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A Meta-analysis of the Effects of Oral Zinc in the
Treatment of Acute and Persistent Diarrhea
Marek Lukacik, MDa, Ronald L. Thomas, PhDb, Jacob V. Aranda, MD, PhDb

aDepartment of Pediatrics, Children’s Medical Center, Medical College of Georgia, Augusta, Georgia; bDepartment of Pediatrics, Wayne State University School of
Medicine, and Children’s 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.

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 of
supplemental oral zinc therapy during recovery from acute or persistent diarrhea.
METHODS. We conducted a meta-analysis of randomized, controlled trials to compare Key Words
the efficacy and safety of supplementary oral zinc with placebo in children with acute diarrhea, zinc
and persistent diarrhea. Results were reported using a pooled relative risk or a Abbreviations
weighted mean difference. A total of 22 studies were identified for inclusion: 16 WHO—World Health Organization
examined acute diarrhea (n ⫽ 15 231), and 6 examined persistent diarrhea (n ⫽ ORS— oral rehydration solution
RR—relative risk
2968). WMD—weighted mean difference
CI— confidence interval
RESULTS. Mean duration of acute diarrhea and persistent diarrhea was significantly cAMP—3⬘,5⬘-cyclic monophosphate
lower for zinc compared with placebo. Presence of diarrhea between zinc and K—potassium
placebo at day 1 was not significantly different in acute diarrhea or persistent Ca— calcium
diarrhea trials. At day 3, presence was significantly lower for zinc in persistent Accepted for publication Jul 24, 2007

diarrhea trials (n ⫽ 221) but not in acute diarrhea trials. Vomiting after therapy was Address correspondence to Marek Lukacik,
MD, Children’s Medical Center Department of
significantly higher for zinc in 11 acute diarrhea trials (n ⫽ 4438) and 4 persistent Pediatrics, Medical College of Georgia, 1120
diarrhea trials (n ⫽ 2969). Those who received zinc gluconate in comparison with 15th St, Augusta, GA 30912. E-mail: mlukacik@
zinc sulfate/acetate vomited more frequently. Overall, children who received zinc

reported an 18.8% and 12.5% reduction in average stool frequency, 15.0% and PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2008 by the
15.5% shortening of diarrhea duration, and a 17.9% and 18.0% probability of American Academy of Pediatrics
reducing diarrhea over placebo in acute and persistent trials, respectively.

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

D IARRHEAL 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 disease
accounted 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 million
children died annually from diarrhea.3 Newer data from the World Health Organization (WHO) show that diarrheal
disease 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 oral
rehydration 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 newer
approaches 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 by
the balance of dietary intake, absorption, and losses. A zinc deficiency state may exist in children with acute diarrhea

326 LUKACIK et al
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either the zinc treatment or the Lilacs (1982–2006). the Cochrane Central meta-analysis.21 Fischer Walker et al16 (2006) 4. Acute diarrhea was defined as tacted to verify extracted data values derived from lasting up to 14 days. glu. We held average duration of diarrhea and lished. 2000) and Second (Paris. placebo was assigned within 24 hours. including dysentery. vom- Our meta-analysis was performed to include new studies iting frequency by therapy type. 1 and 60 months). 3. France. rollment/randomization. A comprehensive review on full manuscripts were then obtained for all abstracts that this subject was recently published.98 Gastroenterology. Study groups who. stool frequency re- published since the last meta-analysis and to examine duction. 2018 .7%) PEDIATRICS Volume 121. studies were verified by reviewing the bibliographies and reference lists of identified trials. generally. Intervention with oral zinc salt supplementation. Duration was The search strategy used computerized bibliographic measured in either days or hours. Both pub- Valery et al19 (2005) 3.17 lished and unpublished trials were included in an effort to control for publication bias.26 ⫾ 3. primary outcomes. Data previously obtained during the course of the study. authors of selected studies were con- rhea. All 3 authors from acute or persistent diarrhea. concealment of allocation had to be met to satisfy inclu. Definitions of diarrhea varied somewhat in all included conate.6 An alternative view were deemed relevant on the basis of the inclusion is that zinc may be working as a pharmacologic agent at criteria.6%) 391/554 (70.2%) 226/554 (40. The final database entries were presence of diarrhea at days 1. the definitions stated length of duration. collected. In persistent diarrhea co-interventions.6%) 20/108 (18. CINAHL (1982–2006). ized.6%) 100/108 (92. After en- Register of Controlled Trials (2006).41 ⫾ 1. after randomiza. Hepatology and Nutrition. received zinc supplementation and ORS or zinc that they persisted up to 14 days in duration.aappublications. Twenty-two trials met inclusion criteria: 16 pub- the level of gene expression. supplemented with vitamin A were excluded. independently extracted data from the same articles us- ing a data extraction sheet and subsequently compared results for by guest on March 3. allows a risk for selection bias. Citations of appropriate Data are means ⫾ SD.34 ⫾ 2. and as a result of intestinal loss. with persistent diarrhea lasting graphs and/or to provide additional information in a ⬎14 days.49 ⫾ 3. or acetate) if applied at ⱖ5 mg/day for any studies. Data on vomiting frequency. TABLE 2 Number of Children With Diarrhea at Days 1.7 The efficacy of zinc in the lished studies relative to the definition of acute diarrhea treatment of diarrhea is supported by several random- and 6 relative to persistent diarrhea. despite 1 and 2. integrity of ran- Inclusion Criteria domization. All comparisons between treatment groups or 1 loose. they are noted in Tables sion because inadequate allocation concealment. When necessary. TABLE 1 Average Duration of Diarrhea (Days) trolled Trials (2006). 2004) World Congress of Pediatric Patel et al20 (2005) 4. controlled trials that showed reduction of diarrhea duration. and 5) using similar verified by the statistician (Dr Thomas).93 ⫾ 3. Number 2. and concealment of allocation. 3.90 4. Definitions ing for any zinc salt type or formulation (sulfate. with either acute or persistent diar. 3. Few studies patient characteristics (primarily children aged between satisfied criteria for inclusion on every datum variable. generally.6%) 55/107 (51. allow.30 ⫾ 5.1%) 526/556 (94.5%) Fischer Walker et al16 (2006) 538/554 (97.4%) 55/108 (50.31 3. The data thus obtained were METHODS checked for consistency among authors.9%) 22/107 (20. and probability of diarrhea continuation the efficacy and safety of zinc therapy during recovery were extracted as secondary outcomes. For the purpose of this searches of Medline (1966 –2006). the use of randomization. Current Con. and stool frequency. Identified titles of ab- stracts with potential relevance were downloaded. the definitions were similar. and 5 as our of zinc in the treatment of acute and chronic diarrhea. hours were converted to days. February 2008 327 Downloaded from http://pediatrics. stool output. was examined against a control using for diarrhea were the passage of ⱖ3 loose. and abstracts published in Pediatric Reference Zinc Placebo Research (1991–2006) and the First (Boston. Where those instances occurred. Meta-anal- yses on the therapeutic effects8 of zinc in acute and Primary and Secondary Outcomes persistent diarrhea as well as prevention9 of diarrhea Data on 8 clinically relevant outcome measures were with zinc supplementation have been previously pub. from the time of enrollment into Identification of Trials the study until the first formed stool. watery stools a placebo. Definitions for duration of diarrhea varied as well but was defined. Random allocation to treatment groups and scaling form that could be combined with other studies. and 5 Reference Zinc Day 1 Placebo Day 1 Zinc Day 3 Placebo Day 3 Zinc Day 5 Placebo Day 5 Valery et al19 (2005) 98/107 (91. Embase (1974 –2006). trials. with the exception tion.6%) 385/556 (69. Questions Studies that were selected for inclusion tested the same regarding the interpretability of certain data values were primary hypotheses (average duration of diarrhea and resolved by all 3 authors. watery stool with blood within 24 hours for had to be free of confounding by additional agents or between 3 and 7 days in duration.28 4. The published data so far have shown the efficacy presence of diarrhea episodes at days 1.8%) 204/556 (36. In acute trials.

