Oral Zinc for the Treatment of Acute Gastroenteritis in Polish Children:
A Randomized, Double-Blind, Placebo-Controlled Trial
Bernadeta Patro, MD, Henryk Szymański, MD, and Hania Szajewska, MD
Objective To evaluate the efficacy and safety of zinc in the treatment of acute gastroenteritis (AGE) in children in
Poland.
Study design Children aged 3 to 48 months with AGE were enrolled in a randomized, double-blind, placebo-controlled trial in which they received zinc sulfate (10 or 20 mg/day depending on age) or placebo for 10 days. A total of
141 of 160 children recruited were available for intention-to-treat analysis. The primary outcome was the duration of
diarrhea.
Results In the experimental group (n = 69) compared with the control group (n = 72), there was no significant difference in the duration of diarrhea (P > .05). Similarly, there was no significant difference in the groups in secondary
outcome measures such as stool frequency on days 1, 2, and 3, vomiting frequency, intravenous fluid intake, and
the number of children with diarrhea lasting >7 days.
Conclusion Children living in a country where zinc deficiency is rare do not appear to benefit from the use of zinc
in the treatment of AGE. (J Pediatr 2010;157:984-8).
T
he morbidity and mortality rates from acute diarrhea remain significant in children <5 years of age, especially those in
developing countries.1 In the developed world, although the mortality rate is low, gastroenteritis leads to a high number
of physician visits, hospital admissions, and consequently, a significant economic burden. It is estimated that the incidence of diarrhea in European children up to 3 years of age ranges from 0.5 to 1.9 episodes per child per year.2 Most cases of
acute gastroenteritis (AGE) are usually mild and self-limited. Oral or intravenous re-hydration is used as the first-line therapy.
Although this elementary approach is effective in substantially reducing morbidity and mortality rates, new treatment options
are required to address the severity and duration of the symptoms. The administration of zinc appears to be such an option. The
mechanisms underlying the beneficial anti-diarrheal effect of zinc are unclear. In brief, plausible mechanisms include improved
absorption of water and electrolytes by the intestine, faster regeneration of gut epithelium, increased levels of enterocyte brushborder enzymes, and an enhanced immune response.3 However, it is questionable whether administered zinc can exert its actions independent of zinc deficiency in the host.
A number of randomized controlled trials performed in developing countries have shown that zinc supplementation is effective in reducing the duration and severity of diarrhea. On the basis of these findings, the United Nations Children’s Fund
(UNICEF) and the World Health Organization (WHO) currently recommend zinc supplementation as a universal treatment
for all children with AGE.4 However, according to the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases (ESPGHAN/ESPID) recommendations, there is not enough evidence to support its routine use in children with AGE living in Europe, where zinc deficiency is rare.2 Therefore, the aim of
this study was to evaluate the efficacy and safety of zinc supplementation in the treatment of AGE in a different clinical population and setting (ie, in well-nourished, otherwise healthy children living in Poland).
Methods
This was a randomized, double-blind, placebo-controlled trial conducted at 2 pediatric hospitals in Poland. Candidates for inclusion in the study were children 3 to 48 months of age who were diagnosed with AGE lasting less than 5 days but with at least
some degree of dehydration; they had either been admitted to the hospital or visited the hospital emergency ward as an outpatient. Children were excluded from the study when any of these criteria were present: diarrhea lasting <1 day or >5 days,
recent history of diarrhea (last 2 weeks before enrollment day), chronic gastrointestinal disease with diarrheal manifestation
AGE
ESPGHAN/ESPID
HDI
RCT
UNICEF
WHO
Acute gastroenteritis
European Society for Paediatric Gastroenterology, Hepatology, and
Nutrition/European Society for Paediatric Infectious Diseases
Human Development Index
Randomized controlled trial
United Nations Children’s Fund
World Health Organization
From the Department of Paediatrics, The Medical
University of Warsaw, Warsaw, Poland (B.P.,
H. Szajewska); and Department of Paediatrics, St Hedwig
of Silesia Hospital, Trzebnica, Poland (H. Szymański)
Supported in part by the Nutricia Research Foundation.
