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MF1 Anak
Lazzerini M, Ronfani L
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2008, Issue 3
http://www.thecochranelibrary.com
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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Figure 3.
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Figure 4.
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Figure 5.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 6.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 1 Diarrhoea duration (h). . . . . . .
Analysis 1.2. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 2 Diarrhoea on day 3. . . . . . . .
Analysis 1.3. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 3 Diarrhoea on day 5. . . . . . . .
Analysis 1.4. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 4 Diarrhoea on day 7. . . . . . . .
Analysis 1.5. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 5 Stool frequency (stools /day). . . . .
Analysis 1.6. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 6 Adverse events (vomiting). . . . . .
Analysis 2.1. Comparison 2 Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6
months, Outcome 1 Diarrhoea duration (h). . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months,
Outcome 1 Diarrhoea on day 7. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.1. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 1 Diarrhoea duration (h). . . . .
Analysis 4.2. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 2 Diarrhoea on day 3. . . . . . .
Analysis 4.3. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 3 Diarrhoea on day 5. . . . . . .
Analysis 4.4. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 4 Diarrhoea on day 7. . . . . . .
Analysis 4.5. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 5 Stool frequency (stools/day). . . .
Analysis 4.6. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 6 Adverse events (vomiting). . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1
2
2
4
4
6
13
14
14
15
17
18
19
19
19
20
26
46
49
50
51
51
53
54
55
58
61
61
62
62
63
63
64
64
64
64
64
65
[Intervention Review]
Contact address: Marzia Lazzerini, Unit of Research on Health Services and International Health, WHO Collaborating Centre for
Maternal and Child Health, Via dei Burlo 1,34123, Trieste, Italy. lazzerini@burlo.trieste.it.
Editorial group: Cochrane Infectious Diseases Group.
Publication status and date: New, published in Issue 3, 2008.
Review content assessed as up-to-date: 14 January 2008.
Citation: Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database of Systematic Reviews 2008, Issue 3.
Art. No.: CD005436. DOI: 10.1002/14651858.CD005436.pub2.
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Diarrhoea causes around two million child deaths annually. Zinc supplementation could help reduce the duration and severity of
diarrhoea, and is recommended by the World Health Organization and UNICEF.
Objectives
To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea.
Search strategy
In November 2007, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2007,
Issue 4), MEDLINE, EMBASE, LILACS, CINAHL, mRCT, and reference lists. We also contacted researchers.
Selection criteria
Randomized controlled trials comparing oral zinc supplementation ( 5 mg/day for any duration) with placebo in children aged one
month to five years with acute or persistent diarrhoea, including dysentery.
Data collection and analysis
Both authors assessed trial eligibility and methodological quality, extracted and analysed data, and drafted the review. Diarrhoea duration
and severity were the primary outcomes. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using
mean differences (MD) with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses (using the fixedor random-effects model) and assessed heterogeneity.
Main results
Eighteen trials enrolling 6165 participants met our inclusion criteria. In acute diarrhoea, zinc resulted in a shorter diarrhoea duration
(MD -12.27 h, 95% CI -23.02 to -1.52 h; 2741 children, 9 trials), and less diarrhoea at day three (RR 0.69, 95% CI 0.59 to 0.81;
1073 children, 2 trials), day five (RR 0.55, 95% CI 0.32 to 0.95; 346 children, 2 trials), and day seven (RR 0.71, 95% CI 0.52 to 0.98;
4087 children, 7 trials). The four trials (1458 children) that reported on diarrhoea severity used different units and time points, and
the effect of zinc was less clear. Subgroup analyses by age (trials with only children aged less than six months) showed no benefit with
zinc. Subgroup analyses by nutritional status, geographical region, background zinc deficiency, zinc type, and study setting did not
affect the results significance. Zinc also reduced the duration of persistent diarrhoea (MD -15.84 h, 95% CI -25.43 to -6.24 h; 529
Oral zinc for treating diarrhoea in children (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
children, 5 trials). Few trials reported on severity, and results were inconsistent. No trial reported serious adverse events, but vomiting
was more common in zinc-treated children with acute diarrhoea (RR 1.71, 95% 1.27 to 2.30; 4727 children, 8 trials).
Authors conclusions
In areas where diarrhoea is an important cause of child mortality, research evidence shows zinc is clearly of benefit in children aged six
months or more.
BACKGROUND
Problem
Despite improving trends in mortality rates, diarrhoea still causes
18% of all deaths in children under five and accounts for nearly
two million child deaths in developing countries every year (Bryce
2005). It is estimated that on average a child under five years will
have approximately 3.2 episodes of diarrhoea each year (Kosek
2003). Diarrhoea is also an important cause of malnutrition, particularly when it is prolonged (Brown 2003).
Treatment of diarrhoea with oral rehydration solution (ORS) reduces mortality due to dehydration. Zinc supplementation could
help reduce the duration and the severity of diarrhoea, and therefore have an additional benefit over ORS in reducing children
mortality (Jones 2003).
Biological functions
Zinc influences the activity of over 200 enzymes, some of which
are responsible for DNA replication and transcription (Shankar
1998; IZiNCG 2004). Zinc promotes immunity, skin, and mucosal resistance to infection, and the growth and development of
the nervous system (IZiNCG 2004). It is also an important antioxidant and preserves cellular membrane integrity (Bettger 1981;
Bray 1990). Zinc also restores mucosal barrier integrity and enterocyte brush-border enzyme activity (Roy 1992; Shankar 1998),
promotes the production of antibodies against intestinal pathogens
and circulating T lymphocytes, in particular CD4 cells (Sazawal
1997b; Albert 2003; Raqib 2004), and has a direct effect on ion
channels, acting as a K channel blocker of adenosine 3-5-cyclic
monophosphate-mediated chlorine secretion (Hoque 2005).
Zinc dose
There are a number of factors that could influence the size of any
effect when using zinc to treat diarrhoea, and these will be explored
in this review.
Type of diarrhoea
Acute and persistent diarrhoea are very different conditions. Acute
diarrhoea in children in developing countries is usually infective,
while persistent diarrhoea has a number of causes including malnutrition, parasitic infections, tuberculosis, human immunodeficiency virus (HIV), food intolerance, and malabsorption.
Age
Zinc requirement varies with age and is highest in children due to
their rapid rates of growth. Infants, however, have lower requirements (IZiNCG 2004) as healthy normal birthweight infants have
adequate zinc levels at birth from maternal sources even if maternal
stores are suboptimal (Iqbal 2001). Infants may be able to mobilize
hepatic stores accumulated during gestation (Zlotkin 1988) and
are less likely to have had a zinc-depleting illness. Breastfeeding
will provide zinc supplementation and protective immune factors
against infections (Krebs 1999).
Nutritional status
The recommended daily allowance for zinc is markedly higher for
malnourished children (2 to 4 mg/kg/day) than healthy children (3
to 5 mg/day for children under five years) (IZiNCG 2004). This is
because zinc deficiency is considered more severe in malnourished
children and thus the benefit of zinc supplementation may be
greater.
Geographical region
Zinc supplementation may have different effects according to the
level of zinc deficiency in the country. It is important to verify
whether zinc supplementation is effective in countries with high
or even medium or low risk of zinc deficiency (IZiNCG 2004).
have an up-to-date search for trials and will explore more outcome
measures of interest and more possible sources of heterogeneity.
Primary
OBJECTIVES
To evaluate oral zinc supplementation for treating children with
acute or persistent diarrhoea.
METHODS
Types of studies
Randomized controlled trials.
Secondary
Types of participants
Children aged between one month and five years with acute or
persistent diarrhoea, including dysentery.
We excluded trials of infants below one month and studies that exclusively enrolled children with particular conditions such preterm
or low birthweight infants and children with HIV.
Acute diarrhoea is usually defined as three or more loose stools in a
24-hour period. Persistent diarrhoea is defined as diarrhoea lasting
more than 14 days. Dysentery is a diarrhoeal illness in which blood
is observed in the stool. The final day of diarrhoea is usually defined
as the last day meeting the above definition followed by 48 hours
without diarrhoea.
Types of interventions
Intervention
Hospitalization.
Death (from any cause and diarrhoea specific).
Adverse events
Placebo.
Concurrent supplementation of other minerals and vitamins are
eligible only if administered to both intervention and control
group.
