Alimentary Pharmacology and Therapeutics

Systematic review with meta-analysis: ondansetron for

vomiting in children with acute gastroenteritis
E. Tomasik, E. Zi

okowska, M. Koodziej & H. Szajewska

Department of Paediatrics, The

Medical University of Warsaw,
Warsaw, Poland.

Correspondence to:
Prof. H. Szajewska, Department of
Paediatrics, The Medical University of
Warsaw, 02-091 Warsaw, Zwirki i
Wigury 63A, Poland.
E-mail: hania@ipgate.pl

Publication data
Submitted 15 May 2016
First decision 1 June 2016
Resubmitted 11 June 2016
Resubmitted 22 June 2016
Accepted 22 June 2016
As part of AP&Ts peer-review process, a
technical check of this meta-analysis
was performed by Dr Y. Yuan. This
article was accepted for publication after
full peer-review.

SUMMARY
Background
Vomiting in children with acute gastroenteritis is a common symptom, and
it is considered to be the main cause of failure of oral rehydration therapy.
Aim
To systematically update evidence on the effects of ondansetron (5-HT3
serotonin antagonist) for vomiting in children with acute gastroenteritis.
Methods
The Cochrane Library, MEDLINE and EMBASE databases were searched
up to April 2016, with no language restrictions, for randomised controlled
trials (RCTs). Reference lists of reviews and included studies were
examined.
Results
Ten RCTs involving 1215 participants were included. Treatment with
ondansetron compared with placebo increased the chance for vomiting cessation up to 1 h after drug administration, relative risk, RR, 1.49 (95% condence interval 1.171.89), but there was no difference between the groups
after 4, 24 and 48 h. Treatment with ondansetron compared with placebo
reduced the risk of failure of oral rehydration therapy, RR 0.5 (0.370.69),
increased the intake of oral rehydration solution in 1 h and 4 h, mean difference: 43 mL/1 h (15.570.5), and 91 mL/4 h (35147), respectively,
reduced the risk of hospitalisation, RR 0.53 (0.290.97), and reduced the
need for intravenous rehydration, RR 0.45 (0.310.63); however, it had no
effect on the need for return visits to the emergency department, RR 1.14
(0.721.8). Adverse effects were similar in both groups.
Conclusions
Compared with placebo, ondansetron administration for vomiting in children with acute gastroenteritis can improve the efcacy of oral rehydration
therapy.
Aliment Pharmacol Ther

2016 John Wiley & Sons Ltd

doi:10.1111/apt.13728

E. Tomasik et al.
BACKGROUND
Vomiting is a common manifestation of acute gastroenteritis in children, and is the main cause of failure of oral
rehydration therapy. Thus, in some settings, there has
been an exponential increase in the use of
ondansetron,1, 2 a 5-HT3 serotonin antagonist with a
central antiemetic effect.3 Indeed, according to the 2014
European guidelines, ondansetron is considered to be
effective treatment in young children with vomiting
related to acute gastroenteritis.4 Also, the Canadian Pediatric Society recommended that oral ondansetron therapy, as a single dose, should be considered for children
with vomiting related to suspected acute gastroenteritis,
as well as for those who have mild-to-moderate dehydration or who have failed oral rehydration therapy. The
use of ondansetron is not recommended in children with
acute gastroenteritis manifested predominantly as moderate-to-severe diarrhoea, as one of the most common side
effects of ondansetron is increased frequency of diarrhoea.5 The latter, as well as the Food and Drug Administration black box alert published in September 2011
that electrocardiogram monitoring is recommended in
patients receiving ondansetron with potential electrolyte
abnormalities due to the risk of developing prolongation
of the QT interval, which can lead to abnormal and
potentially fatal heart rhythms including Torsade de
Pointes,6 is the reason that before a nal recommendation is made, clearance on its safety for use in children is
needed.
Previously, one of us co-authored a systematic
review that investigated the effectiveness of ondansetron, compared with placebo or no intervention, in
treating vomiting during acute gastroenteritis in children.7 Other systematic reviews/meta-analyses have also
been published.8, 9 However, in the last few years, a
number of new relevant studies have become available.
Here, our aim was to update a 2007 meta-analysis on
the effects and safety of ondansetron administration
for treating vomiting during acute gastroenteritis in
children.
METHODS
This systematic review and meta-analysis follows the
guidelines from the Cochrane Handbook for Systematic
Reviews of Interventions10 and the PRISMA statement
for reporting.11
Criteria for considering studies for this review
Only randomised controlled trials (RCTs) that compared
ondansetron (given orally or intravenously) with placebo
2