3% (9 of 16) of acute diarrhea trials were meta-analysis. and/or statistical) that may occur among study is individually excluded. CIs for the results of individual present or when the distribution of the treatment effects studies (depicted graphically using horizontal lines) were is roughly symmetrical. ␹2 statistic relative to its degree of freedom) provides evidence of heterogeneity of treatment effects (variation in effect estimates beyond chance).” which can be used to provide a meaningful summary.014 was used to calculate standardized gravity ment of allocation.10 a stand-alone program. the analysis software pro- duces a Forrest plot as a schematic description of the Gravity meta-analysis results. K results are then ob- studies must be investigated. any population being studied.3% (2 of 6) were outpatient. The difference between the average of these k ability are termed heterogeneity. If they are not. the types of variability (clinical. 66.11 A low P value (or a large to examine heterogeneity if found. 22 trials identified for inclusion: 16 acute and 6 persis- tent diarrhea trials. The formula the best estimate of the treatment effect. sampling to measure a concept termed “gravity. and outcomes to a z score. and that percent- Comprehensive Meta-Analysis. generally. tained. In a fixed-effects meta- ity) among the obtained effects sizes was formally op. the percentage of the variability in effect size 16) were conducted in outpatient homes and commu- estimates that is attributable to heterogeneity rather nities. where each methodologic. sample size. The fixed- heterogeneity in the results of this meta-analysis are effect estimate and its CI address the question. 2018 . Still. “What is ment of heterogeneity were therefore undertaken to the average treatment effect?” The answers to these examine the extent to which the results of the studies questions are analogous when no heterogeneity is included were consistent. such as blinding and conceal. the test for studies selected for inclusion in the meta-analysis are heterogeneity is irrelevant to the choice of analysis: het. listed in Tables 3 and 4. Strict adherence to the establish which studies might be unusually influential. heterogeneity is present to assessing its impact on the Overall. conducted in inpatient hospital settings. and 43. statistical heterogeneity can also occur when variability in the treatment effects being evaluated in the different trials exists. as erationalized using a ␹2 test of significance. Variability (heterogene. tation and type.” This differ- homogeneous (as indicated in the inclusion criteria) in ence. “What is referred to simply as heterogeneity. Sixteen of these published been developed for quantifying inconsistency across studies met the definition for acute diarrhea and 6 for studies that move the focus away from testing whether persistent diarrhea. and age for each of the 22 tical heterogeneity is inevitable. Briefly. effects estimate and its CI address the question.aappublications.or Random-Effects Model the observed treatment effects are more different from Choice of whether to interpret a fixed-effects or ran- each other than would be expected as a result of random dom-effects model was considered thoroughly. country. Meta-analysis should results and each study’s individual result (when omit- be considered only when a group of trials is sufficiently ted) is taken as an index of “raw gravity. dom-effects estimate may not reflect the actual effect in ence of statistical heterogeneity. meta-analysis once for each of k studies. year. a pooled-effect estimate is termed. The technique recomputes the meta-analysis will differ. The 95% confidence intervals should be included or excluded because studies are com- (CIs) were reported around the weighted effect size. Although all 22 studies were erogeneity will always exist regardless of whether it can randomly assigned clinical trials. 56. Still. with debate on which ones (WMD) was calculated. A useful statistic for quantifying inconsis.12 A value ⬎50% may be were inpatient and 33. help to control for clinical/method. Following convention. or “standardized by guest on March 3. vis-à-vis the combined effect. some statis. divided by the SD of the k differences. it seemed that 515–19 be detected using a statistical test.Statistical Analyses considered substantial heterogeneity. inclusion criteria listed. analysis. 328 LUKACIK et al Downloaded from http://pediatrics. values.7% (4 of 6) than sampling error (chance). amount of zinc supplemen- diversity always occurs in a meta-analysis. meta-analysis. the best estimate of the treatment effect?” The random- Different approaches for identification and measure. interventions. ologic heterogeneity. The program is augmented using Another more recent approach13 proposed jackknife re- accepted computational algorithms. Where appropriate. a general indication of pres. age cutoff was adopted and examined also in our anal- was used to synthesize data that were obtained from the yses.7% (7 of tency is I2. then the ran- examined for poor overlap. It is for these for heterogeneity assesses the dispersion of individual reasons that we chose a fixed-effects model for our outcomes. and denotes meta-analysis. methods have were not double-blinded. is taken as terms of participants. SPSS 15. RESULTS Because some degree of clinical and methodologic The author. monly weighted according to their sample size and/or internal variability. therefore. along with the various stated approaches this value using a Q statistic. This results when Fixed. statistical effect meta-analyses ignore heterogeneity. Of the 6 persistent diarrhea trials. arguments have focused on the inclusion For continuous outcomes. the weighted mean difference or exclusion of some studies.” In any results were reported using a pooled relative risk (RR). Fixed- error (chance) alone. Gee13 proposed that jackknife re- Heterogeneity sampling could be used to examine study influence and Given that studies that are selected for inclusion in a detect outlier studies. These various types of vari.

