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Hypokalemia Among Patients Receiving

Treatment for Multidrug-Resistant


Tuberculosis*
Sonya Shin, MD; Jennifer Furin, MD, PhD; Félix Alcántara, MD;
Anne Hyson, MPH; Keith Joseph, MD; Epifanio Sánchez, MD; and
Michael Rich, MD, MPH

Introduction: Between January 1999 and December 2000, 125 patients in Lima, Peru were
enrolled in individualized treatment for multidrug-resistant tuberculosis (MDR-TB). Hypokale-
mia was observed to be an important adverse effect encountered in this cohort.
Objective: To identify risk factors associated with the development and persistence of hypokale-
mia during MDR-TB therapy, and to review the incidence and management of hypokalemia in
patients receiving MDR-TB therapy.
Methods: A retrospective case series of 125 patients who received individualized therapy for
MDR-TB between January 1, 1999, and December 31, 2000.
Results: Among 115 patients who were screened for electrolyte abnormalities, 31.3% had
hypokalemia, defined as a potassium level of < 3.5 mEq/L. Mean serum potassium at time of
diagnosis was 2.85 mEq/L. Diagnosis of low serum potassium occurred, on average, after 5.1
months of individualized therapy. Multivariate analysis of risk factors for this adverse reaction
identified two causes: administration of capreomycin, and low initial body weight. Normalization
of potassium levels was achieved in 86% of patients.
Conclusions: Electrolyte disturbance was frequently encountered in our cohort of patients with
MDR-TB. Successful screening and management of hypokalemia was facilitated by training the
health-care team in the use of a standardized algorithm. Morbidity from hypokalemia can be
significant; however, effective management of this side effect is possible without sacrificing
MDR-TB treatment efficacy. (CHEST 2004; 125:974 –980)

Key words: capreomycin; electrolyte; hypokalemia; hypomagnesemia; magnesium; multidrug-resistant tuberculosis;


potassium; tuberculosis

Abbreviations: CI ⫽ confidence interval; DOT ⫽ directly observed therapy; MDR-TB ⫽ multidrug-resistant tuberculosis

M ultidrug-resistant tuberculosis (MDR-TB) re-


mains an international public health threat. 1
losis with resistance to both isoniazid and rifampin, is
challenging, with treatment length ranging from 18
Unfortunately, the treatment of MDR-TB, defined to 24 months, including parenteral therapy for a
as infection with strains of Mycobacterium tubercu- minimum of 6 months.2 Patients receiving MDR-TB
therapy tend to have higher rates of adverse reac-
*From the Division of Infectious Diseases (Dr. Shin), and tions and lower cure rates when compared with
Division of Social Medicine and Health Inequalities (Drs. Joseph
and Rich), Brigham and Women’s Hospital, Boston, MA; Part- those receiving treatment for pansusceptible disease.
ners In Health, Boston, MA, and Socios En Salud (Drs. Furin, Yet, effective ambulatory treatment of MDR-TB in
Alćantara, Hyson, and Joseph), Lima, Perú; and Peruvian Na-
tional Tuberculosis Program, Ministry of Health (Dr. Sánchez), resource-poor settings, although difficult, is none-
Lima, Perú. theless possible. In one community-based treatment
This work was performed at Socios En Salud, and Brigham and project in northern Lima, Peru, ⬎ 80% of patients
Women’s Hospital.
Funding for this research was provided by the Bill & Melinda receiving ambulatory individualized therapy for
Gates Foundation. MDR-TB were successfully cured.3 An important
Manuscript received March 25, 2003; revision accepted October component of the success of this project has been
8, 2003.
Reproduction of this article is prohibited without written permis- the aggressive management of adverse reactions
sion from the American College of Chest Physicians (e-mail: through a network of health-care workers from the
permissions@chestnet.org). Ministry of Health and Socios En Salud, a nongov-
Correspondence to: Sonya Shin, MD, Division of Social Medicine
and Health Inequalities, 1620 Tremont St, Third Floor, Boston, ernmental organization.
MA 12120; e-mail: sshin@partners.org Electrolyte disturbance is one of the most chal-