or no intervention administered for vomiting in children

with acute gastroenteritis were included. In the case of
trials with more than one experimental arm, we included
data on ondansetron only. In addition, we considered
only the studies with >80% follow-up.
The primary outcome was the cessation of vomiting.
Secondary outcomes included time of vomiting cessation;
need for intravenous rehydration; need for hospitalisation; need for return visit to the emergency department
(ED); amount of oral rehydration solution intake; length
of stay in ED; failure of oral rehydration therapy; duration of dehydration correction; immediate hospital
admission rate; hospitalisation rates at 72 h after discharge from the ED, and adverse events.

Search methods for identication of studies

The Cochrane Central Register of Controlled Trials
(CENTRAL), MEDLINE (via PubMed (National Library
of Medicine) and EMBASE databases were searched for
relevant studies published up to April 2016. The searches
were carried out independently by three reviewers, with
no language restrictions.
Search strategy
For details, see Table S1. In general, terms used in search
strategy were as follows: antiemetics, ondansetron,
zofran, vomiting, emesis, gastroenteritis, diarrhoea, dehydration, paediatric, child, infant, toddler and randomised.
Searching other resources
Two registries for clinical trials (www.clinicaltrials.gov,
www.clinicaltrialsregister.eu) were screened to identify
unpublished and ongoing studies. Furthermore, the reference lists from identied studies and key review articles
were searched. Certain publication types (i.e. letters to
the editor, abstracts, proceedings from scientic meetings) were excluded.
Selection of studies
An initial screening of the title, abstract and keywords of
every record identied was performed. Three reviewers
(ET, EZ and MK) independently assessed the eligibility
of each potentially relevant study by examining the full
text with the use of inclusion criteria. Any disagreements
were resolved by discussion.
Data extraction and management
Data were extracted with the use of standard extraction
tables. Data were checked by a second reviewer. Disagreements were resolved by discussion.
Aliment Pharmacol Ther
2016 John Wiley & Sons Ltd

Systematic review with meta-analysis: ondansetron for vomiting in acute gastroenteritis

Assessment of risk of bias in included studies
The Cochrane Collaborations tool for assessing risk of
bias was used to establish the risk of bias. Type of randomisation method (selection bias), allocation concealment (selection bias), blinding of participants and
personnel (performance bias), blinding of outcome
assessment (detection bias), incomplete outcome data
(attrition bias), selective reporting (reporting bias) and
other bias (dened as industry support) were considered.12
Measures of treatment effect
The mean difference (MD) with 95% condence interval
(95% CI) was calculated for continuous outcomes, and
relative risk (RR) with 95% CI, for dichotomous outcomes.
Assessment of heterogeneity
v2 and I2 were determined to quantify heterogeneity. For
v2, a P < 0.10 indicated statistical signicance for heterogeneity. I2 = 0% indicated no observed heterogeneity.
I2 50% indicated signicant heterogeneity. All analyses
were based on the random effects model.
Assessment of reporting biases
We planned to use a test for asymmetry of the funnel
plot to assess reporting biases. However, the small number of included studies did not allow us to use this test.
Data synthesis
The data were analysed using the Review Manager (RevMan) [Computer program, version 5.3.; The Nordic
Cochrane Centre, The Cochrane Collaboration, 2014,
Copenhagen]. For the primary outcome, the number
needed to treat (NNT), with the 95% CI, was calculated
using the formula recommended by the Cochrane Handbook [NNT = 1/ACR 9 (1 RR)], where ACR, assumed
control risk, was an average control group risk.
Subgroup analysis
We considered whether ondansetron would have a different effect depending on the mode of administration
(oral vs. intravenous).
Quality of evidence
The quality of evidence for outcomes reported in the
included trials was assessed using the GRADE methodology and GRADEpro [Computer program located at
www.gradepro.org, version (14 August 2015), McMaster
University, 2014]. The GRADE system offers four
Aliment Pharmacol Ther
2016 John Wiley & Sons Ltd

categories of the quality of the evidence (i.e. high, moderate, low and very low).13

