PENGARUH OBAT KEMOTERAPI

1. Oral Ondansetron Administration to
Dehydrated Children in Pakistan: A
Randomized Clinical Trial
Stephen B. Freedman, MDCM, MSc,a
Sajid B. Soofi, FCPS,c
Andrew R. Willan, PhD,d
Sarah Williamson-Urquhart, BScKIN,b
Emaduddin Siddiqui, FCPS,c
Jianling Xie, MD,b
Fady Dawoud, MD,b
Zulfiqar A. Bhutta, PhDc,e
abstract
BACKGROUND: Ondansetron is an effective antiemetic employed to prevent vomiting in children
with gastroenteritis in high-income countries; data from low- and middle-income countries
are sparse.
METHODS: We conducted a randomized, double-blind, placebo-controlled superiority trial in 2
pediatric emergency departments in Pakistan. Dehydrated children aged 6 to 60 months with
$1 diarrheal (ie, loose or liquid) stool and $1 vomiting episode within the preceding 4 hours
were eligible to participate. Participants received a single weight-based dose of oral
ondansetron (8–15 kg: 2 mg; .15 kg: 4 mg) or identical placebo. The primary outcome was
intravenous administration of $20 mL/kg over 4 hours of an isotonic fluid within 72 hours of
random assignment.
RESULTS: All 918 (100%) randomly assigned children completed follow-up. Intravenous
rehydration was administered to 14.7% (68 of 462) and 19.5% (89 of 456) of those
administered ondansetron and placebo, respectively (difference: 24.8%; 95% confidence
interval [CI], 29.7% to 0.0%). In multivariable logistic regression analysis adjusted for other
antiemetic agents, antibiotics, zinc, and the number of vomiting episodes in the preceding
24 hours, children administered ondansetron had lower odds of the primary outcome (odds
ratio: 0.70; 95% CI, 0.49 to 1.00). Fewer children in the ondansetron, relative to the placebo
group vomited during the observation period (difference: 212.9%; 95% CI, 218.0% to
27.8%). The median number of vomiting episodes (P , .001) was lower in the
ondansetron group.
CONCLUSIONS: Among children with gastroenteritis-associated vomiting and dehydration, oral
ondansetron administration reduced vomiting and intravenous rehydration use. Ondansetron
use may be considered to promote oral rehydration therapy success among dehydrated
children in low- and middle-income countries.
WHAT’S KNOWN ON THIS SUBJECT: Ondansetron administration to dehydrated
children with gastroenteritis-associated vomiting in emergency departments in
high-income countries reduces vomiting and intravenous rehydration. Although it
is ineffective among well-hydrated children, evidence of efficacy in dehydrated
children in low- and middle-income countries is lacking.
WHAT THIS STUDY ADDS: Emergency department oral ondansetron administration
to dehydrated children with gastroenteritis-associated vomiting in Pakistan safely
reduces intravenous rehydration fluid administration and vomiting, and it should
be considered to promote oral rehydration therapy in this population.
To cite: Freedman SB, Soofi SB, Willan AR, et al. Oral
Ondansetron Administration to Dehydrated Children in
Pakistan: A Randomized Clinical Trial. Pediatrics. 2019;
144(6):e20192161
a
Sections of Pediatric Emergency Medicine and Gastroenterology, Department of Pediatrics, Alberta Children’s
Hospital and Alberta Children’s Hospital Research Institute and b
Section of Pediatric Emergency Medicine,
Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; c
Centre of
Excellence in Women and Child Health, The Aga Khan University, Karachi, Pakistan; d
Ontario Child Health Support
Unit, SickKids Research Institute, Toronto, Ontario, Canada; and e
Centre for Global Child Health, The Hospital for
Sick Children, Toronto, Ontario, Canada
This work was presented at the annual meeting of the Pediatric Academic Societies; April 24, 2019,
to May 1, 2019; Baltimore, MD.
PEDIATRICS Volume 144, number 6, December 2019:e20192161 ARTICLE
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

2. Globally, nearly 6 million children
,5 years of age still die annually.1
Despite advances in oral rehydration
therapy (ORT) and treatment of
diarrhea, some 500 000 of these
deaths are due to acute
gastroenteritis (AGE).1
Important
contributors to diarrhea-related
mortality include limited access to
services and the stagnated use of
ORT,2,3
particularly in the presence of
vomiting. In Pakistan, 80% of those
who develop severe dehydration have
persistent vomiting, with a high
frequency in the first 6 hours of
therapy.4
Although use of antiemetic
agents such as domperidone or
metoclopramide is commonplace,5,6
they are of limited benefit.7,8
A single oral dose of ondansetron
reduces vomiting and intravenous
rehydration use.9,10
Although
administration in high-income
countries is widespread,11–13
research on its use in low- and
middle-income countries (LMICs) is
limited but is necessary given the
differences in etiology, clinical
phenotypes,14
and complications.5
Consequently, there is a need to
determine if ondansetron can
enhance ORT success in a LMIC
setting.