ORS plus zinc and food fortification interventions (such as milk
fortification) are excluded as the amount of ORS/food consumed,
and hence the zinc intake, would be less certain.
Search set
CIDG SRa
CENTRAL
MEDLINEb
EMBASEb
LILACSb
CINAHL
CCT
zinc
zinc
zinc
zinc
zinc
zinc
zinc
diarrhea
diarrhea
ZINC
ZINC
diarrhea
diarrhea
diarrhea
vomiting
morbidity
1 or 2
1 or 2
morbidity
morbidity
vomiting
adverse effects
2 or 3
diarrhea
diarrhea
2 or 3
2 or 3
adverse effects
1 and 4
diarrhoea
morbidity
1 and 4
1 and 4
vomiting
morbidity
4 or 5
vomiting
vomiting
adverse effects
MORBIDITY
3 and 6
adverse effects
adverse effects
6 or 7
4 or 5 or 6 or 7 Limit 7 to hu- 6 or 7
man
6 or 7
1 and 2 and 8
3 and 8
1 and 2 and 8
1 and 8
10
11
vomiting
9 or 10
12
adverse effects
3 and 4 and 11 -
13
11 or 12
14
3 and (4 or 5) and 13
vomiting
Reference lists
We checked the reference lists of all studies identified by the above
methods.
Selection of studies
All trials identified by the search strategy were screened by both
authors, and full articles were retrieved for all potentially relevant
trials. Both authors independently applied the inclusion criteria
to the full reports using a pilot-tested form and scrutinized publications to ensure each trial was included once. Trial authors were
Data synthesis
Data were analysed using Review Manager 4.2. All results are
presented with 95% confidence intervals (CI).
For dichotomous data, outcome measures were reported using risk
ratio (RR). Given the high variation in control event rates, we did
not calculate the number needed to treat (NNT). For continuous
data summarized by arithmetic means and standard deviations,
we used the mean difference (MD) to combine the results in a
meta-analysis. Continuous data summarized using other summary
statistics that could not be combined in a meta-analysis were presented in a table. We calculated geometric mean ratios and transformed them in the log scale for analysis, and presented them on
the natural scale.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Eighteen trials enrolling 6165 children met our inclusion criteria
(see Characteristics of included studies). The process of trials
selection is reported in Table 2, and the reasons for excluding 80
studies are given in the Characteristics of excluded studies.
166
61 trials
(Continued)
82
5 trials
a See
Walker 2006 IND, Fischer Walker 2006 PAK, Polat 2003 low Zn,
and Polat 2003 normal Zn. Thus the number of total comparisons
is 22.
Type of diarrhoea
Thirteen trials enrolled children with acute diarrhoea: eight used
this reviews definition for acute diarrhoea (Faruque 1999; Dutta
2000; Strand 2002; Al-Sonboli 2003; Polat 2003; Bhatnagar
2004a; Brooks 2005a; Fischer Walker 2006); one defined diar-
Age
Two trials enrolled only children under six months (Brooks 2005a;
Fischer Walker 2006). Nine trials only enrolled children over
six months (Sachdev 1988; Sachdev 1990; Sazawal 1995; Bhutta
1999b; Faruque 1999; Penny 1999; Khatun 2001; Strand 2002;
Roy 2007a). Seven trials included children of different ages greater
than two months (Roy 1997; Roy 1998; Dutta 2000; Al-Sonboli
2003; Polat 2003; Bhatnagar 2004a; Larson 2005).
Nutritional status
Seven trials enrolled only malnourished children (Roy 1997; Roy
1998; Bhutta 1999b; Dutta 2000; Khatun 2001; Polat 2003; Roy
2007a), and one enrolled children regardless of nutritional status (
Larson 2005). The remaining 10 trials enrolled children who were
well nourished or with moderate malnutrition. No trial included
only well-nourished children or only severe malnourished children. There was some variability between trials in the definitions
of malnutrition (most used weight/age; only some used weight/
height); therefore we were unable to follow the definition of malnutrition proposed in the protocol.
All the trials were held in countries ranked as high risk for zinc deficiency (IZiNCG 2004), except for three trials, which were conducted in countries at medium risk: Nepal (Strand 2002); Turkey
(Polat 2003); and Brazil (Al-Sonboli 2003).
Zinc dose
The zinc dose was 20 mg/day in nine trials. Only two trials administered higher zinc doses: 40 mg/day (Dutta 2000); and 22 or
45 mg/day (Al-Sonboli 2003). Two trials, of which one in children aged less than six months only, gave zinc 10 mg/day (Fischer
Walker 2006; Roy 2007a). One trial used zinc 5 mg and 20 mg,
but only in children aged less than six months (Brooks 2005a).
Three trials used different doses depending on age (zinc < 20 mg
in infants under 12 months and > 20 mg in children greater than
12 months), but they did not report result separately for each
treatment group (Faruque 1999; Strand 2002; Bhatnagar 2004a).
We classified these trials as not assignable and could not include
them in the sensitivity analysis for zinc dose. One trial reported a
per kilo dose (3 mg/kg/day) (Bhutta 1999b); we included this in
the meta-analysis for stool output but were not able to include it
in the subgroup analyses.
Geographical region
Fifteen trials were conducted in Asia, two in South America and
one multicentred trial in Asia and Africa (Fischer Walker 2006).
Thus, participants were from Bangladesh (Roy 1997; Roy 1998;
Faruque 1999; Khatun 2001; Brooks 2005a; Larson 2005; Roy
2007a), India (Sachdev 1988; Sachdev 1990; Sazawal 1995; Dutta
2000; Bhatnagar 2004a; Fischer Walker 2006 IND), Pakistan (
Bhutta 1999b; Fischer Walker 2006 PAK), Nepal (Strand 2002),
Turkey (Polat 2003), Brazil (Al-Sonboli 2003), Peru (Penny 1999),
and Ethiopia (Fischer Walker 2006 ETH).
Study setting
Most trials were conducted in hospitals, with the exception of
three community-based studies (Penny 1999; Strand 2002; Fischer
Walker 2006), and one trial was held both in hospital and community (Larson 2005).
Treatment regimen
Duration of treatment
Formulation
Dose frequency
The zinc dose was administered once a day in half of the trials,
while the other half administered it twice a day (Sachdev 1988;
Sachdev 1990; Khatun 2001; Roy 2007a) or three times a day (
Roy 1997; Roy 1998; Dutta 2000; Polat 2003; Bhatnagar 2004a).
Additional treatments
Ten trials administered zinc alone; seven studies used zinc and
multivitamin, which did not contain iron (Sazawal 1995; Roy
1997; Roy 1998; Bhutta 1999b; Khatun 2001; Bhatnagar 2004a;
Roy 2007a). One trial used zinc and vitamin A (Faruque 1999).
No trial used concomitant copper.
Outcomes
Faruque 1999; Penny 1999; Dutta 2000; Khatun 2001; AlSonboli 2003; Polat 2003; Bhatnagar 2004a; Brooks 2005a;
Fischer Walker 2006). Data were presented as means and standard
deviations or means, and 95% CI. One trial reported data as medians and ranges (Roy 2007a), and we could not compare these
to the data from other trials.
Three trials reported on diarrhoea at day three (Penny 1999; Strand
2002; Polat 2003), three trials on diarrhoea at day five (Penny
1999; Dutta 2000; Bhatnagar 2004a), and nine at day seven (
Sazawal 1995; Faruque 1999; Penny 1999; Khatun 2001; Strand
2002; Polat 2003; Bhatnagar 2004a; Fischer Walker 2006; Roy
2007a)
Stool frequency was reported in five trials (Sachdev 1988; Sachdev
1990; Al-Sonboli 2003; Brooks 2005a; Fischer Walker 2006). Two
trials did not report cumulative data for the whole hospitalization
period (Bhutta 1999b; Polat 2003); instead they reported data on
some given days (respectively, days two and four, and days one,
seven, and 14), and these data could not be compared to the data
from other trials.
Six trials reported data on stool output (Roy 1997; Bhutta 1999b;
Dutta 2000; Khatun 2001; Bhatnagar 2004a; Brooks 2005a). Definitions and measurement units varied consistently between trials
(see Table 3). Stool output was evaluated using pre-weighed disposable diapers with urine collected separately in two trials (Dutta
2000; Bhatnagar 2004a) and using pre-weighed containers with
urine collected separately in one trial (Roy 1997). In one trial,
stool weight was measured by using metabolic beds, and urine
was collected separately using urine bags. The methods were not
clearly stated in two trials (Bhutta 1999b; Khatun 2001).
