Articulo publicado en el PEDIATRICS por Marek Lukacik, MDa, Ronald L. Thomas, PhDb, Jacob V. Aranda, MD, PhDb. sobre el uso de zinc en la diarrea aguda y persistente, donde se verifica que acorta la duracion de la enfermedad.

1. 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
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2. 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
ORS— oral rehydration solution
examined acute diarrhea (n 15 231), and 6 examined persistent diarrhea (n
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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3. TABLE 1 Average Duration of Diarrhea (Days) trolled Trials (2006); and abstracts published in Pediatric
Reference Zinc Placebo Research (1991–2006) and the First (Boston, 2000) and
Second (Paris, France, 2004) World Congress of Pediatric
Patel et al20 (2005) 4.34 2.28 4.41 1.98
Gastroenterology, Hepatology and Nutrition. Both pub-
Valery et al19 (2005) 3.26 3.31 3.30 5.21
Fischer Walker et al16 (2006) 4.93 3.90 4.49 3.17 lished and unpublished trials were included in an effort
to control for publication bias. Citations of appropriate
Data are means SD. Data previously obtained during the course of the study.
studies were verified by reviewing the bibliographies and
reference lists of identified trials. Identified titles of ab-
stracts with potential relevance were downloaded, and
as a result of intestinal loss. A comprehensive review on
full manuscripts were then obtained for all abstracts that
this subject was recently published.6 An alternative view
were deemed relevant on the basis of the inclusion
is that zinc may be working as a pharmacologic agent at
criteria. Twenty-two trials met inclusion criteria: 16 pub-
the level of gene expression.7 The efficacy of zinc in the
lished studies relative to the definition of acute diarrhea
treatment of diarrhea is supported by several random-
and 6 relative to persistent diarrhea.
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 Primary and Secondary Outcomes
persistent diarrhea as well as prevention9 of diarrhea Data on 8 clinically relevant outcome measures were
with zinc supplementation have been previously pub- collected. We held average duration of diarrhea and
lished. The published data so far have shown the efficacy presence of diarrhea episodes at days 1, 3, and 5 as our
of zinc in the treatment of acute and chronic diarrhea. primary outcomes. Data on vomiting frequency, vom-
Our meta-analysis was performed to include new studies iting frequency by therapy type, stool frequency re-
published since the last meta-analysis and to examine duction, and probability of diarrhea continuation
the efficacy and safety of zinc therapy during recovery were extracted as secondary outcomes. All 3 authors
from acute or persistent diarrhea. independently extracted data from the same articles us-
ing a data extraction sheet and subsequently compared
results for agreement. The data thus obtained were
METHODS
checked for consistency among authors, integrity of ran-
Inclusion Criteria domization, and concealment of allocation. Questions
Studies that were selected for inclusion tested the same regarding the interpretability of certain data values were
primary hypotheses (average duration of diarrhea and resolved by all 3 authors. The final database entries were
presence of diarrhea at days 1, 3, and 5) using similar verified by the statistician (Dr Thomas). Few studies
patient characteristics (primarily children aged between satisfied criteria for inclusion on every datum variable.
1 and 60 months), with either acute or persistent diar- When necessary, authors of selected studies were con-
rhea, including dysentery. Acute diarrhea was defined as tacted to verify extracted data values derived from
lasting up to 14 days, with persistent diarrhea lasting graphs and/or to provide additional information in a
14 days. Random allocation to treatment groups and scaling form that could be combined with other studies.
concealment of allocation had to be met to satisfy inclu- Where those instances occurred, they are noted in Tables
sion because inadequate allocation concealment, despite 1 and 2.
the use of randomization, allows a risk for selection bias.
