zinc with oral rehydration therapy reduces stool.10

7/23/2019 Zinc With Oral Rehydration Therapy Reduces Stool.10

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Zinc With Oral Rehydration Therapy Reduces Stool Output and

Duration of Diarrhea in Hospitalized Children: A Randomized

Controlled Trial

*Shinjini Bhatnagar, *Rajiv Bahl, *Punit K. Sharma, *Geeta T. Kumar, S. K. Saxena, and

*Maharaj K. Bhan

*Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India, and Department of Pediatrics, Kasturba

Hospital, New Delhi, India.

ABSTRACTObjectives:The authors evaluated the effect of zinc treatment

as an adjunct to oral rehydration therapy on stool output anddiarrheal duration in children with acute noncholera diarrheawith dehydration.Methods:This double-blind, randomized, controlled trial wasconducted at two urban hospitals in New Delhi. A total of 287dehydrated male patients, ages 3 to 36 months, with diarrheafor 72 hours were enrolled. They were assigned to zinc orplacebo by a randomization scheme stratified by age ( or >12months) and weight for height (65%80% or >80% NationalCentre for Health Statistics median). Participants in the zincgroup received 15 mg (12 months) or 30 mg (>12 months)elemental zinc daily in three divided doses for 14 days. Themain outcome measures were stool output and diarrhealduration.

Results: Zinc treatment reduced total stool output (ratio ofgeometric means, 0.69; 95% confidence interval [CI]: 0.48,

0.99) and stool output per day of diarrhea (ratio of geometricmeans, 0.76; 95% CI: 0.59, 0.98). The risk of continued diar-rhea was lower (relative hazards, 0.76; 95% CI: 0.59, 0.97) andthe proportion of diarrheal episodes lasting 5 days (oddsratio, 0.49; 95% CI: 0.25, 0.97) or 7 days was less (oddsratio, 0.09; 95% CI: 0.01, 0.73) in the zinc group.Conclusions: This study demonstrates a beneficial effect ofzinc administered during acute diarrhea on stool output, diar-rheal duration, and proportion of episodes lasting more than 7days. The effects are large enough to merit routine use of zincduring acute diarrhea in developing countries. JPGN 38:3440,

2004. Key Words: Acute diarrheaRandomized controlledtrialStool outputZinc. 2003 Lippincott Williams &Wilkins, Inc.

INTRODUCTION

Use of oral rehydration solution (ORS) in the treat-ment of diarrhea reduces the risk of mortality throughprevention and treatment of dehydration but does notdecrease diarrheal duration or stool output (1). Zinc de-ficiency is common in children from developing coun-tries because of the lack of intake of animal foods, highdietary phytate that limits zinc absorption, and inad-equate food intake (2). There are also increased fecallosses of zinc during diarrhea (3,4). In observationalstudies, low plasma zinc levels have been associated with

increased severity of diarrhea (5,6). Administration of 20to 40 mg of zinc to children with mild gastroenteritisresults in lower diarrheal duration and stool frequency inplacebo-controlled trials in developing countries (710).Stool output should be the main outcome assessed inclinical studies for new therapeutic interventions in acutediarrhea because it can be measured more objectivelythan stool frequency and is a useful proxy indicator forrisk of dehydration. Most of the previous studies of zinclevels during acute diarrhea measured episode durationand stool frequency as the outcomes (710). Two earlierstudies (11,12) that reported an effect on stool output in

children supplemented with zinc included small numbersand the subjects studied were moderate to severely mal-nourished.

In this double-blind, randomized, controlled study, wedetermined the efficacy of zinc in reducing stool outputand diarrheal duration when administered as an adjunctto oral rehydration therapy in hospitalized children ages3 to 36 months with acute diarrhea and dehydration.

Received April 28, 2003; accepted July 20, 2003.Address correspondence and reprint requests to Dr. Maharaj K.

Bhan, Department of Pediatrics, All India Institute of MedicalSciences, New Delhi, 110029, India (e-mail: [email protected]).

Funded by the World Health Organization, Geneva, and the IndianCouncil of Medical Research, New Delhi, India.