mo Sachdev et al18 (1990) India Sulfate 20 mg 20/20 6–18 Roy et al21 (1998) Bangladesh Acetate 20 mg 95/95 3–24 Khatun et al34 (2001) Bangladesh Acetate 20 mg 24/24 6–24 Bhutta et al33 (1999) Pakistan Sulfate 3 mg/kg 43/44 6–36 Penny et al35 (1999) Peru Gluconate 20 mg 139/136 6–35 Bhandari et al36 (2002) India Gluconate 10/20 mg 1228/1236 6–30 Mortality obtained are presented initially for acute diarrhea (last- Mortality was originally a primary outcome in this meta. ceived a placebo (WMD: 0. TABLE 3 Characteristics of Acute Diarrhea Trials Reference Country Zinc Supplement Zinc Dosage Zinc/Control Group. most likely. zinc syrup. India Sulfate 10 mg 554/556 1–5 a Three study groups were examined (control. 0.5/45 mg 37/37 3–60 Polat et al29 (2003)b Turkey Sulfate 20 mg 92/90 2–29 Bhatnagar et al24 (2004) India Sulfate 15/30 mg 143/144 3–36 Valery et al19 (2005)c Australia Sulfate 20/40 mg 107/108 0–11. Brooks et al enrolled only male children.1% (82 of 215) were 12 to 23 months. Ethiopia.30 with insignifi- deaths in the placebo group. 38. of both acute and persistent trials. Thirty deaths were attributed those who received zinc experienced a significantly to drowning. February 2008 329 Downloaded from http://pediatrics. 95% CI: 0. there were 13 in the zinc.22–32 (n ⫽ 15 231). of statistically significant heterogeneity (Q ⫽ 95. I2 ⫽ 84. Although those who received zinc had a shorter child. All study participants were included in our analyses. the outcomes 0. and only 16. without excluding those with low zinc levels. in which diarrhea and acute lower respiratory infection.58. Number 2.19. Because acute and persistent diarrhea als17.15.009%.25. average duration of diarrhea. TABLE 4 Characteristics of Persistent Diarrhea Trials Reference Country Zinc Supplement Zinc Dosage Zinc/Control Group. however.27. distinct disease entities.21 reported mortality outcome. One PEDIATRICS Volume 121.04 to 0. septicemia in 1 215. In the other acute diarrhea cant differences between zinc and placebo groups in trial. the difference in 4 tri- arrhea in 1 child. 5 mg of zinc acetate. and zinc/ORS). d Three groups were used (control. mo 17 Sachdev et al (1988) India Sulfate 20 mg 25/25 6–18 Sazawal et al31 (1995) India Gluconate 20 mg 456/481 6–35 Roy et al30 (1997) Bangladesh Acetate 20 mg 57/54 3–24 Faruque et al27 (1999) Bangladesh Acetate 14/40 mg 343/341 6–23 Hidayat et al28 (1998) Indonesia Acetate 4/5 mg/kg 739/659 3–25 Dutta et al26 (2000) India Sulfate 40 mg 44/36 3–24 Strand et al32 (2002) Nepal Gluconate 15/30 mg 445/449 6–35 Bahl et al23 (2002)a India Gluconate 15/30 mg 404/401 6–35 Al-Sonboli et al22 (2003) Brazil Sulfate 22. however.21 In the largest acute diarrhea outpatient Duration of Acute Diarrhea trial15 (n ⫽ 8070).20 and 1 was a persistent diarrhea trial.8% (36 of 215) were ⱖ24 months.19. (lasting ⬎14 days).3%). We examined only those who used 20 mg of zinc versus control subjects. 37 of 4096) age duration of acute diarrhea15– by guest on March 3. ⱖ24 Patel et al20 (2005) India Sulfate/copper sulfate 40 mg/5 mg 102/98 6–59 Brooks et al25 (2005)d Bangladesh Acetate 20 mg 86/89 1–6 Baqui et al15 (2002) Bangladesh Acetate 20 mg 3974/4096 3–59 Fischer Walker et al16 (2006) Pakistan.30 was very small. SE: 0.19.20. When re.1% (97 of 215) were 0 to 11 months of age. The investi. and continued di.02. ing up to 14 days) and followed by persistent diarrhea analysis. b Four study groups were examined: low/normal zinc in 2 intervention groups and low/normal zinc in 2 control groups. c Children up to 11 years of age were included. P ⬍ . 45. 12–23. N Age.21 the causes of death were to nonsignificant in sample sizes that ranged from 50 to septicemia with diarrhea in 3 children. not attributable to zinc intervention). intervention group almost entirely to fewer deaths from Figure 1 depicts a Forrest plot for these results. de- gators attributed the lower noninjury death rate in the grees of freedom [df]Q ⫽ 15. died in the placebo group. 33 children (0. Table 5. average duration of diarrhea.18 days ranging from 0.40 days. 33 of 3974) died In 16 trials that examined the primary measure of aver- in the zinc-treated group and 37 (0.478 In the persistent diarrhea trial.20.001.18 ⫾ 0.21– stricted to noninjury deaths.20 2 children in the placebo group died of septicemia. P values ranged from . We combined the groups into either intervention or control. bronchopneumonia in 1 child. only 315. making it diffi- cult to compare across all included trials. Diarrhea every study is displayed as a point estimate with CIs. We included only those who received zinc syrup or a control. and 20 mg of zinc acetate).24. N Age.aappublications.008%. 2018 .001. and acute lower respiratory infection together accounted Examination of significant heterogeneity in the acute for 10 deaths in the zinc intervention group and 20 diarrhea trials revealed 5 trials17. and the remaining were not injury related lower average duration of diarrhea than those who re- (ie. Fig 1) but also with the presence treated group and 27 in the placebo group.20. with an average difference of are. P ⬍ . Two of these Results for Acute Diarrhea Trials were acute diarrhea trials.

