Zinc Diarrhea

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DOI:10.1542/peds.2007-09212008;121;326-336Pediatrics

Marek Lukacik, Ronald L. Thomas and Jacob V. ArandaPersistent Diarrhea

A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and

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ARTICLE

A Meta-analysis of the Effects of Oral Zinc in the

Treatment of Acute and Persistent DiarrheaMarek Lukacik,MDa, RonaldL. Thomas, PhDb, Jacob V.Aranda, MD, PhDb

aDepartment of Pediatrics, Childrens Medical Center, Medical College of Georgia, Augusta, Georgia; bDepartment of Pediatrics, Wayne State University School of

Medicine, and Childrens Hospital of Michigan, Detroit, Michigan, and National Institute of Child Health and Human Development, Pediatric Pharmacology

Research Unit Network, Wayne State University, Detroit, Michigan

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT

OBJECTIVE. Children in developing countries are at a high risk for zinc deficiency.Supplemental zinc has previously been shown to provide therapeutic benefits in

diarrhea. The objective of this study was to examine the efficacy and safety ofsupplemental oral zinc therapy during recovery from acute or persistent diarrhea.

METHODS. We conducted a meta-analysis of randomized, controlled trials to comparethe efficacy and safety of supplementary oral zinc with placebo in children with acuteand persistent diarrhea. Results were reported using a pooled relative risk or aweighted mean difference. A total of 22 studies were identified for inclusion: 16examined acute diarrhea (n 15 231), and 6 examined persistent diarrhea (n 2968).

RESULTS. Mean duration of acute diarrhea and persistent diarrhea was significantlylower for zinc compared with placebo. Presence of diarrhea between zinc andplacebo at day 1 was not significantly different in acute diarrhea or persistentdiarrhea trials. At day 3, presence was significantly lower for zinc in persistent

diarrhea trials (n 221) but not in acute diarrhea trials. Vomiting after therapy wassignificantly higher for zinc in 11 acute diarrhea trials (n 4438) and 4 persistentdiarrhea trials (n 2969). Those who received zinc gluconate in comparison withzinc sulfate/acetate vomited more frequently. Overall, children who received zincreported an 18.8% and 12.5% reduction in average stool frequency, 15.0% and15.5% shortening of diarrhea duration, and a 17.9% and 18.0% probability ofreducing diarrhea over placebo in acute and persistent trials, respectively.

CONCLUSIONS. Zinc supplementation reduces the duration and severity of acute and persistent diarrhea; however, themechanisms by which zinc exerts its antidiarrheal effect have not been fully elucidated.

DIARRHEAL DISEASES POSE a significant public health problem on a global scale and especially in developing

countries. It is estimated that there are 1.5 billion episodes of diarrhea per year and that diarrheal diseaseaccounted for 21% of all deaths in children who were younger than 5 years. This is equivalent to 2.5 million deaths

in the same age group.1,2

This compares more favorably with the results of a previous study from 1982 in which on the basis of a review

of active surveillance data from studies conducted in the 1950s, 1960s, and 1970s, it was estimated that 4.6 millionchildren died annually from diarrhea.3 Newer data from the World Health Organization (WHO) show that diarrhealdisease accounts for 18% of the 10.6 million deaths in children who were younger than 5 years. 4

One of the major advances in the reduction of mortality from diarrhea was the introduction of WHO oralrehydration solution (ORS)5; however, WHO ORS does not significantly decrease stool output and duration of

diarrhea, and therefore other approaches to add to or to enhance the available ORS have been sought. Several newerapproaches have included the addition of zinc to the treatment regimen. Zinc is an essential micronutrient and

protects cell membranes from oxidative damage. Zinc is not stored in the body, so the level of zinc is determined bythe balance of dietary intake, absorption, and losses. A zinc deficiency state may exist in children with acute diarrhea

www.pediatrics.org/cgi/doi/10.1542/peds.2007-0921

doi:10.1542/peds.2007-0921

KeyWords

diarrhea, zinc

Abbreviations

WHOWorld Health Organization

ORSoral rehydration solution

RRrelative risk

WMDweighted mean difference

CIconfidence interval

cAMP3,5-cyclic monophosphate

Kpotassium

Cacalcium

Accepted for publication Jul 24, 2007

Address correspondence to Marek Lukacik,MD, Childrens Medical Center Department of