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lenging adverse reactions related to MDR-TB man- Holmes et al12 observed electrolyte abnormalities
agement, in particular because of the paucity of in 3 of 67 patients (4.5%) receiving capreomycin.
presenting symptoms and potential morbidity asso- The level of potassium ranged from 2.9 to 3.2
ciated with this disorder. Reasons for electrolyte mEq/L, with concomitant hypocalcemia, hypomag-
disturbance among patients treated for MDR-TB are nesemia, and a hypochloremic alkalosis. Two pa-
likely multifactorial. Both potassium and magnesium tients had received therapy for ⬎ 20 months, while
deficiencies are associated with a number of chronic one patient had been receiving tuberculosis treat-
diseases, such as tuberculosis, malnutrition, alcohol- ment for 6 months.
ism, and diabetes mellitus.4 – 6 In addition, diarrhea Electrolyte disturbances may be manifested as
and vomiting caused by antituberculous agents can minor complaints such as fatigue, cramps, nausea,
contribute to GI electrolyte loss. and irritability, or by serious complications, including
There is also evidence that the use of aminoglyco- tetany, seizures, and lethal cardiac arrhythmias.
sides and capreomycin causes renal wasting of elec- Given the nonspecific early symptoms and significant
trolytes, including potassium, magnesium, and calci- morbidity associated with electrolyte wasting, regu-
um.6 –9 Both aminoglycosides and capreomycin are lar monitoring and replacement is critical. While
thought to induce secondary hyperaldosteronism management approaches vary in the literature cited
leading to urinary loss of potassium and magne- above, correction of electrolyte abnormalities is pos-
sium.10 –12 Because magnesium serves as a co-factor sible without discontinuation of parenteral therapy,
in the adenosine triphosphatase-dependent mecha- through aggressive repletion of potassium and mag-
nism for active transport of sodium and potassium nesium.11,15 In particular, correction of hypomag-
across the cell membrane, further potassium wasting nesemia contributes to the normalization of calcium
occurs as a consequence of resultant intracellular and potassium deficiencies.6,13 Indeed, hypokalemia
magnesium deficiency. Lastly, hypomagnesemia can may be refractory to treatment if hypomagnesemia is
induce hypocalcemia, in part through the suppres- present and not addressed.16 Spironolactone (100 to
sive effect of low magnesium levels on the parathy- 300 mg/d) may also aid in the normalization of serum
roid hormone. potassium and magnesium.13,15 Normalization of
Electrolyte disturbance has been associated with electrolyte values may take up to 4 months after
high cumulative doses of aminoglycosides, in partic- cessation of the offending agent.6
ular with gentamicin.9,13 The incidence of electrolyte We report here on the incidence of hypokalemia
disorders from aminoglycosides is approximately and hypomagnesemia in a cohort of individuals
4.5%.13 Electrolyte disturbance, in particular hypo- treated for MDR-TB; in particular, we explore the
kalemia, appears to occur more frequently with risk factors associated with hypokalemia in our co-
capreomycin, and is reported in 4 to 15% of pa- hort of patients and describe our approach to man-
tients receiving capreomycin therapy for 6 to 26 agement.
months.12,14,15
Hesling15 suspected electrolyte disturbances in 5
patients (14.7%) in a cohort of 34 patients, all of Clinical Case
whom were all receiving capreomycin. Occurrence
did not appear to be related to preexisting renal EB is a 35-year-old man receiving MDR-TB
disease. Death occurred in one patient; pathologic therapy with a regimen of capreomycin, levofloxacin,
inspection showed nonspecific hydropic changes in para-aminosalicylic acid, cycloserine, amoxicillin-
the epithelial lining of the distal tubules. clavulanic acid, clarithromycin, and clofazimine. Af-
In another study by Aquinas and Citron,4 a cohort ter a month of treatment, routine electrolyte screen-
of 40 tuberculosis patients received capreomycin at ing revealed a potassium level of 2.7 mEq/L (normal
15 mg/kg for 6 months. Seven patients were noted to limits, 3.5 to 5.5 mEq/L). Magnesium level was
have at least two serum potassium values ⬍ 3.2 initially within normal limits at 2.3 mEq/L (range,
mEq/L. While the association of hypokalemia with 1.8 to 2.1 mEq/L). The patient denied significant
capreomycin was unclear in five of these individuals, vomiting or diarrhea. He reported mild fatigue and
two patients (5%) had recurrence of hypokalemia on occasional cramping of leg muscles. Figure 1 sum-
resuming capreomycin, with resolution on discontin- marizes the patient’s course, showing the correlation
uation of the injectable. Interestingly, among the of serum potassium and magnesium with daily sup-
remaining 33 individuals, a statistically significant plementation with potassium chloride and magne-
rise in serum potassium was observed in the second sium sulfate. After discontinuation of capreomycin in
6 months of treatment vs the first 6 months. The January of 2001, the electrolyte deficiencies resolved
authors postulated that this trend was due to re- and potassium and magnesium supplementation
sponse of tuberculosis to chemotherapy. were discontinued within 1 month.