071 .025 .151 NS Fischer Walker et al16 (2006) 554 556 . Effect. significant heterogeneity meet the criterion for statistical significance (␣ ⫽ .880. neity was found (Q ⫽ 10.022 .136 .011 Dutta et al26 (2000) 44 36 1.0%). nonsignificant.20. dfQ ⫽ 5.233 . The effect size index in this plot is the significant difference in the occurrence of acute diarrhea standard mean difference.05.811 2.2 days lower) with zinc use also had a 54. ministered an ORS before treatment assignment. the occurrence of statistically significant heteroge- lia. so a point estimate of 0.067 . Occurrence of Diarrhea at Day 3 trial25 found no difference at all between treatment Six acute diarrhea trials16.4%. 2018 . 95% CI: 0.187) and plotted standardized gravity value (3. upper limit of the 95% CI for the standard difference.91–1.403 .32 that provided zinc 0. 330 LUKACIK et al Downloaded from http://pediatrics.924 .141 .000 N1 indicates sample size for zinc group.05. N2.118 .0 indicate a better out. Values ⬍0.946 Brooks et al25 (2005) 86 89 ⫺. standard difference. TABLE 5 Mean Duration of Acute Diarrhea Reference N1 N2 Lower Upper Effect SE P 17 Sachdev et al (1988) 25 25 ⫺. and sample sizes for each study when removed. rence of diarrhea at day 3 (RR: 0.727 .025 Faruque et al27 (1999) 341 340 . standardized gravity values.3%). although the sever.03.27.08).225 .000 Al-Sonboli et al22 (2003) 37 37 .31.0%). sample size for the placebo group.066 . all acute diarrhea trials23.122 .441 .org/ by guest on March 3.297 . Upper.261 .03. then the P did occur (Q ⫽ 10. Occurrence of Diarrhea at Day 1 Five acute diarrhea trials16.120 .079 Patel et al20 (2005) 102 98 ⫺.25.20.371 . Participants in all 5 trials had been admitted for currence of diarrhea at day 3.347 .616 . lower limit of the 95% CI for the standard difference.0 at day 1 was found (RR: 1.32 collected data for oc- groups. the occurrence of statistically signif- trials received zinc sulfate and 2 received acetate.246 .000 Strand et al32 (2002) 445 449 .045 .006 .260 .006 Baqui et al15 (2002) 3974 4096 .531.19.386 . value would exceed .36).435 1.243 . One trial15 in which average duration was signifi. dfQ ⫽ 5.97.32 reported the occur- rence of diarrhea at day 1 (n ⫽ 3100). however.000 Bahl et al23 (2002) 404 401 ⫺. 95% CI: 0.27.769 . then the study would from a low of 0.817 Valery et al19 (2005) 107 108 ⫺.128 . Fig 2) were consid- ered outlying values in comparisons with all others.315 . In icant heterogeneity was found (Q ⫽ 10.774).478 Sazawal et al31 (1995) 456 481 .30 ad.05 and the study would not be statistically significant. ever.03. 0. Only 1 trial30 found a significantly gluconate and not zinc sulfate had a shorter duration of (P ⫽ .184 .199 . and 119 from Austra.052 .278 . and values ⬎0.30).272 . NS.0.245 .033 .015 .995 2.030 .284 .60.152 . It is clear that 1 study15 had a great deal of impact on the strength and direction of the estimated effect size value found for average dura- tion of acute diarrhea among all studies. P ⫽ .298 . Table 6 shows the effect sizes.425 1.312 .695.0. Three P ⫽ .016 .257 . Although the variability in effect sizes ranged come for the zinc group.19.412 .009 . I2 ⫽ 62.208 . P ⫽ reflect a better outcome for the placebo group. Four of the trials17.511 Hidayat et al28 (1998) 738 659 . 225. No statistically significant dehydration secondary to diarrhea.05). If the point estimate and CI fell above 0.331 .0 indicates no effect.000 Bhatnagar et al24 (2004) 143 144 ⫺.880.083 Polat et al29 (2003) 92 90 .23.054 . No statistically FIGURE 1 Mean difference in duration of acute diarrhea. calculated raw gravity values. When removed. I2 ⫽ cantly lower (1.4%) than placebo (35. If the CI overlapped 0. P ⫽ .968 to 1.060 . P ⫽ contrast.124 . differences occurred between treatment groups in occur- ity of dehydration ranged.298 .aappublications.016 .20 originated (27.30 from Bangladesh.153 .077 . Two trials17. This is largely attributed to the enormous sample size (n ⫽ 8070) used in the trial.312 .000 Roy et al30 (1997) 37 37 ⫺.99 –1. how- from India. effect size: 0. I2 ⫽ 54.01) lower occurrence of diarrhea at day 3 with zinc diarrhea than placebo (P ⱕ .196 .01.240 . tremendously higher sample size (n ⫽ 8070) than all of the others.208 . Lower.000 . dfQ ⫽ 4.20.039 Fixed combined (16) 7585 7646 .242 . the reaveraged effect size obtained (0.287 . because even very small differ- ences in mean duration of diarrhea would be statistically significant.

