European Journal of Pediatrics

https://doi.org/10.1007/s00431-020-03653-0

REVIEW

Single-dose of ondansetron for vomiting in children and adolescents

with acute gastroenteritis—an updated systematic review
and meta-analysis
Francesco Fugetto 1 & Emanuele Filice 1 & Carlotta Biagi 1 & Luca Pierantoni 1 & Davide Gori 2 & Marcello Lanari 1

Received: 15 January 2020 / Revised: 12 April 2020 / Accepted: 15 April 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
This review aimed to meta-analyze evidence of efficacy and safety of one single dose of ondansetron for vomiting in children and
adolescents with acute gastroenteritis. Database searches of MEDLINE (PubMed), Scopus (Elsevier), Cochrane Central Register
of Controlled Trials (CENTRAL), and ClinicalTrials.gov up to November 2019 were performed. Only randomized clinical trials
versus placebo were considered. Fixed and random effect models were used for the analyses of pooled data. Thirteen randomized
clinical trials (2146 patients) were finally included. One single dose of ondansetron showed to produce (1) higher chance of
vomiting cessation within 8 h (RR 1.41, 95% CI 1.19–1.68; low-quality evidence); (2) lower chances of oral rehydration therapy
failure (RR 0.43, 95% CI 0.34–0.55; high-quality evidence), intravenous hydration needs (RR 0.44, 95% CI 0.34–0.57; high-
quality evidence), and hospitalization rates within 8 h (RR 0.49, 95% CI 0.32–0.75; high-quality evidence); and (3) no statis-
tically significant differences in return visits to emergency department (RR 1.14, 95% CI 0.74–1.76; high-quality evidence)
compared with placebo. Further studies are necessary to better assess long term efficacy and safety of ondansetron in this context.
Conclusions: Mixed evidence was found via few studies about the efficacy and safety of a single dose of ondansetron in the
pediatric population.

What is known:
• Ondansetron use for vomiting in pediatric acute gastroenteritis is increasing worldwide.
• Actual convictions come from studies evaluating one and more than one dose of the drug.
What is new:
• This is the first review to collect data about the effects of one single dose of ondansetron on strong and temporally homogeneous clinical outcomes.
• This study supports the use of one dose of ondansetron in pediatric acute gastroenteritis.
• Further studies are necessary to assess its long-term efficacy and safety.

Keywords Acute gastroenteritis . Vomit . Ondansetron . Children . Adolescents

Communicated by Gregorio Paolo Milani

Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00431-020-03653-0) contains supplementary
material, which is available to authorized users.

* Emanuele Filice Davide Gori

eman.filice@gmail.com; emanuele.filice@studio.unibo.it davide.gori4@unibo.it
Marcello Lanari
Francesco Fugetto
marcello.lanari@unibo.it
francescofugetto@gmail.com; francesco.fugetto@studio.unibo.it
1
Carlotta Biagi Department of Medical and Surgical Sciences (DIMEC), Pediatric
carlottabiagi@yahoo.it Emergency Unit, St. Orsola Hospital, University of Bologna, via
Massarenti 9, 40138 Bologna, Italy
2
Luca Pierantoni Department of Biomedical and Neuromotor Sciences (DIBINEM),
luca.pierantoni@aosp.bo.it University of Bologna, via San Giacomo 12, 40128 Bologna, Italy

