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

Persistent Diarrhea
Marek Lukacik, Ronald L. Thomas and Jacob V. Aranda
Pediatrics 2008;121;326-336
DOI: 10.1542/peds.2007-0921

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ARTICLE

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.

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 of www.pediatrics.org/cgi/doi/10.1542/
peds.2007-0921
supplemental oral zinc therapy during recovery from acute or persistent diarrhea.
doi:10.1542/peds.2007-0921
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 mcg.edu

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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 TABLE 1 Average Duration of Diarrhea (Days)
Reference Zinc
Patel et al20 (2005) 4.34 ⫾ 2.28
Valery et al19 (2005) 3.26 ⫾ 3.31
Fischer Walker et al16 (2006) 4.93 ⫾ 3.90
Data are means ⫾ SD. Data previously obtained during the course of the study.
as a result of intestinal loss. A comprehensive review on
this subject was recently published.6 An alternative view
is that zinc may be working as a pharmacologic agent at
the level of gene expression.7 The efficacy of zinc in the
treatment of diarrhea is supported by several random-
ized, controlled trials that showed reduction of diarrhea
duration, stool output, and stool frequency. Meta-anal-
yses on the therapeutic effects8 of zinc in acute and
persistent diarrhea as well as prevention9 of diarrhea
with zinc supplementation have been previously pub-
lished. The published data so far have shown the efficacy
of zinc in the treatment of acute and chronic diarrhea.
Our meta-analysis was performed to include new studies
published since the last meta-analysis and to examine
the efficacy and safety of zinc therapy during recovery
from acute or persistent diarrhea.
METHODS
Inclusion Criteria
Studies that were selected for inclusion tested the same
primary hypotheses (average duration of diarrhea and
presence of diarrhea at days 1, 3, and 5) using similar
patient characteristics (primarily children aged between
1 and 60 months), with either acute or persistent diar-
rhea, including dysentery. Acute diarrhea was defined as
lasting up to 14 days, with persistent diarrhea lasting
⬎14 days. Random allocation to treatment groups and
concealment of allocation had to be met to satisfy inclu-
sion because inadequate allocation concealment, despite
the use of randomization, allows a risk for selection bias.
Intervention with oral zinc salt supplementation, allow-
ing for any zinc salt type or formulation (sulfate, glu-
conate, or acetate) if applied at ⱖ5 mg/day for any
length of duration, was examined against a control using
a placebo. All comparisons between treatment groups
had to be free of confounding by additional agents or
co-interventions. Study groups who, after randomiza-
tion, received zinc supplementation and ORS or zinc
supplemented with vitamin A were excluded.
Identification of Trials
The search strategy used computerized bibliographic
searches of Medline (1966 –2006); the Cochrane Central
Register of Controlled Trials (2006); Embase (1974 –2006);
Lilacs (1982–2006); CINAHL (1982–2006); Current Con-
TABLE 2 Number of Children With Diarrhea at Days 1, 3, and 5
Reference Zinc Day 1
Valery et al19 (2005) 98/107 (91.6%)
Fischer Walker et al16 (2006) 538/554 (97.1%)
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trolled Trials (2006); and abstracts published in Pediatric
Placebo Research (1991–2006) and the First (Boston, 2000) and
Second (Paris, France, 2004) World Congress of Pediatric
4.41 ⫾ 1.98
Gastroenterology, Hepatology and Nutrition. Both pub-
3.30 ⫾ 5.21
4.49 ⫾ 3.17 lished and unpublished trials were included in an effort
to control for publication bias. Citations of appropriate
studies were verified by reviewing the bibliographies and
reference lists of identified trials. Identified titles of ab-
stracts with potential relevance were downloaded, and
full manuscripts were then obtained for all abstracts that
were deemed relevant on the basis of the inclusion
criteria. Twenty-two trials met inclusion criteria: 16 pub-
lished studies relative to the definition of acute diarrhea
and 6 relative to persistent diarrhea.
Primary and Secondary Outcomes
Data on 8 clinically relevant outcome measures were
collected. We held average duration of diarrhea and
presence of diarrhea episodes at days 1, 3, and 5 as our
primary outcomes. Data on vomiting frequency, vom-
iting frequency by therapy type, stool frequency re-
duction, and probability of diarrhea continuation
were extracted as secondary outcomes. All 3 authors
independently extracted data from the same articles us-
ing a data extraction sheet and subsequently compared
results for agreement. The data thus obtained were
checked for consistency among authors, integrity of ran-
domization, and concealment of allocation. Questions
regarding the interpretability of certain data values were
resolved by all 3 authors. The final database entries were
verified by the statistician (Dr Thomas). Few studies
satisfied criteria for inclusion on every datum variable.
When necessary, authors of selected studies were con-
tacted to verify extracted data values derived from
graphs and/or to provide additional information in a
scaling form that could be combined with other studies.
Where those instances occurred, they are noted in Tables
1 and 2.
Definitions
Definitions of diarrhea varied somewhat in all included
studies. In acute trials, generally, the definitions stated
for diarrhea were the passage of ⱖ3 loose, watery stools
or 1 loose, watery stool with blood within 24 hours for
between 3 and 7 days in duration. In persistent diarrhea
trials, the definitions were similar, with the exception
that they persisted up to 14 days in duration.
Definitions for duration of diarrhea varied as well but
was defined, generally, from the time of enrollment into
the study until the first formed stool. Duration was