RESULTS
Results of the search
For a ow diagram documenting the identication process for the eligible trials, see Figure S1. Table S2 summarises the characteristics of the included trials, and
Table S3 summarises the characteristics of the excluded
trials, including the reasons for exclusion.
In addition to the previously identied four
RCTs,1417 six new RCTs were included.1823 In addition,
six registered trials were identied. Among them, two
RCTs were completed, but no publication was found
(ClinicalTrials.gov
Identier:
NCT01257672,
NCT01257672); one RCT was terminated, but the results
were not published (NCT02028910), and three RCTs
were still recruiting at the time of the writing of this
manuscript
(NCT02246439,
NCT01870635,
NCT01870648). All included trials were placebo-controlled and full peer-reviewed publications. The trials
were conducted in countries such as India,18 Iran,19
Thailand,20 Turkey,23 USA1517, 21, 22 and Venezuela.14
Two trials were carried out in hospitalised patients;14, 20
and the remaining trials in emergency departments.
Altogether, 1215 participants, 609 in the experimental
group and 606 in the control group, were randomised.
The sample sizes ranged from 24 to 214 participants; of
note, sample size calculations were available in four trials
only.1618, 23 In most of the RTCs, the age of participants
varied from 3 months to 15 years; only in one RTC was
the age of patients 1 month to 22 years.17
There was a large variation in the treatment regimens.
In
six
trials,
ondansetron
was
given
orally15, 16, 18, 19, 21, 23 (in the form of tablets,15, 19, 21
orally disintegrating tablets,23 or as a liquid16, 18), and in
four RCTs, intravenously.14, 17, 20, 22 The dosages were
measured in mg per kg (ranged from 0.15 mg/kg17, 2022
to 0.2 mg/kg18, 23 to 0.3 mg/kg)14 or depended on body
weight (the total dose ranged from 1.6 to 8 mg).15, 16, 19
In most studies, the patient were given a single dose;
only in two RCTs were the doses repeated.16, 23
Follow-up ranged from 4 h to 7 days. The denitions of
outcomes, as well as the assessment of the degree of
dehydration, varied as the used scales were different and
some authors did not mention the degree of dehydration
at all.1618, 23
For the assessment of methodological quality and
potential risk of bias, see Figure S2. The methodological
3

E. Tomasik et al.
limitations of trials included unclear sequence generation
(one RCT),14 unclear allocation concealment (two
RCTs),19, 21 unclear blinding of participants and personnel (two RCTs),14, 20 unclear blinding of outcome assessment (two RCTs),14, 20 unclear incomplete outcome data
(one RCT),20 high risk of incomplete outcome data
(three RCT),2123 unclear selective reporting (four
RCTs).17, 18, 20, 22 The risk of other bias was unclear in
six RCT1418, 21

Effects of interventions
Cessation of vomiting. Seven of the included
studies1417, 19, 20, 23 reported data on cessation of vomiting at certain time intervals (Figure 1). Based on the
pooled results of four RCTs1517, 20 (n = 540), compared
with the control group, in the ondansetron group there
was signicantly higher chance for cessation of vomiting

Ondansetron
Study or subgroup

Events

Total

Placebo

after the administration of the rst dose/1 h later (RR

1.49, 95% CI 1.171.89, NNT 4; 95% CI 210). However,
substantial heterogeneity was found (v2 = 9.98; P = 0.02;
I2 = 70%). Subgroup analysis based on the route of
administration showed a reduction in vomiting with oral
administration of ondansetron (two RCTs,15, 16 n = 359,
RR 1.32, 95% CI 1.171.49), but not with intravenous
administration (two RCTs,17, 20 n = 181, RR 2.07, 95%
CI 0.855.08). There was no difference between groups
in the cessation of vomiting 4 h after the administration
of the treatment (1 RCT,19 n = 176, RR 1.05, 95% CI
0.941.19). Similarly, there was no difference between
groups in the cessation of vomiting 24 h after the
administration of treatment (three RCTs14, 16, 23
n = 253, RR 1.12, 95% CI 0.871.44), and no signicant
heterogeneity was found (v2 = 3.27; P = 0.2; I2 = 39%).
Finally, there was no difference between groups in the

