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

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/121/2/326

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

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
a

Department of Pediatrics, Childrens Medical Center, Medical College of Georgia, Augusta, Georgia; bDepartment of Pediatrics, Wayne State University School of
Medicine, and Childrens Hospital of Michigan, Detroit, Michigan, and National Institute of Child Health and Human Development, Pediatric Pharmacology
Research Unit Network, Wayne State University, Detroit, Michigan

The authors have indicated they have no nancial 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
supplemental oral zinc therapy during recovery from acute or persistent diarrhea.

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

METHODS. We conducted a meta-analysis of randomized, controlled trials to compare

the efficacy and safety of supplementary oral zinc with placebo in children with acute
and persistent diarrhea. Results were reported using a pooled relative risk or a
weighted mean difference. A total of 22 studies were identified for inclusion: 16
examined acute diarrhea (n 15 231), and 6 examined persistent diarrhea (n
2968).
RESULTS. Mean duration of acute diarrhea and persistent diarrhea was significantly

lower for zinc compared with placebo. Presence of diarrhea between zinc and
placebo at day 1 was not significantly different in acute diarrhea or persistent
diarrhea trials. At day 3, presence was significantly lower for zinc in persistent
diarrhea trials (n 221) but not in acute diarrhea trials. Vomiting after therapy was
significantly higher for zinc in 11 acute diarrhea trials (n 4438) and 4 persistent
diarrhea trials (n 2969). Those who received zinc gluconate in comparison with
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
15.5% shortening of diarrhea duration, and a 17.9% and 18.0% probability of
reducing diarrhea over placebo in acute and persistent trials, respectively.

Key Words
diarrhea, zinc
Abbreviations
WHOWorld Health Organization
ORS oral rehydration solution
RRrelative risk
WMDweighted mean difference
CI condence interval
cAMP3,5-cyclic monophosphate
Kpotassium
Ca calcium
Accepted for publication Jul 24, 2007
Address correspondence to Marek Lukacik,
MD, Childrens Medical Center Department of
Pediatrics, Medical College of Georgia, 1120
15th St, Augusta, GA 30912. E-mail: mlukacik@
mcg.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright 2008 by the
American Academy of Pediatrics

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.

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

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

TABLE 1 Average Duration of Diarrhea (Days)

Reference

Zinc

Placebo

Patel et al20 (2005)

Valery et al19 (2005)
Fischer Walker et al16 (2006)

4.34 2.28
3.26 3.31
4.93 3.90

4.41 1.98
3.30 5.21
4.49 3.17

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 randomized, controlled trials that showed reduction of diarrhea
duration, stool output, and stool frequency. Meta-analyses on the therapeutic effects8 of zinc in acute and
persistent diarrhea as well as prevention9 of diarrhea
with zinc supplementation have been previously published. 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 diarrhea, 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 inclusion because inadequate allocation concealment, despite
the use of randomization, allows a risk for selection bias.
Intervention with oral zinc salt supplementation, allowing for any zinc salt type or formulation (sulfate, gluconate, or acetate) if applied at 5 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 randomization, received zinc supplementation and ORS or zinc
supplemented with vitamin A were excluded.
Identication 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 (19822006); CINAHL (19822006); Current Con-

trolled Trials (2006); and abstracts published in Pediatric

Research (19912006) and the First (Boston, 2000) and
Second (Paris, France, 2004) World Congress of Pediatric
Gastroenterology, Hepatology and Nutrition. Both published 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 abstracts 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 published 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, vomiting frequency by therapy type, stool frequency reduction, and probability of diarrhea continuation
were extracted as secondary outcomes. All 3 authors
independently extracted data from the same articles using a data extraction sheet and subsequently compared
results for agreement. The data thus obtained were
checked for consistency among authors, integrity of randomization, 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 contacted 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.
Denitions
Definitions of diarrhea varied somewhat in all included
studies. In acute trials, generally, the definitions stated
for diarrhea were the passage of 3 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 enrollment/randomization, either the zinc treatment or the
placebo was assigned within 24 hours.