measured in either days or hours. For the purpose of this
meta-analysis, hours were converted to days. After en-
rollment/randomization, either the zinc treatment or the
placebo was assigned within 24 hours.
Placebo Day 1 Zinc Day 3 Placebo Day 3 Zinc Day 5 Placebo Day 5
100/108 (92.6%) 55/107 (51.4%) 55/108 (50.9%) 22/107 (20.6%) 20/108 (18.5%)
526/556 (94.6%) 391/554 (70.6%) 385/556 (69.2%) 226/554 (40.8%) 204/556 (36.7%)
PEDIATRICS Volume 121, Number 2, February 2008 327
Statistical Analyses
Comprehensive Meta-Analysis,10 a stand-alone program,
was used to synthesize data that were obtained from the
22 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 the
meta-analysis results. The program is augmented using
accepted 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.
Heterogeneity
Given that studies that are selected for inclusion in a
meta-analysis will differ, the types of variability (clinical,
methodologic, and/or statistical) that may occur among
studies must be investigated. These various types of vari-
ability are termed heterogeneity. Meta-analysis should
be considered only when a group of trials is sufficiently
homogeneous (as indicated in the inclusion criteria) in
terms of participants, interventions, and outcomes to
provide a meaningful summary. Strict adherence to the
inclusion criteria listed, such as blinding and conceal-
ment of allocation, help to control for clinical/method-
ologic heterogeneity. Still, statistical heterogeneity can
also occur when variability in the treatment effects being
evaluated in the different trials exists. This results when
the observed treatment effects are more different from
each other than would be expected as a result of random
error (chance) alone. Following convention, statistical
heterogeneity in the results of this meta-analysis are
referred to simply as heterogeneity.
Different approaches for identification and measure-
ment of heterogeneity were therefore undertaken to
examine the extent to which the results of the studies
included were consistent. CIs for the results of individual
studies (depicted graphically using horizontal lines) were
examined 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 formula
for heterogeneity assesses the dispersion of individual
outcomes, vis-à-vis the combined effect, and denotes
this value using a Q statistic.11 A low P value (or a large
␹2 statistic relative to its degree of freedom) provides
evidence of heterogeneity of treatment effects (variation
in effect estimates beyond chance).
Because some degree of clinical and methodologic
diversity always occurs in a meta-analysis, some statis-
tical heterogeneity is inevitable; therefore, the test for
heterogeneity 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 across
studies that move the focus away from testing whether
heterogeneity is present to assessing its impact on the
meta-analysis. A useful statistic for quantifying inconsis-
tency is I2, the percentage of the variability in effect size
estimates that is attributable to heterogeneity rather
than sampling error (chance).12 A value ⬎50% may be
328 LUKACIK et al
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considered substantial heterogeneity, and that percent-
age cutoff was adopted and examined also in our anal-
yses.
Gravity
Another more recent approach13 proposed jackknife re-
sampling to measure a concept termed “gravity.” In any
meta-analysis, arguments have focused on the inclusion
or exclusion of some studies, with debate on which ones
should be included or excluded because studies are com-
monly weighted according to their sample size and/or
internal variability. Gee13 proposed that jackknife re-
sampling could be used to examine study influence and
detect outlier studies. The technique recomputes the
meta-analysis once for each of k studies, where each
study is individually excluded. K results are then ob-
tained. The difference between the average of these k
results and each study’s 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 z score, or “standardized gravity,” which can be used to
establish which studies might be unusually influential.
SPSS 15.014 was used to calculate standardized gravity
values.
Fixed- or Random-Effects Model
Choice 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 is
the 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 these
questions are analogous when no heterogeneity is
present or when the distribution of the treatment effects
is roughly symmetrical. If they are not, then the ran-
dom-effects estimate may not reflect the actual effect in
any population being studied. In a fixed-effects meta-
analysis, a pooled-effect estimate is termed, generally, as
the best estimate of the treatment effect. It is for these
reasons that we chose a fixed-effects model for our
meta-analysis, along with the various stated approaches
to examine heterogeneity if found.
RESULTS
The author, year, country, amount of zinc supplemen-
tation and type, sample size, and age for each of the 22
studies selected for inclusion in the meta-analysis are
listed in Tables 3 and 4. Although all 22 studies were
randomly assigned clinical trials, it seemed that 515–19
were not double-blinded. Sixteen of these published
studies met the definition for acute diarrhea and 6 for
persistent diarrhea.
Overall, 56.3% (9 of 16) of acute diarrhea trials were
conducted in inpatient hospital settings, and 43.7% (7 of
16) 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.
 TABLE 3 Characteristics of Acute Diarrhea Trials
Reference Country Zinc Supplement Zinc Dosage Zinc/Control Group, N Age, 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 22.5/45 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, 12–23, 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, Ethiopia, India Sulfate 10 mg 554/556 1–5
a Three 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 ⱖ24 months. All