Risk ratio

Risk ratio

Events Total

1.1.1 Cessation of vomiting after administration of first dose/first hour

107
107
92
70
Freedman 2006 (orally)
64
74
46
71
Ramsook 2002 (orally)
38
54
27
53
Reeves 2002 (intravenously)
30
Rerksuppaphol 2010 (intravenously)
37
9
37
Subtotal (95% CI)
272
268
Total events
224
152
Heterogeneity: 2 = 0.04; 2 = 9.98, df = 3 (P = 0.02); I2 = 70%
Test for overall effect: Z = 3.28 (P = 0.001)

Weight

M-H, Random, 95% CI

Risk of bias

M-H, Random, 95% CI

A B C D E F G

33.8%
31.4%
23.3%
11.5%
100.0%

1.31 [1.12, 1.54]

1.33 [1.10, 1.62]
1.38 [1.01, 1.89]
3.33 [1.85, 6.01]
1.49 [1.17, 1.89]

+
+
+
+

+
+
+
+

+ + + +
+ + + +
+ + + ?
? ? ? ?

88
88

100.0%
100.0%

1.05 [0.94, 1.19]

1.05 [0.94, 1.19]

+ ? + + + + +

12
56
54
122

3.3%
35.3%
61.4%
100.0%

3.50 [0.91, 13.53]

1.08 [0.78, 1.49]
1.07 [0.91, 1.26]
1.12 [0.87, 1.44]

? + ? ? + + ?
+ + + + + + ?
+ + + + + +

88
88

100.0%
100.0%

1.15 [0.92, 1.44]

1.15 [0.92, 1.44]

+ ? + + + + +

?
?
?
+

1.1.2 Cessation of vomiting after 4 h after administration of treatment

Golshekan 2013 (orally)
Subtotal (95% CI)
Total events
Heterogeneity: not applicable
Test for overall effect: Z = 0.88 (P = 0.38)

78

88
88

78

74
74

1.1.3 Cessation of vomiting 24 h after administration of treatment

Cubeddu 1997 (intravenously)
Ramsook 2002 (orally)
Yilmaz 2010 (orally)
Subtotal (95% CI)

7
37
48

12
64
55
131

2
30
44

76
92
Total events
Heterogeneity: 2 = 0.02; 2 = 3.27, df = 2 (P = 0.20); I2 = 39%
Test for overall effect: Z = 0.86 (P = 0.39)
1.1.4 Cessation of vomiting after 48 h after administration of treatment
Golshekan 2013 (orally)
Subtotal (95% CI)
Total events
Heterogeneity: not applicable
Test for overall effect: Z = 1.25 (P = 0.21)

60

88
88

60

52
52

0.7
Test for subgroup differences: 2 = 6.53, df = 3 (P = 0.09), I2 = 54.1%

0.85

Favors placebo

1.2

1.5

Favors ondansetron

Risk of bias legend

(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

Figure 1 | Ondansetron vs. placebo for vomiting in children with acute gastroenteritis. Cessation of vomiting.
4

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2016 John Wiley & Sons Ltd

Systematic review with meta-analysis: ondansetron for vomiting in acute gastroenteritis

cessation of vomiting 48 h after the administration of
treatment (1 RCT,19 n = 176, RR 1.15, 95% CI
0.921.44).