Journal of Pediatric Gastroenterology and Nutrition38:3440 January 2004 Lippincott Williams & Wilkins, Inc., Philadelphia

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PATIENTS AND METHODS

Study Participants

Male children attending the diarrhea treatment units of theAll India Institute of Medical Sciences and Kasturba Hospital,New Delhi, between April 1997 and December 2000 were en-rolled in the study if they were between 3 and 36 months of age,passed three or more liquid stools daily for 72 hours and hadmild or severe dehydration. Assessment of dehydration wasaccording to World Health Organization (WHO) guidelines(13). Only male patients were enrolled to ensure proper stoolcollection uncontaminated with urine. Participants with severedehydration were given 30 mL/kg/h lactated Ringers solutionintravenously for a maximum of 2 hours, after which they wereconsidered mildly dehydrated and could be enrolled in thestudy. Severe malnutrition (weight for height 12months) and weight for height (65%80% or >80% of theNCHS median). Within each stratum, they were randomly as-signed to receive zinc or placebo. A different randomization listfor each strata and each hospital, using permuted blocks offixed lengths of 10, was prepared at the WHO in Geneva. Thesequence of random numbers was generated using a table ofrandom permutations of 16 numbers. Zinc and placebo syrupspackaged in similar glass bottles and with identical color, tasteand appearance were provided by a pharmaceutical company(American Remedies Ltd., Chennai, Tamil Nadu, India). Each

bottle was labeled with a unique serial number that corre-sponded to the randomization lists before being arranged se-quentially and sent to the investigators. The randomizationcode was kept with the WHO until the trial was completed.Blinding was maintained during data analysis by coding eachgroup with a letter.

Intervention

Both intervention and control syrups contained vitamin Bcomplex (5 mL contained: B1, 2.5 mg; B2, 2.5 mg; B6, 1.0 mg;B12, 3g; C, 50 mg, D-panthenol, 12.5 mg; niacinamide, 25mg), and the one with zinc sulfate had 1 milligram per milliliterof elemental zinc. Participants 12 and >12 months were given15 mL and 30 mL of zinc or placebo solution, respectively, in

three divided doses, and this was continued until cessation ofdiarrhea and after discharge from the hospital for a total periodof 14 days. All doses were offered between meals and repeatedif vomiting occurred within 30 minutes.

Outcome Measures and Definitions

The main outcomes were stool output and time taken forcessation of diarrhea. Diarrhea was considered to have ceased

at the time of the last abnormal stool before a 12-hour periodwhen no stool had been passed or before the passage of twoconsecutive formed stools. An abnormal stool was a waterystool with no fecal matter or a loose stool with a rim of morethan 1 cm of water around it visualized on the diaper.

Monitoring of Participants

Each stool was measured in preweighed disposable diapers;consistency was noted and recorded immediately; urine wasseparated from stools by use of urine collection bags connectedto condoms. Vomitus was weighed on preweighed disposablegauze pads. Monitoring continued for at least 48 hours afterenrollment or until the diarrhea stopped, whichever was later.Nude body weights were taken at enrollment, after rehydrationat 6 hours, and then every 24 hours until the patients partici-pation in the study ended.

Standardization exercises on collection of stool output,vomitus, and measurements of weights and lengths were con-ducted at regular intervals.

Rehydration therapy for mild dehydration was according toWHO guidelines using oral rehydration solution (ORS) 100

mL/kg body weight for a period of 6 hours (13). Immediatelyafter rehydration was completed, feeding was resumed withtraditional milk cereal diet (calorie density: 92.4 cal/100 g;zinc: 0.27 mg/100 g, 0.32 mg/110 kcal) and was offered at therate of 110 kcal/kg/d. Water (zinc content: 0.06 mg/L) wasallowed ad libitum. ORS was given as replacement for ongoingstool losses on a volume-to-weight basis.

Unscheduled intravenous fluids were given during the initial6 hours of rehydration or during the maintenance period if theparticipant experienced severe dehydration despite the intake ofestimated oral fluids. Participants requiring intensive care treat-ment for severe systemic infection continued in the study butwere given additional treatment by physicians.

Serum Zinc and Copper Levels

A venous blood sample (5 mL) was obtained at enrollment.The sample was collected in zinc- and copper-free tubes, spun,and the serum stored at 20C. A second blood sample wasobtained at a follow-up visit after the completion of 14 days oftreatment. The zinc and copper concentration in the serumspecimens was analyzed using a flame furnace atomic absorp-tion spectrophotometer (GBC Avanta, Dandenong, Victoria,Australia) using standard techniques and with SERONORM(Sero AS, Billingstad, Norway) as the reference (14). Meancorpuscular volume was estimated routinely using standardmethods.