study participants were included in our analyses.

d Three groups were used (control, 5 mg of zinc acetate, and 20 mg of zinc acetate). We examined only those who used 20 mg of zinc versus control subjects. Brooks et al enrolled only male 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 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-
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 these
were acute diarrhea trials,15,20 and 1 was a persistent
diarrhea trial.21 In the largest acute diarrhea outpatient
trial15 (n ⫽ 8070), 33 children (0.008%; 33 of 3974) died
in the zinc-treated group and 37 (0.009%; 37 of 4096)
died in the placebo group. Thirty deaths were attributed
to 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 the
intervention group almost entirely to fewer deaths from
diarrhea and acute lower respiratory infection. Diarrhea
and acute lower respiratory infection together accounted
for 10 deaths in the zinc intervention group and 20
deaths in the placebo group. In the other acute diarrhea
trial,20 2 children in the placebo group died of septicemia.
In the persistent diarrhea trial,21 the causes of death were
septicemia with diarrhea in 3 children, septicemia in 1
child, bronchopneumonia in 1 child, and continued di-
arrhea in 1 child. Because acute and persistent diarrhea
are, most likely, distinct disease entities, the outcomes
ing up to 14 days) and followed by persistent diarrhea
(lasting ⬎14 days).
Results for Acute Diarrhea Trials
Duration of Acute Diarrhea
In 16 trials that examined the primary measure of aver-
age duration of acute diarrhea15–17,19,20,22–32 (n ⫽ 15 231),
those who received zinc experienced a significantly
lower average duration of diarrhea than those who re-
ceived a placebo (WMD: 0.24; SE: 0.02; 95% CI: 0.21–
0.27; P ⬍ .001; Table 5, Fig 1) but also with the presence
of statistically significant heterogeneity (Q ⫽ 95.58, de-
grees of freedom [df]Q ⫽ 15, P ⬍ .001, I2 ⫽ 84.3%).
Figure 1 depicts a Forrest plot for these results, in which
every study is displayed as a point estimate with CIs.
Examination of significant heterogeneity in the acute
diarrhea trials revealed 5 trials17,19,20,25,30 with insignifi-
cant differences between zinc and placebo groups in
average duration of diarrhea. P values ranged from .478
to nonsignificant in sample sizes that ranged from 50 to
215. Although those who received zinc had a shorter
average duration of diarrhea, the difference in 4 tri-
als17,19,20,30 was very small, with an average difference of
0.18 ⫾ 0.18 days ranging from 0.04 to 0.40 days. One

