative survival after cryptococcal meningitis by cohort plementation (February 21, 2011) and enhanced attention to weight-based time period. Fourteen-day survival in 2002 (cohort 1) was 49% (95% con- dosing of amphotericin (cohort 3), the incidence of severe hypokalemia fidence interval [CI], 39%–59%), including 8 persons who left against med- declined to 8.5% (12 of 142, P < .001 compared to without supplementa- ical advice ( presumed dead). In 2006–2010 (cohort 2), with universal IV tion). No persons developed clinically significant hyperkalemia with elec- fluids, the 30-day cumulative survival was 62% (95% CI, 55%–69%; trolyte supplementation. The majority of the hypokalemia occurs during the P = .003 vs 2001–2002 cohort). In 2011–2012 (cohort 3), with universal second week of amphotericin therapy, thus with minimal monitoring in co- IV fluids and electrolyte supplementation, 30-day cumulative survival im- hort 1, the lack of detected hypokalemia does not indicate the absence of proved to 78% (95% CI, 70%–85%; P = .021 vs 2006–2010 cohort, hypokalemia. Severe hypokalemia rarely occurs before day 7. Without in- P < .001 vs 2001–2002 cohort). Right-hand censoring occurred at time of tensive K monitoring, absence of hypokalemia at day 14 likely may repre- antiretroviral therapy (ART) initiation (including n = 8 in 2010; n =49 in sent a survival bias. Abbreviation: IV, intravenous. 2011–2012 randomized to early ART; n = 3). administered by study nurses and monitored by study 2009, but similarly negligible incidence of severe hypokalemia physicians. at day 7 and day 14 was recalled (D. B. M., A. M.). However, in the 2010 period of cohort 2 when electrolytes were measured Survival starting at day 5 approximately every 48 hours, the cumulative When limited IV fluids were available and intermittent shortages incidence of severe hypokalemia (K < 2.5 mEq/L) was 38% (8 occurred, the 14-day survival was 49% (45 of 92) in 2001–2002. of 21), with 19 severe hypokalemic events occurring in 8 partic- With universal provision of IV fluids in 2006–2010, the 30-day ipants in the first 14 days of amphotericin. Severe hypokalemia cumulative survival was 62% (log rank P =.003 vs 2001–2002 co- was evenly distributed between the trial’s randomization arms. hort). In 2011–2012, with universal supplementation of fluids After the standardized electrolyte protocol was implemented in and electrolytes, the 30-day cumulative survival improved to February 2011, 15 severe hypokalemic events occurred among 78% (log rank P =.021 vs 2006–2010 cohort) (Figure 3). Cox re- 12 participants for a cumulative incidence of 8.5% (12 of 142) gression models were also used to adjust for baseline GCS, creat- (relative risk = 4.5; 95% CI, 2.1–9.7; P < .001). Thus, a lack of se- inine, opening pressure, and potassium: none of these analyses vere hypokalemia observed in 2001–2009 likely reflects unrec- altered the significance of the survival differences. With fluid ognized severe hypokalemia because of lack of testing between and electrolyte support, 14-day survival improved by 30% despite day 8 and 13 as well as a survival bias, namely those who sur- similar amphotericin-based treatment (0.7–1.0 mg/kg per day) vived to 14 days were more likely the patients without severe hy- regimens and frequency of lumbar punctures (median n =3 in pokalemia during amphotericin therapy. Unintentional missed 2001–2002 and in 2011–2012). There was no association between doses of amphotericin are unlikely because the medication was week 1 deaths and hyperkalemia in any cohort. + 2+ K Mg Supplementation in Cryptococcus OFID 5 � � DISCUSSION fungicidal activity) compared to 14 days of amphotericin (1.0 mg/kg per day) but without electrolyte abnormalities. In that Implementation of a comprehensive electrolyte management study, routine potassium (40 mEq/day) supplementation was protocol was associated with reduced severe hypokalemia and given. Similar high levels of efficacy without toxicity were also improved survival when added to standard amphotericin treat- reported in a similar 7-day randomized trial of amphotericin ment and IV fluids for HIV-associated cryptococcal meningitis (1.0 mg/kg per day) with fluconazole (1200 mg/day) in Malawi in a resource-limited setting. Current Infectious Diseases Soci- [28].An unresolved clinical question, raised by Thomas Harrison ety of America guidelines for cryptococcal treatment mention and colleagues, St. George’s University, London [27, 28], is the that if facilities do not have sufficiently rapid or reliable K ideal length of amphotericin induction, and this question is