We conducted 2 separate but linked
studies in Karachi Pakistan6
to answer
2 questions, and we planned a priori
to publish 2 unique reports. In the first
study, we reported that among
children without dehydration,15
there
were no benefits associated with
ondansetron use. In the second study,
we evaluated whether a single oral
ondansetron dose administered to
children with vomiting and
dehydration secondary to AGE reduces
the probability of intravenous
rehydration fluid administration
compared to the placebo.
METHODS
Design and Setting
We performed a 2-center, randomized,
double-blind, placebo-controlled
superiority trial (Fig 1) in the
emergency departments (EDs) of The
Aga Khan University Hospital for
Women and Children and The Aga
Khan University Hospital, Karachi,
Pakistan. Pediatric emergency
medicine trained physicians treat
∼10 000 and 5000 patients annually in
each of these institutions, respectively.
The study was approved by the ethics
committees of The Aga Khan
University and University of Calgary.
Study Population
Potentially eligible children were
consecutively screened by study-
funded research officers 24 hours/
day, 7 days/week. Eligible children
were aged 0.5 to 5.0 years, weighed
$8.0 kg, and had $1 episode of
diarrhea (ie, a minimum of 1 loose or
liquid stool) and $1 vomiting episode
within the 4 hours preceding triage.13
As previously performed,13
we
employed lower age and weight limits
because infants ,6 months of age are
more likely to have alternative
underlying etiologies (eg, urinary
tract infection), and 8.0 kg
corresponds to the weight at which
the smallest study dose (2 mg) can be
administered. Participants had
FIGURE 1
Consolidated Standards of Reporting Trials flow diagram. a
weight for height below -3z scores of the
median WHO growth standards. b
The one child that was lost to follow-up had complete data for 4
hour emergency department observation period. The child was included in the primary analysis as
he received . 20 ml/kg of intravenous fluids and thus experienced the outcome of interest.
2 FREEDMAN et al
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

3. “some” dehydration quantified by
using the World Health Organization
(WHO) dehydration tool,16,17
which
requires the presence of $2 of the
following: restlessness and/or
irritability, sunken eyes, drinking
eagerly and/or thirst, and skin pinch
retracts slowly.16
Children with the following were
excluded: severe dehydration, bloody
or bilious vomiting, hypotension,18
vomiting or diarrhea for .7 days,
previous abdominal surgery,
hypersensitivity to ondansetron or
any serotonin receptor antagonist,
personal or family history of
prolonged QT syndrome, taking
a medication listed as causing
torsades de pointes (https://
crediblemeds.org/index.php/login/
dlcheck:), previously enrolled in the
study, and those for whom follow-up
would not be possible. We excluded
children whose weight for height was
,23 z scores of the median WHO
growth standards because children
with malnutrition are at greater risk
of electrolyte abnormalities.19
Guardians of all participants provided
written informed consent.
Allocation
Children were randomly assigned to
receive a single ondansetron or
placebo oral disintegrating tablet
(ODT; both provided in-kind by
GlaxoSmithKline, Inc, Philadelphia,
PA) in a 1:1 ratio, stratified by age
(,18 and $18 months) and study
center by using variable block sizes of
4 and 6. Use of an Internet-based
randomization service facilitated
allocation concealment. The study
team was unaware of block sizes.
As is commonly performed in clinical
practice20
and trials,13
doses were
weight based: 8 to 15 kg received
a dose of 2 mg; .15 kg received
a dose of 4 mg. Within the dose range
of 0.13 to 0.26 mg/kg, higher doses of
ondansetron are not superior to
lower doses nor are they associated
with increased side effects.21
The
ODT was placed on the top of each
child’s tongue, and the child was
instructed to swallow 5 seconds
later.13
Fifteen minutes after ODT
administration, ORT was initiated.
Children who vomited $1 times
during that interval received a repeat
dose.13
Blinded individuals included
the ED physicians, research officers,
families, patients, and on-site
pharmacists. The placebo and active
ODTs were of identical size,
appearance, taste, and smell.13
A prespecified computer-generated
randomization list with associated kit
numbers was sent from www.
randomize.net via password-
protected files to the research
pharmacist who prepared, packed,
and shipped all drug kits. At
enrollment, www.randomize.net
randomly selected a kit number from
the remaining kits containing the
assigned treatment. Each kit
contained two 4-mg ondansetron or
placebo ODTs (cut in half if needed to
provide a 2-mg dose) including 1
extra dose in case a repeat dose was
required. If the extra dose was
vomited, no additional medications
were provided.
Study Interventions
Aside from study interventions,
participants received therapy in
keeping with WHO recommendations.