Pediatrics, Medical College of Georgia, 1120

15th St, Augusta, GA 30912. E-mail: mlukacik@

mcg.edu

PEDIATRICS (ISSNNumbers:Print, 0031-4005;

Online, 1098-4275). Copyright 2008by the

AmericanAcademy of Pediatrics

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StatisticalAnalysesComprehensive Meta-Analysis,10 a stand-alone program,was used to synthesize data that were obtained from the22 trials identified for inclusion: 16 acute and 6 persis-tent diarrhea trials. Briefly, the analysis software pro-duces a Forrest plot as a schematic description of themeta-analysis results. The program is augmented usingaccepted computational algorithms. Where appropriate,

results were reported using a pooled relative risk (RR).For continuous outcomes, the weighted mean difference(WMD) was calculated. The 95% confidence intervals(CIs) were reported around the weighted effect size.

HeterogeneityGiven that studies that are selected for inclusion in ameta-analysis will differ, the types of variability (clinical,methodologic, and/or statistical) that may occur amongstudies must be investigated. These various types of vari-ability are termed heterogeneity. Meta-analysis should

be considered only when a group of trials is sufficientlyhomogeneous (as indicated in the inclusion criteria) in

terms of participants, interventions, and outcomes toprovide a meaningful summary. Strict adherence to theinclusion criteria listed, such as blinding and conceal-ment of allocation, help to control for clinical/method-ologic heterogeneity. Still, statistical heterogeneity canalso occur when variability in the treatment effects beingevaluated in the different trials exists. This results whenthe observed treatment effects are more different fromeach other than would be expected as a result of randomerror (chance) alone. Following convention, statisticalheterogeneity in the results of this meta-analysis arereferred to simply as heterogeneity.

Different approaches for identification and measure-

ment of heterogeneity were therefore undertaken toexamine the extent to which the results of the studiesincluded were consistent. CIs for the results of individualstudies (depicted graphically using horizontal lines) wereexamined for poor overlap, a general indication of pres-ence of statistical heterogeneity. Variability (heterogene-ity) among the obtained effects sizes was formally op-erationalized using a 2 test of significance. The formulafor heterogeneity assesses the dispersion of individualoutcomes, vis-a-vis the combined effect, and denotesthis value using a Q statistic.11 A low P value (or a large2 statistic relative to its degree of freedom) providesevidence of heterogeneity of treatment effects (variationin effect estimates beyond chance).

Because some degree of clinical and methodologicdiversity always occurs in a meta-analysis, some statis-tical heterogeneity is inevitable; therefore, the test forheterogeneity is irrelevant to the choice of analysis: het-erogeneity will always exist regardless of whether it can

be detected using a statistical test. Still, methods have been developed for quantifying inconsistency acrossstudies that move the focus away from testing whetherheterogeneity is present to assessing its impact on themeta-analysis. A useful statistic for quantifying inconsis-tency is I2, the percentage of the variability in effect sizeestimates that is attributable to heterogeneity ratherthan sampling error (chance).12 A value 50% may be

considered substantial heterogeneity, and that percent-age cutoff was adopted and examined also in our anal-yses.

GravityAnother more recent approach13 proposed jackknife re-sampling to measure a concept termed gravity. In any

meta-analysis, arguments have focused on the inclusionor exclusion of some studies, with debate on which onesshould be included or excluded because studies are com-monly weighted according to their sample size and/orinternal variability. Gee13 proposed that jackknife re-sampling could be used to examine study influence anddetect outlier studies. The technique recomputes themeta-analysis once for each of k studies, where eachstudy is individually excluded. K results are then ob-tained. The difference between the average of these kresults and each studys individual result (when omit-ted) is taken as an index of raw gravity. This differ-ence, divided by the SD of the k differences, is taken as

a zscore, or standardized gravity, which can be used toestablish which studies might be unusually influential.SPSS 15.014 was used to calculate standardized gravityvalues.

Fixed- or Random-EffectsModelChoice of whether to interpret a fixed-effects or ran-dom-effects model was considered thoroughly. Fixed-effect meta-analyses ignore heterogeneity. The fixed-effect estimate and its CI address the question, What isthe best estimate of the treatment effect? The random-effects estimate and its CI address the question, What is

the average treatment effect? The answers to thesequestions are analogous when no heterogeneity ispresent or when the distribution of the treatment effectsis roughly symmetrical. If they are not, then the ran-dom-effects estimate may not reflect the actual effect inany population being studied. In a fixed-effects meta-analysis, a pooled-effect estimate is termed, generally, asthe best estimate of the treatment effect. It is for thesereasons that we chose a fixed-effects model for ourmeta-analysis, along with the various stated approachesto examine heterogeneity if found.