TABLE 2 Number of Children With Diarrhea at Days 1, 3, 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)

Fischer Walker et al16 (2006)

98/107 (91.6%)
538/554 (97.1%)

100/108 (92.6%)
526/556 (94.6%)

55/107 (51.4%)
391/554 (70.6%)

55/108 (50.9%)
385/556 (69.2%)

22/107 (20.6%)
226/554 (40.8%)

20/108 (18.5%)
204/556 (36.7%)

PEDIATRICS Volume 121, Number 2, February 2008

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

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 persistent diarrhea trials. Briefly, the analysis software produces 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 variability 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 concealment of allocation, help to control for clinical/methodologic 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 measurement 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 presence of statistical heterogeneity. Variability (heterogeneity) among the obtained effects sizes was formally operationalized using a 2 test of significance. The formula
for heterogeneity assesses the dispersion of individual
outcomes, vis-a`-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 statistical heterogeneity is inevitable; therefore, the test for
heterogeneity is irrelevant to the choice of analysis: heterogeneity 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 inconsistency 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

considered substantial heterogeneity, and that percentage cutoff was adopted and examined also in our analyses.
Gravity
Another more recent approach13 proposed jackknife resampling 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 commonly weighted according to their sample size and/or
internal variability. Gee13 proposed that jackknife resampling 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 obtained. The difference between the average of these k
results and each studys individual result (when omitted) is taken as an index of raw gravity. This difference, 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 random-effects model was considered thoroughly. Fixedeffect meta-analyses ignore heterogeneity. The fixedeffect estimate and its CI address the question, What is
the best estimate of the treatment effect? The randomeffects 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 random-effects estimate may not reflect the actual effect in
any population being studied. In a fixed-effects metaanalysis, 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 supplementation 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 51519
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 communities. Of the 6 persistent diarrhea trials, 66.7% (4 of 6)
were inpatient and 33.3% (2 of 6) were outpatient.

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

TABLE 3 Characteristics of Acute Diarrhea Trials

Reference

Country

Zinc Supplement

Zinc Dosage

Zinc/Control Group, N

Age, mo

17

India
India
Bangladesh
Bangladesh
Indonesia
India
Nepal
India
Brazil
Turkey
India
Australia
India
Bangladesh
Bangladesh
Pakistan, Ethiopia, India

Sulfate
Gluconate
Acetate
Acetate
Acetate
Sulfate
Gluconate
Gluconate
Sulfate
Sulfate
Sulfate
Sulfate
Sulfate/copper sulfate
Acetate
Acetate
Sulfate

20 mg
20 mg
20 mg
14/40 mg
4/5 mg/kg
40 mg
15/30 mg
15/30 mg
22.5/45 mg
20 mg
15/30 mg
20/40 mg
40 mg/5 mg
20 mg
20 mg
10 mg

25/25
456/481
57/54
343/341
739/659
44/36
445/449
404/401
37/37
92/90
143/144
107/108
102/98
86/89
3974/4096
554/556

618
635
324
623
325
324
635
635
360
229
336
011, 1223, 24
659
16
359
15

Sachdev et al (1988)
Sazawal et al31 (1995)
Roy et al30 (1997)
Faruque et al27 (1999)
Hidayat et al28 (1998)
Dutta et al26 (2000)
Strand et al32 (2002)
Bahl et al23 (2002)a
Al-Sonboli et al22 (2003)
Polat et al29 (2003)b
Bhatnagar et al24 (2004)
Valery et al19 (2005)c
Patel et al20 (2005)
Brooks et al25 (2005)d
Baqui et al15 (2002)
Fischer Walker et al16 (2006)
a Three

study groups were examined (control, zinc syrup, and zinc/ORS). We included only those who received zinc syrup or a control.
study groups were examined: low/normal zinc in 2 intervention groups and low/normal zinc in 2 control groups. We combined the groups into either intervention or control, without
excluding those with low zinc levels.
c Children up to 11 years of age were included; however, 45.1% (97 of 215) were 0 to 11 months of age; 38.1% (82 of 215) were 12 to 23 months; and only 16.8% (36 of 215) were 24 months. All
study participants were included in our analyses.
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.
b Four