Sample Size Calculations

Trial size was calculated for 90% power and 95% confidenceto detect at least a 33% lower total stool output and 20% lowerduration of diarrhea in the zinc-treated group. The expectedvalues in the control group were based on a previous study inthe same hospital (15). A sample size of 130 per group wasestimated to be sufficient for total stool output and 106 pergroup for duration of diarrhea. Thus, we enrolled approxi-mately 145 children per group to account for a 10% loss tofollow-up.

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Data Analysis

Data were entered into Fox Pro for Windows (version 2.6,Microsoft Corporation) with built-in logic, range, and consis-tency checks. Statistical analysis was undertaken using the Sta-tistical Package for Social Sciences (SPSS, version 9.0, Chi-cago, Illinois) software. The preadmission duration of fever,vomiting, and diarrhea all suggested somewhat greater severityin the placebo group. All effect sizes were estimated adjustedfor these variables and age. Continuous variables with skeweddistribution (e.g., stool and vomitus output, ORS intake, andtotal volume of intravenous fluids received) were normalizedby log transformation, and the values were exponentiated andexpressed as geometric means. The effect on stool weight,vomitus output, ORS intakes, and total volume of intravenousfluids received was estimated by multiple regression analysisand presented as a ratio of geometric means. The effect onweight gain is presented as medians, with the 95% confidenceinterval (CI) and differences between the two groups calculatedusing nonparametric tests. The proportions of participants withdiarrhea continuing beyond 4, 5, 6, or 7 days are presented asadjusted odds ratios from logistic regression models. Cox pro-portional hazards model was used to estimate the relative haz-

ards (RH) of continuation of diarrhea.

RESULTS

Admission Characteristics of Participants

The flow of participants through each stage is de-scribed in Figure 1. Although not statistically significant,preadmission duration of fever, vomiting, and diarrhea

indicated somewhat greater severity in the placebogroup. All other baseline host characteristics were com-parable between the two groups(Table 1). Rotavirus wasdetected in the stools of 41.6% and 46%, respectively, ofpatients in the zinc and the placebo groups. The mean(SD) serum zinc level at baseline was comparable be-tween the intervention and placebo groups (zinc: 76.9g/dL [24.6 g/dL]v placebo 75.4 g/dL [22.6 g/dL];Table 2).

Effect of Zinc Administration on Serum Zinc Level

Serum for zinc estimation could be collected from

only 118 participants (zinc, 47%; placebo, 42%) 14 days

FIG. 1. Trial profile.

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after completion of the intervention. The mean serumzinc level was significantly higher in the zinc group than

the placebo group (difference in means, 11.5 g/dL;95% CI, 2.7, 20.3) (Table 2).

Effect of Zinc Administration on Key

Study Outcomes

The total stool output (g/kg) was lower in the zinc-treated group (ratio of geometric means [GM], 0.69; 95%CI, 0. 48, 0.99). In addition, zinc treatment resulted in

lower stool output per day of diarrhea (ratio of GM, 0.76;95% CI, 0.59, 0.98) (Table 3).

The Kaplan-Meier survival curves (Fig. 2) for posten-rollment duration of diarrhea showed a significantlyfaster recovery from diarrhea in the zinc group (log ranktest:P 0.043), and this difference became evident 72hours after enrollment. The risk of continued diarrhea ona given day in the Cox proportional hazards model waslower (RH for continuation of diarrhea, 0.76; 95% CI,0.59, 0.97) in participants receiving zinc than in thosereceiving placebo (Table 3). The proportion of diarrhealepisodes lasting 5 days (odds ratio [OR], 0.49; 95% CI,0.25, 0.97), or 7 days (OR, 0.09; 95% CI, 0.01, 0.73)was lower in the intervention group.

Effect of Zinc Administration on Total Intakes of

ORS and Water

Consistent with a decreased stool output, the total in-

take of ORS and water (mL/kg) was 18% less in the zincgroup (ratio of GM, 0.82; 95% CI, 0.68, 0.98). The waterintake by itself was significantly lower (difference inmeans, 43.7; 95% CI, 75.5, 11.8) and that of ORSwas somewhat less (ratio of GM, 0.89, 95% CI, 0.72,1.09) in the patients treated with zinc.