Abbreviations
AE Adverse event
CI Confidence interval
ECG Electrocardiogram
ED Emergency department
FDA Food and Drug Administration
H Hours
HT Hydroxytryptamine
IV Intravenous
MD Mean difference
ODT Orally disintegrating tablet
ORT Oral rehydration therapy
RCT Randomized controlled trial
RoB Risk of bias
Introduction
Rationale
Vomiting is a common symptom of acute gastroenteritis in
children and adolescents and represents the main cause of
failure of oral rehydration therapy (ORT) and hospitalization
[1]. Treatment of vomiting and dehydration in patients with
acute gastroenteritis can be challenging. Worldwide approxi-
mately 10% of children younger than 5 years present to hos-
pital with acute gastroenteritis each year [2]. Acute gastroen-
teritis in children causes considerable costs in high-income
countries [3–6].
In many settings, there has been an exponential increase in
the use of ondansetron, a 5-hydroxytryptamine3 serotonin an-
tagonist with a central and peripheral antiemetic effect.
Ondansetron is currently approved by the FDA for prevention
of nausea and vomiting associated with moderate to highly
emetogenic cancer chemotherapy in children older than
4 years, as well as radiotherapy to the abdomen and surgical
procedures in adults [7]. Its use for other causes of vomiting,
including acute gastroenteritis, is off-label. Previously pub-
lished meta-analyses have included only a limited amount of
heterogeneous studies exploring its efficacy and safety [8–10].
Overall the most frequent reported side effects are a mild and
self-limiting diarrhea [11, 12] and QT interval prolongation
[13–17].
Objectives
The objective of this meta-analysis was to provide up-to-date
evidence regarding the efficacy and safety of a single dose of
ondansetron versus placebo prescribed for vomiting due to
acute gastroenteritis in children and adolescents.
Eur J Pediatr
Methods
Protocol and registration
A systematic review and meta-analysis was conducted accord-
ing to the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) [18]. The protocol was regis-
tered in the international prospective register of systematic
reviews (PROSPERO) (ID CRD42019134580).
Search strategy
Databases
Electronic databases were searched to identify relevant studies
published up to November 2019, including MEDLINE
(PubMed), Cochrane Central Register of Controlled Trials
(CENTRAL), and Scopus (Elsevier). Reference lists of select-
ed reviews, original articles, textbooks, organizations’
websites, and guideline clearinghouses were scanned in order
to find additional articles. Investigators and corresponding
authors were contacted to seek information about
unpublished/incomplete studies. A snowball technique was
applied to the search strategy [19].
Search criteria
The search was restricted to RCTs written in the English lan-
guage and included patients younger than 18 years of age. To
achieve the highest sensitivity, a combination of keywords and
indexed terms were used (see Methods, ESM 1, Electronic
Supplementary Material).
Study selection
Design
We considered RCTs evaluating ondansetron administered
orally or IV at any dosage versus placebo, prescribed to termi-
nate or reduce vomiting in children and adolescents under the
age of 18 with clinically suspected acute gastroenteritis.
Outcomes of interest
Studies evaluating at least one of the following were assessed:
cessation of vomiting (i.e., 0 vomiting episodes during the
observation period) within 8 and 24 h after the administration
of the treatment (primary outcomes) [ 20–23]; failure of ORT
(i.e., inability to tolerate a maximum of two trials of ORT,
separated by > 30 min) need for IV rehydration during the
ED stay, hospitalization (i.e., admission at pediatric ward)
within 8 and at 48 h of follow-up, return to the ED after
discharge (i.e., number of participants that revisited the ED
Eur J Pediatr
up to 72 h after discharge), number of diarrhea episodes at
24 h after the administration of the treatment, and any clini-
cally documented or patient-reported adverse events (AE)
(secondary outcomes).
Data collection and analysis
Selection of studies
FF and EF independently assessed the abstracts of studies that
were found in the searches and excluded all irrelevant studies.
The interrater reliability was measured as Cohen’s kappa (k)
and was 0.928. Any disagreement was resolved through dis-
cussion and consensus between the reviewers.
Data extraction and management
Study details were entered into the “Characteristics of includ-
ed studies” table in Review Manager (RevMan) 5 (RevMan
2011) by FF and EF. Outcomes data were collected using a
predetermined form and was entered into RevMan 5 (RevMan
2011).
Risk of bias, assessment of heterogeneity
The risk of bias (RoB) was independently assessed by FF and
DG using The Cochrane Collaboration’s tool [24].
Characteristics of the eligible studies, similarities, and differ-
ences among the types of participants, interventions, and out-
come measures were examined to assess clinical heterogene-
ity. They discussed all disagreements and resolved them by
consulting with a third review author (ML).
Data synthesis, measures of treatment effect
The association between ondansetron use and the outcomes of
interest was assessed through different meta-analyses con-
ducted by FF and DG using the RevMan (v5.3) and the
Comprehensive Meta-Analysis (v3—Biostat 14 North Dean
Street Englewood, NJ 07631, USA) programs. FF and DG
focused their meta-analyses only on the outcomes for which
at least 3 studies were available; otherwise, they reported the
results descriptively. Sensitivity and subgroup analyses were
conducted a posteriori to explore the potential sources of het-
erogeneity and incoherence (for further details see Methods,
ESM 2, Electronic Supplementary Material).
For continuous outcomes, they calculated the mean differ-
ence with 95% CI. For dichotomous data, they calculated the
relative risk with 95% CI. The test for overall effect was
expressed as p value (result considered as statistically signif-
icant if p < 0.05). Risk ratio (RR) was calculated using the
Mantel–Haenszel method and reported with a 95% CI. A
fixed-effect model was used for the analyses. Heterogeneity
was assessed using the Chi-squared test, Q value, and I 2
statistic. If significant heterogeneity was found (p < 0.10 from
the Chi-squared test or Q value or I 2 > 40) or the number of
studies was lower than 5, a random-effects model was used
instead [25].
Rating the confidence in the effect estimates
FF and DG assessed the quality of evidence using the
GRADE working group approach and classified the evidence
as high, moderate, low, or very low [ 26].
Results
Results of the search
The search strategy identified 1591 references (MEDLINE,
696; Scopus, 328; CENTRAL, 567, see Fig. 1).
Included studies
Thirteen placebo-controlled, double-blinded, peer-reviewed
publications (2146 pediatric patients) were included. We re-
stricted the focus to RCTs evaluating ondansetron adminis-
tered orally or IV at any dosage versus placebo and prescribed
to terminate or reduce vomiting in children and adolescents.
Participants and setting
The trials were conducted in different countries and over dif-
ferent periods (see Table 1).
Two RCTs included hospitalized patients [27, 28], while
the remaining were carried out in emergency departments.
The inclusion criteria for enrolment were similar for all stud-
ies, and the age of participants ranged from 3 months to
16 years. All studies included subjects with none to moderate
dehydration, except four [27, 29–31] in which hydration status
was not specified.
Intervention and rehydration therapy
The trials differ in terms of intervention and rehydration ther-
apy (see Table 1 and Results, ESM 3, Electronic
Supplementary Material).
Outcomes
The primary outcomes for this review, i.e., cessation of
vomiting within 8 and 24 h were addressed by nine and one
of the included studies, respectively (see Table 1; Fig. 2).
Secondary outcomes, i.e., failure of ORT and IV rehydration
during the ED stay, hospitalization in a pediatric ward within 8
 Eur J Pediatr