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Figure 1. Summary of potassium and magnesium serum levels and supplementation in case example.

Materials and Methods potassium was 3.5 mEq/L according to all laboratories, the lower
limit of normal magnesium varied among the laboratories per-
forming this test (between 1.5 mEq/L and 2.0 mEq/L). Individ-
Study Population uals with a diagnosed electrolyte disturbance were managed by
The cohort included all 125 patients consecutively enrolled in health-care providers of Socios En Salud and the Peruvian
MDR-TB treatment between January 1, 1999, and December 31, National TB Program.
2000. Patients were enrolled throughout metropolitan Lima in all
Ministry of Health hospitals, health centers, and health posts Study Method
offering tuberculosis therapy. All patients received individualized
therapy for documented MDR-TB through a collaborative effort A case series with retrospective chart review was conducted for
of a nongovernmental organization, Socios En Salud; Harvard all 125 patients consecutively enrolled in the DOTS-Plus pro-
Medical School; and the Peruvian National Tuberculosis gram between January 1, 1999 and December 31, 2000. All
Program. patients had completed at least 16 months of treatment at the
time of chart review, unless treatment had been interrupted due
Treatment Protocol to death or default. All charts were reviewed by a clinician
experienced in MDR-TB management. Variables extracted from
Patients received directly observed therapy (DOT) delivered in the chart review included the following: age; sex; number of
health establishments and in their homes by community health previous treatment regimens; drugs in the individualized regi-
workers.17 Drug resistance was established by conventional or men; presence of a comorbid condition, including diabetes
BACTEC methods (Becton-Dickinson; Sparks, MD) performed mellitus, HIV, renal dysfunction and hypothyroidism; and treat-
by the Massachusetts State Laboratory Institute on sputum ment response. All serum potassium and magnesium results, with
specimens.3 Routine electrolyte (serum potassium and magne- the date and normal limit of each value, were recorded. Man-
sium) monitoring was performed while receiving an injectable agement of electrolyte disturbance was also documented.
agent (ie, streptomycin, amikacin, kanamycin, or capreomycin). Hypokalemia was defined as serum potassium below 3.3
While baseline electrolytes were not universally screened, they mEq/L and hypomagnesemia as serum magnesium of ⬍ 1.5
were checked in 44 patients (35.2%), and findings were normal in mEq/L. Electrolyte correction was defined as a normalization of
all cases. Of note, beginning in July of 2000, the health-care serum potassium or serum magnesium (serum potassium ⱖ 3.5,
team—including physicians, nurses, and health promoters—was serum magnesium ⱖ 1.8), after which all subsequent values
trained in a protocol for monthly electrolyte and creatinine remained above these lower limits. Hypothyroidism was defined
surveillance and management of electrolyte disturbances.18 In as a serum thyroid stimulating hormone ⬎ 10 IU/mL. Renal
addition, all patients had monthly evaluations by a physician dysfunction was defined as two consecutive creatinine values that
trained in MDR-TB management, and any individuals reporting were elevated ⬎ 50% above baseline or nephrotic syndrome as
symptoms suggestive of electrolyte disturbance underwent fur- evidenced by ⬎ 2 g protein in 24-h urine. Body mass index was
ther laboratory testing. Potassium and magnesium serum levels calculated by initial body weight in kilograms divided by the
were performed by various laboratories, depending on the pa- square of height in meters. Poor treatment outcome was defined
tient’s residence. All laboratories reported their normal values as death, abandonment, treatment failure or, if the patient was
with the patient’s results. While the lower limit of normal still in treatment at the time of analysis, positive sputum culture