Effect of Zinc Administration on Use of

Unscheduled Intravenous Fluids

Overall, 23% and 19% participants received intrave-nous fluids in the zinc and placebo groups, respectively,

for any reason; 20.2% (zinc) and 17.4% (placebo) re-quired intravenous fluids for rehydration after the initialcorrection of dehydration (OR, 1.2; 95% CI, 0.66, 2.2).The total GM (95% CI) volume of IV fluids received forrehydration was 57 mL/kg (24, 134) in the zinc groupand 89 mL/kg (32, 252) in the placebo group (ratio ofGM, 0.65; 95% CI, 0.17, 2.5). Other reasons for admin-istering intravenous fluids were hypokalemia (zinc, 3 pa-tients; placebo, 1 patient) and suspected sepsis (zinc, 2patients; placebo, 2 patients).

TABLE 2. Serum zinc and copper levels at enrollment and after 14 days of supplementation in the zinc and placebo groups

Zinc Placebo

Difference in

arithmetic mean (95% CI)

n 132 n 132Mean (SD) serum zinc at enrollment 76.9 (24.6) 75.4 (22.6) 1.6 (4.1, 7.3)

n 62 n 56Mean (SD) serum zinc after 14 days 75.6 (26.9) 64.1 (20.3) 11.5 (2.7, 20.3)

n 59 n 45Mean (SD) serum copper at enrollment 148 (43) 149 (57) 1.3 (20.9, 18.2)Mean (SD) serum copper after 14 days 121 (38) 127 (31) 6.5 (20.4, 7.5)

SD, standard deviation.

TABLE 1. Admission characteristics of participantsenrolled in the zinc and placebo groups

Zincn 143

Placebon 144

Age (months) 11.7 (6.8) 12.3 (6.7)312 n (%) 95 (66.5) 87 (60.4)

1224 n (%) 39 (27.3) 50 (34.7)>24 n (%) 9 (6.3) 7 (4.9)

Weight for height (% NCHS) 82.1 (6.7) 81.3 (6.9)


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Effect of Zinc Administration on Total Food Intake

and Weight Gain

The total intake of calories (/kg/day) from semisolidfood was similar in the two groups (ratio of GM, 0.95;95% CI, 0.80, 1.13). The median and 95% CI for weightgain at the end of the rehydration phase expressed as apercentage of the nude weight at admission was not dif-ferent in the zinc (3.2 [2.4, 4.0]) or the placebo group(2.7 [1.9, 3.4]) (P 0.24). Similarly there were no sta-tistically significant differences in the weight gain (me-dian [95% CI]) at the end of 14 days of therapy, ex-pressed as a percentage of the weight at the end of therehydration phase, between the two groups (zinc, 3.5[2.0, 4.6]); placebo 2.9 [2.1, 3.9]; P 0.94).

Effect of Zinc Administration on Vomiting

There was no significant increase in the number ofchildren who vomited during the first 24 hours (zinc 29%vplacebo 32%; OR 1.1, 95% CI, 0.69, 1.9) or at any timeduring the study (zinc 65% v placebo 59%; OR, 0.74;95% CI, 0.45, 1.2). The amount of vomitus (g/kg) wasthe same in the initial 24 hours (ratio of GM, 1.3; 95%CI, 0.98, 1.74) and for the period of study from enroll-ment to cessation of diarrhea (ratio of GM, 1.2; 95% CI,0.84, 1.6) in both the groups.

Effect of Zinc Administration on Serum Copper

Level and Mean Corpuscular Volume of Red

Blood Cells

The mean serum copper level and mean corpuscularvolume were not significantly different in the zinc andplacebo groups at baseline. After 14 days of therapy withzinc or placebo, there was no significant difference inserum copper level (difference in means, 6.5, 95% CI,20.4, 7.5) or mean corpuscular volume (difference inmeans, 2.2; 95% CI, 1.0, 5.3) (Table 2).

Effect of Zinc Administration on Severity of

Diarrhea in Subgroups

The impact of zinc supplementation examined in sub-

groups based on age (12 months and >12 months),serum zinc level (


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is a trend toward greater effect of zinc on stool outputand diarrheal duration on those with serum zinc level55 g/dL.