RESULTS

The author, year, country, amount of zinc supplemen-tation and type, sample size, and age for each of the 22studies selected for inclusion in the meta-analysis arelisted in Tables 3 and 4. Although all 22 studies wererandomly assigned clinical trials, it seemed that 51519

were not double-blinded. Sixteen of these publishedstudies met the definition for acute diarrhea and 6 forpersistent diarrhea.

Overall, 56.3% (9 of 16) of acute diarrhea trials wereconducted in inpatient hospital settings, and 43.7% (7 of16) were conducted in outpatient homes and commu-nities. Of the 6 persistent diarrhea trials, 66.7% (4 of 6)were inpatient and 33.3% (2 of 6) were outpatient.



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MortalityMortality was originally a primary outcome in this meta-analysis; however, of both acute and persistent trials,only 315,20,21 reported mortality outcome, making it diffi-cult to compare across all included trials. Two of thesewere acute diarrhea trials,15,20 and 1 was a persistentdiarrhea trial.21 In the largest acute diarrhea outpatienttrial15 (n 8070), 33 children (0.008%; 33 of 3974) diedin the zinc-treated group and 37 (0.009%; 37 of 4096)died in the placebo group. Thirty deaths were attributedto drowning, and the remaining were not injury related(ie, not attributable to zinc intervention). When re-stricted to noninjury deaths, there were 13 in the zinc-treated group and 27 in the placebo group. The investi-gators attributed the lower noninjury death rate in theintervention group almost entirely to fewer deaths fromdiarrhea and acute lower respiratory infection. Diarrheaand acute lower respiratory infection together accountedfor 10 deaths in the zinc intervention group and 20deaths in the placebo group. In the other acute diarrheatrial,20 2 children in the placebo group died of septicemia.In the persistent diarrhea trial,21 the causes of death weresepticemia with diarrhea in 3 children, septicemia in 1child, bronchopneumonia in 1 child, and continued di-arrhea in 1 child. Because acute and persistent diarrheaare, most likely, distinct disease entities, the outcomes

obtained are presented initially for acute diarrhea (last-ing up to 14 days) and followed by persistent diarrhea(lasting 14 days).

Results forAcuteDiarrhea Trials

Duration of Acute DiarrheaIn 16 trials that examined the primary measure of aver-age duration of acute diarrhea1517,19,20,2232 (n 15 231),those who received zinc experienced a significantlylower average duration of diarrhea than those who re-ceived a placebo (WMD: 0.24; SE: 0.02; 95% CI: 0.210.27; P .001; Table 5, Fig 1) but also with the presenceof statistically significant heterogeneity (Q 95.58, de-grees of freedom [df]Q 15, P .001, I

2 84.3%).Figure 1 depicts a Forrest plot for these results, in whichevery study is displayed as a point estimate with CIs.

Examination of significant heterogeneity in the acutediarrhea trials revealed 5 trials17,19,20,25,30 with insignifi-cant differences between zinc and placebo groups inaverage duration of diarrhea. P values ranged from .478to nonsignificant in sample sizes that ranged from 50 to215. Although those who received zinc had a shorteraverage duration of diarrhea, the difference in 4 tri-als17,19,20,30 was very small, with an average difference of0.18 0.18 days ranging from 0.04 to 0.40 days. One