Fig. 1 PRISMA 2009 flow

diagram of the included studies

Idenficaon
Records idenfied through Addional records idenfied
[18] database searching through other sources
MEDLINE (n = 696) Scopus (n = 328)
CENTRAL (n = 567)

Records aer duplicates removed

(n = 43)

Screening
Records screened Records excluded
(n = 31) (n = 12)

1 study with
heterogeneous populaon
Eligibility (both children and adults)
Full-text arcles assessed
for eligibility 3 reviews with or without
(n = 20) meta-analysis

3 ongoing trials

Studies included in
qualitave synthesis
(n = 13)
Included

Studies included in
quantave synthesis
(meta-analysis)
(n = 13)

and at 48 h after the administration of the treatment, return to Primary outcomes

the ED, and number of diarrhea episodes at 24 h were reported
in five, eight, five, one, five, and two of the included RCTs,
respectively (see Table 1; Fig. 3). Among the 10 studies
assessing also adverse events [28–37], eight reported on diar-
rhea [28, 30–32, 34, 36–38], while none evaluated ECG
changes.
Risk of bias in included studies
Cessation of vomiting within 8 h after the administration of
the treatment Nine of the included studies [27–30, 33, 34,
36–38] (n = 1748) reported data on cessation of vomiting
within 8 h after the administration of the treatment. Based on
the pooled results, compared with the placebo group, the
group treated with ondansetron had a significantly higher
chance of cessation of vomiting after the administration of
the first dose (RR 1.41, 95% CI 1.19–1.68; I [2] = 86%).

The risk of bias among included studies was variable and
is reported in Figs. 2 and 3.Reviewers’ judgment for each
type of bias is explained and supported with study quotes
in the “risk of bias table” (see Tables, ESM 4, Electronic
Supplementary Material; Suppl Table 1). The GRADE
quality and certainty level of evidence assessment is re-
ported in Tables, ESM 4, Electronic Supplementary
Material; Suppl Tables 2–3.
Cessation of vomiting 24 h after the administration of the
treatment—not meta-analyzed One single study [32] (n =
24) assessed cessation of vomiting 24 h after the administra-
tion of treatment. According to this RCT, treatment with
ondansetron was associated with a higher proportion of pa-
tients experiencing no emetic episodes over 24 h compared
with the placebo (7/12 vs 2/12, p = 0.039).
Secondary outcomes

Effects of interventions Failure of oral rehydration therapy during the emergency

department stay Five of the included RCTs [29, 30, 32, 33,
See Figs. 2–3 and Tables, ESM 4, Electronic Supplementary 35] (n = 679) reported data on the failure of oral rehydration
Material; Suppl Table 3. therapy during the emergency department stay. Pooled results
Table 1 Characteristics of the included studies