TABLE 4 Characteristics of Persistent Diarrhea Trials

Reference

Country

Zinc Supplement

Zinc Dosage

Zinc/Control Group, N

Age, mo

Sachdev et al18 (1990)

Roy et al21 (1998)
Khatun et al34 (2001)
Bhutta et al33 (1999)
Penny et al35 (1999)
Bhandari et al36 (2002)

India
Bangladesh
Bangladesh
Pakistan
Peru
India

Sulfate
Acetate
Acetate
Sulfate
Gluconate
Gluconate

20 mg
20 mg
20 mg
3 mg/kg
20 mg
10/20 mg

20/20
95/95
24/24
43/44
139/136
1228/1236

618
324
624
636
635
630

Mortality
Mortality was originally a primary outcome in this metaanalysis; however, of both acute and persistent trials,
only 315,20,21 reported mortality outcome, making it difficult 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 restricted to noninjury deaths, there were 13 in the zinctreated group and 27 in the placebo group. The investigators 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 diarrhea in 1 child. Because acute and persistent diarrhea
are, most likely, distinct disease entities, the outcomes

obtained are presented initially for acute diarrhea (lasting 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 average duration of acute diarrhea1517,19,20,2232 (n 15 231),
those who received zinc experienced a significantly
lower average duration of diarrhea than those who received 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, degrees 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 insignificant 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 trials17,19,20,30 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

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

329

TABLE 5 Mean Duration of Acute Diarrhea

Reference

N1

N2

Lower

Upper

Effect

SE

17

25
456
37
738
341
44
445
3974
404
92
37
143
102
107
86
554
7585

25
481
37
659
340
36
449
4096
401
90
37
144
98
108
89
556
7646

.371
.128
.312
.015
.045
1.811
.052
.243
.016
.425
.435
.025
.246
.260
.298
.006
.208

.769
.386
.616
.225
.347
2.995
.315
.331
.261
1.030
1.412
.441
.312
.278
.298
.242
.272

.199
.257
.152
.120
.196
2.403
.184
.287
.122
.727
.924
.208
.033
.009
.000
.124
.240

.284
.066
.233
.054
.077
.297
.067
.022
.071
.153
.245
.118
.141
.136
.151
.060
.016

.478
.000
.511
.025
.011
.000
.006
.000
.083
.000
.000
.079
.817
.946
NS
.039
.000

Sachdev et al (1988)
Sazawal et al31 (1995)
Roy et al30 (1997)
Hidayat et al28 (1998)
Faruque et al27 (1999)
Dutta et al26 (2000)
Strand et al32 (2002)
Baqui et al15 (2002)
Bahl et al23 (2002)
Polat et al29 (2003)
Al-Sonboli et al22 (2003)
Bhatnagar et al24 (2004)
Patel et al20 (2005)
Valery et al19 (2005)
Brooks et al25 (2005)
Fischer Walker et al16 (2006)
Fixed combined (16)

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, nonsignicant.

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 duration 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 considered 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 differences in mean duration of diarrhea would be statistically
significant.

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
reect a better outcome for the placebo group, and values 0.0 indicate a better outcome for the zinc group. If the point estimate and CI fell above 0.0, then the study would
meet the criterion for statistical signicance ( .05). If the CI overlapped 0.0, then the P
value would exceed .05 and the study would not be statistically signicant.

trial25 found no difference at all between treatment

groups. Participants in all 5 trials had been admitted for
dehydration secondary to diarrhea, although the severity of dehydration ranged. Four of the trials17,20,25,30 administered 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 .08). Two trials17,20 originated
from India, 225,30 from Bangladesh, and 119 from Australia. One trial15 in which average duration was significantly lower (1.2 days lower) with zinc use also had a
330

LUKACIK et al

Occurrence of Diarrhea at Day 1

Five acute diarrhea trials16,19,20,27,32 reported the occurrence 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
Six acute diarrhea trials16,19,20,23,27,32 collected data for occurrence of diarrhea at day 3. No statistically significant
differences occurred between treatment groups in occurrence of diarrhea at day 3 (RR: 0.97; 95% CI: 0.911.03;
P .36); however, the occurrence of statistically significant 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); however, the occurrence of statistically significant heterogeneity was found (Q 10.880, dfQ 5, P .05, I2
54.0%).