TABLE 3 Characteristics of Acute Diarrhea Trials

Reference Country Zinc Supplement Zinc Dosage Zinc/Control Group, N Age, mo

Sachdev et al17 (1988) India Sulfate 20 mg 25/25 618

Sazawal et al31 (1995) India Gluconate 20 mg 456/481 635

Roy et al30 (1997) Bangladesh Acetate 20 mg 57/54 324

Faruque et al27 (1999) Bangladesh Acetate 14/40 mg 343/341 623

Hidayat et al28 (1998) Indonesia Acetate 4/5 mg/kg 739/659 325

Dutta et al26 (2000) India Sulfate 40 mg 44/36 324

Strand et al32 (2002) Nepal Gluconate 15/30 mg 445/449 635

Bahl et al23 (2002)a India Gluconate 15/30 mg 404/401 635

Al-Sonboli et al22 (2003) Brazil Sulfate 22.5/45 mg 37/37 360

Polat et al29 (2003)b Turkey Sulfate 20 mg 92/90 229

Bhatnagar et al24 (2004) India Sulfate 15/30 mg 143/144 336

Valery et al19 (2005)c Australia Sulfate 20/40 mg 107/108 011, 1223,24

Patel et al20 (2005) India Sulfate/copper sulfate 40 mg/5 mg 102/98 659

Brooks et al25 (2005)d Bangladesh Acetate 20 mg 86/89 16

Baqui et al15 (2002) Bangladesh Acetate 20 mg 3974/4096 359

Fischer Walker et al16 (2006) Pakistan, Ethiopia, India Sulfate 10 mg 554/556 15

aThree study groups were examined (control, zinc syrup, and zinc/ORS). We included only those who received zinc syrup or a control.b Four study groups were examined: low/normal zinc in 2 intervention groups and low/normal zinc in 2 control groups. We combined the groups into either intervention or control, without

excluding those with low zinc levels.c Children up to 11 years of age were included; however, 45.1% (97 of 215) were 0 to 11 months of age; 38.1% (82 of 215) were 12 to 23 months; and only 16.8% (36 of 215) were 24 months. All

study participants were included in our analyses.dThree groups wereused (control,5 mgof zincacetate, and20 mgof zincacetate).We examinedonly those whoused 20mg of zincversuscontrolsubjects.Brooks etal enrolledonlymale children.

TABLE 4 Characteristics of Persistent Diarrhea Trials

Reference Country Zinc Supplement Zinc Dosage Zinc/Control Group,N Age, mo

Sachdev et al18 (1990) India Sulfate 20 mg 20/20 618

Roy et al21 (1998) Bangladesh Acetate 20 mg 95/95 324

Khatun et al34 (2001) Bangladesh Acetate 20 mg 24/24 624

Bhutta et al33 (1999) Pakistan Sulfate 3 mg/kg 43/44 636

Penny et al35 (1999) Peru Gluconate 20 mg 139/136 635

Bhandari et al36 (2002) India Gluconate 10/20 mg 1228/1236 630

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trial25 found no difference at all between treatmentgroups. Participants in all 5 trials had been admitted fordehydration secondary to diarrhea, although the sever-ity of dehydration ranged. Four of the trials17,20,25,30 ad-ministered an ORS before treatment assignment. Threetrials received zinc sulfate and 2 received acetate. Incontrast, all acute diarrhea trials23,31,32 that provided zincgluconate and not zinc sulfate had a shorter duration ofdiarrhea than placebo (P .08). Two trials17,20 originatedfrom India, 225,30 from Bangladesh, and 119 from Austra-lia. One trial15 in which average duration was signifi-cantly lower (1.2 days lower) with zinc use also had a

tremendously higher sample size (n 8070) than all ofthe others.

Table 6 shows the effect sizes, calculated raw gravityvalues, standardized gravity values, and sample sizes foreach study when removed. It is clear that 1 study15 hada great deal of impact on the strength and direction ofthe estimated effect size value found for average dura-tion of acute diarrhea among all studies. When removed,the reaveraged effect size obtained (0.187) and plottedstandardized gravity value (3.531; Fig 2) were consid-ered outlying values in comparisons with all others. Thisis largely attributed to the enormous sample size (n 8070) used in the trial, because even very small differ-ences in mean duration of diarrhea would be statisticallysignificant.

Occurrence of Diarrhea at Day 1Five acute diarrhea trials16,19,20,27,32 reported the occur-rence of diarrhea at day 1 (n 3100). No statisticallysignificant difference in the occurrence of acute diarrheaat day 1 was found (RR: 1.01; 95% CI: 0.991.03; P0.30). Although the variability in effect sizes rangedfrom a low of 0.968 to 1.695, significant heterogeneitydid occur (Q 10.60, dfQ 4, P .03, I

2 62.3%).

Occurrence of Diarrhea at Day 3Six acute diarrhea trials16,19,20,23,27,32 collected data for oc-currence of diarrhea at day 3. No statistically significantdifferences occurred between treatment groups in occur-rence of diarrhea at day 3 (RR: 0.97; 95% CI: 0.911.03;P .36); however, the occurrence of statistically signif-icant heterogeneity was found (Q 10.880, dfQ 5, P0.05, I2 54.0%). Only 1 trial30 found a significantly(P .01) lower occurrence of diarrhea at day 3 with zinc(27.4%) than placebo (35.4%; effect size: 0.774); how-ever, the occurrence of statistically significant heteroge-neity was found (Q 10.880, dfQ 5, P .05, I

2

54.0%).