Author Setting (country) N° of Age range (mean, Ondansetron Outcomes

Eur J Pediatr

participants SD)
Route Dose

Cubeddu 1997 Children’s hospital 36 children 6 months to IV 0.3 mg/kg (single dose) Cessation of vomiting at 24 h
(Venezuela) (21 males, 15 females) 8 years. AEs
Danewa 2016 Emergency pediatric unit of a 170 children 3 months to Oral (syrup) 0.2 mg/kg (single dose) IV rehydration during ED
tertiary care hospital in (99 males, 71 females) 5 years stay
Delhi (India) AEs
Freedman 2006 Children’s hospital in 214 children 6 months to Oral (ODT) 8–15 kg: 2 mg; 15–30 kg: 4 mg; Cessation of vomiting at 8 h
Chicago (USA) (122 males, 92 10 years > 30 kg: 8 mg (single dose) IV rehydration during ED
females) stay
Hospitalization at 8 h
Return visit to ED
AEs
Freedman 2018 Emergency departments in 626 children 6 months to Oral (ODT) 8–15 kg: 2 mg; > 15 kg: 4 mg Cessation of vomiting at 8 h
two hospitals of Karachi (372 males, 254 5.0 years (single dose) IV rehydration during ED
(Pakistan) females) stay
Return visit to ED
AEs
Golshekan Emergency department of 176 children 1 to 10 years Oral (tablet) < 15 kg: 2 mg; 15–30 kg: 4 mg; Cessation of vomiting at 8 h
2013 Children s Hospital in (103 males, 73 > 30 kg: 6 mg (single dose) Hospitalization at 8 h
Rasht (Iran) females) Hospitalization at 48 h
AEs
Hagbom 2017 Emergency department of 81 children 6 months to Oral (syrup) 0.15 mg/kg (single dose) Number of diarrhea episodes
Queen Silvia Children’s (37 males, 44 females) 16 years at 24 h
Hospital in Gothenburg AEs
(Sweden)
Marchetti 2016 15 pediatric emergency 356 children 1 to 6 years Oral 0.15 mg/kg (single dose) Cessation of vomiting at 8 h
departments (Italy) (176 males, 180 (syrup) IV rehydration during ED
females) stay
Hospitalization at 8 h
Return visit to ED
AEs
Ramsook 2002 Emergency department of a 145 children 6 months to Oral (syrup) 1.6 mg every 8 h for patients aged Cessation of vomiting at 8 h
university-affiliated hospi- (82 males, 63 females) 12 years 6 months to 1 year, 3.2 mg IV rehydration during ED
tal in Texas (USA) every 8 h for patients aged 1 to stay
3 years, and 4 mg every 8 h for Return visit to ED
patients aged 4 to 12 years (six AEs
doses in total)
Rang 2019 Pediatric Ward of an Giang 61 children 11 to 60 months IV IV ondansetron at a dose of Cessation of vomiting at 8 h
General Hospital (South (35 males, 26 females) 0.2 mg/Kg up to maximal dose IV rehydration during ED
Vietnam) of 8 mg (single dose) stay
Number of diarrhea episodes
at 24 h
AEs
Rerksuppaphol Pediatric ward of the 74 children 3 months to IV 0.15 mg/kg up to maximal dose of Cessation of vomiting at 8 h
2010 Srinakharinwirot (38 males, 36 females) 15 years 8 mg (single dose)
University Hospital
(Thailand)
Roslund 2008 1 to 10 years Oral (ODT) Cessation of vomiting at 8 h
 Eur J Pediatr

Cessation of vomiting at 8 h
strongly favor the group who received ondansetron over pla-

IV rehydration during ED

IV rehydration during ED
cebo (RR 0.43, 95% CI 0.34 to 0.55; I 2 = 0%).

Hospitalization at 8 h
Hospitalization at 8 h
Return visit to ED
IV rehydration during the emergency department stay Eight
of the included RCTs [28, 30, 33–38] (n = 1662) reported data
Outcomes

stay on IV rehydration rates during the ED stay. Based on the

stay
AEs
pooled results of these studies, compared with the placebo,
the group treated with ondansetron had a significantly lower
chance of requiring IV rehydration during emergency depart-
ment stay (RR 0.44, 95% CI 0.34 to 0.57; I 2 = 0%).
< 15 kg: 2 mg; 15–30 kg: 4 mg;

0.2 mg/kg at 8 h intervals (three

>30 kg: 6 mg (single dose)

0.15 mg/kg (single dose)

Hospitalization within 8 h after the administration of the

treatment Five of the included RCTs [29, 33, 36, 38, 39]
(n = 823) reported data on hospitalization rates within 8 h of
doses in total)

administration of the treatment. Pooled results strongly favor

the group who received ondansetron over placebo (RR 0.49,
Dose

95% CI 0.32 to 0.75; I [2] = 0%).

Hospitalization 48 h after the administration of the

treatment—not meta-analyzed One study [29] (n = 135) re-
ported data on hospitalization rates at 48 h. The experimenters
Ondansetron

Oral (ODT)

found no statistically significant difference between treatment

and placebo groups (2/72 vs 2/65, p > 0.05).
Route

IV

Return visits to the ED Five of the included RCTs [33, 34,

36–38] (n = 764) reported data on the return visits to the ED
Age range (mean,

at any time after discharge. From the analysis, no statistically

significant differences were found between treatment and pla-
5 months to

5 months to
10 years

8 years

cebo groups (RR 1.14, 95% CI 0.74 to 1.76; I 2 = 0).