Concomitant medication
administration was at the discretion
of the clinical team. The protocol
emphasized a targeted weight-based
ORT protocol during the 4-hour
observation period and caregiver
education regarding oral rehydration
solution (ORS) administration.
Breastfeeding continued ad lib in
addition to giving WHO ORS. If the
child vomited, caregivers waited
10 minutes and then resumed giving
ORS more slowly. Children whose
dehydration, assessed by using the
WHO tool, had resolved were
discharged; those with some
dehydration after 4 hours had ORT
treatment repeated for another
4 hours with food administration.
Should children deteriorate and
develop “severe” dehydration, rapid
intravenous rehydration was
administered.12,21
The need for
hospitalization was determined by
the treating physician. Postdischarge
care was in keeping with WHO
recommendations.16
Caregivers
whose children were suitable for
discharge were provided with a 2-day
supply of ORS and were instructed to
give as much fluid as the child desired
to prevent dehydration. To reduce the
likelihood of persistent diarrhea,
participants were also provided with
a 2-week supply of 20-mg zinc tablets
to be administered daily for 14
days.22
Caregivers were instructed to
initiate zinc therapy a minimum of
30 minutes after study drug
administration.
Data
Data were collected by research
officers. During the 4-hour study
observation period, the following
were recorded every 60 minutes: oral
intake, intravenous fluids, and
episodes of vomiting, diarrhea, and
urination. We placed urine collection
bags on children who could not
urinate into measurement containers.
Stool was quantified by weighing
diapers for infants and toddlers and
the use of collection devices for
children who were toilet trained.
Although the WHO tool was employed
to assess dehydration regarding
eligibility, we employed the clinical
dehydration scale (CDS) score23,24
to
perform repeat dehydration
assessments during ED monitoring
because the CDS allows for a better
quantification of dehydration and
thus is better suited to serve as
a covariate during analysis.
Participants were reassessed
24 hours after discharge at their
home or the enrolling institution. If
there were no signs of dehydration
and vomiting and diarrhea had
resolved, 48- and 72-hour follow-up
was done by telephone. For children
with ongoing symptoms or signs of
PEDIATRICS Volume 144, number 6, December 2019 3
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

4. dehydration, a repeat in-person
reassessment in 24 hours was
required.
Study Outcomes
The primary outcome was
intravenous rehydration defined as
the administration of $20 mL/kg
over 4 hours of an isotonic fluid for
the purpose of rehydration within
72 hours of random assignment. This
outcome was selected because we
sought to include only those who had
an intravenous line inserted for
hydration purposes. It excludes those
who received only maintenance fluids
and those who had the intravenous
line inserted for medication
administration, while capturing those
who received brief bolus fluid
therapy or greater-than-maintenance
fluids for several hours. The 72-hour
time frame balances the potential
benefits and side effects of
ondansetron.
Secondary outcomes identified
a priori were the (1) presence and (2)
frequency of vomiting during the 4-
hour observation period, (3)
hospitalization for .24 hours defined
as the interval from ED arrival to
hospital discharge, (4) volume of ORS
consumed during the 4-hour
observation period, (5) presence of
some dehydration at any time after
discharge up to the 72-hour follow-up
assessment, and (6) number of
diarrheal (ie, loose or liquid) stools
during the 72 hours after random
assignment. The composite outcome
of treatment failure includes
intravenous rehydration, nasogastric
rehydration for .24 hours, or death
within 72 hours. Nasogastric
rehydration was included in our
composite outcome measure because
it is preferred to intravenous
rehydration as second-line
rehydration treatment, after ORT, in
numerous guidelines.25
Statistical Analysis
The planned sample size of 868
patients was estimated to provide
90% power to detect an absolute
between-group difference of 10% in
the risk of receiving $20 mL/kg over
4 hours of an isotonic fluid for the
purpose of rehydration within
72 hours of random assignment (risk
ratio: 0.67) at a baseline risk of 30%
(under the assumption of a 2-sided
5% level of significance) and a lack of
primary outcome ascertainment of
5%. The consensus among
investigators was that the probability
of intravenous rehydration among
children administered the placebo
was higher than the 17% previously
reported by the International Study
Group on Reduced-Osmolarity ORS26