Outcome
Units
N zinc
Values zinc
N placebo
Values
placebo
Total (mL)
Mean (95% 85
CI)
229 (180 to 45
256)
Brooks
Total (mL)
2005a (20
mg)
Mean (95% 86
CI)
240 (200 to 44
266)
ACUTE
DIARRHOEA
Age <
months
Brooks
2005a
mg)
(5
(Continued)
Total (g/kg)
Geo132
metric mean
(95% CI)
Per
day Geo132
of diarrhoea metric mean
(g/kg/day)
(95% CI)
78 (68 to 91)
Dutta 2000
Total (kg)
1.5 (1.3 to 36
1.7)
Roy 1997
Per
day Median
of diarrhoea (range)
(g/kg/day)
37
238 (35 to 37
2416)
329 (32 to
1464)
Per
Mean (95% 43
day of diar- CI)
rhoea, day 1
(g/kg/day)
116.8 (85.8 44
to 147.8)
Per
Mean (95% 43
day of diar- CI)
rhoea, day 7
(g/kg/day)
66.7 (40.9 to 44
92.4)
Per
day Mean (95% 43
of diarrhoea, CI)
day 14 (g/
kg/day)
24.9 (20.1 to 44
29.7)
CuMean (95% 24
mulative day CI)
1 (mg/kg)
127 (113 to 24
141)
CuMean (95% 24
mulative day CI)
7 (mg/kg)
528 (472 to 24
584)
Mean (95% 44
CI)
P = 0.06
PERSISTENT DIARRHOEA
Age >
months
Bhutta
1999b
Khatun
2001
a Arithmetic
10
b
Geometric mean ratio (95% CI) for geometric means, adjusted for confounders. (Stool output using zinc is 0.69 and 0.76 times that
of participants using placebo, which means a 31% and 24% less stool output under zinc treatment.)
CI: confidence intervals.
Three community trials reported information on hospitalization (Penny 1999; Strand 2002; Fischer Walker 2006). The declared follow-up period for these trials was until recovery from
diarrhoea in two trials (Strand 2002; Fischer Walker 2006), and
15 days in another trial (Penny 1999).
Death was reported in six trials. These trials had as follow-up times
the duration of hospital stay (Roy 1998; Khatun 2001; Brooks
2005a), 15 days (Penny 1999), until the diarrhoea episode was
over (Fischer Walker 2006), and six months (Roy 2007a).
Data on vomiting were available in 12 trials. All these trials reported percentage of children who vomited. Only one trial stated
case definitions with vomiting defined as a forceful emptying of
stomach contents, and regurgitation as the unforced return of any
amount of the swallowed syrup, liquids, or foods (Larson 2005).
Three trials reported on copper plasma levels (Bhutta 1999b;
Strand 2002; Bhatnagar 2004a), but the data were not comparable
because they used different units of measurement
Allocation sequence
Allocation concealment
Blinding
Al-Sonboli 2003
Adequate
Unclear
Bhatnagar 2004a
Adequate
Adequate
Bhutta 1999b
Adequate
Adequate
Brooks 2005a
Adequate
Unclear
Dutta 2000
Adequate
Adequate
Faruque 1999
Adequate
Adequate
11
(Continued)
Adequate
Adequate
Khatun 2001
Unclear
Unclear
Unclear
Larson 2005
Adequate
Adequate
Penny 1999
Adequate
Adequate
Polat 2003
Adequate
Adequate
Roy 1997
Adequate
Adequate
Roy 1998
Adequate
Unclear
Roy 2007a
Adequate
Adequate
Sachdev 1988
Unclear
Unclear
Unclear
Unclear
Sachdev 1990
Unclear
Unclear
Unclear
Unclear
Sazawal 1995
Adequate
Adequate
Strand 2002
Adequate
Adequate
Blinding
Fifteen trials were double blinded. The use of blinding was unclear
in the remaining three (Sachdev 1988; Sachdev 1990; Khatun
2001).
Inclusion of all randomized participants
Allocation concealment
Twelve trials reported methods that assured adequate allocation
concealment. The remaining six were unclear (Sachdev 1988;
Sachdev 1990; Roy 1998; Khatun 2001; Al-Sonboli 2003; Brooks
2005a).
Eleven trials included more than 90% of the randomized participants in the analysis. Three included less than 90%, which we
assessed as inadequate (Roy 1997; Bhutta 1999b; Roy 2007a), and
the number included was unclear in the remaining four trials (
Sachdev 1988; Sachdev 1990; Roy 1998; Dutta 2000).
12
Effects of interventions
Diarrhoea duration was reduced with zinc by -12.27 h (mean difference, 95% CI -23.02 to -1.52 h, Figure 1) in a comparison involving nine trials (13 comparisons) and 2741 children, although
there was significant heterogeneity between trials (P = < 0.00001,
I2 84.3%). When stratified by age, no benefit was evident in children under six months (1334 children, 2 trials), but it was evident
in trials of older children (MD -16.67 h, 95% CI -31.03 to -2.31
h; 731 children, 2 trials); no statistical heterogeneity was detected.
One trial conducted in infants less than six months stratified for
breastfeeding, but it did not detect a difference between exclusively
and not exclusively breastfed infants (Fischer Walker 2006, 1074
children).
Figure 1. Zinc vs placebo for acute diarrhoea: diarrhoea duration (h)
13
Treatment with zinc also resulted in less diarrhoea at day three (RR
0.69, 95% CI 0.59 to 0.81; 1073 children, 2 trials, 3 comparisons,
Figure 2), day five (RR 0.55, 95% CI 0.32 to 0.95; 346 children,
2 trials, Figure 3), and day seven (RR 0.71, 95% CI 0.51 to 0.98,
REM; 4087 children, 7 trials, 10 comparisons, Figure 4). There
was significant heterogeneity between trials (P = 0.0001, I2 73%),
although this was markedly reduced if results were stratified by age:
no benefit of zinc was detected in children under six months (1074
children, 3 comparisons), while zinc had a benefit in children older
than six months (RR 0.70, 95% CI 0.57 to 0.85, REM; 2565
children, 4 trials).
Figure 2. Zinc vs placebo for acute diarrhoea: diarrhoea on day 3
14
One trial reported on children aged less than six months with
no evidence of a difference (Brooks 2005a). Three trials reported
on children aged less than and greater than six months; two trials showed a reduction in stool output with zinc (Dutta 2000;
Bhatnagar 2004a), while one trial showed no evidence of an effect
(Roy 1997).
1.5. Hospitalization
15
1.6. Death
Three trials reported on death: two trials (316 children) did not
observe any deaths (Brooks 2005a; Roy 2007a); and one trial (1034
children) reported one death in each treatment group (Fischer
Walker 2006).
Eight trials reported vomiting, which was significantly more common in the zinc group (RR 1.71, 95% CI 1.27 to 2.30, REM;
4727 children, 8 trials, 10 comparisons, Figure 5), and across all
age groups. There was significant heterogeneity among trials (P =
0.001, I2 69.3%), and differences in control event rates.
Two trials reported on copper levels, with no significant differences
between the zinc and placebo groups. The mean serum copper
after 14 days was 121 mg/L in zinc group versus 127 mg/L in the
control in one trial (Bhatnagar 2004a), while the mean change
in serum copper on the last day of supplementation (seven days
after recovery) was -1.1 5.5 mol/dL in the zinc group versus 1.5 4.2 mol/dL in the placebo group in the second trial (Strand
2002).
16
Reasons for heterogeneity were explored for mean diarrhoea duration and diarrhoea at day seven, after excluding trials only enrolling
children aged under six months (Analysis 2.1 and Analysis 3.1).
Adjusting for nutritional status, geographical region, background
zinc deficiency, zinc type (acetate or sulfate), and study setting did
not alter the significance of the result. A zinc dose of 20 mg/day
did not reduce mean diarrhoea duration, but it significantly reduced diarrhoea at day seven (Analysis 1.1, no higher doses used
for this outcome). It was not possible to draw any conclusions on
the role of gender as separate results for male and female participants were not available. All the subgroups presented significant
heterogeneity, and this indicates that no single feature can explain
heterogeneity alone. We were unable to construct funnel plots to
look for evidence of publication bias as none of the outcomes had
sufficient numbers of trials to do this.