The authors declare no conflicts of interest.
0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2010.05.049
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Vol. 157, No. 6 December 2010
(eg, food allergy, celiac disease), weight-to-height ratio <5th
percentile, severe dehydration, coexistence of serious systemic disease(s), administration of antibiotics (during current infection), exclusive or >50% breastfeeding, history of
immunodeficiency, and administration of immunosuppressive therapy.
Parents provided informed consent for all study participants. The Ethical Committee at the Medical University
of Warsaw approved the study. All children eligible for
recruitment were assessed for the inclusion and exclusion
criteria. The physician examined each child, and the hydration status was evaluated (as defined by the method
of WHO).5 Nude body weight and height were recorded,
and the nutritional status was assessed with weight-forage, height-for-age, and weight-height ratio percentiles.
Stool samples were collected to investigate the etiology
of the diarrhea. Tests performed included bacteriological
culture to detect bacterial pathogens (Salmonella spp, Shigella spp, Escherichia coli) and chromatographic immunoassay (VIKIA Rota-Adeno; BioMerieux, Lyon, France) to
detect rotaviruses and adenoviruses.
Dehydration was managed according to ESPGHAN/ESPID2 and WHO guidelines.5 After re-hydration, early refeeding with the patient’s usual diet was practiced. Patients
were assigned randomly to receive either placebo or zinc sulfate at a dose of 10 mg (for patients <6 months of age) or 20
mg (for children >6 months) daily, in 2 doses, for 10 days.
Zinc was supplied as a syrup containing 2 mg of zinc in 1
mL of sirupus simplex; sirupus simplex is a solution of 64
parts of saccharose in 36 parts of purified water. The placebo
was identically supplied and formulated. There was no difference between zinc and the placebo in appearance; a minor
metallic aftertaste of zinc was hardly detectable. The study
products were provided by the pharmacy department in
the hospital in Warsaw for both centers. The syrup was offered between meals to prevent the negative influence of
some dietary factors on absorption.6 Each parent of an included child received a diary to record the number and consistency of stools and to specify the time of the day (1-hour
period) when the stool was passed. They were also asked to
record any vomiting episodes and any other symptoms that
they considered to be important or to represent an adverse
event. Children were examined by the physician every day
until they were discharged from the hospital. Discharged
children and outpatients were followed up with hospital visits
or with daily telephone calls, depending on the patient’s condition and the parents’ decision. Treatment compliance was
assessed with direct interview of the parents and review of the
diary cards.
Randomization
Two different randomization lists for each center were
computer-generated by an investigator at the Medical University of Warsaw. Block randomization of block size 6 was
done. The glass bottles containing the products were labeled
with the patient’s number corresponding to the randomization list by an independent individual who was not involved
in patient enrollment. Randomization codes were secured
until the completion of data collection and initial analysis.
All investigators, participants, outcome assessors, and data
analysts were blinded to the assigned treatment for the duration of the study.
Primary and Secondary Outcome Measures
The primary outcome measure was the duration of diarrhea.
Diarrhea was defined as the passage of $3 loose stools in
a 24-hour period. The duration of diarrhea was defined as
the time from administration of zinc/placebo to the cessation
of diarrhea (the passage of 2 formed stools or no stool for 12
hours on the last day meeting the criteria for diarrhea). Secondary outcome measures were stool frequency on days 1, 2,
and 3, vomiting frequency on days 1, 2, and 3, total intravenous fluid intake, the number of children with diarrhea lasting >7 days, and adverse events.
Sample Size
The sample size was calculated on the basis of the assumption
that a 1-day reduction in the primary outcome measure (diarrhea duration) would be a clinically important difference in
the study groups. We estimated that with a power of 80%, an
a level of 0.05, and a 20% dropout rate, 160 children would
be required.