Intervention with oral zinc salt supplementation, allow- Definitions
ing for any zinc salt type or formulation (sulfate, glu- Definitions of diarrhea varied somewhat in all included
conate, or acetate) if applied at 5 mg/day for any studies. In acute trials, generally, the definitions stated
length of duration, was examined against a control using for diarrhea were the passage of 3 loose, watery stools
a placebo. All comparisons between treatment groups or 1 loose, watery stool with blood within 24 hours for
had to be free of confounding by additional agents or between 3 and 7 days in duration. In persistent diarrhea
co-interventions. Study groups who, after randomiza- trials, the definitions were similar, with the exception
tion, received zinc supplementation and ORS or zinc that they persisted up to 14 days in duration.
supplemented with vitamin A were excluded. Definitions for duration of diarrhea varied as well but
was defined, generally, from the time of enrollment into
Identification of Trials the study until the first formed stool. Duration was
The search strategy used computerized bibliographic measured in either days or hours. For the purpose of this
searches of Medline (1966 –2006); the Cochrane Central meta-analysis, hours were converted to days. After en-
Register of Controlled Trials (2006); Embase (1974 –2006); rollment/randomization, either the zinc treatment or the
Lilacs (1982–2006); CINAHL (1982–2006); Current Con- 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) 98/107 (91.6%) 100/108 (92.6%) 55/107 (51.4%) 55/108 (50.9%) 22/107 (20.6%) 20/108 (18.5%)
Fischer Walker et al16 (2006) 538/554 (97.1%) 526/556 (94.6%) 391/554 (70.6%) 385/556 (69.2%) 226/554 (40.8%) 204/556 (36.7%)
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4. Statistical Analyses considered substantial heterogeneity, and that percent-
Comprehensive Meta-Analysis,10 a stand-alone program, age cutoff was adopted and examined also in our anal-
was used to synthesize data that were obtained from the yses.
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 Gravity
meta-analysis results. The program is augmented using Another more recent approach13 proposed jackknife re-
accepted computational algorithms. Where appropriate, sampling to measure a concept termed “gravity.” In any
results were reported using a pooled relative risk (RR). meta-analysis, arguments have focused on the inclusion
For continuous outcomes, the weighted mean difference or exclusion of some studies, with debate on which ones
(WMD) was calculated. The 95% confidence intervals should be included or excluded because studies are com-
(CIs) were reported around the weighted effect size. monly weighted according to their sample size and/or
internal variability. Gee13 proposed that jackknife re-
Heterogeneity sampling could be used to examine study influence and
Given that studies that are selected for inclusion in a detect outlier studies. The technique recomputes the
meta-analysis will differ, the types of variability (clinical, meta-analysis once for each of k studies, where each
methodologic, and/or statistical) that may occur among study is individually excluded. K results are then ob-
studies must be investigated. These various types of vari- tained. The difference between the average of these k
ability are termed heterogeneity. Meta-analysis should results and each study’s individual result (when omit-
be considered only when a group of trials is sufficiently ted) is taken as an index of “raw gravity.” This differ-
homogeneous (as indicated in the inclusion criteria) in ence, divided by the SD of the k differences, is taken as
terms of participants, interventions, and outcomes to a z score, or “standardized gravity,” which can be used to
provide a meaningful summary. Strict adherence to the establish which studies might be unusually influential.
inclusion criteria listed, such as blinding and conceal- SPSS 15.014 was used to calculate standardized gravity
ment of allocation, help to control for clinical/method- values.
ologic heterogeneity. Still, statistical heterogeneity can
also occur when variability in the treatment effects being
evaluated in the different trials exists. This results when Fixed- or Random-Effects Model
the observed treatment effects are more different from Choice of whether to interpret a fixed-effects or ran-
each other than would be expected as a result of random dom-effects model was considered thoroughly. Fixed-
error (chance) alone. Following convention, statistical effect meta-analyses ignore heterogeneity. The fixed-
heterogeneity in the results of this meta-analysis are effect estimate and its CI address the question, “What is
referred to simply as heterogeneity. the best estimate of the treatment effect?” The random-
Different approaches for identification and measure- effects estimate and its CI address the question, “What is
ment of heterogeneity were therefore undertaken to the average treatment effect?” The answers to these
examine the extent to which the results of the studies questions are analogous when no heterogeneity is
included were consistent. CIs for the results of individual present or when the distribution of the treatment effects
studies (depicted graphically using horizontal lines) were is roughly symmetrical. If they are not, then the ran-
examined for poor overlap, a general indication of pres- dom-effects estimate may not reflect the actual effect in
ence of statistical heterogeneity. Variability (heterogene- any population being studied. In a fixed-effects meta-
ity) among the obtained effects sizes was formally op- analysis, a pooled-effect estimate is termed, generally, as
erationalized using a 2 test of significance. The formula the best estimate of the treatment effect. It is for these
for heterogeneity assesses the dispersion of individual reasons that we chose a fixed-effects model for our
outcomes, vis-a-vis the combined effect, and denotes
` meta-analysis, along with the various stated approaches
this value using a Q statistic.11 A low P value (or a large to examine heterogeneity if found.