Failure of oral rehydration therapy. Pooled results of

two RCTs18, 19 (n = 343) showed a reduction in the risk
of failure of oral rehydration therapy in those treated
with ondansetron (oral administration) compared with
those treated with placebo (RR 0.5, 95% CI 0.370.69; no
signicant heterogeneity was found) (Figure 2).
Hospitalisation. Based on the pooled results of ve studies (n = 626),15, 17, 2123 there was a signicantly reduced
Ondansetron
Study or subgroup

Events

Total

Intravenous rehydration. Pooled results of three

RCTs15, 18, 21 (n = 484) showed a reduction in the risk
of need for intravenous rehydration in those treated with
Risk ratio

Risk ratio

Placebo
Events Total

risk of hospitalisation in the ondansetron group

compared with the placebo group (RR 0.53, 95% CI
0.290.97; no signicant heterogeneity was found) (Figure 2). Subgroup analysis based on the route of administration found a reduced risk of hospitalisation with oral
administration of ondansetron (three RCTs,15, 21, 23
n = 429, RR 0.46, 95% CI 0.211.00), but not with intravenous administration (two RCTs,17, 22 n = 197, RR 0.5,
95% CI 0.131.97).

Weight

M-H, Random, 95% CI

Risk of bias
A B C D E F G

M-H, Random, 95% CI

1.2.1 Failure of oral rehydration therapy

Danewa 2016 (orally)
Golshekan 2013 (orally)
Subtotal (95% CI)
Total events

26
12

84
88
172

51
24

83
88
171

75.0%
25.0%
100.0%

0.50 [0.35, 0.72]

0.50 [0.27, 0.94]
0.50 [0.37, 0.69]

+ + + + + ? ?
+ ? + + + + +

107
53
55
44
54
313

16.6%
40.4%
16.4%
13.4%
13.3%
100.0%

0.80 [0.22, 2.90]

0.86 [0.47, 1.58]
0.46 [0.13, 1.69]
0.21 [0.05, 0.93]
0.22 [0.05, 0.96]
0.53 [0.29, 0.97]

+
+
+
+
+

83
107
55
245

29.6%
40.4%
30.0%
100.0%

0.56 [0.30, 1.07]

0.45 [0.26, 0.79]
0.34 [0.18, 0.65]
0.45 [0.31, 0.63]

103
71
53
42
42
311

59.7%
2.5%
10.1%
7.0%
20.7%
100.0%

1.08 [0.59, 1.95]

8.64 [0.47, 157.62]
1.31 [0.31, 5.57]
1.40 [0.25, 7.97]
0.91 [0.33, 2.50]
1.14 [0.72, 1.80]

38
75
Heterogeneity: 2 = 0.00; 2 = 0.00, df = 1 (P = 0.98); I2 = 0%
Test for overall effect: Z = 4.30 (P < 0.0001)

1.2.2 Hospitalization
5
4
107
Freedman 2006 (orally)
16
14
54
Reeves 2002 (intravenously)
51
3
7
Roslund 2008 (orally)
Stork 2006 (intravenously)
2
46
9
2
9
55
Yilmaz 2010 (orally)
313
Subtotal (95% CI)
46
Total events
25
Heterogeneity: 2 = 0.14; 2 = 5.61, df = 4 (P = 0.23); I2 = 29%
Test for overall effect: Z = 2.07 (P = 0.04)

+
+
?
+
+

+
+
+
+
+

+
+
+
+
+

+
+

+ ?
? ?
+ ?
? +
+

1.2.3 Intravenous rehydration

Danewa 2016 (orally)
Freedman 2006 (orally)
Roslund 2008 (orally)
Subtotal (95% CI)

12
15
9

84
107
48
239

21
33
30

+ + + + + ? ?
+ + + + + + ?
+ ? + + + ?

84
36
Total events
Heterogeneity: 2 = 0.00; 2 = 1.17, df = 2 (P = 0.56); I2 = 0%
Test for overall effect: Z = 4.54 (P < 0.00001)
1.2.4 Return visit to emergency department
Freedman 2006 (orally)
Ramsook 2002 (orally)
Reeves 2002 (intravenously)
Roslund 2008 (orally)
Yilmaz 2010 (orally)
Subtotal (95% CI)

19
4
4
3
7

107
74
54
45
54
334

17
0
3
2
6

+
+
+
+
+

+ + + +
+ + + +
+ + + +
? + +
+ + +

+ ?
+ ?
? ?
+ ?
+ +

28
Total events
37
Heterogeneity: 2 = 0.00; 2 = 2.27, df = 4 (P = 0.69); I2 = 0%
Test for overall effect: Z = 0.55 (P = 0.58)