because all study participants have
some dehydration. On the basis of
local expert opinion, sample size
calculations employed a minimally
clinically important difference of
TABLE 1 Baseline Clinical Characteristics of Participants by Treatment Group
Ondansetron, n = 462 Placebo, n = 456
Age, mo 18 (12–30) 18 (12–29)
Male 271 (58.7) 279 (61.2)
Wt, kg 10.0 (8.6–12.0) 10.0 (8.6–12.0)
Chronic medical conditions 0 5 (1.1)
Time interval, last vomit to medication administration, h 1.5 (0.8–2.5) 1.6 (0.8–2.7)
Maximal vomit episodes per 24-h period 5 (3–6) 5 (3–7)
Vomit episodes in past 24 h 4 (3–6) 4 (3–6)
Vomiting duration, d 1 (1–2) 1 (1–2)
Maximal diarrheal episodes per 24-h period 4 (2–6) 3 (2–6)
Diarrheal episodes in past 24 h 3 (2–5) 3 (2–5)
Diarrhea duration, d 1 (1–2) 1 (1–2)
Fevera
122 (26.4) 104 (22.8)
Previous ED visit, current illness 60 (13.0) 62 (13.6)
Previous intravenous rehydration, current illness 20 (4.3) 25 (5.5)
Previous hospitalization, current illness 4 (0.9) 6 (1.3)
Medications administered, past 24 hb
Antacids
Omeprazole and/or ranitidine 4 (0.9) 4 (0.9)
Antipyretics 51 (11.0) 46 (10.1)
Acetaminophen 45 (9.7) 44 (9.6)
Ibuprofen 6 (1.3) 6 (1.3)
Antibiotics and/or antihelminthics 69 (14.9) 60 (13.2)
Azithromycin and/or clarithromycin 1 (0.2) 0 (0)
Amoxicillin and/or ampicillin 1 (0.2) 1 (0.2)
Cefixime and/or cefotaxime/ceftriaxone 31 (6.7) 25 (5.5)
Diloxanide and/or mebendazole 6 (1.3) 10 (2.2)
Metronidazole 41 (8.9) 36 (7.9)
Other 8 (1.7) 3 (0.7)
Antiemetics 97 (21.0) 86 (18.9)
Dimenhydrinate 32 (6.9) 31 (6.8)
Domperidone 76 (16.5) 63 (13.8)
Metoclopramide 1 (0.2) 4 (0.9)
Antihistamines and/or anticholinergics
Cetirizine, clemastine, cyclizine, and/or
diphenhydramine
9 (1.9) 10 (2.2)
Nutrition
Zinc 10 (2.2) 14 (3.1)
Probiotics
Saccharomyces boulardii and/or Lactobacilus
aicdophilus
13 (2.8) 14 (3.1)
Rotavirus vaccine received 201 (43.5) 193 (42.3)
Exclusively breastfed 14 (3.0) 9 (2.0)
CDS score23
2 (2–3) 2 (2–3)
Data are n (%) or median (IQR).
a Fever was defined as an adjusted rectal temperature of $38.0°C. Axillary and oral temperatures were adjusted to rectal
temperatures by adding 1.1°C and 0.6°C, respectively.27
b Some children received .1 medication in the past 24 h.
4 FREEDMAN et al
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

5. 10%. Because of delays in data entry
and concerns about completeness, an
additional 50 patients were recruited.
Full outcome data were not available
until the final analysis. All children
randomly assigned were included in
the primary and secondary analyses.
Analyses were undertaken by
intention-to-treat principles. The
proportion of children receiving
intravenous rehydration by 72 hours
was analyzed by using a Mantel-
Haenszel test, stratified by clinical
center and age. Prespecified subgroup
analyses based on subject age,
duration of illness, and baseline
diarrhea and vomiting frequency in
the preceding 24 hours were
conducted. Secondary analysis of the
primary outcome employed
a multivariable logistic regression
model fitted with treatment group
and baseline covariates (ie,
antiemetic, antibiotics, zinc
administration before random
assignment, and the number of
vomiting episodes in 24 hours before
random assignment), which
potentially predict intravenous
rehydration and were associated with
the outcome.
The Mantel-Haenszel test, stratified
by clinical center, was used to analyze
the secondary outcomes of vomiting
(yes or no), hospitalization, presence
of some dehydration recurring within
72 hours, and treatment failure. The
van Elteren test, stratified by clinical
center, was used for the continuous
variables of vomiting frequency,
volume of ORS consumed, and
diarrheal stool frequency.
Because missing baseline values were
present in ,1% of cases, imputation
was not required. A Bonferroni
correction was used to correct for
multiple comparisons, and adjusted P
values are reported. The analysis plan
was prespecified in the protocol and
was performed with SPSS version
22.0 (IBM SPSS Statistics, IBM
Corporation) and SAS version 9.4
(SAS Institute, Inc, Cary, NC).
RESULTS
Among 918 randomly assigned
children (median age, 18.0
[interquartile range (IQR), 12.0–30.0]
months) recruited between June 5,
2014, and December 12, 2017 (Fig 1),
462 were assigned to ondansetron
and 456 to placebo. Baseline
characteristics (Table 1), laboratory
parameters (Supplemental Table 5),
and cointerventions (Table 2) were
similar between groups. The
intervention or placebo medication
was vomited by 3.5% (16 of 462) and
3.7% (17/456) of those in the
ondansetron and placebo groups,
respectively. Primary outcome data
were available for 100% (918 of
918) of study participants; 72-hour
follow-up was completed for 99.9%
(917 of 918; Supplemental Table 6).