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

TABLE 6 Acute Diarrhea: Gravity Values for Duration of Diarrhea

Reference
19

Valery et al (2005)
Strand et al32 (2002)
Sazawal et al31 (1995)
Sachdev et al17 (1988)
Roy et al30 (1997)
Polat et al29 (2003)
Patel et al20 (2005)
Hidayat et al28 (1998)
Fischer Walker et al16 (2006)
Faruque et al27 (1999)
Dutta et al26 (2000)
Brooks et al25 (2005)
Bhatnagar et al24 (2004)
Baqui et al15 (2002)
Bahl et al23 (2002)
Al-Sonboli et al22 (2003)

Effect Size

Raw Gravity

Standardized Gravity

Sample Size

0.243
0.243
0.239
0.240
0.240
0.234
0.243
0.252
0.249
0.242
0.233
0.243
0.240
0.187
0.246
0.237

0.00481
0.00481
0.00081
0.00181
0.00181
0.00419
0.00481
0.01381
0.01081
0.00381
0.00519
0.00481
0.00181
0.05119
0.00781
0.00119

0.332
0.332
0.056
0.125
0.125
0.289
0.332
0.953
0.746
0.263
0.358
0.332
0.125
3.531
0.539
0.082

215
894
937
50
74
182
200
1397
1110
681
80
175
287
8070
805
74

FIGURE 2
Standardized gravity results.

Occurrence of Diarrhea at Day 5

Similarly, in the same 6 acute diarrhea trials,16,19,20,23,27,32
no statistically significant differences occurred between

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

0.94; 95% CI: 0.84 1.05; P .26). Similar to day 3
results, the occurrence of statistically significant heteroPEDIATRICS Volume 121, Number 2, February 2008

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

331

TABLE 7 Effects of Zinc Therapy of Acute Diarrhea

Reference

Country

Stool Frequency Reduction

Probability of Diarrhea Continuation

17

India
India
Bangladesh
Bangladesh
Indonesia
India
Nepal
India
Brazil
Turkey
India
Australia
India
Bangladesh
Bangladesh
Pakistan, Ethiopia, India

18% lower frequency

39% lower frequency
28% lower stool output
Not reported
Not reported
38% lower stool output
8% lower frequency
17% lower frequency
59% lower frequency
14% lower frequency
25% lower stool output
Not reported
Not reported
0% lower frequency
Not reported
5% higher frequency

9% shorter duration
19% shorter duration
14% reduction in probability
20% reduction in probability
11% reduction in probability
32% shorter duration
26% reduction in probability
11% reduction in probability
Not reported
20% shorter duration
30% reduction in probability
Not reported
19% reduction in probability, 7% shorter duration
12% reduction in probability, 0% shorter duration
24% shorter duration
9% shorter duration

Sachdev et al (1988)
Sazawal et al31 (1995)
Roy et al30 (1997)
Faruque et al27 (1999)
Hidayat et al28 (1998)
Dutta et al26 (2000)
Strand et al32 (2002)
Bahl et al23 (2002)
Al-Sonboli et al22 (2003)
Polat et al29 (2003)
Bhatnagar et al24 (2004)
Valery et al19 (2005)
Brooks et al25 (2005)
Brooks et al25 (2005)
Baqui et al15 (2002)
Fischer Walker et al16 (2006)

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 dened 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 rst 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 rst 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

Sachdev et al18 (1990)

Roy et al21 (1998)
Penny et al35 (1999)
Bhutta et al33 (1999)
Khatun et al34 (2001)
Fixed combined (5)