2 statistic relative to its degree of freedom) provides
evidence of heterogeneity of treatment effects (variation
in effect estimates beyond chance). RESULTS
Because some degree of clinical and methodologic The author, year, country, amount of zinc supplemen-
diversity always occurs in a meta-analysis, some statis- tation and type, sample size, and age for each of the 22
tical heterogeneity is inevitable; therefore, the test for studies selected for inclusion in the meta-analysis are
heterogeneity is irrelevant to the choice of analysis: het- listed in Tables 3 and 4. Although all 22 studies were
erogeneity will always exist regardless of whether it can randomly assigned clinical trials, it seemed that 515–19
be detected using a statistical test. Still, methods have were not double-blinded. Sixteen of these published
been developed for quantifying inconsistency across studies met the definition for acute diarrhea and 6 for
studies that move the focus away from testing whether persistent diarrhea.
heterogeneity is present to assessing its impact on the Overall, 56.3% (9 of 16) of acute diarrhea trials were
meta-analysis. A useful statistic for quantifying inconsis- conducted in inpatient hospital settings, and 43.7% (7 of
tency is I2, the percentage of the variability in effect size 16) were conducted in outpatient homes and commu-
estimates that is attributable to heterogeneity rather nities. Of the 6 persistent diarrhea trials, 66.7% (4 of 6)
than sampling error (chance).12 A value 50% may be were inpatient and 33.3% (2 of 6) were outpatient.
328 LUKACIK et al
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5. 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, 24
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 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.
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- ing up to 14 days) and followed by persistent diarrhea
analysis; however, of both acute and persistent trials, (lasting 14 days).
only 315,20,21 reported mortality outcome, making it diffi-
cult to compare across all included trials. Two of these
Results for Acute Diarrhea Trials
were acute diarrhea trials,15,20 and 1 was a persistent
diarrhea trial.21 In the largest acute diarrhea outpatient Duration of Acute Diarrhea
trial15 (n 8070), 33 children (0.008%; 33 of 3974) died In 16 trials that examined the primary measure of aver-
in the zinc-treated group and 37 (0.009%; 37 of 4096) age duration of acute diarrhea15–17,19,20,22–32 (n 15 231),
died in the placebo group. Thirty deaths were attributed those who received zinc experienced a significantly
to drowning, and the remaining were not injury related lower average duration of diarrhea than those who re-
(ie, not attributable to zinc intervention). When re- ceived a placebo (WMD: 0.24; SE: 0.02; 95% CI: 0.21–
stricted to noninjury deaths, there were 13 in the zinc- 0.27; P .001; Table 5, Fig 1) but also with the presence
treated group and 27 in the placebo group. The investi- of statistically significant heterogeneity (Q 95.58, de-
gators attributed the lower noninjury death rate in the grees of freedom [df]Q 15, P .001, I2 84.3%).
intervention group almost entirely to fewer deaths from Figure 1 depicts a Forrest plot for these results, in which
diarrhea and acute lower respiratory infection. Diarrhea every study is displayed as a point estimate with CIs.
and acute lower respiratory infection together accounted Examination of significant heterogeneity in the acute
for 10 deaths in the zinc intervention group and 20 diarrhea trials revealed 5 trials17,19,20,25,30 with insignifi-
deaths in the placebo group. In the other acute diarrhea cant differences between zinc and placebo groups in
trial,20 2 children in the placebo group died of septicemia. average duration of diarrhea. P values ranged from .478
In the persistent diarrhea trial,21 the causes of death were to nonsignificant in sample sizes that ranged from 50 to
septicemia with diarrhea in 3 children, septicemia in 1 215. Although those who received zinc had a shorter
child, bronchopneumonia in 1 child, and continued di- average duration of diarrhea, the difference in 4 tri-
arrhea in 1 child. Because acute and persistent diarrhea als17,19,20,30 was very small, with an average difference of
are, most likely, distinct disease entities, the outcomes 0.18 0.18 days ranging from 0.04 to 0.40 days. One
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6. 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
Five acute diarrhea trials16,19,20,27,32 reported the occur-
rence of diarrhea at day 1 (n 3100). No statistically
FIGURE 1
Mean difference in duration of acute diarrhea. The effect size index in this plot is the
significant difference in the occurrence of acute diarrhea
standard mean difference, so a point estimate of 0.0 indicates no effect. Values 0.0 at day 1 was found (RR: 1.01; 95% CI: 0.99 –1.03; P
reflect a better outcome for the placebo group, and values 0.0 indicate a better out- 0.30). Although the variability in effect sizes ranged
come for the zinc group. If the point estimate and CI fell above 0.0, then the study would from a low of 0.968 to 1.695, significant heterogeneity
meet the criterion for statistical significance ( .05). If the CI overlapped 0.0, then the P did occur (Q 10.60, dfQ 4, P .03, I2 62.3%).