PEDIATRICS Volume 121, Number 2, February 2008 329

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 TABLE 5 Mean Duration of Acute Diarrhea
Reference N1 N2 Lower Upper Effect SE P
17
Sachdev et al (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.

tremendously higher sample size (n ⫽ 8070) than all of

the others.
Table 6 shows the effect sizes, calculated raw gravity
values, standardized gravity values, and sample sizes for
each study when removed. 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. When removed,
the reaveraged effect size obtained (0.187) and plotted
standardized gravity value (3.531; Fig 2) were consid-
ered outlying values in comparisons with all others. This
is 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 statistically
significant.

Occurrence of Diarrhea at Day 1

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. Values ⬍0.0
reflect a better outcome for the placebo group, and values ⬎0.0 indicate a better out-
come for the zinc group. If the point estimate and CI fell above 0.0, then the study would
meet the criterion for statistical significance (␣ ⫽ .05). If the CI overlapped 0.0, then the P
value would exceed .05 and the study would not be statistically significant.
Five acute diarrhea trials16,19,20,27,32 reported the occur-
rence of diarrhea at day 1 (n ⫽ 3100). No statistically
significant difference in the occurrence of acute diarrhea
at day 1 was found (RR: 1.01; 95% CI: 0.99 –1.03; P ⫽
0.30). Although the variability in effect sizes ranged
from a low of 0.968 to 1.695, significant heterogeneity
did occur (Q ⫽ 10.60, dfQ ⫽ 4, P ⫽ .03, I2 ⫽ 62.3%).

Occurrence of Diarrhea at Day 3

trial25 found no difference at all between treatment
groups. Participants in all 5 trials had been admitted for
dehydration secondary to diarrhea, although the sever-
ity of dehydration ranged. Four of the trials17,20,25,30 ad-
ministered an ORS before treatment assignment. Three
trials received zinc sulfate and 2 received acetate. In
contrast, all acute diarrhea trials23,31,32 that provided zinc
gluconate and not zinc sulfate had a shorter duration of
diarrhea than placebo (P ⱕ .08). Two trials17,20 originated
from 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
Six acute diarrhea trials16,19,20,23,27,32 collected data for oc-
currence of diarrhea at day 3. No statistically significant
differences occurred between treatment groups in occur-
rence of diarrhea at day 3 (RR: 0.97; 95% CI: 0.91–1.03;
P ⫽ .36); however, the occurrence of statistically signif-
icant heterogeneity was found (Q ⫽ 10.880, dfQ ⫽ 5, P ⫽
0.05, 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, I2 ⫽
54.0%).

330 LUKACIK et al
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 TABLE 6 Acute Diarrhea: Gravity Values for Duration of Diarrhea
Reference Effect Size Raw Gravity Standardized Gravity Sample Size
19
Valery et al (2005) 0.243 ⫺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

FIGURE 2
Standardized gravity results.

Occurrence of Diarrhea at Day 5 treatment groups in occurrence of diarrhea at day 5 (RR:

Similarly, in the same 6 acute diarrhea trials,16,19,20,23,27,32 0.94; 95% CI: 0.84 –1.05; P ⫽ .26). Similar to day 3
no statistically significant differences occurred between results, the occurrence of statistically significant hetero-

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 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, 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
data reporting of outcome measures: For this meta-analysis, shortening of diarrhea duration was defined as the percentage ratio of the mean number of days of diarrhea in each study group. 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
total stool weight per kilogram of body weight and reporting the median. The ratio of the median was then taken. The resulting percentage was interpreted as a lowering of stool output in one group
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 Mean Duration of 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

geneity was found (Q ⫽ 18.957, dfQ ⫽ 5, P ⫽ .002, I2 ⫽ Reduction in Stool Frequency