Overall, 20.9% (192 of 918) of
children had an intravenous cannula
inserted during the study period
(placebo: 105 of 456 [23.0%];
ondansetron: 87 of 462 [18.8%]; OR:
0.77; 95% confidence interval [CI],
0.56 to 1.07).
Primary Outcome
The administration of $20 mL/kg
over 4 hours of an intravenous
rehydration solution within 72 hours
of random assignment occurred in
14.7% (68 of 462) vs 19.5% (89 of
456) of those in the ondansetron and
placebo groups, respectively (odds
ratio [OR]: 0.71; 95% CI, 0.50 to 1.00;
difference: 4.8%; 95% CI, 0.0% to
9.7%; Table 3). Employing
a multivariable logistic regression
model fitted with the treatment group
and adjusted for the administration of
other antiemetics, antibiotics, and
zinc before random assignment
(Supplemental Tables 7 and 8) and
the number of vomiting episodes in
the preceding 24 hours yielded an OR
of 0.70 (95% CI, 0.49 to 1.00) in favor
of the ondansetron treatment arm.
Antibiotic administration (OR: 1.75;
95% CI, 1.08 to 2.84) and the number
of vomit episodes in the preceding
24 hours (OR: 1.12; 95% CI, 1.06 to
1.19 per episode) were also
associated with intravenous
rehydration (Supplemental Tables 7
TABLE 2 ED and Discharge Cointerventions
Ondansetron
(n = 462), n (%)
Placebo
(n = 456), n (%)
Antacid in the ED 10 (2.2) 26 (5.7)
Omeprazole 10 (2.2) 25 (5.5)
Ranitidine 0 (0) 1 (0.2)
Antibiotic in the ED 114 (24.7) 99 (21.7)
Amoxicillin 5 (1.1) 1 (0.2)
Azithromycin 5 (1.1) 12 (2.6)
Cefixime 28 (6.1) 18 (3.9)
Ceftriaxone 38 (8.2) 39 (8.6)
Ciprofloxacin 20 (4.3) 10 (2.2)
Metronidazole 22 (4.8) 24 (5.3)
Antibiotic recommended at discharge or given after discharge 112 (24.2) 98 (21.5)
Any antibiotics during the whole study period 125 (27.1) 109 (23.9)
Antiemetic in the ED 168 (36.4) 180 (39.5)
Dimenhydrinate 1 (0.2) 2 (0.4)
Domperidone 154 (33.3) 157 (34.4)
Ondansetron 18 (3.9) 28 (6.1)
Metoclopramide 1 (0.2) 1 (0.2)
Antihistamine in the ED
Cetirizine 5 (1.1) 3 (0.7)
Antipyretic in the ED 82 (17.7) 69 (15.1)
Acetaminophen 59 (12.8) 52 (11.4)
Ibuprofen 25 (5.4) 18 (3.9)
Other in the ED
Saccharomyces boulardii 119 (25.8) 117 (25.7)
Zinc 84 (18.2) 73 (16.0)
PEDIATRICS Volume 144, number 6, December 2019 5
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

6. and 8). There was no evidence of
interaction between treatment
group and age (Fig 2), presence
of $3 diarrheal stools in the
preceding 24 hours, or presence of
$3 vomits in the preceding 24 hours
(Table 4, Supplemental Tables 9
and 10).
Secondary Outcomes
Overall, 13.2% (61 of 462) of
children in the ondansetron group
vomited during the 4-hour
observation period compared with
26.1% (119 of 456) in the placebo
group (OR: 0.43; 95% CI, 0.31 to 0.61;
difference: 12.9%; 95% CI: 7.8% to
18.0%; Table 3, Fig 3). There were
fewer vomiting episodes in the
ondansetron group (P , .001;
Table 3) but no difference in the
volume of oral fluids consumed
during the observation period. The
proportion of children hospitalized
.24 hours and that had some
dehydration develop at any time up
to 72 hours after discharge did not
differ between groups. The number of
diarrheal stools during the 72-hour
follow-up period and the median
volume of diarrhea during the 4-hour
observation period were similar
between groups. Primary and
secondary outcomes were similar at
both study sites (Supplemental
Tables 9–11).
Adverse Events
No serious adverse events or
admissions to the step-down units or
ICUs were reported. Reported
adverse events were similar between
groups (Supplemental Table 11).