0.01
Test for subgroup differences: 2 = 11.22, df = 3 (P = 0.01), I2 = 73.3%

0.1

Favors ondansetron

10

100

Favors placebo

Risk of bias legend

(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

Figure 2 | Ondansetron vs. placebo for vomiting in children with acute gastroenteritis. Dichotomous outcomes.
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2016 John Wiley & Sons Ltd

E. Tomasik et al.
ondansetron compared with placebo (RR 0.45, 95% CI
0.310.63; no signicant heterogeneity was found) (Figure 2). In all of the included trials, ondansetron was
administered orally.

Return visit to emergency department. A meta-analysis

of ve RCTs1517, 21, 23 (n = 645) showed no difference
between the groups in return visits to the emergency
department (RR 1.14, 95% CI 0.721.80; no signicant
heterogeneity was found) (Figure 2). The results were
the same when only trials in which ondansetron was
given orally were evaluated (four RCTs, n = 538, RR
1.12, 95% CI 0.691.82).
Amount of oral rehydration solution intake. Two
RCTs15, 18 provided data on the amount of oral rehydration solution intake, although at different time intervals.
Still, both trials showed in the ondansetron group compared with the placebo, there was increased intake of
oral rehydration solution during 115 or 4 h18 (MD
43 mL/1 h, 95% CI 15.5470.46 and 91 mL/4 h, 95% CI
35.14146.86 respectively) (Figure 3).
Diarrhoea. Five studies (Table S4) provided data regarding diarrhoeal episodes in different outcomes measures;
therefore, we report the results in a narrative format.
Evidence about the number of episodes of diarrhoea
experienced by children while in the ED is inconclusive;
one RCT showed a signicant difference in the number
of diarrhoeal stools between children in the ondansetron
group compared with the placebo group,15 while another
did not show a signicant difference.16 In a 24-h followup, two trials14, 16 showed signicantly more episodes of
diarrhoea in the ondansetron group compared with the
Placebo

Ondansetron
Study or subgroup

Mean

SD

Total

1.3.1 Intake of oral rehydration solution in 1 h (mL)

239
112
107
Freedman 2006 (orally)
107
Subtotal (95% CI)
Heterogeneity: not applicable
Test for overall effect: Z = 3.07 (P = 0.002)

placebo group. Based on the results of one trial, a similar

effect in both groups was observed at 48 h.16 Two trials
did not include data on diarrhoeal stools.20, 22

Other secondary outcomes. One RCT15 reported that

mean length of stay in the emergency department was
reduced in the ondansetron group compared with the
placebo group (106  53 vs. 120  63 min, respectively,
P = 0.02). One RCT18 reported that compared with placebo group, in the ondansetron group the median duration of dehydration correction was signicantly reduced
(6 vs. 4 h, respectively, P < 0.001). One RCT showed a
reduction in the risk of immediate hospital admission
rate at the end of the rst 8 h in those treated with
ondansetron compared with placebo (1.8% vs. 22.2%,
respectively, RR 0.08; 95% CI 0.010.61).23 Other outcomes of interest such as time of vomiting cessation and
hospitalisation rates at 72 h after discharge from the
emergency department were not reported in any of the
included studies.
Adverse events. Of the 10 trials included in the review,
nine reported on adverse events. In ve of them,1721
therapy was well tolerated and adverse events were similar in both groups. In three trials,14, 16, 23 there were differences between the groups. In these trials, one RCT
(n = 24) reported that cough was more frequent in the
ondansetron group compared with the placebo group;
however, the difference was not signicant (3/12 vs.
0/12, respectively, RR 7.00; 95% CI 0.4122.4).14 One
RCT (n = 145) reported development of a macular rash
in one patient 30 min after receiving ondansetron16; one
trial reported urticaria in a child in the placebo group15;
and one trial reported abdominal distension in a child in
Mean difference

Mean

SD

Total

Weight

IV, Random, 95% CI

196

92

107
107

100.0%
100.0%

43.00 [15.54, 70.46]

43.00 [15.54, 70.46]

554

175

83

100.0%

91.00 [35.14, 146.86]