73.6%).
Vomiting
In 11 acute diarrhea trials16,17,19,22–25,29–32 (n ⫽ 4438), the
proportion of participants who vomited after the initial
dose was significantly higher with zinc (278 [12.7%] of
2196) use than with placebo (171 [7.6%] of 2242; RR:
1.55; 95% CI: 1.30 –1.84; P ⱕ 0.001%; Q ⫽ 25.54, P ⫽
.004).
Vomiting After Administration of Zinc Sulfate or Gluconate
In 3 acute diarrhea trials,23,31,32 a significantly higher
proportion of patients who received zinc gluconate vom-
ited (160 [14.6%] of 1095) than zinc sulfate/acetate
therapy16,17,19,22,24,25,29,30 (118 [10.7%] of 1101; RR: 1.18;
95% CI: 1.05–1.31; P ⫽ .006).
Shortening of Diarrhea Duration
Eight trials of acute diarrhea15–17,20,25,26,29,31 found an av-
erage shortening of diarrhea duration of 15.0% for those
who received zinc in comparison with placebo (Table 7).
Seven trials of acute diarrhea17,22,23,25,29,31,32 found an av-
erage reduction in stool frequency of 22.1% with zinc
therapy in comparison with placebo. One single trial16
found a 5.0% higher stool frequency using zinc than
placebo.
Stool Output
Three trials of acute diarrhea24,26,30 found an average
lowering of stool output of 30.3%.
Probability of Diarrhea Reduction
Eight acute diarrhea trials20,23–25,27,28,30,32 measured the
probability of diarrhea reduction and found a 17.9%
reduction using zinc compared with placebo.
Results for Persistent Diarrhea Trials
Duration of Persistent Diarrhea
In 5 persistent diarrhea trials18,21,33–35 (n ⫽ 489), those
who received zinc also experienced a significantly lower
average duration of diarrhea than the placebo group
(WMD: 0.30; SE: 0.09; 95% CI: 0.12– 0.48; P ⬍ .001;
Table 8) but without significant heterogeneity (Q ⫽ 3.08,