SD)

Number of diarrhea episodes 24 h after the administration of

the treatment—not meta-analyzed Two studies [28, 31] (n =
141) reported data on the number of diarrhea episodes 24 h
106 children (47 males,

137 children (74 males,

109 children (70 males,

after treatment administration. Hagbom and collegues [31]

found no differences in the number of events (number of in-
59 females)

63 females)

39 females)

cluded patients, 80; median ± IQR = 1.00 ± 5.00 vs 3.5 ± 9.00

participants

in drug and placebo group respectively; p = 0.063). Similarly,

N° of

Rang [28] reported that the number of diarrhea episodes did

not differ in the treatment group compared with the placebo
group (number of included patients, 61; median (range), 5 (2–
Emergency departments (one
medical center in Chicago

academic hospital (USA)

18) vs 6 (1–18); p = 0.913).

Emergency department of a
Emergency department of a

university hospital, one

government hospital)
single tertiary care

Adverse events—not meta-analyzed Of the 13 trials included

Setting (country)

in the review, 10 [28–37] reported on adverse events. In six of

ODT, orally disintegrating tablet

them [28, 29, 31, 35–37], therapy was well tolerated and ad-
(Turkey)
(USA)

verse events were similar in both groups. Cubeddu [32] (n =

ED, emergency department

24) found cough to be more frequent in the ondansetron treat-

ed group compared with the placebo group (3/12 vs. 0/12,
Table 1 (continued)

AEs, adverse events

respectively, RR 7.00; 95% CI 0.4 to 122.4); however, this

IV, intravenous

difference was not statistically significant. Ramsook [34] (n =

Yilmaz 2010
Stork 2006

145) reported the development of a macular rash in one patient

Author

30 min after receiving ondansetron; no urticaria or respiratory

symptoms were associated, and it was unclear whether this
Eur J Pediatr
Fig. 2 Forest plot of comparison: primary outcomes
rash was drug related or a viral exanthem. The same study
reported also higher numbers of diarrheal episodes at 24 and
48 h follow-up among patients who received ondansetron
when compared with those who received placebo (64 vs. 54,
p = 0.02; 62 vs. 51, p = 0.015, respectively). However, as it
was not possible to infer standard deviation from the study
data and the study protocol provided for a total of six doses
of ondansetron over 48 h, we did not include this outcome in
the final analysis. Freedman [33] reported more episodes of
diarrhea during ORT among patients who received
ondansetron when compared with the placebo group (1.4 vs.
0.5, p < 0.001), but this data was not included in the final
analysis owing to the absence of standard deviation and pop-
ulation size. No additional events were recorded. Finally,
Yilmaz [25] reported abdominal distension in a child in the
experimental group and higher rates of diarrheal episodes
while undergoing ORT between children who received
ondansetron than those who received placebo at 24 h (p =
0.04). However, as the study protocol provided for a total of
three doses of ondansetron at 8-h intervals, this outcome was
not included in the final analysis. Of note, none of the included
studies reviewed ECG characteristics of included patients.
Risk of bias across studies
Substantial heterogeneity was found among the studies in-
cluded in the primary outcome analysis. Using random-
effects analysis, it was found that at least a part of the hetero-
geneity was due to differences in age and proportion of males
included in the population in each RCT.
There was some asymmetry observed in the funnel plot for
the primary study outcome analysis, suggesting possible
publication bias or small study effects (See Figures, ESM 5,
Electronic Supplementary Material; Fig. 1).
Discussion
Summary of evidence
Previously published studies [9, 10, 40] provided some evi-
dence supporting the role of ondansetron in the treatment of
acute gastroenteritis in the pediatric population (see
Discussion, ESM 6, Electronic Supplementary Material). In
line with those, the trials included in this study provided low-
certainty evidence that appeared to favor a single dose of
ondansetron over placebo to augment the probability of ces-
sation of vomiting within 8 h after the administration of the
treatment. This meta-analysis also found high-certainty evi-
dence that a single oral dose of ondansetron was associated
with lower chances of oral rehydration therapy failures, IV
rehydration needs in the emergency department, and hospital-
ization rates at 8 h after study the treatment. No differences in
terms of return visits to the emergency department were
found. Because of the lack and wide heterogeneity of the
studies, the other prespecified outcomes could not be assessed
through the meta-analysis. However, the few included studies
that did report on this outcome observed that ondansetron is
associated with higher rates of vomiting resolution after 24 h
(one RCT) and does not produce any effect on the hospitali-
zation rates at 48 h (one RCT) or frequency of diarrhea at 24 h
(two RCTs). Furthermore, no clinically significant adverse
events could be linked to ondansetron use, after the analysis
of six RCTs.