DISCUSSION
In this 2-center trial, young children
with some dehydration were less
likely to receive intravenous
rehydration if they received
ondansetron compared with children
who received the placebo. This effect
stems from the reduction in vomiting
associated with ondansetron
administration. These results are
TABLE 3 Participant Clinical Outcomes by Treatment Group
Data are n (%) or median (IQR) unless otherwise stated. N/A, not applicable.
a P values presented for secondary outcomes are adjusted by using the Bonferroni correction procedure; for secondary outcomes, adjustment was performed for 7 comparisons; for
other outcomes, adjustment was performed for 11 comparisons. Statistical tests performed were either the van Elteren test stratified by enrollment center and age (,18 and $18
mo) (continuous variables) or the Cochran-Mantel-Haenszel test stratified by enrollment center and age (,18 and $18 mo) (categorical variables).
b Hospital length of stay was defined as a total length of stay from the ED arrival until discharge.
c Dehydration status was assessed employing the WHO dehydration assessment approach.
d Diarrhea was defined as loose or liquid stools.
e Treatment failure is a composite outcome measure that includes children who experienced any of the following: intravenous rehydration ($20 mL/kg per 4 h), nasogastric
rehydration for .24 h, death within 72 h from any cause, in or out of hospital. No children experienced the outcome of death or nasogastric rehydration.
6 FREEDMAN et al
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

7. important because .500 000
children continue to die each year
from AGE,1
and most deaths in LMICs
could be prevented by the use of
known and cost-effective
interventions.28
The evidence from
this study has the potential to lead to
further evaluations in more rural
contexts where a disproportionate
number of children die.29
It is important to consider our results
in the context of the companion study
that included 626 children without
dehydration in which the authors
identified no benefits associated with
ondansetron administration.15
Participants in the current study were
older, had more frequent vomiting,
and higher CDS scores. They were
thus more likely to benefit from an
effective antiemetic. Although the
absolute reduction in intravenous
rehydration use was lower than
anticipated, the reduction was
significant, and the number needed to
treat is 21. The benefits are
symptomatically meaningful with the
number needed to treat to prevent
vomiting being 8. Because these
benefits are in keeping with findings
FIGURE 2
Impact of age in 6-month increments on the primary outcome. IVF, intravenous fluid.
TABLE 4 A Priori Specified Subgroup Analysis of the Primary Outcome
n Ondansetron, n (%) Placebo, n (%) OR (95% CI) Pa
Baseline diarrhea episodes in a 24-h period
$3 episodes 556 50 (17.4) 60 (22.3) 0.75 (0.49 to 1.15) ..99
,3 episodes 362 18 (10.3) 29 (15.5) 0.58 (0.31 to 1.10) .57
Age
,18 mo 449 34 (15.2) 49 (21.7) 0.62 (0.38 to 1.02) .35
$18 mo 469 34 (14.2) 40 (17.4) 0.81 (0.49 to 1.34) ..99
Baseline duration of illness
,48 h 475 38 (15.5) 34 (14.8) 1.07 (0.65 to 1.78) ..99
$48 h 443 30 (13.8) 55 (24.3) 0.46 (0.28 to 0.71) .02
The statistical test performed was the Cochran-Mantel-Haenszel test stratified by the enrollment center.
a P values presented are adjusted by using the Bonferroni correction procedure for 6 comparisons.
PEDIATRICS Volume 144, number 6, December 2019 7
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

8. from high-income countries where
the absolute reductions in vomiting
and intravenous rehydration are 25%
and 19%, respectively,30
ondansetron
use may be considered to promote
ORT success in children similar to
those enrolled in our study.
The lower than anticipated
intravenous rehydration rate likely
relates to the baseline frequency of
vomiting, which was lower than
anticipated. The median frequency of
vomiting in the preceding 24 hours
was only 4; other reports have
exceeded 9.13,31
The connection
between ondansetron benefits and
vomiting frequency is highlighted by
our multivariable regression model
that retained vomiting frequency as
an independent predictor of
treatment failure. Although it is also
possible that concomitant antiemetic
administration (ie, domperidone)
may have played a role, authors of
most studies have found it to be
ineffective.7,8
Additionally, it may be
that in this academic tertiary care
center, there was greater adherence
to guidelines with an emphasis on
ORT, and the use of higher
thresholds for intravenous
rehydration may be in routine use
than in earlier reports.
In Delhi, India,17
25% of children
with some dehydration who were
administered the placebo received
intravenous fluids compared with
14% of children who were
administered ondansetron (relative
risk: 0.56). Benefits attributed to
ondansetron administration included
expedited resolution of dehydration,
reduced vomiting, and greater
satisfaction.17
Thus, our findings,
supported by previous LMIC work17
and evidence from high-income
countries,10
lead to the conclusion
that despite being of borderline
statistical significance,32
it is highly
likely that ondansetron
administration to children with
dehydration is beneficial in resource-
poor settings. Identification of an
effective antiemetic in this setting is
important because although
domperidone has been revealed to be
ineffective at treating gastroenteritis-
associated vomiting,7,8
it is routinely
employed in LMICs. This is likely
because of the propensity for self-
medication in LMICs,33
the desire to
treat vomiting in children with
dehydration, and the widespread34
belief that domperidone is
effective.8,35
Because both
ondansetron and domperidone are
readily available in Pakistan,
educational efforts disseminating
recent evidence are needed to
improve care.