Statistical Methods
The statistical analyses were conducted with StatsDirect software version 2.7.7 (StatsDirect Ltd., Altrincham, United Kingdom). The Mann-Whitney U test was used to compare the
means of continuous variables because of their non-normal
distribution. The Shapiro-Wilk W test was used to investigate
a sample for evidence of ‘‘non-normality.’’ Proportions were
compared with the Fisher exact test. The difference in study
groups was considered significant when the P value was
<.05. All statistical tests were 2-tailed and performed at the
5% level of significance. We analyzed the results of this study
on the basis of intention to treat.
Results
We enrolled 160 children from a group of 249 eligible patients
between February 2008 and December 2009. The main reason
for exclusion at this stage of the study was lack of parental consent. The Figure (available at www.jpeds.com) shows the flow
of participants through each stage of the study. Eighty-one
children were assigned to the zinc group, and 79 children
were assigned to the placebo group. Four patients in the
experimental group and 3 patients in the control group did
not receive the allocated intervention because of their
parents’ decision and refusal to drink, respectively. Nine
patients in the zinc group and 8 patients in the placebo
group discontinued the intervention because of refusal to
drink and parents’ decision. Most of these parents decided
not to continue administration of the syrup because the
symptoms of diarrhea had ceased. Nineteen patients
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(11.8%) were lost to follow-up (12 in the zinc group and 7 in
the placebo group), thus data from 141 patients were available
for the intention-to-treat analysis.
The baseline characteristics of the enrolled children are detailed in Table I. In approximately half the cases (47%), a viral
etiology of AGE was confirmed. Rotavirus was the leading
pathogen responsible for 43% of the cases of diarrhea. A
bacterial etiology was confirmed in 10.6% of the patients.
Only 12.5% of all participants were outpatients seeking help
at the hospital emergency ward; most participants (87.5%)
were inpatients.
The outcome measures are summarized in Table II. The
median duration of diarrhea was 58 hours in the zinc
group, compared with 39 hours in the placebo group. No
significant difference was observed in the groups (P > .05).
The proportion of children with diarrhea lasting >7 days
was slightly higher in the control group (4.2% versus
1.4%), but the difference in groups was not statistically
significant. Zinc administration did not influence the
severity of the diarrhea measured as stool frequency. There
were no differences in the groups in the number of bowel
movements on days 1, 2, and 3. Similarly, there was no
significant difference in vomiting frequency or total
intravenous fluid intake in the groups.
Adverse Events
The proportions of patients who experienced any adverse
event were similar in the zinc and placebo groups: 5 (6.1%)
of 81 patients and 6 (7.5%) of 79 patients, respectively. Abdominal pain, cough, rash, and vomiting after administration of the syrup were reported in both groups at similar
frequencies. Only 1 patient in the zinc group reported an ab-
Table I. Baseline characteristics of the study children
Mean (SD) age, months
Sex (female/male)
Body weight (SD), kg
Breastfed (%)
Dehydration
Mild (%)
Moderate (%)
Need for intravenous fluids at
enrollment (%)
Fever >38.0 Co (%)
Vomiting (%)
Diarrhea before enrollment (SD), days
Number of stools 24 hours
before enrollment (SD)
Blood in stool (%)
Etiology
Rotavirus (%)
Adenovirus (%)
Salmonella (%)
E coli (%)
Shigella (%)
Setting
Hospital (%)
Outpatient (%)
986
Placebo
n = 79
Zinc
n = 81
20.8 (11.4)
1.4
11.3 (2.9)
12 (15.2)
22.3 (12.6)
1.0
11.4 (2.8)
13 (16.0)
63 (80)
16 (20)
67 (85)
59 (73)
22 (27)
60 (74)
46 (58.2)
64 (81)
2.3 (1.2)
6.5 (3.9)
44 (54.3)
66 (81.5)
2.0 (1.1)
7.6 (4.7)
8 (10.1)
8 (9.9)
30 (38.0)
4 (5.0)
7 (8.9)
1 (1.3)
39 (48.1)
2 (2.5)
7 (8.6)
2 (2.5)
-
72 (91.1)
7 (8.9)
68 (84.0)
13 (16.0)
Vol. 157, No. 6
normal aftertaste associated with the administration of the
syrup. No severe adverse events were observed.