976 Clinical Investigations

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results (ie, any positive culture result within the last two recorded tients are shown in Table 1. Forty of the 115 patients
monthly cultures). Conversely, favorable treatment outcome was (34.8%) were found to have an electrolyte distur-
defined as either cure or, if still in treatment, culture-negative
status. Patients were considered to be culture negative if, at the bance during the course of individualized therapy.
time of analysis, their two most recent monthly culture findings Thirty-six patients (31.3%) had hypokalemia, 18 pa-
were confirmed negative. Death from all causes was included in tients (15.7%) had hypomagnesemia, and 14 patients
death as an outcome. (12.2%) had both low potassium and magnesium. In
general, our cohort was young, with a mean age of
Statistical Analysis
30.1 years (range, 11 to 75 years); approximately half
All data were recorded in Microsoft Excel 98 (Microsoft of the patients were male, and patients were infected
Corporation; Seattle, WA); all statistical analysis was performed by strains resistant to roughly six drugs. There were
using SAS (version 8.2; SAS Institute; Cary, NC). Reported
no patients with HIV in this cohort.
p values are two-sided Fisher exact tests. Multivariable analysis
was performed using logistic regression. Kaplan-Meier estimates, As shown in Table 1, in a univariate analysis,
and Cox proportional-hazards models were used to identify factors significantly associated with the occurrence of
variables associated with time to resolution of hypokalemia. hypokalemia were choice of injectable, hypomag-
nesemia, hypothyroidism, and low initial weight.
These significant variables (capreomycin, initial
Results weight, and hypothyroidism) were included in a
Patient charts were available for all 125 patients; multivariable analysis, wherein only capreomycin
however, electrolyte data were not available for 10 (p ⬍ 0.0001) and initial weight (p ⫽ 0.004) were
patients. Among these cases, three individuals died significantly associated with occurrence of hypokale-
within the first month of treatment. Among the mia, with adjusted hazard ratios of 36.1 (95% confi-
remaining seven patients, two individuals were cured dence interval [CI]10.10 to 129.57) and 0.93 (95%
at the time of analysis, two were in treatment and CI, 0.88 to 0.98), respectively. Of note, among the 44
culture negative, one died 17 months into individu- patients receiving capreomycin, the incidence of
alized therapy, and two defaulted (both in their hypokalemia was 68.2%. Conversely, use of strepto-
second month of treatment). Serum electrolyte data mycin as the choice of injectable was associated with
were therefore available for 115 of the 125 patients lower rates of hypokalemia; among the 39 individuals
(92%). Subsequent analysis was performed among who received streptomycin, only 1 patient acquired
this cohort of 115 individuals. hypokalemia. Higher mortality rates were observed
Demographic and baseline variables for 115 pa- among those patients with hypokalemia, with a crude

Table 1—Patient Characteristics Among 115 Patients Receiving MDR-TB Therapy*

With Hypokalemia Without Hypokalemia Crude Relative Risk


Characteristics (n ⫽ 36) (n ⫽ 79) p Value (95% CI)

Age 31.7 ⫾ 10.0 29.3 ⫾ 9.6 0.22


Male gender 18 (50.0) 47 (59.5) 0.42 0.89 (0.68–1.14)
No. of drugs to which 5.6 ⫾ 1.6 5.8 ⫾ 1.7 0.58
strain resistant
No. of previous 3.5 ⫾ 1.6 3.5 ⫾ 1.3 0.99
treatments
Initial weight, kg 52.2 ⫾ 11.2 58.2 ⫾ 12.1 0.01
Body mass index 20.2 ⫾ 3.9 21.7 ⫾ 3.8 0.059
Injectable drug
Amikacin 2 (5.6) 1 (1.3) 0.23 2.09 (0.42–10.40)
Capreomycin 30 (83.3) 14 (17.7) ⬍ 0.0001 2.88 (1.86–4.46)
Kanamycin 3 (8.3) 26 (32.9) 0.005 0.69 (0.56–0.85)
Streptomycin 1 (2.8) 38 (48.1) ⬍ 0.0001 0.55 (0.45–0.69)
Hypomagnesemia 14 (38.9) 4 (5.1) ⬍ 0.0001 3.48 (1.46–8.31)
Comorbid conditions
Diabetes mellitus 0 (0) 2 (2.5) 1.0 0.68 (0.60–0.77)
Hypothyroidism 16 (44.4) 17 (21.5) 0.015 1.47 (1.03–2.09)
Renal dysfunction 2 (5.6) 1 (1.3) 0.23 2.09 (0.42–10.40)
Treatment outcome
Favorable outcome 25 (69.4) 62 (78.5) 0.35 0.85 (0.61–1.18)
Death 8 (22.2) 8 (10.1) 0.14 1.43 (0.87–2.38)
*Data are presented as mean ⫾ SD or No. (%).