Fig. 3 Forest plot of comparison: secondary outcomes
Strengths
Although past studies [9, 10, 40] have investigated
ondansetron for vomiting in children and adolescents with
acute gastroenteritis, analyses included data from studies
Eur J Pediatr
evaluating both one and multiple doses of the drug. To our
knowledge, this meta-analysis is the first comprehensive study
to examine the efficacy and adverse events of a single dose of
ondansetron given for acute gastroenteritis on strong and tem-
porally homogeneous clinical outcomes.
Eur J Pediatr
This meta-analysis suggests some perspectives for future
research. First, very few to no good-quality data were avail-
able for the two most relevant side effects of ondansetron (i.e.,
diarrhea and ECG modifications). With this respect, it remains
unclear whether QT prolongation associated to ondansetron is
intrinsic or, through electrolyte abnormalities, a diarrhea-
mediated effect [41, 42]. Second, owing to the limited number
of studies evaluating IV ondansetron administration (two
RCTs), a subgroup analysis addressing the impact of admin-
istration route (i.v. versus p.o.) on drug efficacy was not pos-
sible. Third, as vomiting may be influenced by the content and
palatability of fluid intake, the use of different oral rehydration
therapies across included studies poses a challenge and limits
data interpretation. A more standardized comparison should
be performed in future research. Finally, while at least one
economic analysis carried out in such setting showed that
the administration of oral ondansetron was associated with
lower direct and indirect costs compared with no pharmaco-
logical treatment [43], further studies addressing its cost-
effectiveness in the emergency department are desiderable.
Limitations
This meta-analysis has some limitations. First, for each out-
come included in the meta-analysis, the lack of enough evi-
dence along with the inclusion of some studies with high or
unclear risk of bias may have led to overestimates or under-
estimates of the reported effects. To address this issue, we
pooled together only data coming from series comparable in
study design, assessed the quality of evidence through a val-
idated tool, defined the level of certainty of evidence for each
outcome, and conducted a sensitivity analysis filtering for the
main source of bias found (i.e., absence of full masking).
Second, studies included in primary outcome analysis showed
to be heterogeneous; however, because of the magnitude and
direction of overall effects, such heterogeneity can be consid-
ered of limited statistical significance [24]. Third, the paucity
and heterogeneity of the studies prevented the estimation of
important moderator variables such as the age of the included
patients and the setting on the effect-sizes.
Conclusions
Mixed evidence suggests that ondansetron affects cessation of
vomiting, oral rehydration therapy failures, need for intrave-
nous rehydration, and hospitalization prevention in children
with acute gastroenteritis. No differences could be examined
in adverse events as the number of studies presenting these
outcomes in a homogenous way was limited, and further stud-
ies are necessary.
Authors’ contributions FF conceptualized and designed the study and
data collection instruments, collected data, carried out the primary and
secondary analyses, drafted the initial manuscript, and reviewed and re-
vised the manuscript.
EF designed the data collection instruments, collected data, carried out
the initial analyses, drafted the initial manuscript, and reviewed and re-
vised the manuscript.
CB/LP designed the data collection instruments, collected data, carried
out the initial analyses, drafted the initial manuscript, and reviewed and
revised the manuscript.
DG designed the data collection instruments, carried out the primary
and secondary analyses, drafted the initial manuscript, and reviewed and
revised the manuscript.
ML conceptualized and designed the study, coordinated and super-
vised data collection, carried out the secondary analyses, and critically
reviewed the manuscript for important intellectual content.
All authors approved the final manuscript as submitted and agree to be
accountable for all aspects of the work.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Funding There is no funding source.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
References
1. Elliot EJ (2007) Acute gastroenteritis in children. BMJ. 334(7583):
35–40
2. Van Damme P, Giaquinto C, Huet F et al (2007) Multicenter prospec-
tive study of the burden of rotavirus acute gastroenteritis in Europe,
2004-2005: the REVEAL study. J Infect Dis 195(1):S4–S16
3. King CK, Glass R, Bresee JS et al (2003) Managing acute gastro-
enteritis among children. MMWR Recomm Rep 52(RR16):1–16
4. Lorgelly PK, Joshi D, Iturriza Gómara M et al (2008) Infantile
gastroenteritis in the community: a cost-of-illness study.
Epidemiol Infect 136(1):34–43
5. Barker SF, Zomer E, O'Toole J et al (2018) Cost of gastroenteritis in
Australia: a healthcare perspective. PLoS One 13(4):e0195759
6. Majowicz SE, McNab WB, Sockett P et al (2006) Burden and cost of
gastroenteritis in a Canadian community. J Food Prot 69(3):651–659
7. GlaxoSmithKline, Research Triangle Park. Ondansetron (marketed as
Zofran) information. Food and Drug Administration (FDA). https://
www.accessdata.fda.gov/drugsatfda_docs/label/2016/020103s035_
020605s019_020781s019lbl.pdf. Accessed 11 Jul 2019
8. Guarino A, Ashkenazi S, Gendrel D, Lo Vecchio A, Shamir R,
Szajewska H, European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition, European Society for Pediatric
Infectious Diseases (2014) European Society for Pediatric
Gastroenterology, Hepatology, and nutrition/European Society for
Pediatric Infectious Diseases evidence-based guidelines for the
management of acute gastroenteritis in children in Europe: update
2014. J Pediatr Gastroenterol Nutr 59(1):132–152
9. Fedorowicz Z, Jagannath VA, Carter B (2011) Antiemetics for re-
ducing vomiting related to acute gastroenteritis in children and ad-
olescents. Cochrane Database Syst Rev 9:CD005506
10. Tomasik E, Ziółkowska E, Kołodziej M, Szajewska H (2016)
Systematic review with meta-analysis: ondansetron for vomiting