17
There was no evidence of a benefit with zinc in the one trial that
reported on diarrhoea at days three (Analysis 4.2) and five (Analysis
4.3) (Penny 1999), and two trials that reported on diarrhoea at
day seven (Analysis 4.4) (Penny 1999; Khatun 2001).
2.5. Hospitalization
2.6. Death
One trial reported one death in the zinc group compared to five
deaths in the placebo group, out of 95 participants in each group
(Roy 1998). Two trials did not observe deaths in any participants,
irrespective of their allocated group (Penny 1999; Khatun 2001).
18
DISCUSSION
We identified 18 randomized controlled trials that compared zinc
with placebo in young children. Thirteen trials focused on acute
diarrhoea and the other five on persistent diarrhoea. Overall, zinc
was effective for diarrhoea in children aged over six months. Two
large trials were conducted in children aged less than six months
with acute diarrhoea, and they showed no evidence of an effect on
any of the outcomes.
Zinc reduced acute diarrhoea duration. The size of the effect was
clinically important, particularly for diarrhoea at day seven, which
is an indicator for the risk of persistent diarrhoea. This benefit
withstood extensive subgroup analysis for nutritional status, geographic region, background zinc deficiency, zinc type, and study
setting. Evidence on diarrhoea severity was less clear, as fewer trials
reported on this, and different units and time points were used.
Zinc also reduced the duration of persistent diarrhoea, but evidence was inconsistent regarding the severity of persistent diarrhoea.
No conclusions regarding zincs impact on hospitalization or death
can be drawn from this review as trials were not designed to look at
these outcomes, and most were conducted in hospital where death
rates were low. Large community trials would be needed to explore
whether zinc treatment for diarrhoea reduces hospitalization rates.
Treatment with zinc was associated with an increase in vomiting,
although the reduction in diarrhoea seems to outweigh this. This
increase was consistent across trials in all age groups, including
one large trial with adequate allocation concealment that was designed to look at safety. This trial reported that vomiting was limited to one episode in most children and mainly occurred within
10 minutes of administration (Larson 2005). Zinc has a metallic
after-taste, and development of a more palatable formulation may
minimize this. There was no clear evidence of copper deficiency
resulting from zinc supplementation at the regimens used.
In general, the methodological quality of the trials included in this
review was good. Most trials were conducted in countries with
a high risk of zinc deficiency, but the few trials in countries at
medium risk also showed a benefit of zinc. Applicability of these
results to countries is likely to depend on local zinc deficiency
and population characteristics, such as the degree of malnutrition.
Nearly all trials were conducted in hospital where participants were
likely to adhere to the intervention, although one large community
trial also showed a benefit with zinc.
Our results agree with those of an earlier systematic review of zinc
for treating diarrhoea (Bhutta 2000b), except for the new finding
of no effect of zinc in children aged less than six months. The
review adds several new trials, includes a more extensive subgroup
analysis, and reports on diarrhoea at different time points, diarrhoea severity, and adverse events.
The results of this review in children over six months support
the current WHO/UNICEF policy to give zinc to children with
diarrhoea (WHO/UNICEF 2004).
AUTHORS CONCLUSIONS
Implications for practice
In areas where diarrhoea is an important cause of child mortality,
research evidence shows zinc is clearly of benefit in children aged
six months or more with diarrhoeal diseases.
ACKNOWLEDGEMENTS
The editorial base for the Cochrane Infectious Diseases Group
is funded by the UK Department for International Development (DFID) for the benefit of developing countries. We thank
Katharine Jones for her help in reviewing the text.
19
REFERENCES
Khatun UH, Malek MA, Black RE, Sarkar NR, Wahed MA,
Fuchs G, et al.A randomized controlled clinical trial of zinc,
20
21
22
23
24
Additional references
Albert 2003
Albert MJ, Qadri F, Wahed MA, Ahmed T, Rahman AS, Ahmed F,
et al.Supplementation with zinc, but not vitamin A, improves
seroconversion to vibriocidal antibody in children given an oral
cholera vaccine. Journal of Infectious Diseases 2003;187(6):90913.
Beshgetoor 1998
Beshgetoor D, Hambidge M. Clinical conditions altering copper
metabolism in humans. American Journal of Clinical Nutrition
1998;67(5 Suppl):1017S21S.
Bettger 1981
Bettger WJ, ODell BL. A critical physiological role of zinc in the
structure and function of biomembranes. Life Sciences 1981;28
(13):142538.
Bhutta 2000b
Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat
A, et al.Therapeutic effects of oral zinc in acute and persistent
diarrhea in children in developing countries: pooled analysis of
randomized controlled trials. American Journal of Clinical Nutrition
2000;72(6):151622.
Bray 1990
Bray TM, Bettger WJ. The physiological role of zinc as an
antioxidant. Free Radical Biology & Medicine 1990;8(3):28191.
Brown 2003
Brown KH. Diarrhea and malnutrition. Journal of Nutrition 2003;
133 Suppl(1):32832.
Bryce 2005
Bryce J, Boschi-Pinto C, Shibuya K, Black RE, WHO Child
Health Epidemiology Reference Group. WHO estimates of the
causes of death in children. Lancet 2005;365(9465):114752.
Dijkhuizen 2001
Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal.
Effects of iron and zinc supplementation in Indonesian infants on
micronutrient status and growth. Journal of Nutrition 2001;131
(11):28605.
Fischer Walker 2005
Fischer Walker C, Kordas K, Stoltzfus RJ, Black RE. Interactive
effects of iron and zinc on biochemical and functional outcomes in
supplementation trials. American Journal Clinical Nutrition 2005;
82(1):512.
Fontaine 2001
Fontaine O. Effect of zinc supplementation on clinical course of
acute diarrhoea. Journal of Health, Population, and Nutrition 2001;
19(4):33946.
Garenne 2005
Garenne M, Becher H, Ye Y, Kouyate B, Muller O. Sex-specific
responses to zinc supplementation in Nouna, Burkina Faso. Journal
of Pediatric Gastroenterology and Nutrition 2007;44(5):61928.
Gunshin 1997
Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF,
Boron WF, et al.Cloning and characterization of a mammalian
25
WHO/UNICEF 2004
World Health Organization. Dept. of Child and Adolescent
Health and Development/UNICEF. Clinical management of acute
diarrhoea: WHO/UNICEF joint statement [WHO/FCH/CAH/04.7;
UNICEF/PD/Diarrhoea/01]. Geneva: World Health Organization,
2004.
Zlotkin 1988
Zlotkin SH, Cherian MG. Hepatic metallothionein as a source of
zinc and cysteine during the first year of life. Pediatric Research
1988;24(3):3269.
Zlotkin 2003
Zlotkin S, Arthur P, Schauer C, Antwi KY, Yeung G, Piekarz A.
Home-fortification with iron and zinc sprinkles or iron sprinkles
alone successfully treats anemia in infants and young children.
Journal of Nutrition 2003;133(4):107580.
26
CHARACTERISTICS OF STUDIES
RCT
Generation of allocation sequence: random numbers
Allocation concealment: no details
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 91.4% (8.6% lost at follow up)
Participants
Number: 81
Inclusion criteria: age 3 to 60 months; diarrhoea < 7 days or 1 or more loose stool containing blood in
the previous 24 h and at least mild dehydration
Exclusion criteria: suspected or confirmed severe systemic infections; antimicrobial or antidiarrhoeal treatment within 72 h before admission; severe malnutrition (< 60% median for weight for age of the NCHC
standards)
Interventions
Outcomes
Notes
Location: Brazil
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
No details
Bhatnagar 2004a
Methods
RCT
Generation of allocation sequence: table of random numbers
Allocation concealment: central randomization performed at a site remote from trial location (World
Health Organization, Geneva)
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 93% (7% lost at follow up)
Participants
Number: 287
Inclusion criteria: male; 3 to 36 months; acute diarrhoea (< 72 h) with mild dehydration
Exclusion criteria: severe malnutrition (weight/height < 65% of NCHS median); visible blood in stool;
severe systemic illness
27
Bhatnagar 2004a
(Continued)
Interventions
Outcomes
Notes
Location: India
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Bhutta 1999b
Methods
RCT
Generation of allocation sequence: random numbers
Allocation concealment: central randomization by independent pharmacy; table block randomization
maintained in the pharmacy
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 100% (11% lost at follow up)
Participants
Number: 87
Inclusion criteria: 6 to 36 months; persistent diarrhoea (> 4 unformed stools/day for at least 14 days);
malnutrition (weight-for-age z score < -2.0)
Exclusion criteria: kwashiorkor; clinical signs of vitamin A or zinc deficiency; needing intravenous fluids
or unable to tolerate oral feeds after a 24-h period of stabilization
Interventions
Outcomes
Notes
Location: Pakistan
Risk of bias
Oral zinc for treating diarrhoea in children (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
28
Bhutta 1999b
(Continued)
Item
Authors judgement
Description
Allocation concealment?