83

100.0%

91.00 [35.14, 146.86]

Mean difference
IV, Random, 95% CI

1.3.2 Intake of oral rehydration solution in 4 h (mL)

193

84

Subtotal (95% CI)

Heterogeneity: not applicable
Test for overall effect: Z = 3.19 (P = 0.001)

84

Danewa 2016 (orally)

645

200
Test for subgroup differences: 2 = 2.28, df = 1 (P = 0.13), I2 = 56.2%

100
Favors placebo

100

200

Favors ondansetron

Figure 3 | Ondansetron vs. placebo for vomiting in children with acute gastroenteritis. Amount of oral rehydration
solution intake in 1 and 4 h (mL).
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Systematic review with meta-analysis: ondansetron for vomiting in acute gastroenteritis

the experimental group.23 In one trial, no information
about adverse events was reported.22
The GRADE assessment for outcomes related to
ondansetron administration is presented in Table S5.
Using the GRADE, the overall quality of evidence for all
assessed outcomes was rated as high or moderate.

DISCUSSION
Summary of evidence
Our review demonstrated that the administration of
ondansetron compared with placebo offers some benets
in the management of vomiting in children with acute
gastroenteritis. Combined data showed in the ondansetron group compared with the placebo group, there was
a higher chance for vomiting cessation up to 1 h after
drug administration, although there was no difference
between the groups after 4, 24 and 48 h. The lack of an
effect after 24 and 48 h is not surprising, as vomiting
during acute gastroenteritis is usually self-limited.
Ondansetron compared with placebo reduced the risk of
failure of oral rehydration therapy, increased intake of
oral rehydration solution, reduced the risk of hospitalisation and reduced the need for intravenous rehydration;
however, it had no effect on the need for return visits to
the emergency department. Evidence on the effect of
ondansetron on the diarrhoeal stools is inconclusive.
While some studies showed an increased number of
diarrhoeal stools in the ondansetron group compared
with the placebo group, other trials failed to show such
an effect. Adverse effects were similar in both groups.
Whereas earlier studies have suggested that ondansetron
may not be suitable for use in adults with arrhythmias,
this has not been shown in our analysis, and arrhythmias
are unlikely to occur with a single administration of
ondansetron.24
Strengths and limitations
This systematic review has several strengths. The
methodology developed by the Cochrane Collaboration
was followed. Reporting was in line with the PRISMA
statement. A comprehensive literature search, including
reviewing the references in identied studies, with no
restriction by language, reduced the risk that relevant
studies were missed. The use of pre-specied criteria for
assessment of the risk of bias and analysis adds to the
strengths. However, this review has some limitations.
While the analyses were dened a priori, the protocol of
the review has not been registered. Literature on the use
of ondansetron remains limited. Only 10 trials were
Aliment Pharmacol Ther
2016 John Wiley & Sons Ltd

included. While the quality of included trials was generally satisfactory, not all included trials were free of the
risk of bias. Examples of bias include unclear allocation
concealment, sequence generation, and blinding, no
intention-to-treat analysis and incomplete outcome data.
The sample size calculations were not always available.
Included trials showed heterogeneity in dosage regimens
and routes of ondansetron administration. The limited
data available do not allow one to form rm conclusions
regarding which route of ondansetron (oral or intravenous) is preferable, and each has its advantages and
disadvantages. For some outcomes, such as in case of
oral rehydration solution intake, the condence interval
of the summary estimate was wide, resulting in uncertainty. The degree of dehydration was not clear in some
of the included trials due to the use of unvalidated dehydration scales1618, 23; only three RCTs used a WHO
scale.14, 19, 20 The rest of the RCTs dened dehydration
according to other validated scales.15, 21, 22 In many trials, the follow-up period was short (672 h); only in one
RCT was the period of follow-up 37 days.15 In two
RCTs, there was no follow-up period reported.18, 20 Indications for hospitalisation were not standardised, so they
may have differed between the studies. Finally, a lack of
data on the aetiology of the acute gastroenteritis does
not allow one to identify children who would benet
most from the administration of ondansetron. For example, children with norovirus infection have signicantly
more episodes of vomiting than children with other viral
infections. Taken together, while some ndings are
promising, they must be interpreted with caution.