value would exceed .05 and the study would not be statistically significant.
Occurrence of Diarrhea at Day 3
trial25 found no difference at all between treatment Six acute diarrhea trials16,19,20,23,27,32 collected data for oc-
groups. Participants in all 5 trials had been admitted for currence of diarrhea at day 3. No statistically significant
dehydration secondary to diarrhea, although the sever- differences occurred between treatment groups in occur-
ity of dehydration ranged. Four of the trials17,20,25,30 ad- rence of diarrhea at day 3 (RR: 0.97; 95% CI: 0.91–1.03;
ministered an ORS before treatment assignment. Three P .36); however, the occurrence of statistically signif-
trials received zinc sulfate and 2 received acetate. In icant heterogeneity was found (Q 10.880, dfQ 5, P
contrast, all acute diarrhea trials23,31,32 that provided zinc 0.05, I2 54.0%). Only 1 trial30 found a significantly
gluconate and not zinc sulfate had a shorter duration of (P .01) lower occurrence of diarrhea at day 3 with zinc
diarrhea than placebo (P .08). Two trials17,20 originated (27.4%) than placebo (35.4%; effect size: 0.774); how-
from India, 225,30 from Bangladesh, and 119 from Austra- ever, the occurrence of statistically significant heteroge-
lia. One trial15 in which average duration was signifi- neity was found (Q 10.880, dfQ 5, P .05, I2
cantly lower (1.2 days lower) with zinc use also had a 54.0%).
330 LUKACIK et al
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7. 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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8. 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%). 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
Vomiting found a 5.0% higher stool frequency using zinc than
In 11 acute diarrhea trials16,17,19,22–25,29–32 (n 4438), the placebo.
proportion of participants who vomited after the initial
dose was significantly higher with zinc (278 [12.7%] of
Stool Output
2196) use than with placebo (171 [7.6%] of 2242; RR:
Three trials of acute diarrhea24,26,30 found an average
1.55; 95% CI: 1.30 –1.84; P 0.001%; Q 25.54, P
lowering of stool output of 30.3%.
.004).
Probability of Diarrhea Reduction
Vomiting After Administration of Zinc Sulfate or Gluconate Eight acute diarrhea trials20,23–25,27,28,30,32 measured the
In 3 acute diarrhea trials,23,31,32 a significantly higher probability of diarrhea reduction and found a 17.9%
proportion of patients who received zinc gluconate vom- reduction using zinc compared with placebo.
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; Results for Persistent Diarrhea Trials
95% CI: 1.05–1.31; P .006).
Duration of Persistent Diarrhea
In 5 persistent diarrhea trials18,21,33–35 (n 489), those
Shortening of Diarrhea Duration who received zinc also experienced a significantly lower
Eight trials of acute diarrhea15–17,20,25,26,29,31 found an av- average duration of diarrhea than the placebo group
erage shortening of diarrhea duration of 15.0% for those (WMD: 0.30; SE: 0.09; 95% CI: 0.12– 0.48; P .001;
who received zinc in comparison with placebo (Table 7). Table 8) but without significant heterogeneity (Q 3.08,
332 LUKACIK et al
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9. 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.