cur- monitoring, amphotericin use may not be safe [8]. However, rently being tested in a phase III trial (ISRCTN45035509). further guidance is not provided, and magnesium is not men- Finally, in resource-limited settings without access to KCl tioned [8, 22]. pharmaceutical preparations, foods rich in potassium may be In the high-income countries, electrolytes are checked fre- readily available and could provide suitable potassium replace- quently and replaced rapidly in hospitalized patients; however, ment while on amphotericin. For example, the average US avo- in the many resource-limited settings, unique barriers exist for cado has ∼6.5 mEq of potassium per 100 g, whereas a banana the close monitoring of electrolytes. Laboratory facilities may has approximately two thirds of that amount [29]. In a patient not be reliably available or not able to return results rapidly able to tolerate food or nasogastric feeding, this may be a rea- enough to be acted upon in a clinically useful fashion. Electro- sonable alternative method of potassium supplementation. lyte replacements themselves may be unavailable in many Defaulting to fluconazole monotherapy to avoid amphoteri- settings, and cost, although low relative to many other medica- cin toxicity is a poor strategy. The survival with fluconazole tions, can be a barrier. Thus, although a comprehensive electro- monotherapy is ∼30% worse than with amphotericin, in cross- lyte management strategy would be ideal, this may not be cohort comparisons [10]. Although the lure of less toxicity in realistic in all settings. Yet, amphotericin-induced electrolyte fluconazole monotherapy may be appealing, as we have demon- wasting is a universal expectation, and so the issue must be ad- strated here, the electrolyte toxicity of amphotericin is manage- dressed. In many illnesses, this may be inconsequential; howev- able, and acute kidney injury is relatively infrequent (∼8%) with er, for any illness treated with electrolyte wasting medications, IV fluid prehydration [11]. As mentioned above, in 2001–2002 + 2+ such as amphotericin, K and Mg replacement becomes ex- (cohort 1), IV fluids were of limited quantity and intermittently tremely important [23–25]. Stakeholders who influence health available. In 2006–2009 (cohort 2), all participants received 1 policy in low- and middle-income countries should view elec- liter of 0.9% NaCl NS before amphotericin. In 2010–2012 trolyte management as part of the package of care for proper (COAT trial patients in cohorts 2 and 3), participants received cryptococcal treatment. 2 liters of NS daily according to trial standard operating proce- Multiple alternatives to the comprehensive electrolyte re- dures. Persistent significant chronic kidney injury is rare: in the placement strategy detailed above are possible. Amphotericin 2006–2009 Kampala cohort [17], 95% of survivors had a serum predictably depletes potassium and magnesium [14, 26]. Thus, creatinine <2 mg/dL at 5 weeks after cryptococcal meningitis di- scheduled supplementation only without additional measure- agnosis, with 80% <1.5 mg/dL. In 2010–2012, 99% of survivors ment or replacement doses would be feasible. Although there had creatinine <2 mg/dL at 5 weeks. is some risk of hyperkalemia due to replacement, the predict- Cost is often considered as a barrier to therapeutic interven- able nature of electrolyte wasting allows for scheduled replace- tions. As an example of the costs of these medications; 1 non- ment without significant fear of hyperkalemia. Furthermore, profit medical wholesaler in Kampala, Uganda supplies the because amphotericin’s effect on electrolyte wasting is known following prices of 1 vial of 10 mEq IV KCl for $1.04 and oral to be cumulative and dose dependent [11, 14, 26], increasing 8 mEq KCl for $3.30 per 100 tablets [30]. Magnesium prices are the potassium supplementation during the second week should similar [30]. Although these purchases would require some re- be well tolerated. This strategy would reduce overall hypokale- sources, the cost is quite affordable when one considers the im- mia but likely leave some small percentage of patients (∼10%) mediate 30-day survival benefit. Supporting local industry and severely hypokalemic; moreover, routine replacement would local avocado or banana farmers may be a wiser investment have an acceptable, potential risk of hyperkalemia should than importing supplies. even routine monitoring be difficult to obtain. The main limitation is the historical comparison of 3 cohorts A second strategy would be to use shorter 1-week courses of over time. Although fluid and electrolyte management was the amphotericin. In a prospective study in Uganda by Muzoora major change, other unseen bias influencing mortality may et al [27], 5 days of amphotericin (1.0 mg/kg per day) with ad- exist. Severity of illness was similar among cohorts and, if any- junctive fluconazole (1200 mg/days) was well tolerated with ap- thing, increased over time with higher proportions with altered proximately 75% of the rate of microbiologic clearance (ie, early mental status and higher CRAG titers during 2006–2012. 