FIGURE 1

Mean difference in duration of acute diarrhea. The effect size index in this plot is the

standard mean difference, so a point estimate of 0.0 indicates no effect. Values0.0

reflect a better outcome for the placebo group, and values 0.0 indicate a better out-

come forthe zincgroup. If thepointestimate andCI fellabove0.0,then thestudywould

meet the criterion for statistical significance( .05). Ifthe CI overlapped 0.0, thentheP

value would exceed .05 and the study would not be statistically significant.

TABLE 5 MeanDurationof AcuteDiarrhea

Reference N1 N2 Lower Upper Effect SE P

Sachdev et al17 (1988) 25 25 .371 .769 .199 .284 .478

Sazawal et al31 (1995) 456 481 .128 .386 .257 .066 .000

Roy et al30 (1997) 37 37 .312 .616 .152 .233 .511

Hidayat et al28 (1998) 738 659 .015 .225 .120 .054 .025

Faruque et al27 (1999) 341 340 .045 .347 .196 .077 .011

Dutta et al26 (2000) 44 36 1.811 2.995 2.403 .297 .000

Strand et al32 (2002) 445 449 .052 .315 .184 .067 .006

Baqui et al15 (2002) 3974 4096 .243 .331 .287 .022 .000

Bahl et al23 (2002) 404 401 .016 .261 .122 .071 .083

Polat et al29 (2003) 92 90 .425 1.030 .727 .153 .000

Al-Sonboli et al22 (2003) 37 37 .435 1.412 .924 .245 .000

Bhatnagar et al24 (2004) 143 144 .025 .441 .208 .118 .079

Patel et al20 (2005) 102 98 .246 .312 .033 .141 .817

Valery et al19 (2005) 107 108 .260 .278 .009 .136 .946

Brooks et al25 (2005) 86 89 .298 .298 .000 .151 NS

Fischer Walker et al16 (2006) 554 556 .006 .242 .124 .060 .039

Fixed combined (16) 7585 7646 .208 .272 .240 .016 .000

N1 indicates sample size for zinc group; N2, sample size for the placebo group; Lower, lower limit of the 95% CI for the standard difference;

Upper, upper limit of the 95% CI for the standard difference; Effect, standard difference; NS, nonsignificant.



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Occurrence of Diarrhea at Day 5Similarly, in the same 6 acute diarrhea trials, 16,19,20,23,27,32

no statistically significant differences occurred between

treatment groups in occurrence of diarrhea at day 5 (RR:0.94; 95% CI: 0.84 1.05; P .26). Similar to day 3results, the occurrence of statistically significant hetero-

FIGURE 2

Standardized gravity results.

TABLE 6 AcuteDiarrhea:Gravity Values forDurationofDiarrhea

Reference Effect Size Raw Gravity Standardized Gravity Sample Size

Valery et al19 (2005) 0.243 0.00481 0.332 215

Strand et al32 (2002) 0.243 0.00481 0.332 894

Sazawal et al31 (1995) 0.239 0.00081 0.056 937

Sachdev et al17 (1988) 0.240 0.00181 0.125 50

Roy et al30 (1997) 0.240 0.00181 0.125 74

Polat et al29 (2003) 0.234 0.00419 0.289 182

Patel et al20 (2005) 0.243 0.00481 0.332 200

Hidayat et al28 (1998) 0.252 0.01381 0.953 1397

Fischer Walker et al16 (2006) 0.249 0.01081 0.746 1110

Faruque et al27 (1999) 0.242 0.00381 0.263 681

Dutta et al26 (2000) 0.233 0.00519 0.358 80

Brooks et al25 (2005) 0.243 0.00481 0.332 175

Bhatnagar et al24 (2004) 0.240 0.00181 0.125 287

Baqui et al15 (2002) 0.187 0.05119 3.531 8070

Bahl et al23 (2002) 0.246 0.00781 0.539 805

Al-Sonboli et al22 (2003) 0.237 0.00119 0.082 74



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geneity was found (Q 18.957, dfQ 5, P .002, I2

73.6%).