243 ⫺0.289 182 Patel et al20 (2005) 0.00381 ⫺0.84 –1.00181 ⫺0.01081 ⫺0.082 74 FIGURE 2 Standardized gravity results. Similar to day 3 no statistically significant differences occurred between results.05119 3.953 1397 Fischer Walker et al16 (2006) 0.249 ⫺0.263 681 Dutta et al26 (2000) 0.056 937 Sachdev et al17 (1988) 0.233 0. the occurrence of statistically significant hetero- PEDIATRICS Volume 121.00481 ⫺0.16.00181 ⫺0.00081 ⫺0.00119 0.237 0.240 ⫺0.94.00481 ⫺0.32 0.234 0. February 2008 331 Downloaded from http://pediatrics.252 ⫺0.242 ⫺0.00781 ⫺0. Occurrence of Diarrhea at Day 5 treatment groups in occurrence of diarrhea at day 5 (RR: Similarly.240 ⫺0.358 80 Brooks et al25 (2005) 0.00181 ⫺0.332 175 Bhatnagar et al24 (2004) 0.243 ⫺0.125 50 Roy et al30 (1997) 0.246 ⫺0.00519 0.05.243 ⫺0.23.239 ⫺0. TABLE 6 Acute Diarrhea: Gravity Values for Duration of Diarrhea Reference Effect Size Raw Gravity Standardized Gravity Sample Size 19 Valery et al (2005) 0.539 805 Al-Sonboli et al22 (2003) 0.00481 ⫺0.aappublications.01381 ⫺0. in the same 6 acute diarrhea trials.125 287 Baqui et al15 (2002) 0.332 215 Strand et al32 (2002) by guest on March 3.00481 ⫺0.187 0.531 8070 Bahl et al23 (2002) 0.125 74 Polat et al29 (2003) 0.19. 95% CI: 0. 2018 . P ⫽ .243 ⫺0.332 200 Hidayat et al28 (1998) 0.26).00419 0.240 ⫺0.20.746 1110 Faruque et al27 (1999) 0.27.332 894 Sazawal et al31 (1995) 0. Number 2.