in children with acute gastroenteritis. Aliment Pharmacol Ther
44(5):438–446
11. Leung AK, Robson WL (2007) Acute gastroenteritis in children;
role of anti-emetic medication for gastroenteritis-related vomiting.
Pediatr Drugs 9:175–184
12. Li ST, DiGiuseppe D, Christakis DA (2003) Antiemetic use for
acute gastroenteritis in children. Arch Pediatr Adolesc Med 157:
475–479
13. Freedman SB, Uleryk E, Rumantir M, Finkelstein Y (2014)
Ondansetron and the risk of cardiac arrhythmias: a systematic re-
view and postmarketing analysis. Ann Emerg Med 64:19–25
14. U.S. Food and Drug Administration. FDA drug safety communica-
tion: new information regarding QT prolongation with ondansetron
(Zofran). https://www.fda.gov/Drugs/DrugSafety/ucm310190.htm.
Accessed 11 Jul 2019
15. Government of Canada. Recalls and Safety Alerts. ZOFRAN
(ondansetron) – Association with Changes in Electrical Activity
in the Heart – For Health Professionals, October 3, 2012. http://
www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/
15080a-eng.php. Accessed 11 Jul 2019
16. Cheng A (2011) Emergency department use of oral ondansetron for
acute gastroenteritis-related vomiting in infants and children.
Paediatr Child Health 16(3):177–179
17. Food and Drug Administration (FDA). https://www.fda.gov/drugs/
drug-safety-and-availability/fda-drug-safety-communication-
abnormal-heart-rhythms-may-be-associated-use-zofran-
ondansetron. Accessed Jul 11, 2019
18. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC,
Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D
(2009) The PRISMA statement for reporting systematic reviews
and meta-analyses of studies that evaluate health care interventions:
explanation and elaboration. J Clin Epidemiol 62(10):e1–e34
19. Greenhalgh T, Peacock R (2005) Effectiveness and efficiency of
search methods in systematic reviews of complex evidence: audit
of primary sources. BMJ. 331(7524):1064–1065
20. Roila F, Del Favero A (1995) Ondansetron clinical pharmacokinet-
ics. Clin Pharmacokinet 29(2):95–109
21. Mondick JT, Johnson BM, Haberer LJ, Sale ME, Adamson PC,
Coté CJ, Croop JM, Russo MW, Barrett JS, Hoke JF (2010)
Population pharmacokinetics of intravenous ondansetron in oncol-
ogy and surgical patients aged 1-48 months. Eur J Clin Pharmacol
66(1):77–86
22. Elkomy MH, Sultan P, Carvalho B, Peltz G, Wu M, Clavijo C,
Galinkin JL, Drover DR (2015) Ondansetron pharmacokinetics in
pregnant women and neonates: towards a new treatment for neona-
tal abstinence syndrome. Clin Pharmacol Ther 97(2):167–176
23. Blackwell CP, Harding SM (1989) The clinical pharmacology of
ondansetron. Eur J Cancer Clin Oncol 25(Suppl 1):S21–S24 dis-
cussion S25–7
24. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic
Reviews of Interventions. Version 5.1.0. http://handbook.
cochrane.org. Updated March 2011. Accessed 20 Jan 2019
25. Bender R, Lange S (2001) Adjusting for multiple testing–when and
how? J Clin Epidemiol 54(4):343–349
26. Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A
(2011) GRADE guidelines: a new series of articles in the journal of
clinical epidemiology. J Clin Epidemiol 64(4):380–382
27. Rerksuppaphol S, Rerksuppaphol L (2010) Efficacy of intravenous
ondansetron to prevent vomiting episodes in acute gastroenteritis: a
randomized, double blind, and controlled trial. Pediatr Rep 2:e17
28. Rang NN, Chanh TQ, My PT, Tien TTM (2019) Single-dose intra-
venous ondansetron in children with gastroenteritis: a randomized
controlled trial. Indian Pediatr 56(6):468–471