Yes
Brooks 2005a
Methods
RCT
Generation of allocation sequence: random numbers
Allocation concealment: bottles labelled with randomization numbers; no other details
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 95% (5% lost at follow up)
Participants
Number: 275
Inclusion criteria: male, 1 to 6 months; onset < 72 h; some dehydration or > 100 mL of watery stool
within a 4-observation period
Exclusion criteria: clinical signs of zinc deficiency; kwashiorkor, weight/age < 60% NCHS; grossly bloody
stool comorbidity; cholera
Interventions
1. Zinc acetate: 20 mg
2. Zinc acetate: 5 mg
3. Placebo
Outcomes
1. Death
2. Average duration of diarrhoea
3. Stool output
4. Stool frequency
5. Adverse events (vomiting)
Notes
Location: Bangladesh
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
Participants
Interventions
1. Zinc acetate: 20 mg
2. Placebo
29
(Continued)
Outcomes
Notes
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
Participants
Interventions
1. Zinc acetate: 5 mg
2. Placebo
Outcomes
Notes
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
Dutta 2000
Methods
RCT
Generation of allocation sequence: table of random numbers
Allocation concealment: code numbers kept in a sealed envelope; zinc and placebo bottles identical
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 100%
Participants
Number: 80
Inclusion criteria: male, 3 to 24 months; malnourished (< 80% Harvard Standard weight for age); clinical
signs of dehydration
Exclusion criteria: antibiotics; systemic infections; chronic diseases; need for intensive care; exclusively
breastfed
Interventions
30
Dutta 2000
(Continued)
Outcomes
Notes
Location: India
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Faruque 1999
Methods
RCT
Generation of allocation sequence: random numbers
Allocation concealment: bottles serially numbered according to the randomization schedule to correspond
to the serial number of the participant; supplements prepared by pharmaceutical company and provided
in dark-coloured bottles
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 96% at day 7 (4% lost at follow up)
Participants
Number: 684
Inclusion criteria: children 6 to 24 months with acute diarrhoea, some dehydration and no severe dehydration; underweight or stunted children were not excluded
Exclusion criteria: marasmus; kwashiorkor; systemic illnesses
Interventions
1. Zinc acetate: 14.2 mg (first 417 children) or 40 mg (other 273 children randomized)
2. Placebo
Both groups: vitamin A
Outcomes
Notes
Location: Bangladesh
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Bottles serially numbered according to the randomization schedule to correspond to the serial number
of the participant; supplements prepared by pharmaceutical company and provided in dark-coloured
bottles
31
RCT
Generation of allocation sequence: random numbers
Allocation concealment: randomization scheme assigned in Geneva and kept secure until completion
of data collection and initial analysis; upon enrolment, infants assigned chronological study identifiers
corresponding to a pre-labelled blister pack of either zinc or placebo tablets
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 97% (3% lost at follow up)
Participants
Number: 1110
Inclusion criteria: infants 1 to 5 months of age with acute diarrhoea (< 72 h)
Exclusion criteria: severe malnutrition (< -3 z score weight for age); signs of pneumonia if < 2 months
(cough and difficult or fast breathing with a respiratory rate of > 60 breaths/min); signs severe pneumonia
if 2 to 5 months of age (cough or difficult fast breathing and chest indrawing, nasal flaring, or grunting)
; required hospitalization (overnight stay at a healthcare facility) for any reason; known major congenital
malformation; any other serious pre-existing medical condition; lived out of or planned to move out of
study area within following 3 months; previously enrolled in the study
Interventions
1. Zinc sulfate: 10 mg
2. Placebo
Outcomes
1. Death
2. Average duration of diarrhoea
3. Diarrhoea at day 7
4. Stool frequency
5. Hospitalisation
6. Adverse events (vomiting)
Notes
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Participants
Interventions
Outcomes
32
Notes
(Continued)
Location: Ethiopia
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Participants
Interventions
Outcomes
Notes
Location: India
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Participants
Interventions
Outcomes
Notes
Location: Pakistan
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
33
Khatun 2001
Methods
RCT
Generation of allocation sequence: no details
Allocation concealment: no details
Blinding: unclear
Inclusion of all randomized participants in the analysis: 96% (4% lost at follow up)
Participants
Number: 100
Inclusion criteria: 6 to 36 months; moderately malnourished (61% to 75% of the median NCHS median
weight for age); persistent diarrhoea
Exclusion criteria: systemic infection; clinical signs of vitamin A deficiency; received vitamin A supplementation within 3 months; received prior antibiotics therapy; bloody mucoid diarrhoea; kwashiorkor;
no longer received breast milk
Interventions
1. Zinc acetate: 20 mg
2. Placebo
Both groups: multivitamins
Outcomes
1. Death
2. Average duration of diarrhoea
3. Diarrhoea at day 7
4. Stool output
5. Adverse events (vomiting)
Notes
Location: Bangladesh
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
No details
Larson 2005
Methods
RCT
Generation of allocation sequence: random numbers
Allocation concealment: opaque envelopes numbered in which the assigned zinc tablet, placebo tablet, or
a similar-sized button was placed; randomization schedule kept in a locked cabinet
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 100% (none lost at follow up)
Participants
Number: 1067
Inclusion criteria: child aged 3 to 59 months; acute diarrhoea; having taken oral rehydration solution as
instructed; no vomiting in the past 2 h for the short-stay ward or 30 minutes in the outpatient clinic, and
no longer dehydrated
Exclusion criteria: returning to the hospital with diarrhoea; receiving zinc
Interventions
1. Zinc sulfate: 20 mg
2. Placebo
34
Larson 2005
(Continued)
Outcomes
Notes
Location: Bangladesh
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Penny 1999
Methods
RCT
Generation of allocation sequence: computer-generated random numbers
Allocation concealment: randomization numbers linked to letter codes, each indicating 1 treatment group;
codes kept secret; supplements provided by independent laboratories
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 100% (none lost at follow up)
Participants
Number: 413
Inclusion criteria: 6 to 36 months, persistent diarrhoea
Exclusion criteria: vitamins or minerals within 6 weeks; major congenital malformation affecting growth;
severe dehydration; requiring hospitalization
Interventions
1. Zinc gluconate: 20 mg
2. Placebo
Outcomes
1. Death
2. Hospitalization
3. Diarrhoea at day 3
4. Diarrhoea at day 5
5. Diarrhoea at day 7
6. Adverse events (vomiting)
Notes
Location: Peru
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
35
Polat 2003
Methods
RCT
Generation of allocation sequence: random numbers
Allocation concealment: bottles labelled with randomization numbers, no other details
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 91% (9% lost to follow up)
Participants
Number: 200
Inclusion criteria: 2 to 29 months; malnourished children (weight for age scale, score < 76% according
to NCHS standards); acute non-bacterial diarrhoea
Exclusion criteria: concomitant illness or oedema
Interventions
1. Zinc sulfate: 20 mg
2. Placebo
Outcomes
Notes
Location: Turkey
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Participants
Number: 76
Children with low zinc serum levels
Interventions
Outcomes
Notes
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
36
Participants
Number: 106
Children with normal zinc serum levels
Interventions
Outcomes
Notes
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Roy 1997
Methods
RCT
Generation of allocation sequence: table of random numbers
Allocation concealment: bottles labelled with randomization numbers
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 67.6% (32.4% lost at follow up)
Participants
Number: 111
Inclusion criteria: 2 to 24 months; weight below the 76th centile of weight-for-age according to the NCHS
standard 18 (by Gomez classification, protein energy malnutrition grades II and III included)
Exclusion criteria: systemic infection or oedema
Interventions
1. Zinc acetate: 20 mg
2. Placebo
Both groups: multivitamin
Outcomes
Notes
Location: Bangladesh
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
37
Roy 1998
Methods
RCT
Generation of allocation sequence: random numbers
Allocation concealment: no details
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: unclear if any lost to follow up; 11% discontinued
intervention
Participants
Number: 190
Inclusion criteria: 3 to 24 months; persistent diarrhoea; underweight (low weight-for-age)using a cut-off
of 70% weight/age of the 50th centile of the NCHS standard; wasted (low weight/height) using a cut-off
of 80%; short (low height/age) using a cut-off of less than 95% of the height/age standard
Exclusion criteria: none stated
Interventions
1. Zinc acetate: 20 mg
2. Placebo
Both groups: multivitamin
Outcomes
1. Death
2. Average duration of diarrhoea
3. Adverse events
Notes
Location: Bangladesh
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
No details
Roy 2007a
Methods
RCT
Generation of allocation sequence: table of random numbers