20
73
87
43
24
247

20
68
86
44
24
242

0.123
0.201
0.134
0.295
0.167
0.120

1.182
0.466
0.742
0.558
1.010
0.478

0.530
0.133
0.438
0.132
0.422
0.299

0.322
0.169
0.154
0.215
0.292
0.091

.096
.430
.004
.537
.144
.001

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

73.6%).
Vomiting
In 11 acute diarrhea trials16,17,19,2225,2932 (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 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 vomited (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: 1.051.31; P .006).
Shortening of Diarrhea Duration
Eight trials of acute diarrhea1517,20,25,26,29,31 found an average shortening of diarrhea duration of 15.0% for those
who received zinc in comparison with placebo (Table 7).
332

LUKACIK et al

Reduction in Stool Frequency

Seven trials of acute diarrhea17,22,23,25,29,31,32 found an average 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 trials20,2325,27,28,30,32 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 trials18,21,3335 (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,

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

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% reduction when zinc was used over placebo.
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
reect a better outcome for the placebo group, and values 0.0 indicate a better outcome for the zinc group. If the point estimate and CI fell above 0.0, then the study would
meet the criterion for statistical signicance ( .05). If the CI overlapped 0.0, then the P
value would exceed .05 and the study would not be statistically signicant.

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 statistically significant differences occurred between treatment groups in occurrence of diarrhea at day 1 (RR:
1.00; 95% CI: 0.931.08; 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 significantly 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 significantly higher proportion vomited on zinc (41 [2.8%]
of 1482) than with placebo (2 [0.001%] of 1487; RR:
3.64; 95% CI: 1.0213.02; P .047; Q 5.91, P .116).
Vomiting After Zinc Sulfate or 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% reduction in frequency.

DISCUSSION
On the basis of these findings, which now add to the
large body of previously published clinical data and update previous meta-analyses and systematic reviews,8,37
zinc therapy is useful for treating both acute and persistent diarrhea and for their prophylaxis. Still, as extensively 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 differences between zinc and placebo on the average duration
of diarrhea (at least a P .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 .43). Still, the average
stool frequency reductions, shortening of diarrhea durations, and probabilities of a shortening of diarrhea duration 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 difficult because there are many different diarrheal agents,
with such a variety of infectious agents, including bacteria, parasites, and viruses. Identification of specific diarrheal agents is complicated by the lack of access to
laboratory tests in many developing countries. Viral gastroenteritis 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, followed by nonbloody diarrhea. Although not normally
fatal, the diarrhea caused by the virus can be quite
severe, leading to potentially life-threatening dehydration. 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

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

333

TABLE 9 Effects of Zinc Therapy of Persistent Diarrhea

Reference
18

Sachdev et al (1990)
Roy et al21 (1998)
Khatun et al34 (2001)
Bhutta et al33 (1999)
Penny et al35 (1999)
Bhandari et al36 (2002)

Country

Stool Frequency Reduction

Probability of Diarrhea Continuation

India
Bangladesh
Bangladesh
Pakistan
Peru
Nepal

22% lower frequency

Not reported
7% lower frequency
9% lower frequency
Not reported
12% lower frequency

19% shorter duration

7% shorter duration
17% shorter duration
14% reduction in probability
19% shorter duration
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 dened 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 rst 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 rst 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 included an improved absorption of water and electrolytes
by the intestine and quicker regeneration of gut epithelium.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 dehydration and reducing mortality led to treatment modifications 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 absorption 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 secretion, 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 3,5cyclic monophosphate (cAMP)-induced chloride-dependent fluid secretion. Treatment with ORS would have its
greatest effect on reducing fluid loss by increasing small
intestine absorption. Thus, zinc therapy after pretreatment 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 pretreatment with ORS had already maximized the small
intestine absorption rate.
Zinc inhibits cAMP-induced chloride secretion by specifically 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 toxininduced but not Escherichia coli
heat-stable enterotoxin-induced ion secretion in cultured Caco-2 cells. One study42 showed that cAMP acted
as the intracellular effector of heat-labile enterotoxininduced fluid secretion. Guanosine 3,5-cyclic monophosphate mediates heat-stableinduced fluid secretion.
If substantiated, then the effectiveness of zinc would be
334