Antibiotic use was common in our
study. It is indicated in recent reports
in the region that antimicrobial
agents are prescribed to nearly 40%
of children with acute watery
diarrhea due to viral pathogens and
60% of unknown etiology.36
The
excessive use of antimicrobial agents
in Southeast Asia has led to
a resistance crisis.37
Our findings
further these concerns with use also
being associated with increased
intravenous rehydration usage (OR:
1.75; 95% CI, 1.08 to 2.84), which
may reflect the propensity of
antibiotics to cause diarrhea in
exposed children.38
Although we had intended to conduct
stool microbial analyses, because of
an insufficient number of specimens
submitted, this objective was not
completed. Although not different
between groups, the extensive
coadministration of antiemetics such
as domperidone was not anticipated.
Although a more restrictive approach
to concomitant medication use could
have been employed, we focused on
conducting a pragmatic real-world
trial.39
Although, in theory,
concomitant antiemetic use could
have influenced the outcomes of the
study because this was a randomized
clinical trial, it is unlikely to have
altered the effect of the intervention.
Moreover, we incorporated this
covariate in regression models to
further minimize any impact it may
have had. It should be noted that
dehydration assessment using clinical
scores is suboptimal.40
Although
concerns have been raised regarding
use of the WHO dehydration tool,41
in
keeping with local standards of care,
we used it to determine eligibility.
The CDS score23,24
was used to assess
dehydration as an outcome because,
unlike the WHO tool, it can be
employed as a quantitative tool.
Future studies investigating
FIGURE 3
Number of vomiting episodes during the 4 hours after study drug administration.
8 FREEDMAN et al
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

9. ondansetron use barriers in LMIC
settings are needed.
CONCLUSIONS
Among children with gastroenteritis-
associated vomiting and dehydration,
oral ondansetron administration
reduces vomiting and intravenous
rehydration use. These findings
should be replicated in a larger
multicenter trial, and if successful,
ondansetron use should be
considered to promote ORT success
among dehydrated children in LMICs.
ACKNOWLEDGMENTS
We thank the extended study team
based at the Alberta Children’s
Hospital, Calgary, Alberta, Canada,
and the team based in Karachi,
Pakistan. We also thank our funders:
(1) the Thrasher Research Fund
(award 10025), (2) Bill and Melinda
Gates Foundation (grant
OPP1058793), and (3) Alberta
Children’s Hospital Foundation.
We also thank GlaxoSmithKline, Inc,
for supplying the study drug and
placebo.
ABBREVIATIONS
AGE: acute gastroenteritis
CDS: clinical dehydrationscale
CI: confidence interval
ED: emergency department
IQR: interquartile range
LMIC: low- and middle-income
country
ODT: oral disintegrating tablet
OR: odds ratio
ORS: oral rehydration solution
ORT: oral rehydration therapy
WHO: World Health Organization
Dr Freedman designed, conceived, and developed the trial, secured funding, oversaw all aspects of data collection analysis, wrote the manuscript, had full access to
all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis; Dr Soofi executed the trial, recruited patients,
acquired data, was a treating clinician, and critically revised the manuscript; Dr Willan wrote the statistical plan, analyzed the data, and critically revised the
manuscript; Ms Williamson-Urquhart developed and executed the trial, oversaw all aspects of data collection and analysis, and critically revised the manuscript; Dr
Siddiqui executed the trial, performed data extraction (entering and monitoring), oversaw local data collection, and critically revised the manuscript; Dr Xie
analyzed data and critically revised the manuscript; Dr Dawood monitored data entry, performed query management, reviewed data for accuracy, and prepared the
data for analysis; Dr Bhutta designed, conceived, and developed the trial, secured funding, and critically revised the manuscript; and all authors approved the final
manuscript as submitted and agree to be accountable for all aspects of the work.
The authors of this trial commit to making requested, deidentified participant data (including data dictionaries) and study protocols, the statistical analysis plan,
and the informed consent form available after reasonable request after publication of the manuscript up until 5 years after publication. Requests for access to data
require evidence of ethics approval of a methodologically sound proposal for use, and data sharing agreements must be in place. Requests should be addressed to
the corresponding author at stephen.freedman@ahs.ca.
The lead author (S.B.F.) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported, no important aspects of the study
have been omitted, and any discrepancies from the study as planned (and, if relevant, registered) have been explained.
This trial has been registered at www.clinicaltrials.gov (identifier NCT01870648).