Discussion
In our study, zinc supplementation of young children
with AGE had no beneficial effect on diarrhea duration
or severity. The proportion of children who experienced
diarrhea lasting >7 days was similar in both groups.
Zinc therapy was well tolerated, and it was not associated
with an increased frequency of vomiting. The results of
our study are inconsistent with the results of previously
conducted studies, subsequent systematic reviews, and
meta-analyses7-10 that have shown an anti-diarrheal effect
of zinc in children <5 years of age. This beneficial effect
of zinc was mainly associated with diarrhea duration. Furthermore, all the conducted studies were performed in
countries with a medium (India, Bangladesh, Indonesia,
Nepal, Brazil, Turkey, Pakistan, Egypt, Philippines) or
low (Ethiopia) Human Development Index (HDI11; assessed at the time when the study was performed), where
malnutrition and zinc deficiency are important problems.12 No studies that assessed the effects of zinc for
the treatment of AGE in children <5 years of age were
performed in a country with a high or very high HDI,
an index considered to be a standard means of measuring
well-being, especially child welfare, where zinc deficiency
is rare. However, in several randomized controlled trials
(RCTs),13-17 no advantageous effect of zinc therapy on diarrhea duration or severity was observed, or an observed
effect was not statistically significant. The common feature
of these studies is the sufficient zinc status of the participants (ie, exclusively well-nourished participants17; infants <6 months of age likely to have adequate total
body zinc acquired in utero15,16; subjects with normal serum zinc levels13,14). Although we do not have precise
data, on the basis of available indicators of risk of zinc
deficiency (eg, the percentage of the population at risk
for inadequate zinc intake), we can conclude that Polish
children are also not a population at high risk of zinc deficiency.12 This observation supports the hypothesis that
the anti-diarrheal effect of zinc is dependent on zinc deficiency.
The other aspect to consider is whether zinc is equally effective against all types of infectious diarrhea or whether its
action is pathogen specific. Available data on the etiology
of the diarrhea from earlier studies are limited. Authors of
only a few RCTs13,14,18-21 performed diagnostic microbiology. In our study, a viral pathogen (mainly rotavirus) was
identified in approximately half the patients with AGE. Our
results are inconsistent with the results of the study by Bhatnagar et al, in which the proportion of viral infection was
comparable.
We investigated the efficacy of zinc administration in a different clinical setting. Our population consisted of young
children with diarrhea who were living in Europe, where
Patro, Szymański, and Szajewska
ORIGINAL ARTICLES
December 2010
Table II. Outcome measures
Outcome measure
Diarrhea duration in hours, median (range)
Stool frequency (n/day), median (range)
Day 1
Day 2
Day 3
Vomiting frequency (n/day), median (range)
Day 1
Day 2
Day 3
Total intravenous fluid intake (mL/kg), median (range)
Diarrheal episodes lasting >7 days, n (%)
Placebo
n = 72
Zinc
n = 69
Effect size
(95% CI)
P value*
39 (12-196)
58 (12-187)
Median difference 4 (–5-18)
.33
4 (0-38)
3 (0-14)
2 (0-13)
5 (0-20)
3 (0-17)
2 (0-10)
1 (0-2)
0 (0-1)
0 (0-1)
.13
.30
.31
0 (0-4)
0 (0-3)
0 (0-10)
72 (0-318)
3 (4.2)
0 (0-7)
0 (0-4)
0 (0-5)
73 (0-425)
1 (1.4)
0 (0-0)
0 (0-0)
0 (0-0)
0 (–33-12)
Relative risk
0.35 (0.04-3.26)
.68
.37
.91
.48
.61
*Mann-Whitney test or Fisher exact test (as appropriate).