332 LUKACIK et al
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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. Values ⬍0.0
reflect a better outcome for the placebo group, and values ⬎0.0 indicate a better out-
come for the zinc group. If the point estimate and CI fell above 0.0, then the study would
meet the criterion for statistical significance (␣ ⫽ .05). If the CI overlapped 0.0, then the P
value would exceed .05 and the study would not be statistically significant.
dfQ ⫽ 4, P ⫽ .544, I2 ⫽ 29.9%). Figure 3 depicts the
Forrest plot for these results.
Occurrence of Diarrhea at Day 1
In 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: 0.93–1.08; P ⫽ .98), and no statistically
significant variability occurred among the effect sizes
(Q ⫽ 0.01, dfQ ⫽ 1, P ⫽ .93).
Occurrence of Diarrhea at Day 3
In 2 trials of persistent diarrhea34,35 (n ⫽ 221), a signifi-
cantly lower occurrence of diarrhea at day 3 occurred in
those who were treated with zinc in comparison with
placebo (RR: 0.70; 95% CI: 0.51– 0.94; P ⫽ .02). No
statistically significant variability occurred among the
effect sizes (Q ⫽ 0.33, dfQ ⫽ 1, P ⫽ .56).
Occurrence of Diarrhea at Day 5
This was not examined; fewer than 2 studies reported.
Vomiting
In 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: 1.02–13.02; P ⫽ .047; Q ⫽ 5.91, P ⫽ .116).
Vomiting After Zinc Sulfate or Gluconate
In 4 persistent diarrhea trials,18,21,35,36 those who received
zinc gluconate35,36 vomited more frequently (41 [3%] of
1367) than did those who received zinc sulfate/acetate
(0 [0%] of 115; RR: 1.09; 95% CI: 0.94 –1.09; P ⫽ .07).
Shortening of Diarrhea Duration
In 4 persistent diarrhea trials,18,21,34,35 those who received
zinc experienced a 15.5% average shortening of diarrhea
duration than those who got a placebo (Table 9).
Reduction in Stool Frequency
Four trials of persistent diarrhea found that those who
received zinc also experienced an average of 9.8% re-
duction in frequency.
Downloaded from www.pediatrics.org at Indonesia:AAP Sponsored on November 7, 2008
Stool Output
Stool output was not measured in the persistent trials.
Probability of Diarrhea Reduction
Two persistent diarrhea trials33,36 that measured the
probability 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 the
large 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 much
information is lacking relative to the mechanisms by
which zinc physiologically exerts its antidiarrheal effect.
In this meta-analysis, 5 (31.3%) of 16 acute diarrhea
studies17,19,20,25,30 found no statistically significant differ-
ences between zinc and placebo on the average duration
of diarrhea (at least a P ⱖ .48). Similarly, 2 (40.0%) of 5
persistent diarrhea studies21,33 also found no statistically
significant differences in average duration of diarrhea
between treatments (at least a P ⱖ .43). Still, the average
stool frequency reductions, shortening of diarrhea dura-
tions, and probabilities of a shortening of diarrhea dura-
tion reported were higher in studies with zinc therapy in
comparison with placebo.
To the majority of individuals, diarrhea means an
increased frequency or decreased consistency of bowel
movements. In many developed countries, the average
number 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 normally
makes up a large percentage of fecal matter. Given this,
diarrhea is distinguished from diseases that cause only
an increase in the number of bowel movements or fecal
incontinence.
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 to
laboratory tests in many developing countries. Viral gas-
troenteritis caused by rotavirus is the primary cause of
diarrhea among infants worldwide. Other causes include
bacterial pathogens such as Vibrio cholerae, Shigella, and
Salmonella. Protozoa such as Cryptosporidium parvum and
Giardia lamblia are 2 of the most common protozoan
diarrheal agents. The primary symptoms of rotavirus
infection are fever and vomiting for several days, fol-
lowed by nonbloody diarrhea. Although not normally
fatal, the diarrhea caused by the virus can be quite
severe, leading to potentially life-threatening dehydra-
tion. Although easily treated with intravenous fluids in
developed nations, these supplies are often unavailable
in the developing world, and the dehydration that is
caused by rotavirus is a significant cause of mortality.
In fact, conclusions from these randomized trials for
PEDIATRICS Volume 121, Number 2, February 2008 333
 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 ⫽ 12.5%; average shortening of duration ⫽ 15.5%; average probability of diarrhea reduction ⫽ 18.0%.
Variances in data reporting of outcome measures: For this meta-analysis, shortening of diarrhea duration was defined as the percentage ratio of
the mean number of days of diarrhea in each study group. 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 total stool weight per kilogram of body weight and reporting the median. The
ratio of the median was then taken. The resulting percentage was interpreted as a lowering of stool output in one group 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.