FIGURE 3
Mean difference in duration of persistent diarrhea. The effect size index in this plot is the DISCUSSION
standard mean difference, so a point estimate of 0.0 indicates no effect. Values 0.0 On the basis of these findings, which now add to the
reflect a better outcome for the placebo group, and values 0.0 indicate a better out- large body of previously published clinical data and up-
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
date previous meta-analyses and systematic reviews,8,37
value would exceed .05 and the study would not be statistically significant. 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
dfQ 4, P .544, I2 29.9%). Figure 3 depicts the
which zinc physiologically exerts its antidiarrheal effect.
Forrest plot for these results.
In this meta-analysis, 5 (31.3%) of 16 acute diarrhea
studies17,19,20,25,30 found no statistically significant differ-
Occurrence of Diarrhea at Day 1 ences between zinc and placebo on the average duration
In 2 trials of persistent diarrhea34,35 (n 221), no statis- of diarrhea (at least a P .48). Similarly, 2 (40.0%) of 5
tically significant differences occurred between treat- persistent diarrhea studies21,33 also found no statistically
ment groups in occurrence of diarrhea at day 1 (RR:
significant differences in average duration of diarrhea
1.00; 95% CI: 0.93–1.08; P .98), and no statistically
between treatments (at least a P .43). Still, the average
significant variability occurred among the effect sizes
stool frequency reductions, shortening of diarrhea dura-
(Q 0.01, dfQ 1, P .93).
tions, and probabilities of a shortening of diarrhea dura-
tion reported were higher in studies with zinc therapy in
Occurrence of Diarrhea at Day 3 comparison with placebo.
In 2 trials of persistent diarrhea34,35 (n 221), a signifi- To the majority of individuals, diarrhea means an
cantly lower occurrence of diarrhea at day 3 occurred in increased frequency or decreased consistency of bowel
those who were treated with zinc in comparison with movements. In many developed countries, the average
placebo (RR: 0.70; 95% CI: 0.51– 0.94; P .02). No number of bowel movements is 3 per day; however,
statistically significant variability occurred among the diarrhea is associated with an increase in stool weight,
effect sizes (Q 0.33, dfQ 1, P .56). mainly as a result of excess water, which normally
makes up a large percentage of fecal matter. Given this,
Occurrence of Diarrhea at Day 5 diarrhea is distinguished from diseases that cause only
This was not examined; fewer than 2 studies reported. an increase in the number of bowel movements or fecal
incontinence.
Vomiting Determining the exact causes of diarrhea can be dif-
In 4 persistent diarrhea trials18,21,35,36 (n 2969), a sig- ficult because there are many different diarrheal agents,
nificantly higher proportion vomited on zinc (41 [2.8%] with such a variety of infectious agents, including bac-
of 1482) than with placebo (2 [0.001%] of 1487; RR: teria, parasites, and viruses. Identification of specific di-
3.64; 95% CI: 1.02–13.02; P .047; Q 5.91, P .116). arrheal agents is complicated by the lack of access to
laboratory tests in many developing countries. Viral gas-
Vomiting After Zinc Sulfate or Gluconate troenteritis caused by rotavirus is the primary cause of
In 4 persistent diarrhea trials,18,21,35,36 those who received diarrhea among infants worldwide. Other causes include
zinc gluconate35,36 vomited more frequently (41 [3%] of bacterial pathogens such as Vibrio cholerae, Shigella, and
1367) than did those who received zinc sulfate/acetate Salmonella. Protozoa such as Cryptosporidium parvum and
(0 [0%] of 115; RR: 1.09; 95% CI: 0.94 –1.09; P .07). Giardia lamblia are 2 of the most common protozoan
diarrheal agents. The primary symptoms of rotavirus
Shortening of Diarrhea Duration infection are fever and vomiting for several days, fol-
In 4 persistent diarrhea trials,18,21,34,35 those who received lowed by nonbloody diarrhea. Although not normally
zinc experienced a 15.5% average shortening of diarrhea fatal, the diarrhea caused by the virus can be quite
duration than those who got a placebo (Table 9). severe, leading to potentially life-threatening dehydra-
tion. Although easily treated with intravenous fluids in
Reduction in Stool Frequency developed nations, these supplies are often unavailable
Four trials of persistent diarrhea found that those who in the developing world, and the dehydration that is
received zinc also experienced an average of 9.8% re- caused by rotavirus is a significant cause of mortality.