LUKACIK et al

limited to heat-labileinduced diarrhea or to diarrhea

mediated by cAMP but not either 3,5-cyclic monophosphate or intracellular Ca. It has been reported also43
that a zinc-sensing receptor triggers the release of intracellular Ca2 and regulates ion transport. A micromolar
concentration of extracellular zinc set off a massive release of calcium from intracellular pools in the colonocytic 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 rehydration therapy is more available, there are still significant
setbacks in distributing the therapy. An antisecretory
drug vaccine would be a much more cost-effective solution. An antisecretory drug vaccine could induce immunity without the childrens needing to go through multiple 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 burden 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 motility and regeneration and/or restoration of gut epithelium. 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 systems? 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 transporter for enterocytes? Answers to these and other
questions will hopefully drive the creation of a treatment drug that collectively induces cation absorption;
inhibits anion secretion; reduces stool frequency and
output; reduces diarrhea duration; and is safe, tolerable, and inexpensive.

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

ACKNOWLEDGMENT
We thank William D. Lyman, PhD, for help and suggestions in writing this article.

21.

REFERENCES

22.

1. Black RE, Morris SS, Bryce J. Where and why are 10 million
children dying every year? Lancet. 2003;361(9376):2226 2234
2. Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal
disease, as estimated from studies published between 1992 and
2000. Bull World Health Organ. 2003;81(3):197204
3. Snyder JD, Merson MH. The magnitude of the global problem
of acute diarrhoeal disease: a review of active surveillance data.
Bull World Health Organ. 1982;60(4):605 613
4. Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates
of the causes of death in children. Lancet. 2005;365(9465):
11471152
5. Claeson M, Merson MH. Global progress in the control of
diarrheal diseases. Pediatr Infect Dis J. 1990;9(5):345355
6. Hoque KM, Binder HJ. Zinc in the treatment of acute diarrhea:
current status and assessment. Gastroenterology. 2006;130(7):
22012205
7. Blanchard RK, Cousins RJ. Regulation of intestinal gene expression by dietary zinc: induction of uroguanylin mRNA by
zinc deficiency. J Nutr. 2000;130(5S suppl):1393S1398S
8. Bhutta ZA, Bird SM, Black RE, et al. Therapeutic effects of oral
zinc in acute and persistent diarrhea in children in developing
countries: pooled analysis of randomized controlled trials. Am J
Clin Nutr. 2000;72(6):1516 1522
9. Bhutta ZA, Black RE, Brown KH, et al. Prevention of diarrhea
and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators Collaborative Group. J Pediatr. 1999;
135(6):689 697
10. Comprehensive Meta-Analysis: A Computer Program for Research
Synthesis [computer program]. Englewood, NJ: Biostat Inc;
2003
11. Cohen J. The earth is round (p . 05). Am Psychol. 1994;49(12):
9971003
12. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring
inconsistency in meta-analyses. BMJ. 2003;327(7414):
557560
13. Gee T. Capturing study influence: the concept of gravity in
meta-analysis. Counsel Psychother Health J. 2005;1:5275
14. SPSS 15.0 for Windows [computer program]. Version 15.0. Chicago, IL: SPSS Inc; 2006
15. Baqui AH, Black RE, El Arifeen S, et al. Effect of zinc supplementation started during diarrhoea on morbidity and mortality
in Bangladeshi children: community randomised trial. BMJ.
2002;325(7372):1059
16. Fischer Walker CL, Bhutta ZA, Bhandari N, et al. Zinc supplementation for the treatment of diarrhea in infants in Pakistan,
India and Ethiopia. J Pediatr Gastroenterol Nutr. 2006;43(3):
357363
17. Sachdev HP, Mittal NK, Mittal SK, Yadav HS. A controlled trial
on utility of oral zinc supplementation in acute dehydrating
diarrhea in infants. J Pediatr Gastroenterol Nutr. 1988;7(6):
877 881
18. Sachdev HP, Mittal NK, Yadav HS. Oral zinc supplementation
in persistent diarrhoea in infants. Ann Trop Paediatr. 1990;
10(1):63 69
19. Valery PC, Torzillo PJ, Boyce NC, et al. Zinc and vitamin A
supplementation in Australian Indigenous children with acute
diarrhoea: a randomised controlled trial. Med J Aust. 2005;
182(10):530 535
20. Patel AB, Dhande LA, Rawat MS. Therapeutic evaluation of
zinc and copper supplementation in acute diarrhea in children:

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.
38.

39.

double blind randomized trial. Indian Pediatr. 2005;42(5):

433 442
Roy SK, Tomkins AM, Mahalanabis D, et al. Impact of zinc
supplementation on persistent diarrhoea in malnourished
Bangladeshi children. Acta Paediatr. 1998;87(12):12351239
Al-Sonboli N, Gurgel RQ, Shenkin A, Hart CA, Cuevas LE. Zinc
supplementation in Brazilian children with acute diarrhoea.
Ann Trop Paediatr. 2003;23(1):3 8
Bahl R, Bhandari N, Saksena M, et al. Efficacy of zinc-fortified
oral rehydration solution in 6- to 35-month-old children with
acute diarrhea. J Pediatr. 2002;141(5):677 682
Bhatnagar S, Bahl R, Sharma PK, Kumar GT, Saxena SK, Bhan
MK. Zinc with oral rehydration therapy reduces stool output
and duration of diarrhea in hospitalized children: a randomized
controlled trial. J Pediatr Gastroenterol Nutr. 2004;38(1):34 40
Brooks WA, Santosham M, Roy SK, et al. Efficacy of zinc in
young infants with acute watery diarrhea. Am J Clin Nutr.
2005;82(3):605 610
Dutta P, Mitra U, Datta A, et al. Impact of zinc supplementation
in malnourished children with acute watery diarrhoea. J Trop
Pediatr. 2000;46(5):259 263
Faruque AS, Mahalanabis D, Haque SS, Fuchs GJ, Habte D.
Double-blind, randomized, controlled trial of zinc or vitamin A
supplementation in young children with acute diarrhoea. Acta
Paediatr. 1999;88(2):154 160
Hidayat A, Achadi A, Sunoto, Soedarmo SP. The effect of zinc
supplementation in children under three years of age with acute
diarrhea in Indonesia. Med J Indonesia. 1998;7(4):237241
Polat TB, Uysalol M, Cetinkaya F. Efficacy of zinc supplementation on the severity and duration of diarrhea in malnourished Turkish children. Pediatr Int. 2003;45(5):555559
Roy SK, Tomkins AM, Akramuzzaman SM, et al. Randomised
controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea. Arch Dis Child. 1997;
77(3):196 200
Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S.
Zinc supplementation in young children with acute diarrhea in
India. N Engl J Med. 1995;333(13):839 844
Strand TA, Chandyo RK, Bahl R, et al. Effectiveness and efficacy of zinc for the treatment of acute diarrhea in young
children. Pediatrics. 2002;109(5):898 903
Bhutta ZA, Nizami SQ, Isani Z. Zinc supplementation in malnourished children with persistent diarrhea in Pakistan. Pediatrics. 1999;103(4). Available at: www.pediatrics.org/cgi/
content/full/103/4/e42
Khatun UH, Malek MA, Black RE, et al. A randomized controlled clinical trial of zinc, vitamin A or both in undernourished children with persistent diarrhea in Bangladesh. Acta
Paediatr. 2001;90(4):376 380
Penny ME, Peerson JM, Marin RM, et al. Randomized, community-based trial of the effect of zinc supplementation, with and
without other micronutrients, on the duration of persistent childhood diarrhea in Lima, Peru. J Pediatr. 1999;135(2 Pt 1):208 217
Bhandari N, Bahl R, Taneja S, et al. Substantial reduction in
severe diarrheal morbidity by daily zinc supplementation in
young north Indian children. Pediatrics. 2002;109(6). Available
at: www.pediatrics.org/cgi/content/full/109/6/e86
Black RE. Zinc deficiency, infectious disease and mortality in the
developing world. J Nutr. 2003;133(5 suppl 1):1485S1489S
Bettger WJ, ODell BL. A critical physiological role of zinc in
the structure and function of biomembranes. Life Sci. 1981;
28(13):14251438
Gebhard RL, Karouani R, Prigge WF, McClain CJ. The effect of
severe zinc deficiency on activity of intestinal disaccharidases
and 3-hydroxy-3-methylglutaryl coenzyme A reductase in the
rat. J Nutr. 1983;113(4):855 859