I2 ⫽ Reduction in Stool Frequency 73. Probability of Diarrhea Reduction Vomiting After Administration of Zinc Sulfate or Gluconate Eight acute diarrhea trials20.32 a significantly higher probability of diarrhea reduction and found a 17.530 0.742 0.123 1. average lowering of stool output ⫽ 30.23.0% higher stool frequency using zinc than In 11 acute diarrhea trials16.295 0.30 (118 [10.438 0.537 Khatun et al34 (2001) 24 24 ⫺0.8%. 95% CI: 0.21. Probability of diarrhea duration was calculated by authors using various statistical approaches. TABLE 8 Mean Duration of Persistent Diarrhea Reference N1 N2 Lower Upper Effect SE P Sachdev et al18 (1990) 20 20 ⫺0.182 0.23–25. by taking a ratio of the total stool weight per kilogram of body weight and reporting the median.6%] of 2242.3%. or hazards ratio. India 5% higher frequency 9% shorter duration Average stool frequency reduction ⫽ 18. P ⱕ 0.12– 0.32 found an av- erage reduction in stool frequency of 22. in 2 studies. RR: 1.215 .430 Penny et al35 (1999) 87 86 0. 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.08. SE: 0.1% with zinc therapy in comparison with placebo.002. In another study.422 0.09. The ratio of the median was then taken. shortening of diarrhea duration was defined as the percentage ratio of the mean number of days of diarrhea in each study group.466 by guest on March 3. it was reported as the total stool output until the last first formed stool.32 measured the In 3 acute diarrhea trials.55. The resulting percentage was interpreted as a lowering of stool output in one group or the other. measured in grams per kilogram for each group.478 0. dfQ ⫽ 5.292 .29. It was then reported as a shorter percentage of time with diarrhea for one group or the other. 7% shorter duration Brooks et al25 (2005) Bangladesh 0% lower frequency 12% reduction in probability. those Shortening of Diarrhea Duration who received zinc also experienced a significantly lower Eight trials of acute diarrhea15–17.54. 95% CI: 1.23. The geometric mean was then taken and a ratio between groups obtained. Q ⫽ 25.25.31. P ⫽ .33–35 (n ⫽ 489). Lower stool output was calculated. average duration of diarrhea than the placebo group erage shortening of diarrhea duration of 15.05–1. One single trial16 Vomiting found a 5.299 0. TABLE 7 Effects of Zinc Therapy of Acute Diarrhea Reference Country Stool Frequency Reduction Probability of Diarrhea Continuation 17 Sachdev et al (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. proportion of participants who vomited after the initial dose was significantly higher with zinc (278 [12. Seven trials of acute diarrhea17.001. reduction using zinc compared with placebo.167 1. 0% shorter duration Baqui et al15 (2002) Bangladesh Not reported 24% shorter duration Fischer Walker et al16 (2006) Pakistan.31.30 found an average 1.26.3%.096 Roy et al21 (1998) 73 68 ⫺0.9%.7%] of 1101.48.006).001 geneity was found (Q ⫽ 18.201 0. risk ratio. P ⬍ . average shortening of duration ⫽ 15. Table 8) but without significant heterogeneity (Q ⫽ 3. Duration of Persistent Diarrhea In 5 persistent diarrhea trials18.154 .6%] of 1095) than zinc sulfate/acetate therapy16.010 0.29. ited (160 [14.004 Bhutta et al33 (1999) 43 44 ⫺0.7%] of Stool Output 2196) use than with placebo (171 [7.27.004).25.30. The group with the lower percentage was interpreted as a lowering of stool output in one group or another.0% for those (WMD: 0. the placebo.558 0.091 . Ethiopia. such as the odds ratio.29–32 (n ⫽ 4438). P ⫽ .18.0%.120 0.19.133 0. P ⫽ lowering of stool output of 30.22.9% proportion of patients who received zinc gluconate vom.30 –1.22. Results for Persistent Diarrhea Trials 95% CI: 1.26.22–25.17.20. This difference in statistic negated a comparison in the meta-analysis. who received zinc in comparison with placebo (Table 7).84.132 0.322 .957. Variances in data reporting of outcome measures: For this meta-analysis.28.31 found an av. RR: Three trials of acute diarrhea24. average probability of diarrhea reduction ⫽ 17. 2018 .144 Fixed combined (5) 247 242 0.169 .25.001%.29. 332 LUKACIK et al Downloaded from http://pediatrics. .134 0.