6 OFID Bahr et al � � Quantitative cultures were performed in cohorts 2 and 3; how- survival with amphotericin B deoxycholate therapy. Second, ever, the method was different, and so direct comparison would routine, proactive potassium and magnesium supplementation not be accurate. One of the major improvements in clinical care is superior to a reactive approach of replacing electrolytes once a during the trial of cohort 2 and 3 was improved safety monitor- life-threatening deficiency has been identified. Third, more op- ing with more frequent detection of laboratory abnormalities. In erational research is needed to determine whether potentially 2001–2002, K monitoring at day 1, 7, and 14 only detected 2% shorter courses of 5, 7, or 10 days of amphotericin have a with hypokalemia at day 7. Yet lack of monitoring did not more favorable risk/benefit in resource-limited regions com- equate to absence of hypokalemia during the second week of pared to 2 weeks of amphotericin [33]. Using initial quantitative amphotericin, based on a 38% incidence of hypokalemia in CSF culture burden to guide therapy duration may be more ra- 2010 with more frequent monitoring. Likewise, monitoring tional than giving all persons 14 days of amphotericin [33]. In alone without action did not decrease mortality or hypokalemia conclusion, in comparing 3 cohorts of patients with cryptococ- in 2010. One might also argue that caregiver or institutional expe- cal meningitis treated with amphotericin in Kampala, Uganda, rience may have been gained over time, which explained the sur- survival significantly improved with a comprehensive electro- vival benefit. However, we believe this explanation is also unlikely lyte monitoring and replacement strategy. given that the medical officers and nurses caring for the patients directly changedwitheachstudy (A.K.; D. B. M./A.M.; H. N.). Supplementary Material Other specific changes were made. First, the cryptococcal Supplementary material is available online at Open Forum Infectious Dis- antigen lateral flow assay (Immy, Norman, Oklahoma) was im- eases (http://OpenForumInfectiousDiseases.oxfordjournals.org/). plemented in April 2011 as a point-of-care test to decrease time-to-diagnosis. Although exceedingly helpful, the severity Acknowledgments of illness and demographics remained similar. Second, concom- itant fluconazole 800 mg/day was given starting in 2010 during We thank support and input from Drs. Thomas Harrison, Tihana Bicanic, Graeme Meintjes, Yukari Manabe, Radha Rajasingham, Paul Boh- induction therapy and as enhanced consolidation until the CSF janen, and Melanie Lo, as well as Ali El Bireer, and the MU-JHU laboratory was known to be sterile. This fluconazole regimen was in place staff. We thank Dr. Meagan O′Brien for clinical care in 2001–2002, and during the initial 2 months of the COAT trial when the inves- Dr. Merle Sande for mentorship. We also thank the Accordia Global Health Foundation for support of the Infectious Disease Institute. tigators detected an association between hypokalemia and mor- Financial support. This work was supported by the National Institute tality. Based on a 2013 trial, the addition of fluconazole to of Allergy and Infectious Diseases and Fogarty International Center at the amphotericin did not have a statistical survival benefitover4 National Institutes of Health (K23AI073192, U01AI089244, R25TW009345, T32AI055433) and the University of Minnesota Foundation. weeks of amphotericin alone [31]. The higher dose fluconazole (800 mg/day) “enhanced” consolidation therapy was used in References 2010–2012, but this is of unproven significance in terms of any potential benefit. Although fluconazole adjunctive therapy with 1. Jarvis JN, Meintjes G, Williams A, et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. amphotericin leads to more rapid clearance of Cryptococcus BMC Infect Dis 2010; 10:67. from the CSF [15, 18], this alone is unlikely to explain the im- 2. Durski KN, Kuntz KM, Yasukawa K, et al. Cost-effective diagnostic proved survival in the third cohort [31]. 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