VomitingIn 11 acute diarrhea trials16,17,19,2225,2932 (n 4438), theproportion of participants who vomited after the initialdose was significantly higher with zinc (278 [12.7%] of2196) use than with placebo (171 [7.6%] of 2242; RR:1.55; 95% CI: 1.301.84; P 0.001%; Q 25.54, P.004).

Vomiting After Administration of Zinc Sulfate or GluconateIn 3 acute diarrhea trials,23,31,32 a significantly higherproportion of patients who received zinc gluconate vom-ited (160 [14.6%] of 1095) than zinc sulfate/acetatetherapy16,17,19,22,24,25,29,30 (118 [10.7%] of 1101; RR: 1.18;95% CI: 1.051.31; P .006).

Shortening of Diarrhea DurationEight trials of acute diarrhea1517,20,25,26,29,31 found an av-erage shortening of diarrhea duration of 15.0% for thosewho received zinc in comparison with placebo (Table 7).

Reduction in Stool FrequencySeven trials of acute diarrhea17,22,23,25,29,31,32 found an av-erage reduction in stool frequency of 22.1% with zinctherapy in comparison with placebo. One single trial16

found a 5.0% higher stool frequency using zinc thanplacebo.

Stool OutputThree trials of acute diarrhea24,26,30 found an averagelowering of stool output of 30.3%.

Probability of Diarrhea ReductionEight acute diarrhea trials20,2325,27,28,30,32 measured theprobability of diarrhea reduction and found a 17.9%reduction using zinc compared with placebo.

Results forPersistent Diarrhea Trials

Duration of Persistent DiarrheaIn 5 persistent diarrhea trials18,21,3335 (n 489), thosewho received zinc also experienced a significantly loweraverage duration of diarrhea than the placebo group(WMD: 0.30; SE: 0.09; 95% CI: 0.120.48; P .001;Table 8) but without significant heterogeneity (Q 3.08,

TABLE 7 Effects of Zinc Therapy of AcuteDiarrhea

Reference Country Stool Frequency Reduction Probability of Diarrhea Continuation

Sachdev et al17 (1988) India 18% lower frequency 9% shorter duration

Sazawal et al31 (1995) India 39% lower frequency 19% shorter duration

Roy et al30 (1997) Bangladesh 28% lower stool output 14% reduction in probability

Faruque et al27 (1999) Bangladesh Not reported 20% reduction in probability

Hidayat et al28 (1998) Indonesia Not reported 11% reduction in probability

Dutta et al26 (2000) India 38% lower stool output 32% shorter duration

Strand et al32 (2002) Nepal 8% lower frequency 26% reduction in probability

Bahl et al23 (2002) India 17% lower frequency 11% reduction in probability

Al-Sonboli et al22 (2003) Brazil 59% lower frequency Not reported

Polat et al29 (2003) Turkey 14% lower frequency 20% shorter duration

Bhatnagar et al24 (2004) India 25% lower stool output 30% reduction in probability

Valery et al19 (2005) Australia Not reported Not reported

Brooks et al25 (2005) India Not reported 19% reduction in probability, 7% shorter duration

Brooks et al25 (2005) Bangladesh 0% lower frequency 12% reduction in probability, 0% shorter duration

Baqui et al15 (2002) Bangladesh Not reported 24% shorter duration

Fischer Walker et al16 (2006) Pakistan, Ethiopia, India 5% higher frequency 9% shorter duration

Average stool frequency reduction 18.8%; average lowering of stool output 30.3%; average shortening of duration 15.0%; average probability of diarrhea reduction 17.9%. Variances in

datareporting of outcome measures:For thismeta-analysis, shortening of diarrheaduration wasdefinedas thepercentage ratioof themean number of daysof diarrheain eachstudygroup. It was

then reported as a shorter percentage of time with diarrhea for one group or the other. Probability of diarrhea duration was calculated by authors using various statistical approaches, such as the

odds ratio, risk ratio, or hazards ratio. This difference in statistic negated a comparison in the meta-analysis. Stool frequency reduction was calculated by taking a ratio of the average diarrhea

frequency in some studies per 24 hours or by the risk ratio of the mean number of stools in the first 4 days of another study. Lower stool output was calculated, in 2 studies, by taking a ratio of the

totalstoolweightper kilogramof bodyweightandreporting themedian. Theratioof themedianwasthen taken. Theresultingpercentagewas interpreted asa loweringof stooloutputin onegroup

or the other. In another study, it was reported as the total stool output until the last first formed stool, measured in grams per kilogram for each group. The geometric mean was then taken and a

ratio between groups obtained. The group with the lower percentage was interpreted as a lowering of stool output in one group or another.