29. Golshekan K, Badeli H, Rezaieian S, Mohammadpour H,
Hassanzadehrad A (2013) Effect of oral ondansetron on decreasing
Eur J Pediatr
the vomiting associated with acute gastroenteritis in Iranian chil-
dren. Iran J Pediatr 23:557–563
30. Yilmaz HL, Yildizdas RD, Sertdemir Y (2010) Clinical trial: oral
ondansetron for reducing vomiting secondary to acute gastroenter-
itis in children – a double-blind randomized study. Aliment
Pharmacol Ther 31:82–91
31. Hagbom M, Novak D, Ekström M, Khalid Y, Andersson M, Lindh
M, Nordgren J, Svensson L (2017) Ondansetron treatment reduces
rotavirus symptoms-a randomized double-blinded placebo-con-
trolled trial. PLoS One 12(10):e0186824
32. Cubeddu LX, Trujillo LM, Talmaciu I et al (1997) Antiemetic ac-
tivity of ondansetron in acute gastroenteritis. Aliment Pharmacol
Ther 11:185–191
33. Freedman SB, Adler M, Seshadri R, Powell EC (2006) Oral
ondansetron for gastroenteritis in a pediatric emergency depart-
ment. N Engl J Med 354:1698–1705
34. Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D
(2002) A randomized clinical trial comparing oral ondansetron with
placebo in children with vomiting from acute gastroenteritis. Ann
Emerg Med 39:397–403
35. Danewa AS, Shah D, Batra P, Bhattacharya SK, Gupta P (2016)
Oral ondansetron in management of dehydrating diarrhea with
vomiting in children aged 3 months to 5 years: a randomized con-
trolled trial. J Pediatr 169:105–109
36. Marchetti F, Bonati M, Maestro A, Zanon D, Rovere F, Arrighini A,
Barbi E, Bertolani P, Biban P, da Dalt L, Guala A, Mazzoni E,
Pazzaglia A, Perri PF, Reale A, Renna S, Urbino AF, Valletta E,
Vitale A, Zangardi T, Clavenna A, Ronfani L, on behalf of the
SONDO (Study ONdansetron vs DOmperidone) Investigators
(2016) Oral Ondansetron versus domperidone for acute gastroen-
teritis in pediatric emergency departments: multicenter double blind
randomized controlled trial. PLoS One 11(11):e0165441
37. Freedman SB, Soofi SB, Willan AR, Williamson-Urquhart S, Ali
N, Xie J, Dawoud F, Bhutta ZA (2019) Oral Ondansetron admin-
istration to nondehydrated children with diarrhea and associated
vomiting in emergency Departments in Pakistan: a randomized
controlled trial. Ann Emerg Med 73(3):255–265
38. Roslund G, Hepps TS, McQuillen KK. The role of oral ondansetron
in children with vomiting as a result of acute gastritis/gastroenteritis
who have failed oral rehydration therapy: a randomized controlled
trial. Ann Emerg Med. 2008;52:22–9. Erratum in: Ann Emerg Med.
2008;52:406
39. Stork CM, Brown KM, Reilly TH, Secreti LL, Brown LH (2006)
Emergency department treatment of viral gastritis using intravenous
ondansetron or dexamethasone in children. Acad Emerg Med 13:
1027–1033
40. Canziani BC, Uestuener P, Fossali EF, Lava SAG, Bianchetti MG,
Agostoni C, Milani GP (2018) Clinical practice: nausea and
vomiting in acute gastroenteritis: physiopathology and manage-
ment. Eur J Pediatr 177:1–5
41. Hoffman RJ, Alansari K (2018) Effect of intravenous ondansetron
on QTc interval in children with gastroenteritis. Am J Emerg Med
36(5):754–757
42. Trefz FM, Lorch A, Feist M, Sauter-Louis C, Lorenz I (2013) The
prevalence and clinical relevance of hyperkalaemia in calves with
neonatal diarrhoea. Vet J 195(3):350–356. https://doi.org/10.1016/j.
tvjl.2012.07.002
43. Freedman SB, Steiner MJ, Chan KJ (2010) Oral ondansetron ad-
ministration in emergency departments to children with gastroen-
teritis: an economic analysis. PLoS Med 7(10):e1000350
Publisher’s note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.