Allocation concealment: bottles identical labelled with sequential numbers that had earlier been allocated
to either intervention or control according to the randomization
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 100% (11% lost at follow up)
Participants
Number: 56
Inclusion criteria: aged 12 to 59 months; moderately malnourished (weight/age 61% to 75% of NCHS
median); history suggestive of dysentery (eg bloody-mucoid diarrhoea or febrile diarrhoea less than 5days duration); with culture-proven shigellosis
Exclusion criteria: severe malnutrition; receiving zinc supplementation; measles in the last 6 months; living
beyond 2 h of travel time; complications such as haemolytic uraemic syndrome or other systemic illness,
including pneumonia, meningitis, and septicaemia
Interventions
1. Zinc acetate: 10 mg
2. Placebo
Both groups: multivitamins
38
Roy 2007a
(Continued)
Outcomes
1. Death
2. Average duration of diarrhoea
3. Diarrhoea at day 7
Notes
Location: Bangladesh
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Sachdev 1988
Methods
RCT
Generation of allocation sequence: no details
Allocation concealment: no details
Blinding: unclear
Inclusion of all randomized participants in the analysis: no details
Participants
Number: 50
Inclusion criteria: children 6 to 18 months; dehydration secondary to acute diarrhoea of < 4 days duration
Exclusion criteria: antibiotics; severe malnutrition (grades III and IV); concomitant features (meningitis,
pneumonia, liver disease, otitis media, fever > 39 C)
Interventions
1. Zinc sulfate: 20 mg
2. Placebo
Outcomes
Notes
Location: India
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
No details
39
Sachdev 1990
Methods
RCT
Generation of allocation sequence: no details
Allocation concealment: no details
Blinding: unclear
Inclusion of all randomized participants in the analysis: no details
Participants
Number: 40
Inclusion criteria: 6 to 18 months; persistent diarrhoea
Exclusion criteria: another diarrhoeal episode 1 month prior; critically ill; obvious parenteral infections;
severe malnutrition (grade III and IV)
Interventions
1. Zinc sulfate: 20 mg
2. Placebo
Outcomes
Notes
Location: India
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
No details
Sazawal 1995
Methods
RCT
Generation of allocation sequence: random numbers
Allocation concealment: children allocated to sequential numbers indicating zinc or placebo; code kept
by World Health Organization, not available for investigators
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 98% (2% lost at follow up)
Participants
Number: 947
Inclusion criteria: 6 to 35 months; diarrhoea for 7 days; permanent resident in study area; stunted defined
(length for age less than -2 standard deviation)
Exclusion criteria: second visit; malnutrition requiring hospitalization; not provide consent
Interventions
1. Zinc gluconate: 20 mg
2. Placebo
Both groups: multivitamin
Outcomes
1. Diarrhoea at day 7
2. Stool frequency
3. Adverse events (vomiting)
40
Sazawal 1995
(Continued)
Notes
Location: India
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Strand 2002
Methods
RCT
Generation of allocation sequence: random numbers
Allocation concealment: packing with serial number; list kept in Copenhagen; capsule identical in appearance; syrup identical in appearance and taste
Blinding: participants and assessors
Inclusion of all randomized participants in the analysis: 99% (1% lost at follow up)
Participants
Number: 899
Inclusion criteria: 6 to 35 months; diarrhoea < 96 h
Exclusion criteria: massive dose of vitamin A; requiring hospitalization; family intended to leave Bhaktapur
within 2 months
Interventions
Outcomes
1. Diarrhoea at day 3
2. Diarrhoea at day 7
3. Adverse events (vomiting)
4. Adverse events (copper levels)
Notes
Location: Nepal
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
Packing with serial number; list kept in Copenhagen; capsule identical in appearance; syrup identical in appearance and taste
41
Interventions (3 types of micronutrients for food fortification)considered in this RCT not relevant
Agustina 2007
Interventions (probiotic, prebiotic, fibre, and micronutrients mixture) considered in this RCT not relevant
Alarcon 2004
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Awasthi 2006
Bahl 2002
Intervention (zinc-fortified oral rehydration solution) considered in this RCT not relevant
Baqui 2002
Baqui 2003
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Baqui 2006
Behrens 1990
Bhandari 2002
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Bhandari 2005
Not a RCT
Bhandari 2007
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Bhatnagar 2004b
Not a RCT
Bhutta 2000a
Black 2001
Not a RCT
Bobat 2005
Borges 2007
Not a RCT
Brooks 2005b
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Brown 2007
Carbajal 2000
Carcamo 2006
Doherty 1998
Not a placebo-controlled RCT, and criteria for inclusion of children was malnutrition, not diarrhoea
42
(Continued)
Ebrahimi 2006
Ellis 2007
Not a RCT
Gardner 2005
Not a RCT
Garenne 2007
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Gregorio 2007
Intervention (zinc-fortified oral rehydration solution) considered in this RCT not relevant
Gupta 2003
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Gupta 2007
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Heinig 2006
Outcomes (growth, morbidity, and motor development)considered in this RCT not relevant
Hidayat 1998
Community RCT, but results could not be compared with other studies because of methodological problems
(enrolling the same children more than once) and types of outcomes (episodes of diarrhoea and not children
with diarrhoea)
Hoque 2006
Review
Jimenez 2000
Kelly 1999
Intervention and the population (micronutrient supplementation in AIDS diarrhoea-wasting syndrome) considered in this RCT not relevant
Lind 2004
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lira 1998
Long 2006
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lopez 2005
Intervention and outcomes (multiple micronutrient supplementation for anaemia, micronutrient status,
growth, and morbidity)considered in this RCT not relevant
Luabeya 2007
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Makonnen 2003a
Makonnen 2003b
Meeks 1998
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Mller 2001
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Nasrin 2005
Not a RCT
43
(Continued)
Osendarp 2002
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Patel 2005
Penny 2004a
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Penny 2004b
Not a RCT
Polat 2006
Rahman 2001
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rahman 2005
Raqib 2004
Richard 2006
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rosado 1997
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rosado 1998
Not a RCT
Roy 1992
Roy 1999
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Roy 2007b
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Roy 2007c
Population (children aged between 3 and 14 years) considered in this RCT not relevant
Ruel 1997
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sabatier 1997
Samuel 1995
Not a RCT
Sazawal 1996
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 1997a
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 2004a
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 2007a
Sazawal 2007b
Sazawal 2007c
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
44
(Continued)
Shamir 2005
Shankar 1998
Sharieff 2006
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sur 2003
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Tielsch 2006
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Tielsch 2007
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Umeta 2000
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Untoro 2005
Intervention and the outcomes (multiple micronutrient supplements for anaemia, micronutrient status,
growth, and morbidity)considered in this RCT not relevant
Valery 2005
Population (all children aged under 11 years) considered in this RCT not relevant
Walden 2004
Not a RCT
Walker 2007
RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Winch 2006
Not a RCT
45
No. of
studies
No. of
participants
13
2741
5
2
1334
731
676
3
1
2
1073
891
182
2
2
346
346
10
3
4
3
4087
1074
2565
448
7
5
1
1
1458
1334
50
74
10
3
3
4
4727
1334
1878
1515
Statistical method
Effect size
46
Comparison 2.
months
Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6
No. of
studies
No. of
participants
8
4
1071
Subtotals only
-17.49 [-29.25, 5.74]
336
[-39.34, -
346
1061
1333
74
1151
256
-26.98
14.62]
-21.22
2.49]
-20.85
8.06]
-19.51
7.59]
-31.20
15.97]
-19.21
6.14]
-24.34
0.80]
306
[-36.86,
154
755
652
-17.69
1.49]
-32.74
26.90]
-20.79
6.68]
-21.07
8.03]
Statistical method
Effect size
[-44.93,
[-33.65, [-31.43, [-46.43, [-32.29, [-47.88, -
Comparison 3. Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months
No. of
studies
7
4
No. of
participants
Statistical method
Effect size
2775
Subtotals only
0.68 [0.55, 0.83]
238
1
6
266
2747
47
1940
1073
3
4
6
1
1628
1385
2122
891
No. of
studies
No. of
participants
529
388
141
1
1
1
1
2
2
1
1
4
3
1
221
221
505
364
141
Statistical method
Effect size
-15.84 [-25.43, 6.24]
-16.01 [-26.16, 5.86]
-14.40 [-43.77,
14.97]
Totals not selected
Not estimable
Totals not selected
Not estimable
0.52 [0.27, 1.02]
0.52 [0.27, 1.02]
Totals not selected
Not estimable
1.97 [0.37, 10.59]
1.97 [0.37, 10.59]
Not estimable
48
Analysis 1.1. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 1 Diarrhoea duration (h).