TABLE 8 MeanDurationof Persistent Diarrhea

Reference N1 N2 Lower Upper Effect SE P

Sachdev et al18 (1990) 20 20 0.123 1.182 0.530 0.322 .096

Roy et al21 (1998) 73 68 0.201 0.466 0.133 0.169 .430

Penny et al35 (1999) 87 86 0.134 0.742 0.438 0.154 .004

Bhutta et al33 (1999) 43 44 0.295 0.558 0.132 0.215 .537

Khatun et al34 (2001) 24 24 0.167 1.010 0.422 0.292 .144

Fixed combined (5) 247 242 0.120 0.478 0.299 0.091 .001



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dfQ 4, P .544, I2 29.9%). Figure 3 depicts the

Forrest plot for these results.

Occurrence of Diarrhea at Day 1In 2 trials of persistent diarrhea34,35 (n 221), no statis-tically significant differences occurred between treat-ment groups in occurrence of diarrhea at day 1 (RR:1.00; 95% CI: 0.931.08; P .98), and no statisticallysignificant variability occurred among the effect sizes(Q 0.01, dfQ 1, P .93).

Occurrence of Diarrhea at Day 3In 2 trials of persistent diarrhea34,35 (n 221), a signifi-cantly lower occurrence of diarrhea at day 3 occurred inthose who were treated with zinc in comparison withplacebo (RR: 0.70; 95% CI: 0.510.94; P .02). Nostatistically significant variability occurred among the

effect sizes (Q 0.33, dfQ 1, P .56).

Occurrence of Diarrhea at Day 5This was not examined; fewer than 2 studies reported.

VomitingIn 4 persistent diarrhea trials18,21,35,36 (n 2969), a sig-nificantly higher proportion vomited on zinc (41 [2.8%]of 1482) than with placebo (2 [0.001%] of 1487; RR:3.64; 95% CI: 1.0213.02; P .047; Q 5.91, P .116).

Vomiting After Zinc Sulfate or GluconateIn 4 persistent diarrhea trials,18,21,35,36 those who received

zinc gluconate35,36 vomited more frequently (41 [3%] of1367) than did those who received zinc sulfate/acetate(0 [0%] of 115; RR: 1.09; 95% CI: 0.941.09; P .07).

Shortening of Diarrhea DurationIn 4 persistent diarrhea trials,18,21,34,35 those who receivedzinc experienced a 15.5% average shortening of diarrheaduration than those who got a placebo (Table 9).

Reduction in Stool FrequencyFour trials of persistent diarrhea found that those whoreceived zinc also experienced an average of 9.8% re-duction in frequency.

Stool OutputStool output was not measured in the persistent trials.

Probability of Diarrhea ReductionTwo persistent diarrhea trials33,36 that measured theprobability of diarrhea reduction found an 18.0% reduc-tion when zinc was used over placebo.

DISCUSSION

On the basis of these findings, which now add to thelarge body of previously published clinical data and up-date previous meta-analyses and systematic reviews,8,37

zinc therapy is useful for treating both acute and persis-tent diarrhea and for their prophylaxis. Still, as exten-sively addressed in a recent systematic review,6 muchinformation is lacking relative to the mechanisms bywhich zinc physiologically exerts its antidiarrheal effect.In this meta-analysis, 5 (31.3%) of 16 acute diarrheastudies17,19,20,25,30 found no statistically significant differ-

ences between zinc and placebo on the average durationof diarrhea (at least a P .48). Similarly, 2 (40.0%) of 5persistent diarrhea studies21,33 also found no statisticallysignificant differences in average duration of diarrhea

between treatments (at least a P .43). Still, the averagestool frequency reductions, shortening of diarrhea dura-tions, and probabilities of a shortening of diarrhea dura-tion reported were higher in studies with zinc therapy incomparison with placebo.

To the majority of individuals, diarrhea means anincreased frequency or decreased consistency of bowelmovements. In many developed countries, the averagenumber of bowel movements is 3 per day; however,

diarrhea is associated with an increase in stool weight,mainly as a result of excess water, which normallymakes up a large percentage of fecal matter. Given this,diarrhea is distinguished from diseases that cause onlyan increase in the number of bowel movements or fecalincontinence.