shortening of diarrhea dura- (Q ⫽ 0. Number 2. RR: teria. as exten- sively addressed in a recent systematic review. ficult because there are many different diarrheal agents. P ⫽ .94 –1. To the majority of individuals. of diarrhea (at least a P ⱖ .94. statistically significant variability occurred among the diarrhea is associated with an increase in stool weight.35 (n ⫽ 221). 95% CI: 0. In this meta-analysis. Protozoa such as Cryptosporidium parvum and (0 [0%] of 115.98). P ⫽ . dfQ ⫽ 1.25. 95% CI: 0. The primary symptoms of rotavirus Shortening of Diarrhea Duration infection are fever and vomiting for several days. and 1367) than did those who received zinc sulfate/acetate Salmonella. a sig. parasites. Occurrence of Diarrhea at Day 5 diarrhea is distinguished from diseases that cause only This was not examined. P ⫽ .34. these supplies are often unavailable Four trials of persistent diarrhea found that those who in the developing world.18.35. Other causes include zinc gluconate35.35 (n ⫽ 221). P ⫽ . February 2008 333 Downloaded from http://pediatrics. Values ⬍0.21. fewer than 2 studies reported. Probability of Diarrhea Reduction Two persistent diarrhea trials33. Identification of specific di- 3.02– by guest on March 3.36 vomited more frequently (41 [3%] of bacterial pathogens such as Vibrio cholerae. If the point estimate and CI fell above 0.116). dfQ ⫽ 1.01. In many developed countries. Stool Output Stool output was not measured in the persistent trials.001%] of 1487.00. so a point estimate of 0.05 and the study would not be statistically significant. 95% CI: 1.33.0%) of 5 tically significant differences occurred between treat.43). zinc therapy is useful for treating both acute and persis- tent diarrhea and for their prophylaxis. an increase in the number of bowel movements or fecal incontinence. Shigella. Given this.93).09.aappublications. 5 (31. tions. In fact.56).05). If the CI overlapped 0. severe. Although not normally zinc experienced a 15. and probabilities of a shortening of diarrhea dura- tion reported were higher in studies with zinc therapy in Occurrence of Diarrhea at Day 3 comparison with placebo.3%) of 16 acute diarrhea studies17. including bac- of 1482) than with placebo (2 [0.02). duction in frequency. I2 ⫽ 29. Viral gas- Vomiting After Zinc Sulfate or Gluconate troenteritis caused by rotavirus is the primary cause of In 4 persistent diarrhea trials.30 found no statistically significant differ- Occurrence of Diarrhea at Day 1 ences between zinc and placebo on the average duration In 2 trials of persistent diarrhea34. Vomiting Determining the exact causes of diarrhea can be dif- In 4 persistent diarrhea trials18.544. and values ⬎0. which now add to the reflect a better outcome for the placebo group.36 those who received diarrhea among infants worldwide. Figure 3 depicts the which zinc physiologically exerts its antidiarrheal effect. Q ⫽ 5. which normally makes up a large percentage of fecal matter. arrheal agents is complicated by the lack of access to laboratory tests in many developing countries. Similarly. caused by rotavirus is a significant cause of mortality.51– 0. 2 (40. 95% CI: 0. the average significant variability occurred among the effect sizes stool frequency reductions. a signifi.91.0 indicate a better out. P ⫽ .20.64. effect sizes (Q ⫽ 0. P ⫽ .36 (n ⫽ 2969). and no statistically between treatments (at least a P ⱖ . persistent diarrhea studies21. Forrest plot for these results.0 indicates no effect.36 that measured the probability of diarrhea reduction found an 18.8% re.8.8%] with such a variety of infectious agents. P ⫽ .0 On the basis of these findings. mainly as a result of excess water. RR: 1.33 also found no statistically ment groups in occurrence of diarrhea at day 1 (RR: significant differences in average duration of diarrhea 1. conclusions from these randomized trials for PEDIATRICS Volume 121.18.9%).37 value would exceed . and viruses. diarrhea means an cantly lower occurrence of diarrhea at day 3 occurred in increased frequency or decreased consistency of bowel those who were treated with zinc in comparison with movements. FIGURE 3 Mean difference in duration of persistent diarrhea. large body of previously published clinical data and up- come for the zinc group. P ⫽ .70. Although easily treated with intravenous fluids in Reduction in Stool Frequency developed nations. then the P date previous meta-analyses and systematic reviews.0.93–1. then the study would meet the criterion for statistical significance (␣ ⫽ .0.35 those who received lowed by nonbloody diarrhea.21. fol- In 4 persistent diarrhea trials. Still. In 2 trials of persistent diarrhea34.07).19. Giardia lamblia are 2 of the most common protozoan diarrheal agents.08.09.02. the average placebo (RR: 0.5% average shortening of diarrhea fatal.047. no statis. and the dehydration that is received zinc also experienced an average of 9.21. the diarrhea caused by the virus can be quite duration than those who got a placebo (Table 9). however. The effect size index in this plot is the DISCUSSION standard mean difference. 2018 . Still.48). leading to potentially life-threatening dehydra- tion. No number of bowel movements is 3 per day.0% reduc- tion when zinc was used over placebo.35.6 much information is lacking relative to the mechanisms by dfQ ⫽ 4. nificantly higher proportion vomited on zinc (41 [2.