Review:
Study or subgroup
Zinc
Placebo
Mean Difference
Weight
IV,Random,95% CI
Mean Difference
Mean(SD)
Mean(SD)
IV,Random,95% CI
86
120 (111.9)
44
120 (113.9)
4.1 %
85
120 (111.3)
45
120 (113.9)
4.1 %
80
127 (44.2)
83
133.2 (58.8)
8.4 %
185
133.2 (127.2)
183
110.4 (99.1)
6.9 %
273
105.6 (73.9)
270
97.9 (59.3)
9.3 %
32.8 %
709
625
341
147.6 (122.4)
340
169.5 (122.4)
7.9 %
Sachdev 1988
25
82 (42.9)
25
90.5 (40)
7.0 %
366
365
37
28.8 (19.2)
37
60 (43.2)
8.5 %
Bhatnagar 2004a
132
55.8 (37)
134
64.6 (45.6)
9.5 %
Dutta 2000
44
70.4 (10)
36
103.4 (17.1)
9.9 %
40
105.6 (31.2)
36
146.4 (40.8)
8.3 %
52
122.8 (33.6)
54
124.8 (38.4)
8.8 %
Roy 1997
37
120 (60)
37
139.2 (32.7)
7.2 %
342
334
1417
1324
-50
-25
Favours zinc
25
50
Favours placebo
49
Analysis 1.2. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 2 Diarrhoea on day 3.
Review:
Study or subgroup
Zinc
Placebo
n/N
n/N
Risk Ratio
Weight
118/442
159/449
69.3 %
442
449
69.3 %
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
16/40
29/36
13.4 %
23/52
40/54
17.2 %
92
90
30.7 %
539
100.0 %
534
0.1 0.2
0.5
Favours zinc
10
Favours placebo
50
Analysis 1.3. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 3 Diarrhoea on day 5.
Review:
Study or subgroup
Zinc
Placebo
n/N
n/N
Risk Ratio
Weight
17/132
27/134
84.4 %
0/44
4/36
15.6 %
176
170
100.0 %
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Favours zinc
10 100 1000
Favours placebo
Analysis 1.4. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 4 Diarrhoea on day 7.
Review:
Study or subgroup
Zinc
Placebo
n/N
n/N
Risk Ratio
Weight
22/80
27/83
11.8 %
57/185
43/183
13.6 %
56/273
39/270
13.1 %
538
536
38.4 %
12.7 %
M-H,Random,95% CI
Risk Ratio
M-H,Random,95% CI
34/341
53/340
0.01
0.1
Favours zinc
10
100
Favours placebo
(Continued . . . )
51
(. . .
Study or subgroup
Zinc
Placebo
Risk Ratio
Weight
n/N
n/N
3/28
7/28
4.5 %
Sazawal 1995
70/456
90/481
14.2 %
Strand 2002
33/442
58/449
12.7 %
1267
1298
44.1 %
Roy 2007a
M-H,Random,95% CI
Continued)
Risk Ratio
M-H,Random,95% CI
1/132
9/134
2.0 %
5/40
16/36
6.9 %
8/52
20/54
8.6 %
224
224
17.5 %
100.0 %
2029
2058
0.01
0.1
Favours zinc
10
100
Favours placebo
52
Analysis 1.5. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 5 Stool frequency (stools /day).
Review:
Study or subgroup
Zinc
Placebo
Mean Difference
Weight
IV,Fixed,95% CI
Mean Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
86
5 (4.66)
44
5 (4.7)
1.0 %
85
5 (4.63)
45
5 (4.7)
1.0 %
80
4 (0.8)
83
4 (0.6)
59.9 %
185
5.6 (3.1)
183
5.6 (3.4)
6.4 %
273
4.9 (1.8)
270
4.9 (1.8)
31.0 %
99.2 %
0.5 %
0.5 %
0.2 %
37
0.2 %
687
100.0 %
709
625
25
7.6 (4)
25
25
9.3 (4.3)
25
37
4.1 (4.1)
37
37
10 (10.2)
771
-10
-5
Favours zinc
10
Favours placebo
53
Analysis 1.6. Comparison 1 Zinc vs placebo for acute diarrhoea, Outcome 6 Adverse events (vomiting).
Review:
Study or subgroup
Zinc
Placebo
n/N
n/N
Risk Ratio
12/86
3/44
15/85
4/45
47/538
33/536
709
625
M-H,Random,95% CI
Risk Ratio
M-H,Random,95% CI
0/25
0/25
Sazawal 1995
2/456
2/481
145/442
85/449
923
955
86/132
79/134
139/534
64/533
8/40
2/36
12/52
3/54
758
757
Strand 2002
2390
2337
10 100 1000
Favours placebo
54
Analysis 2.1. Comparison 2 Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding
children < 6 months, Outcome 1 Diarrhoea duration (h).