Agreement and disagreement with other studies or

reviews
Our ndings are in line with the results of previously
published meta-analyses. However, compared with our
2007 systematic review,7 as well as two subsequently
published reviews,8, 9 the current review included more
trials involving more patients. Thus, the current metaanalysis more precisely denes the role of ondansetron
in enhancing the efcacy of oral rehydration therapy
in the management of acute gastroenteritis. A 2008
meta-analysis of six RCTs found that ondansetron
therapy decreased the risk of persistent vomiting,
reduced the need for intravenous uids and decreased
the risk of immediate hospital admission in children
with vomiting due to gastroenteritis. However, compared with placebo, ondansetron signicantly increased
diarrhoeal episodes in treated patients in three RCTs,
and it did not have an effect on return to care. The
7

E. Tomasik et al.
researchers concluded that future treatment guidelines
should incorporate ondansetron therapy for select children with gastroenteritis. They also suggested that
given the costs related to intravenous therapy or hospitalisation, ondansetron therapy is likely to be costeffective.9 A more recent Cochrane review (search date:
March 2012)25 included seven RCTs that compared
ondansetron with placebo therapy, and out of these,
four RCTs investigated oral administration. Children
younger than 18 years of age who presented with
vomiting and had a clinical diagnosis of gastroenteritis
were included. Compared with placebo, ondansetron
signicantly increased the proportion of children with
cessation of vomiting with both oral and intravenous
administration. The use of ondansetron also reduced
the need for intravenous therapy and the immediate
hospital admission rate. However, in three of the
RCTs, there was an increased rate of episodes of diarrhoea in the ondansetron group (P < 0.05). The
authors of the Cochrane review concluded that healthcare policy makers should consider the wider use of
ondansetron.
Our review did not address the cost-effectiveness of
ondansetron administration in emergency departments.
However, at least one economic analysis carried out in
high-income countries such as the USA and Canada
showed that the emergency department administration
of oral ondansetron compared with no administration
resulted in signicant monetary savings from both societal and healthcare perspectives.26 Similar studies are
needed to address the cost-effectiveness of using ondansetron in economically less privileged settings.
Risk of fatal cardiac arrhythmias is one of the concern
associated with ondansetron administration.6 However, a
2014 systematic review and post-marketing analysis
found no reports describing an arrhythmia associated
with single oral ondansetron administration. The authors
concluded that there is no need for routine ECG and
electrolyte screening in patients with no known risk factors who are administered a single oral ondansetron
dose. In contrast, intravenous administration of

ondansetron, particularly in high doses and in high-risk

population with pre-existing cardiac disease (e.g. heart
failure, personal or family history suggestive of long-QT
syndrome, other arrhythmias) or disorders associated
with electrolyte abnormalities (e.g. short-gut syndrome,
diuretic use, renal disease) may warrant routine ECG
and electrolyte screening.27

CONCLUSIONS
Off-label use of ondansetron for management of vomiting in children with acute gastroenteritis is common.
Current evidence supports oral or intravenous administration of ondansetron to increase the success rate of
oral rehydration therapy, and this intervention may be
endorsed in the management of children with acute
gastroenteritis treated in emergency departments.
SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Identication process for eligible trials.
Figure S2. Assessment of methodological quality and
potential risk of bias.
Table S1. Search strategy for MEDLINE.
Table S2. Characteristics of included studies.
Table S3. Characteristics of excluded studies.
Table S4. Ondansetron compared with placebo
effect on diarrhoeal stools.
Table S5. GRADE evidence prole summarising the
effects of ondansetron vs. placebo for management of
vomiting in children with acute gastroenteritis.
AUTHORSHIP
Guarantor of the article: Hania Szajewska.
Author contributions: HS initially conceptualised this study. ET, EZ
and MK were responsible for data collection, data analysis, data
interpretation and preparation of the rst draft. HS assumed the
main responsibility for the writing of this manuscript. All authors
contributed to (and agreed upon) the nal version of this manuscript.

ACKNOWLEDGEMENT
Declaration of personal and funding interests. None.

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