duction in frequency. In fact, conclusions from these randomized trials for
PEDIATRICS Volume 121, Number 2, February 2008 333
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10. 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- limited to heat-labile–induced diarrhea or to diarrhea
cluded an improved absorption of water and electrolytes mediated by cAMP but not either 3 ,5 -cyclic mono-
by the intestine and quicker regeneration of gut epithe- phosphate or intracellular Ca. It has been reported also43
lium.38 Increased levels of brush border (apical) enzymes that a zinc-sensing receptor triggers the release of intra-
suggesting a zinc transporter for enterocytes39 and a cellular Ca2 and regulates ion transport. A micromolar
stronger immune response that increased clearance of concentration of extracellular zinc set off a massive re-
pathogens from the intestine40 were also described. lease of calcium from intracellular pools in the colono-
Efficacy of oral rehydration therapy in correcting de- cytic cell line. A sustained increase in intracellular Ca
hydration and reducing mortality led to treatment mod- level may augment K efflux and a hyperpolarization of
ifications of ORS with zinc therapy. Success with zinc cell membrane potential, leading to an advantageous
therapy has generally been attributed to a decrease in electrical gradient for chloride secretion.
the volume of small intestinal fluid and sodium absorp- Although the alternative treatment of oral rehydra-
tion triggered by zinc delivery. Still, the mechanisms by tion therapy is more available, there are still significant
which zinc improves fluid and electrolyte transportation setbacks in distributing the therapy. An antisecretory
have not been elucidated fully. This includes the effect of drug vaccine would be a much more cost-effective solu-
zinc on intestinal ion transport, whether zinc initiates or tion. An antisecretory drug vaccine could induce immu-
increases cation absorption and/or suppresses anion se- nity without the children’s needing to go through mul-
cretion, and whether deficiency enhances the likelihood
tiple infections and the risks associated with infections.
of secretory diarrhea.
By preventing children from acquiring infection, a drug
Most likely, the location of the effect of zinc is in the
vaccine could greatly reduce the number of deaths as a
small intestine, given its inhibition of adenosine 3 ,5 -
result of diarrheal diseases and greatly reduce the bur-
cyclic monophosphate (cAMP)-induced chloride-depen-
den on the health system.
dent fluid secretion. Treatment with ORS would have its
greatest effect on reducing fluid loss by increasing small The model for an antisecretory drug should perform
intestine absorption. Thus, zinc therapy after pretreat- by inhibiting intestinal chloride and HCO3 secretion6 in
ment with ORS may not have shown a beneficial effect contrast to focusing on decreasing gastrointestinal mo-
(reduced average duration of diarrhea) over placebo in 5 tility and regeneration and/or restoration of gut epithe-
trials17,19,20,25,30 of this meta-analysis simply because pre- lium. Accelerated research directed to achieving a
treatment with ORS had already maximized the small clearer understanding of the biology, chemistry, and
intestine absorption rate. pathobiology of zinc in the gastrointestinal system is
Zinc inhibits cAMP-induced chloride secretion by spe- necessary. Does zinc maintain intestinal defense sys-
cifically inhibiting basolateral potassium (K) channels tems? What is the relationship of zinc to intestinal
with no blockage effect on calcium (Ca)-mediated K fluid balance? Definitively what are the linkages of
channels in in vitro studies with the rat ileum.41 Zinc also intestinal zinc transporters to body zinc status? Is
inhibits cholera toxin–induced but not Escherichia coli there a brush border (apical) membrane zinc trans-
heat-stable enterotoxin-induced ion secretion in cul- porter for enterocytes? Answers to these and other
tured Caco-2 cells. One study42 showed that cAMP acted questions will hopefully drive the creation of a treat-
as the intracellular effector of heat-labile enterotoxin- ment drug that collectively induces cation absorption;
induced fluid secretion. Guanosine 3 ,5 -cyclic mono- inhibits anion secretion; reduces stool frequency and
phosphate mediates heat-stable–induced fluid secretion. output; reduces diarrhea duration; and is safe, tolera-
If substantiated, then the effectiveness of zinc would be ble, and inexpensive.
334 LUKACIK et al
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G956 –G963 98(20):11749 –11754
HIGH-STAKES FLIMFLAM
“It’s time to rein in the test zealots who have gotten such a stranglehold on
the public schools in the US. 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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13. 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:
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