the efficacy of zinc treatment on diarrhea duration in-
cluded an improved absorption of water and electrolytes
by the intestine and quicker regeneration of gut epithe-
lium.38 Increased levels of brush border (apical) enzymes
suggesting a zinc transporter for enterocytes39 and a
stronger immune response that increased clearance of
pathogens from the intestine40 were also described.
Efficacy of oral rehydration therapy in correcting de-
hydration and reducing mortality led to treatment mod-
ifications of ORS with zinc therapy. Success with zinc
therapy has generally been attributed to a decrease in
the volume of small intestinal fluid and sodium absorp-
tion triggered by zinc delivery. Still, the mechanisms by
which zinc improves fluid and electrolyte transportation
have not been elucidated fully. This includes the effect of
zinc on intestinal ion transport, whether zinc initiates or
increases cation absorption and/or suppresses anion se-
cretion, and whether deficiency enhances the likelihood
of secretory diarrhea.
Most likely, the location of the effect of zinc is in the
small intestine, given its inhibition of adenosine 3⬘,5⬘-
cyclic monophosphate (cAMP)-induced chloride-depen-
dent fluid secretion. Treatment with ORS would have its
greatest effect on reducing fluid loss by increasing small
intestine absorption. Thus, zinc therapy after pretreat-
ment with ORS may not have shown a beneficial effect
(reduced average duration of diarrhea) over placebo in 5
trials17,19,20,25,30 of this meta-analysis simply because pre-
treatment with ORS had already maximized the small
intestine absorption rate.
Zinc inhibits cAMP-induced chloride secretion by spe-
cifically inhibiting basolateral potassium (K) channels
with no blockage effect on calcium (Ca)-mediated K
channels in in vitro studies with the rat ileum.41 Zinc also
inhibits cholera toxin–induced but not Escherichia coli
heat-stable enterotoxin-induced ion secretion in cul-
tured Caco-2 cells. One study42 showed that cAMP acted
as the intracellular effector of heat-labile enterotoxin-
induced fluid secretion. Guanosine 3⬘,5⬘-cyclic mono-
phosphate mediates heat-stable–induced fluid secretion.
If substantiated, then the effectiveness of zinc would be
limited to heat-labile–induced diarrhea or to diarrhea
mediated by cAMP but not either 3⬘,5⬘-cyclic mono-
phosphate or intracellular Ca. It has been reported also43
that a zinc-sensing receptor triggers the release of intra-
cellular Ca2⫹ and regulates ion transport. A micromolar
concentration of extracellular zinc set off a massive re-
lease of calcium from intracellular pools in the colono-
cytic cell line. A sustained increase in intracellular Ca
level may augment K efflux and a hyperpolarization of
cell membrane potential, leading to an advantageous
electrical gradient for chloride secretion.
Although the alternative treatment of oral rehydra-
tion therapy is more available, there are still significant
setbacks in distributing the therapy. An antisecretory
drug vaccine would be a much more cost-effective solu-
tion. An antisecretory drug vaccine could induce immu-
nity without the children’s needing to go through mul-
tiple infections and the risks associated with infections.
By preventing children from acquiring infection, a drug
vaccine could greatly reduce the number of deaths as a
result of diarrheal diseases and greatly reduce the bur-
den on the health system.
The model for an antisecretory drug should perform
by inhibiting intestinal chloride and HCO3 secretion6 in
contrast to focusing on decreasing gastrointestinal mo-
tility and regeneration and/or restoration of gut epithe-
lium. Accelerated research directed to achieving a
clearer understanding of the biology, chemistry, and
pathobiology of zinc in the gastrointestinal system is
necessary. Does zinc maintain intestinal defense sys-
tems? What is the relationship of zinc to intestinal
fluid balance? Definitively what are the linkages of
intestinal zinc transporters to body zinc status? Is
there a brush border (apical) membrane zinc trans-
porter for enterocytes? Answers to these and other
questions will hopefully drive the creation of a treat-
ment drug that collectively induces cation absorption;
inhibits anion secretion; reduces stool frequency and
output; reduces diarrhea duration; and is safe, tolera-
ble, and inexpensive.

334 LUKACIK et al
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ACKNOWLEDGMENT
We thank William D. Lyman, PhD, for help and sugges-
tions in writing this article.
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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. 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 Harvard’s Graduate School of Education, 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.’ The short answer, he said, is no. If teachers, administrators, politicians
and others have a stake in raising the test scores of students—as opposed to
improving student learning, which is not the same thing—there are all kinds
of incentives to raise those scores by any means necessary. ‘We’ve 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. That’s 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 what’s been happening? ‘We’ve had high-stakes testing, really,
since the 1970s in some states,’ said Dr. Koretz. ‘We’ve 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 of
test scores.’”
Herbert B. New York Times. October 9, 2007
Noted by JFL, MD

336 LUKACIK et al
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 A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and
Persistent Diarrhea
Marek Lukacik, Ronald L. Thomas and Jacob V. Aranda
Pediatrics 2008;121;326-336
DOI: 10.1542/peds.2007-0921
Updated Information including high-resolution figures, can be found at:
& Services http://www.pediatrics.org/cgi/content/full/121/2/326
References This article cites 39 articles, 7 of which you can access for free
at:
http://www.pediatrics.org/cgi/content/full/121/2/326#BIBL
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