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relative risk of 1.43 (95% CI, 0.87 to 2.38); however, ards ratio, 3.56 [95% CI, 1.49 to 8.51]) and absence
this association was not statistically significant. of hypomagnesemia (adjusted hazard ratio, 0.46
At the time of analysis, favorable outcome was [95% CI, 0.21 to 0.998]); the effect of hypomag-
observed in 87 patients (75.7%) and poor outcome in nesemia is demonstrated in the Kaplan-Meier curves
28 patients (24.3%). Among those with favorable shown in Figure 2.
outcome, 29 patients (25.2%) were cured and 58 We also assessed the effect of implementing a
patients (50.4%) were culture negative in treatment. protocol for routine electrolyte surveillance. Prior to
Patients with poor outcome included 16 patients August 1, 2000, electrolytes were monitored in 66 of
(13.9%) who died, 3 patients (2.6%) who abandoned 75 individuals (88%). In contrast, electrolytes were
therapy, and 9 patients (7.8%) who remained culture monitored in 49 of all 50 individuals (98.0%) en-
positive despite at least 16 months of treatment. rolled from August 1, 2000, to December 31, 2000.
None were classified as treatment failures. While the use of capreomycin decreased (44%
The mean duration of individualized therapy at among the early cohort vs 22% among the late
the time of diagnosis of hypokalemia was 5.1 months cohort), the rates of hypokalemia among those re-
(SD, 4.0). The average potassium was 2.85 mEq/L ceiving capreomycin remained fairly constant (69.7%
on presentation, with a nadir of 2.65 mEq/L, occur- vs 63.6%). The value of the initial low potassium was
ring approximately 6 weeks after diagnosis of hypo- similar (2.9 vs 3.0), but diagnoses were made earlier
kalemia. Approximately 86% of those with hypoka- after our programmatic intervention (5.3 vs 2.4
lemia went on to normalize, with a mean duration of months, p ⫽ 0.053). In addition, hypokalemia was
potassium disturbance of 6.6 months (SD, 3.9). Most corrected in 100% of all individuals after the inter-
individuals with hypokalemia received oral or IV vention (vs 87.0 in the earlier group). While these
potassium supplementation (88.9%), as well as oral changes were not statistically significant in this uni-
or IV magnesium (86.1%); in addition, approximately variate analysis, the implementation of a program-
36% received amiloride (at doses of 12.5 to 50 mg/d). wide protocol appeared to shorten the time to
Given the association of higher mortality associ- diagnosis of hypokalemia and improve rates of elec-
ated with hypokalemia, we further examined the trolyte resolution.
relationship between hypokalemia and death. In a
univariate analysis among those with hypokalemia,
the only factor significantly associated with higher Discussion
mortality was lack of resolution of hypokalemia
(p ⫽ 0.0004). We subsequently analyzed factors as- Hypokalemia and hypomagnesemia are important
sociated with time to resolution of hypokalemia. In a adverse reactions of MDR-TB therapy, particularly
multivariable model, factors associated with earlier among patients receiving capreomycin. We describe
time to resolution were male gender (adjusted haz- here a high incidence of electrolyte disorders in the

Figure 2. Time to resolution of hypokalemia.