PEDIATRICS Volume 121, Number 2, February 2008

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

335

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

Zinc deprivation and zinc repletion: effect on the response of
rats to infection with Strongyloides ratti. Am J Clin Nutr. 1990;
52(1):173177
41. Hoque KM, Rajendran VM, Binder HJ. Zinc inhibits cAMPstimulated Cl secretion via basolateral K-channel blockade in
rat ileum. Am J Physiol Gastrointest Liver Physiol. 2005;288(5):
G956 G963

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

toxin-induced, but not Escherichia coli heat-stable enterotoxin-induced, ion secretion in human enterocytes. J Infect Dis.
2005;191(7):10721077
43. Hershfinkel M, Moran A, Grossman N, Sekler I. A zincsensing receptor triggers the release of intracellular Ca2
and regulates ion transport. Proc Natl Acad Sci USA. 2001;
98(20):11749 11754

HIGH-STAKES FLIMFLAM
Its time to rein in the test zealots who have gotten such a stranglehold on
the public schools in the US. Politicians and others have promoted highstakes 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 magically swing open the gates to successful learning, it is questionable in many
cases whether the tests themselves are anything more than a shell game.
Daniel Koretz, a professor at Harvards Graduate School of Education, told me
in a recent interview that its important to ask whether you can trust
improvements in test scores when you are holding people accountable for the
tests. The short answer, he said, is no. If teachers, administrators, politicians
and others have a stake in raising the test scores of studentsas opposed to
improving student learning, which is not the same thingthere are all kinds
of incentives to raise those scores by any means necessary. Weve now had
four or five different waves of educational reform, said Dr. Koretz, that were
based on the idea that if we can just get a good test in place and beat people
up to raise scores, kids will learn more. Thats really what No Child Left
Behind is. The problem is that you can raise scores the hard way by teaching
more effectively and getting the students to work harder, or you can take
shortcuts and start figuring out ways, as Dr. Koretz put it, to game the
system. Guess whats been happening? Weve had high-stakes testing, really,
since the 1970s in some states, said Dr. Koretz. Weve had maybe six good
studies that ask: If the scores go up, can we believe them? Or are people
taking shortcuts? And all of those studies found really substantial inflation of
test scores.
Herbert B. New York Times. October 9, 2007
Noted by JFL, MD

336

LUKACIK et al

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010

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
& Services

including high-resolution figures, can be found at:

http://www.pediatrics.org/cgi/content/full/121/2/326

References

This article cites 39 articles, 8 of which you can access for free
at:
http://www.pediatrics.org/cgi/content/full/121/2/326#BIBL

Citations

This article has been cited by 2 HighWire-hosted articles:

http://www.pediatrics.org/cgi/content/full/121/2/326#otherarticle
s

Subspecialty Collections

This article, along with others on similar topics, appears in the

following collection(s):
Infectious Disease & Immunity
http://www.pediatrics.org/cgi/collection/infectious_disease

Permissions & Licensing

Information about reproducing this article in parts (figures,

tables) or in its entirety can be found online at:
http://www.pediatrics.org/misc/Permissions.shtml

Reprints

Information about ordering reprints can be found online:

http://www.pediatrics.org/misc/reprints.shtml

Downloaded from www.pediatrics.org. Provided by Indonesia:AAP Sponsored on January 25, 2010