Determining the exact causes of diarrhea can be dif-ficult because there are many different diarrheal agents,with such a variety of infectious agents, including bac-teria, parasites, and viruses. Identification of specific di-arrheal agents is complicated by the lack of access tolaboratory tests in many developing countries. Viral gas-troenteritis caused by rotavirus is the primary cause ofdiarrhea among infants worldwide. Other causes include

bacterial pathogens such as Vibrio cholerae, Shigella, andSalmonella. Protozoa such as Cryptosporidium parvum andGiardia lamblia are 2 of the most common protozoandiarrheal agents. The primary symptoms of rotavirusinfection are fever and vomiting for several days, fol-lowed by nonbloody diarrhea. Although not normallyfatal, the diarrhea caused by the virus can be quitesevere, leading to potentially life-threatening dehydra-tion. Although easily treated with intravenous fluids indeveloped nations, these supplies are often unavailablein the developing world, and the dehydration that iscaused by rotavirus is a significant cause of mortality.

In fact, conclusions from these randomized trials for

FIGURE 3

Mean difference in duration of persistent diarrhea. The effect size index in this plot is the

standard mean difference, so a point estimate of 0.0 indicates no effect. Values0.0

reflect a better outcome for the placebo group, and values 0.0 indicate a better out-

come forthe zincgroup. If thepointestimate andCI fellabove0.0,then thestudywould

meet the criterion for statistical significance( .05). Ifthe CI overlapped 0.0, thentheP

value would exceed .05 and the study would not be statistically significant.



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40. Fenwick PK, Aggett PJ, Macdonald DC, Huber C, Wakelin D.

Zinc deprivation and zinc repletion: effect on the response of

rats to infection with Strongyloides ratti. Am J Clin Nutr. 1990;

52(1):173177

41. Hoque KM, Rajendran VM, Binder HJ. Zinc inhibits cAMP-

stimulated Cl secretion via basolateral K-channel blockade in

rat ileum. Am J Physiol Gastrointest Liver Physiol. 2005;288(5):

G956G963

42. Canani RB, Cirillo P, Buccigrossi V, et al. Zinc inhibits cholera

toxin-induced, but not Escherichia coli heat-stable entero-

toxin-induced, ion secretion in human enterocytes. J Infect Dis.

2005;191(7):10721077

43. Hershfinkel M, Moran A, Grossman N, Sekler I. A zinc-

sensing receptor triggers the release of intracellular Ca2

and regulates ion transport. Proc Natl Acad Sci USA. 2001;

98(20):1174911754

HIGH-STAKESFLIMFLAM

Its time to rein in the test zealots who have gotten such a stranglehold on

the public schools in the US. Politicians and others have promoted high-

stakes testing as a panacea that would bring accountability to teaching and

substantially boost the classroom performance of students. Measuring, said

President Bush, in a discussion of his No Child Left Behind law, is the

gateway to success. Not only has high-stakes testing largely failed to magi-

cally swing open the gates to successful learning, it is questionable in many

cases whether the tests themselves are anything more than a shell game.

Daniel Koretz, a professor at Harvards Graduate School of Education, told me

in a recent interview that its important to ask whether you can trust

improvements in test scores when you are holding people accountable for the

tests. The short answer, he said, is no. If teachers, administrators, politicians

and others have a stake in raising the test scores of studentsas opposed to

improving student learning, which is not the same thingthere are all kinds

of incentives to raise those scores by any means necessary. Weve now had

four or five different waves of educational reform, said Dr. Koretz, that were

based on the idea that if we can just get a good test in place and beat people

up to raise scores, kids will learn more. Thats really what No Child Left

Behind is. The problem is that you can raise scores the hard way by teaching

more effectively and getting the students to work harder, or you can take

shortcuts and start figuring out ways, as Dr. Koretz put it, to game the

system. Guess whats been happening? Weve had high-stakes testing, really,

since the 1970s in some states, said Dr. Koretz. Weve had maybe six good

studies that ask: If the scores go up, can we believe them? Or are people

taking shortcuts? And all of those studies found really substantial inflation oftest scores.

Herbert B.New York Times. October 9, 2007

Noted by JFL, MD



13/13

DOI:10.1542/peds.2007-09212008;121;326-336Pediatrics

Marek Lukacik, Ronald L. Thomas and Jacob V. ArandaPersistent Diarrhea

A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and

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