the major problem is diarrhea frequency and the associated
economic burden. Contrary to other studies, this RCT was
performed in a country with a high HDI. The participants
were well-nourished, otherwise healthy children who were,
therefore, unlikely to be zinc deficient. The dose of zinc
and duration of treatment were in accordance with the
WHO recommendations.4
We chose an adequate study design and made some efforts
to avoid systematic bias (eg, proper generation of the random
allocation sequence, allocation concealment, blinding). The
major potential limitation of this trial is the relatively high
percentage of patients either lost to follow-up or who discontinued the intervention. However, the noncompliance rate
tended to increase with recovery from the diarrhea. All available data were included in the intention-to-treat analysis.
Also, we cannot exclude the potential risk of poor adherence
associated with using diaries to record measured outcomes
(mainly during the period after discharge and in outpatients). To minimize this risk, direct interview of the parents
was undertaken.
We did not evaluate serum zinc levels to estimate the risk
of zinc deficiency in the enrolled patients. To our knowledge,
currently there are no sufficiently sensitive biomarkers of individual zinc status to identify mild to moderate zinc deficiency.12 Because most of our patients (87.5%) were
admitted to the hospital, we cannot rule out a different pattern of response to treatment in a fully outpatient setting.
Despite the growing number of studies evaluating zinc
supplementation for the treatment of AGE in children,
there are still some questions to be answered in the areas
of basic and applied research. The results of our study did
not confirm that zinc supplementation is effective in the
treatment of AGE in a country in which zinc deficiency
it not a problem. However, our findings are not in opposition to the results of earlier studies that have indicated
beneficial effects of administered zinc in populations in
which malnutrition is common. However, the recommendations of UNICEF and WHO on zinc supplementation
as a universal treatment for diarrhea in these populations
cannot be simply extrapolated to all children from devel-
oped countries; rather, in line with the ESPGHAN/ESPID
recommendations, the UNICEF and WHO recommendations should apply to any malnourished child. n
Submitted for publication Mar 3, 2010; last revision received Apr 14, 2010;
accepted May 26, 2010.
Reprint requests: Bernadeta Patro, MD, Department of Paediatrics, The
Medical University of Warsaw, 01-184 Warsaw, Dzialdowska 1, Poland.
E-mail: abpatro@yahoo.com.
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Double-Blind, Placebo-Controlled Trial
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Patro, Szymański, and Szajewska
ORIGINAL ARTICLES
December 2010
Assessed for eligibility
n=249
Excluded
n=105
Enrollment
Reason:
not meeting inclusion criteria
refused to participate
Randomized
n=160
Allocated to placebo group
n=79
Received allocated intervention
n= 76
Allocation
Did not receive allocated intervention
n=3
Reason: refused to drink syrup
Lost to follow-up n= 7
Reason: parent’s decision,
technical difficulties
Discontinued intervention
n=8
Reason: refused to drink syrup,
parent’s decision
Did not receive allocated intervention
n=4
Reason: parent’s decision
Follow-Up
Analyzed n=72
Excluded from analysis n=7
Reason: lost to follow-up
Allocated to zinc group
n=81
Received allocated intervention
n= 77
Lost to follow-up n= 12
Reason: parent’s decision,
technical difficulties
Discontinued intervention
n= 9
Reason: refused to drink syrup,
parent’s decision
Analyzed n=69
Analysis
Excluded from analysis n=12
Reason: lost to follow-up
Figure. Flow diagram of the progress of patients through the study.
Oral Zinc for the Treatment of Acute Gastroenteritis in Polish Children: A Randomized,
Double-Blind, Placebo-Controlled Trial
988.e1