chemistry. TABLE 9 Effects of Zinc Therapy of Persistent Diarrhea Reference Country Stool Frequency Reduction Probability of Diarrhea Continuation 18 Sachdev et al (1990) India 22% lower frequency 19% shorter duration Roy et al21 (1998) Bangladesh Not reported 7% shorter duration Khatun et al34 (2001) Bangladesh 7% lower frequency 17% shorter duration Bhutta et al33 (1999) Pakistan 9% lower frequency 14% reduction in probability Penny et al35 (1999) Peru Not reported 19% shorter duration Bhandari et al36 (2002) Nepal 12% lower frequency 22% reduction in probability Average stool frequency reduction ⫽ 12. limited to heat-labile–induced diarrhea or to diarrhea cluded an improved absorption of water and electrolytes mediated by cAMP but not either 3⬘. This difference in statistic negated a comparison in the meta-analysis. tolera- If substantiated. Although the alternative treatment of oral rehydra- tion triggered by zinc delivery.5%.0%. and intestine absorption rate. An antisecretory have not been elucidated fully. then the effectiveness of zinc would be ble.5⬘-cyclic mono.38 Increased levels of brush border (apical) enzymes that a zinc-sensing receptor triggers the release of intra- suggesting a zinc transporter for enterocytes39 and a cellular Ca2⫹ and regulates ion transport. there are still significant which zinc improves fluid and electrolyte transportation setbacks in distributing the therapy. Lower stool output was calculated. 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. average shortening of duration ⫽ 15. leading to an advantageous therapy has generally been attributed to a decrease in electrical gradient for chloride secretion. By preventing children from acquiring infection. dent fluid secretion. lease of calcium from intracellular pools in the colono- Efficacy of oral rehydration therapy in correcting de. average probability of diarrhea reduction ⫽ 18. inhibits anion secretion. zinc therapy after pretreat. measured in grams per kilogram for each group. Accelerated research directed to achieving a treatment with ORS had already maximized the small clearer understanding of the biology. reduces stool frequency and phosphate mediates heat-stable–induced fluid secretion. Treatment with ORS would have its The model for an antisecretory drug should perform greatest effect on reducing fluid loss by increasing small intestine absorption. In another study. whether zinc initiates or tion. reduces diarrhea duration. it was reported as the total stool output until the last first formed by guest on March 3. the mechanisms by tion therapy is more available.30 of this meta-analysis simply because pre. Variances in data reporting of outcome measures: For this meta-analysis. pathobiology of zinc in the gastrointestinal system is Zinc inhibits cAMP-induced chloride secretion by spe. The geometric mean was then taken and a ratio between groups obtained. porter for enterocytes? Answers to these and other tured Caco-2 cells.20.25. Does zinc maintain intestinal defense sys- cifically inhibiting basolateral potassium (K) channels tems? What is the relationship of zinc to intestinal with no blockage effect on calcium (Ca)-mediated K fluid balance? Definitively what are the linkages of channels in in vitro studies with the rat ileum. 334 LUKACIK et al Downloaded from http://pediatrics. given its inhibition of adenosine 3⬘. the volume of small intestinal fluid and sodium absorp. shortening of diarrhea duration was defined as the percentage ratio of the mean number of days of diarrhea in each study group. The group with the lower percentage was interpreted as a lowering of stool output in one group or another. lium. Still. phosphate or intracellular Ca. 2018 . This includes the effect of drug vaccine would be a much more cost-effective solu- zinc on intestinal ion transport. The resulting percentage was interpreted as a lowering of stool output in one group or the other. output. the location of the effect of zinc is in the vaccine could greatly reduce the number of deaths as a small intestine. and inexpensive. necessary. Probability of diarrhea duration was calculated by authors using various statistical approaches. cytic cell line. by inhibiting intestinal chloride and HCO3 secretion6 in ment with ORS may not have shown a beneficial effect contrast to focusing on decreasing gastrointestinal mo- (reduced average duration of diarrhea) over placebo in 5 tility and regeneration and/or restoration of gut epithe- trials17. Thus. and whether deficiency enhances the likelihood tiple infections and the risks associated with infections. ment drug that collectively induces cation absorption. One study42 showed that cAMP acted questions will hopefully drive the creation of a treat- as the intracellular effector of heat-labile enterotoxin. nity without the children’s needing to go through mul- cretion. by taking a ratio of the total stool weight per kilogram of body weight and reporting the median. induced fluid secretion. Success with zinc cell membrane potential.5⬘-cyclic mono- by the intestine and quicker regeneration of gut epithe. The ratio of the median was then taken.41 Zinc also intestinal zinc transporters to body zinc status? Is inhibits cholera toxin–induced but not Escherichia coli there a brush border (apical) membrane zinc trans- heat-stable enterotoxin-induced ion secretion in cul. Guanosine 3⬘.5%.19. An antisecretory drug vaccine could induce immu- increases cation absorption and/or suppresses anion se.5⬘- result of diarrheal diseases and greatly reduce the bur- cyclic monophosphate (cAMP)-induced chloride-depen- den on the health system. It has been reported also43 lium. risk ratio. a drug Most likely. or hazards ratio. such as the odds ratio.aappublications. and is safe. It was then reported as a shorter percentage of time with diarrhea for one group or the other. of secretory diarrhea. level may augment K efflux and a hyperpolarization of ifications of ORS with zinc therapy. A sustained increase in intracellular Ca hydration and reducing mortality led to treatment mod. in 2 studies. A micromolar stronger immune response that increased clearance of concentration of extracellular zinc set off a massive re- pathogens from the intestine40 were also described. the efficacy of zinc treatment on diarrhea duration in.

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in a discussion of his No Child Left Behind law.aappublications. That’s really what No Child Left Behind is. et al. Huber C. Sekler I. 42. Binder HJ. administrators. Koretz put it. Moran A. A zinc- stimulated Cl secretion via basolateral K-channel blockade in sensing receptor triggers the release of intracellular Ca2⫹ rat ileum. October 9. can we believe them? Or are people taking shortcuts?” And all of those studies found really substantial inflation of test scores. 2007 Noted by JFL.’ The problem is that you can raise scores the hard way by teaching more effectively and getting the students to work harder. toxin-induced. told me in a recent interview that it’s important to ask ‘whether you can trust improvements in test scores when you are holding people accountable for the tests. Proc Natl Acad Sci USA. Cirillo P. Aggett PJ. Fenwick PK. Hoque KM. Grossman N.’” Herbert B. 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. ‘is the gateway to success. really. kids will learn more. Am J Physiol Gastrointest Liver Physiol. Daniel Koretz. Buccigrossi V. If teachers.’ said Dr.40. 52(1):173–177 2005. New York Times. as Dr. Am J Clin Nutr. politicians and others have a stake in raising the test scores of students—as opposed to improving student learning.’ said President Bush. Hershfinkel M. 2001. G956 –G963 98(20):11749 –11754 HIGH-STAKES FLIMFLAM “It’s time to rein in the test zealots who have gotten such a stranglehold on the public schools in the US. Zinc inhibits cholera Zinc deprivation and zinc repletion: effect on the response of toxin-induced. but not Escherichia coli heat-stable entero- rats to infection with Strongyloides ratti. ‘that were based on the idea that if we can just get a good test in place and beat people up to raise scores. ‘We’ve now had four or five different waves of educational reform. which is not the same thing—there are all kinds of incentives to raise those scores by any means necessary. Wakelin D. Zinc inhibits cAMP. or you can take shortcuts and start figuring out ways.’ said Dr. J Infect Dis.’ The short answer. 1990. Koretz. a professor at Harvard’s Graduate School of Education. MD 336 LUKACIK et al Downloaded from http://pediatrics.288(5): and regulates ion transport. it is questionable in many cases whether the tests themselves are anything more than a shell game.’ Not only has high-stakes testing largely failed to magi- cally swing open the gates to successful learning. Koretz. since the 1970s in some states. Macdonald by guest on March 3. ‘Measuring. 2018 . is no. Rajendran VM. he said. Canani RB. Guess what’s been happening? ‘We’ve had high-stakes testing. ‘We’ve had maybe six good studies that ask: “If the scores go up. ion secretion in human enterocytes. to ‘game’ the system. 43. 2005.191(7):1072–1077 41.

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