978 Clinical Investigations

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largest cohort published to date. Numerous factors management is reasonable. Contributing factors to
may contribute to such high rates of electrolyte electrolyte disturbance—such as vomiting, diarrhea,
disturbances, including disease chronicity and poor and dehydration—should be addressed. In general,
nutritional status. On average, our patients had potassium supplementation is provided if the serum
received at least three previous treatment regimens, potassium is ⬍ 3.5 mEq/L. In our program, patients
and approximately one third had low body mass usually receive electrolyte repletion on an ambula-
indices. In addition, administration of parenteral tory basis with close monitoring of electrolyte re-
therapy in our cohort tended to be prolonged, sponse. Hospitalization is reserved for individuals
usually lasting at least 8 months. Finally, our patients who are symptomatic, require frequent electrolyte
received more antituberculous drugs than cohorts monitoring, or require IV supplementation. Aggres-
described by Holmes et al,11 Hesling,14 and Aquinas sive repletion is necessary, as demonstrated in Fig-
and Citron.4 Therefore, concomitant side effects, ure 1. Individuals with electrolyte abnormalities
such as vomiting and diarrhea, may have been more usually require supplementation for the duration of
common. In fact, elevated rates of electrolyte distur- parenteral therapy. While electrolyte disturbances
bance have also been observed in a contemporary do not require discontinuation of injectable therapy,
cohort in Tomsk, treated with similarly aggressive capreomycin may be replaced by an aminoglycoside,
regimens.19 if susceptibility to an alternative injectable is dem-
In our cohort, use of capreomycin and low initial onstrated.
body weight were associated with an increased like- The use of potassium-sparing diuretics (spirolac-
lihood of acquiring hypokalemia. While we would tone, triamterene, or amiloride) was not associated
recommend screening all patients receiving inject- with resolution of hypokalemia in our cohort; how-
able therapy on a monthly basis, it may be prudent to ever, we reserved amiloride for those individuals
monitor individuals with low body weight more with refractory electrolyte disturbances and used
closely. In addition, even though continuation of lower doses compared with previously mentioned
capreomycin is often necessary (used in our cohort literature. Of note, caution should be used when
for individuals with resistance to all aminoglyco- potassium-sparing diuretics are administered in con-
sides), malnutrition may be a correctable risk factor junction with potassium supplements, since hyper-
for electrolyte disturbance. kalemia or orthostasis can result.
Hypomagnesemia often accompanied hypokale- Despite an association between hypokalemia and
mia and was likely induced by the same mechanism mortality, rates of poor treatment outcome and
of electrolyte wasting. Since magnesium deficiencies mortality were not significantly greater among those
presented on average 2.7 months after diagnosis of patients with electrolyte disturbances. Nonetheless,
hypokalemia, we have concluded that monitoring among individuals with hypokalemia, failure to re-
serum potassium alone is sufficient to monitor for solve this electrolyte disorder was significantly asso-
electrolyte abnormalities. Serum magnesium and ciated with death. Whether hypokalemia contributed
calcium levels may be checked in hypokalemic to their mortality or reflects another factor associated
and/or symptomatic individuals. In areas where se- with greater morbidity remains to be determined. Of
rum magnesium and/or calcium levels are not avail- note, the average duration from time to diagnosis of
able, empiric repletion of magnesium and calcium is hypokalemia to death was 4.1 months among the
a reasonable alternative. eight individuals who had hypokalemia and died.
Even more interesting are the effects of gender Therefore, it is unlikely patients died too quickly for
and magnesium deficiency on time to correction of electrolyte disorders to be corrected. While no au-
hypokalemia. While women may have higher base- topsies were performed, none of these deaths were
line rates of electrolyte disturbances,20,21 it is also believed to be due to cardiac arrhythmia, seizure, or
possible that some biological or social factor not coma. A larger cohort will be needed to understand
assessed in this analysis impacts the outcome of the contribution of electrolyte disorders to the mor-
women. This phenomenon was also observed in the tality of individuals treated for MDR-TB.
association of gender with poor MDR-TB treatment Our study does have certain limitations, including
outcome.3 The association of hypomagnesemia with a limited sample size. We plan to assess a larger
refractory hypokalemia, however, has been well de- cohort in the future, with the hopes of understanding
scribed and suggests a role for empiric magnesium the risk factors associated with occurrence and per-
supplementation in all patients identified with low sistence of electrolyte imbalances, as well as the
potassium. In addition, the poor correlation between relationship between electrolyte disorders and mor-
serum and total-body magnesium also justifies em- tality. Furthermore, while this analysis has been
piric, instead of sliding-scale, magnesium repletion. helpful in shaping our management strategies in
Once diagnosed, a staged approach to electrolyte Peru, relevance to other settings may vary. Our

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cohort is relatively young and healthy. Importantly, urinary electrolyte excretion in healthy subjects. Clin Phar-
there were no patients with HIV within this cohort. macol Ther 2000; 67:16 –21
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may be less relevant for programs with high rates of Intern Med 1975; 82:646 – 649
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