Review:
Comparison: 2 Zinc vs placebo for mean acute diarrhoea duration: subgroup analysis excluding children < 6 months
Outcome: 1 Diarrhoea duration (h)
Study or subgroup
Zinc
N
Placebo
Mean(SD)
Mean Difference
Mean(SD)
Weight
IV,Random,95% CI
Mean Difference
IV,Random,95% CI
37
28.8 (19.2)
37
60 (43.2)
26.3 %
Bhatnagar 2004a
132
55.8 (37)
134
64.6 (45.6)
32.6 %
Faruque 1999
341
147.6 (122.4)
340
169.5 (122.4)
22.8 %
Sachdev 1988
25
82 (42.9)
25
90.5 (40)
18.4 %
100.0 %
535
536
44
70.4 (10)
36
103.4 (17.1)
33.6 %
40
105.6 (31.2)
36
146.4 (40.8)
22.9 %
52
112.8 (33.6)
54
124.8 (38.4)
25.8 %
Roy 1997
37
120 (60)
37
139.2 (32.7)
17.7 %
100.0 %
173
163
132
55.8 (37)
134
64.6 (45.6)
47.2 %
44
70.4 (10)
36
103.4 (17.1)
52.8 %
100.0 %
176
170
37
28.8 (19.2)
37
60 (43.2)
18.8 %
341
147.6 (122.4)
340
169.5 (122.4)
16.3 %
40
105.6 (31.2)
36
146.4 (40.8)
17.8 %
52
122.8 (33.6)
54
124.8 (38.4)
20.1 %
Roy 1997
37
120 (60)
37
139.2 (32.7)
13.8 %
Sachdev 1988
25
82 (42.9)
25
90.5 (40)
13.2 %
Faruque 1999
-100
-50
Favours zinc
50
100
Favours placebo
(Continued . . . )
55
Study or subgroup
Zinc
532
Placebo
Mean(SD)
Mean Difference
Mean(SD)
Weight
IV,Random,95% CI
(. . . Continued)
Mean Difference
IV,Random,95% CI
529
100.0 %
132
55.8 (37)
134
64.6 (45.6)
17.9 %
44
70.4 (10)
36
103.4 (17.1)
20.0 %
341
147.6 (122.4)
340
169.5 (122.4)
12.5 %
40
105.6 (31.2)
36
146.4 (40.8)
13.6 %
52
122.8 (33.6)
54
124.8 (38.4)
15.4 %
Roy 1997
37
120 (60)
37
139.2 (32.7)
10.5 %
Sachdev 1988
25
82 (42.9)
25
90.5 (40)
10.1 %
100.0 %
100.0 %
100.0 %
Dutta 2000
Faruque 1999
671
662
37
28.8 (19.2)
37
37
60 (43.2)
37
55.8 (37)
134
64.6 (45.6)
25.2 %
44
70.4 (10)
36
103.4 (17.1)
28.2 %
341
147.6 (122.4)
340
169.5 (122.4)
17.6 %
Roy 1997
37
120 (60)
37
139.2 (32.7)
14.9 %
Sachdev 1988
25
82 (42.9)
25
90.5 (40)
14.2 %
100.0 %
Bhatnagar 2004a
Dutta 2000
Faruque 1999
579
572
37
28.8 (19.2)
37
60 (43.2)
33.2 %
40
105.6 (31.2)
36
146.4 (40.8)
31.4 %
52
122.8 (33.6)
54
124.8 (38.4)
35.4 %
129
100.0 %
27.5 %
127
40
105.6 (31.2)
36
146.4 (40.8)
-100
-50
Favours zinc
50
100
Favours placebo
(Continued . . . )
56
Study or subgroup
Zinc
Placebo
Mean Difference
Weight
Mean(SD)
Mean(SD)
52
122.8 (33.6)
54
124.8 (38.4)
31.0 %
Roy 1997
37
120 (60)
37
139.2 (32.7)
21.2 %
Sachdev 1988
25
82 (42.9)
25
90.5 (40)
20.3 %
100.0 %
154
IV,Random,95% CI
(. . . Continued)
Mean Difference
IV,Random,95% CI
152
37
28.8 (19.2)
37
60 (43.2)
41.9 %
Dutta 2000
44
70.4 (10)
36
103.4 (17.1)
58.1 %
100.0 %
81
73
341
147.6 (122.4)
340
169.5 (122.4)
54.2 %
37
120 (60)
37
139.2 (32.7)
45.8 %
100.0 %
378
377
37
28.8 (19.2)
37
60 (43.2)
15.8 %
Bhatnagar 2004a
132
55.8 (37)
134
64.6 (45.6)
19.5 %
Dutta 2000
44
70.4 (10)
36
103.4 (17.1)
21.9 %
40
105.6 (31.2)
36
146.4 (40.8)
14.9 %
52
122.8 (33.6)
54
124.8 (38.4)
16.8 %
Sachdev 1988
25
82 (42.9)
25
90.5 (40)
11.0 %
100.0 %
330
322
-100
-50
Favours zinc
50
100
Favours placebo
57
Analysis 3.1. Comparison 3 Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding
children < 6 months, Outcome 1 Diarrhoea on day 7.
Review:
Comparison: 3 Zinc vs placebo for acute diarrhoea on day 7: subgroup analysis excluding children < 6 months
Outcome: 1 Diarrhoea on day 7
Study or subgroup
Zinc
Placebo
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1/132
9/134
4.3 %
Faruque 1999
34/341
53/340
25.6 %
Sazawal 1995
70/456
90/481
42.3 %
Strand 2002
33/442
58/449
27.8 %
1371
1404
100.0 %
5/40
16/36
38.7 %
8/52
20/54
45.1 %
Roy 2007a
3/28
7/28
16.1 %
120
118
100.0 %
1/132
9/134
100.0 %
132
134
100.0 %
34/341
53/340
22.0 %
5/40
16/36
7.0 %
8/52
20/54
8.1 %
Roy 2007a
3/28
7/28
2.9 %
Sazawal 1995
70/456
90/481
36.2 %
Strand 2002
33/442
58/449
23.8 %
0.01
0.1
Favours zinc
10
100
Favours placebo
(Continued . . . )
58
(. . .
Study or subgroup
Zinc
Placebo
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
n/N
n/N
1359
1388
100.0 %
M-H,Fixed,95% CI
1/132
9/134
5.7 %
34/341
53/340
33.9 %
3/28
7/28
4.5 %
70/456
90/481
55.9 %
957
983
100.0 %
5/40
16/36
17.9 %
8/52
20/54
20.9 %
33/442
58/449
61.2 %
534
539
100.0 %
34/341
53/340
45.1 %
3/28
7/28
6.0 %
33/442
58/449
48.9 %
811
817
100.0 %
1/132
9/134
6.7 %
5/40
16/36
12.7 %
8/52
20/54
14.8 %
70/456
90/481
65.9 %
680
705
100.0 %
Strand 2002
Sazawal 1995
0.01
0.1
Favours zinc
10
100
Favours placebo
(Continued . . . )
Oral zinc for treating diarrhoea in children (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
59
(. . .
Study or subgroup
Zinc
Placebo
Risk Ratio
Weight
n/N
n/N
1/132
9/134
4.6 %
34/341
53/340
27.5 %
5/40
16/36
8.7 %
8/52
20/54
10.2 %
Roy 2007a
3/28
7/28
3.6 %
70/456
90/481
45.4 %
1049
1073
100.0 %
33/442
58/449
100.0 %
442
449
100.0 %
Bhatnagar 2004a
Faruque 1999
Sazawal 1995
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI
0.01
0.1
Favours zinc
10
100
Favours placebo
60
Analysis 4.1. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 1 Diarrhoea duration (h).
Review:
Study or subgroup
Zinc
Placebo
Mean Difference
Weight
IV,Fixed,95% CI
Mean Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
Bhutta 1999b
43
122.4 (79.2)
44
132 (64.8)
9.9 %
Khatun 2001
44
69.6 (33.6)
44
84 (33.6)
46.7 %
Penny 1999
87
69.4 (67.4)
86
89.5 (92.2)
15.9 %
Sachdev 1990
20
88.2 (27.4)
20
108.6 (45.8)
16.8 %
89.3 %
10.7 %
68
10.7 %
262
100.0 %
194
194
73
153.6 (86.4)
73
68
168 (91.2)
267
-100
-50
Favours zinc
50
100
Favours placebo
Analysis 4.2. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 2 Diarrhoea on day 3.
Review:
Study or subgroup
Zinc
Placebo
n/N
n/N
23/87
32/86
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
0.1 0.2
0.5
Favours zinc
10
Favours placebo
61
Analysis 4.3. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 3 Diarrhoea on day 5.
Review:
Study or subgroup
Zinc
Placebo
n/N
n/N
23/87
32/86
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
0.1 0.2
0.5
Favours zinc
10
Favours placebo
Analysis 4.4. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 4 Diarrhoea on day 7.
Review:
Study or subgroup
Zinc
Placebo
n/N
n/N
Risk Ratio
Weight
Khatun 2001
3/24
13/24
61.8 %
Penny 1999
8/87
8/86
38.2 %
111
110
100.0 %
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
10 100 1000
Favours placebo
62
Analysis 4.5. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 5 Stool frequency
(stools/day).
Review:
Study or subgroup
Zinc
Placebo
Mean Difference
Mean(SD)
Mean(SD)
20
8.8 (4)
20
11.2 (4.3)
Mean Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
-10
-5
Favours zinc
10
Favours placebo
Analysis 4.6. Comparison 4 Zinc vs placebo for persistent diarrhoea, Outcome 6 Adverse events (vomiting).
Review:
Study or subgroup
Zin
Placebo
n/N
n/N
Risk Ratio
Khatun 2001
0/24
0/24
Penny 1999
4/139
2/137
0/20
0/20
183
181
0/73
0/68
73
68
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Sachdev 1990
10 100 1000
Favours placebo
(Continued . . . )
63
(. . .
Study or subgroup
Zin
Placebo
n/N
n/N
256
249
Risk Ratio
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI
10 100 1000
Favours placebo
HISTORY
Protocol first published: Issue 3, 2005
Review first published: Issue 3, 2008
CONTRIBUTIONS OF AUTHORS
Both authors contributed equally to the preparation of the review.
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
No sources of support supplied
External sources
Department for International Development (DFID), UK.
64
2005, Issue 3
Protocol published (Lazzerini 2005).
INDEX TERMS
Medical Subject Headings (MeSH)
Diarrhea [ drug therapy; mortality]; Randomized Controlled Trials as Topic; Time Factors; Zinc [deficiency; therapeutic use]
65