DISCUSSION

This study has demonstrated that zinc treatment has agenuine antidiarrheal effect because it significantly re-duces stool output in severe acute gastroenteritis associ-ated with dehydration. The group of patients studied hadrelatively more severe diarrhea than those studied earlierbecause they had dehydration and required hospitaliza-tion. The study also showed that zinc treatment signifi-cantly reduced average diarrheal duration and the pro-portion of prolonged episodes in hospitalized patients,which confirms earlier findings in children with mildgastroenteritis (810,16). The significant reduction instool output per diarrheal day indicates that the benefiton total stool output is not only due to shortened diar-rheal duration in the zinc group. Consistent with the re-duced stool output, the total fluid intake also was sig-nificantly less in patients treated with zinc.

The reduction in prolonged episodes after zinc treat-ment is important because persistent episodes are asso-

ciated with increased case fatality and growth faltering(17). In addition, approximately 25% of patients do notrecover within 5 to 6 days when receiving the treatmentrecommended by WHO for acute diarrhea, which con-sists of ORS and continued feeding (1,17). Caregivers ofchildren with these prolonged episodes feel frustrated.Physicians who have no additional specific treatment tooffer and may resort to prescribing undesirable dietarychanges or antimicrobial agents.

Earlier studies of zinc in acute diarrhea have foundbeneficial effects with daily doses two times the recom-mended daily allowance (RDA) (811). We chose a3RDA dose to compensate for excessive losses of zincduring an episode of diarrhea and for possible impair-ment in absorption of ingested zinc among these pediat-ric patients (3,18). It appears from the findings of thecurrent study that the effects on episode duration with thehigher dose are similar to those seen with use of 2RDAof zinc in earlier studies. Therefore, currently there is noindication to use more than 2RDA of zinc for treatingacute diarrhea.

Decreased stool output and duration of illness duringacute diarrhea by zinc administration is biologicallyplausible. Zinc is said to improve absorption of water andelectrolytes by helping in early regeneration of intestinalmucosa, restoration of enteric enzymes, and enhance-ment of humoral and cellular immunity (1924). In mal-nourished guinea pigs, zinc has also been shown to haveantisecretory properties (25). It is unclear from thefindings of this and other studies whether the efficacy ofzinc is mediated through correction of deficiency aloneor if there is also a pharmacologic effect. One wouldhave expected a greater impact of zinc supplementa-tion in children with low serum zinc levels, but no such

trend is seen. In fact, the findings were in the oppositedirection. It is likely that often, low serum zinc levelsin children with gastroenteritis may be a reflection ofinfection.

Concerns have been raised about a possible adverseeffect of oral zinc on copper absorption, which may haveimportant consequences in malnourished children(26,27). In this trial, short-term use of zinc for as long as14 days did not appear to affect serum copper levels.

FIG. 3. Effect of zinc supplementa-tion on severity of diarrhea in sub-

groups. GM, geometric mean.

ZINC TREATMENT IN ACUTE DIARRHEA 39



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The need for unscheduled intravenous fluids for rehy-dration after the initial correction of dehydration wassimilar in the two groups. We cannot exclude the possi-bility of zinc causing a modest, but important, reductionin this outcome, but final determination of such an effectwhich would require a larger study.

The findings of the current study, together with pre-vious reports, establish the efficacy of zinc in acute di-arrhea in developing countries. The effects are substan-tial and clinically important. Thus, we recommend theuse of zinc during acute diarrhea. In addition, the use ofzinc during acute diarrhea for preventing prolonged epi-sodes may avoid inappropriate use of antimicrobial andantidiarrheal drugs. Zinc can be administered as syrup ormixed with ORS. The former approach achieves betterstandardization of dose and duration. The latter approachhas not been well evaluated, and its efficacy deserves tobe assessed in future studies.

Acknowledgements: The authors thank Dr. Olivier Fon-taine, MD, Medical Officer, from the Division of Child Healthand Development, World Health Organization, Geneva, whoaided in the design and monitoring of the study; and the Nor-wegian Council for Higher Educations program for Develop-ment Research and Education, which provided core support toour unit. The authors thank the medical and nursing staff of theunit for their help, and the patients and their parents. The au-thors also thank the pharmaceutical company American Rem-edies Ltd. for providing the drug and placebo.

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