DOI: https://doi.org/10.1542/peds.2019-2161
Accepted for publication Sep 4, 2019
Address correspondence to Stephen B. Freedman, MDCM, MSc, Alberta Children’s Hospital Research Institute, Alberta Children’s Hospital, University of Calgary, 28
Oki Drive NW, Calgary, AB, Canada T3B 6A8. E-mail: stephen.freedman@ahs.ca
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2019 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Funded by the Bill and Melinda Gates Foundation, the Thrasher Research Fund, and the Alberta Children’s Hospital Foundation. Dr Freedman is the Alberta
Children’s Hospital Foundation Professor in Child Health and Wellness. None of the study funders played any role in the study design, data collection, data analysis,
data interpretation, or writing of the article. The corresponding author had full access to all the data in the study, takes responsibility for the integrity of the data
and the accuracy of the data analysis, and had final responsibility for the decision to submit for publication. The researchers conducted the work independently of
the funders.
POTENTIAL CONFLICT OF INTEREST: The authors declare in-kind support in the form of provision of the study drug and placebo by GlaxoSmithKline, Inc; Dr
Freedman provides consultancy services to Takeda Pharmaceutical Company, Ltd.
REFERENCES
1. Liu L, Oza S, Hogan D, et al. Global,
regional, and national causes of under-
5 mortality in 2000-15: an updated
systematic analysis with implications
for the Sustainable Development Goals.
Lancet. 2016;388(10063):3027–3035
2. Countdown to 2030 Collaboration.
Countdown to 2030: tracking progress
towards universal coverage for
PEDIATRICS Volume 144, number 6, December 2019 9
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

10. reproductive, maternal, newborn, and
child health. Lancet. 2018;391(10129):
1538–1548
3. United Nations Children’s Fund.
Diarrhoeal disease. Available at: https://
data.unicef.org/topic/child-health/
diarrhoeal-disease/. Accessed June 11,
2019
4. Ibrahim S, Isani Z. Sagodana based
verses rice based oral rehydration
solution in the management of acute
diarrhoea in Pakistani children. J Pak
Med Assoc. 1997;47(1):16–19
5. Rahman AE, Moinuddin M, Molla M,
et al; Persistent Diarrhoea Research
Group. Childhood diarrhoeal deaths in
seven low- and middle-income
countries. Bull World Health Organ.
2014;92(9):664–671
6. . The World Bank Group. World bank
country and lending groups. Available
at: https://datahelpdesk.worldbank.
org/knowledgebase/articles/906519.
Accessed June 11, 2019w
7. Leitz G, Hu P, Appiani C, et al. Safety and
efficacy of low dose domperidone for
treating nausea and vomiting due to
acute gastroenteritis in children
[published online ahead of print June 7,
2019]. J Pediatr Gastroenterol Nutr. doi:
10.1097/MPG.0000000000002409
8. Marchetti F, Bonati M, Maestro A, et al;
SONDO (Study Ondansetron vs
Domperidone) Investigators. Oral
ondansetron versus domperidone for
acute gastroenteritis in pediatric
emergency departments: multicenter
double blind randomized controlled
trial. PLoS One. 2016;11(11):e0165441
9. Carter B, Fedorowicz Z. Antiemetic
treatment for acute gastroenteritis in
children: an updated Cochrane
systematic review with meta-analysis
and mixed treatment comparison in
a Bayesian framework. BMJ Open. 2012;
2(4):e000622
10. Freedman SB, Pasichnyk D, Black KJ,
et al; Pediatric Emergency Research
Canada Gastroenteritis Study Group.
Gastroenteritis therapies in developed
countries: systematic review and meta-
analysis. PLoS One. 2015;10(6):e0128754
11. Rutman L, Klein EJ, Brown JC. Clinical
pathway produces sustained
improvement in acute gastroenteritis
care. Pediatrics. 2017;140(4):e20164310
12. Hendrickson MA, Zaremba J, Wey AR,
Gaillard PR, Kharbanda AB. The use of
a triage-based protocol for oral
rehydration in a pediatric emergency
department. Pediatr Emerg Care. 2018;
34(4):227–232
13. Freedman SB, Adler M, Seshadri R,
Powell EC. Oral ondansetron for
gastroenteritis in a pediatric
emergency department. N Engl J Med.
2006;354(16):1698–1705
14. Platts-Mills JA, Liu J, Rogawski ET, et al;
MAL-ED Network Investigators. Use of
quantitative molecular diagnostic
methods to assess the aetiology,
burden, and clinical characteristics of
diarrhoea in children in low-resource
settings: a reanalysis of the MAL-ED
cohort study. Lancet Glob Health. 2018;
6(12):e1309–e1318
15. Freedman SB, Soofi SB, Willan AR, et al.
Oral ondansetron administration to
nondehydrated children with diarrhea
and associated vomiting in emergency
departments in Pakistan: a randomized
controlled trial. Ann Emerg Med. 2019;
73(3):255–265
16. World Health Organization. Pocket Book
of Hospital Care for Children:
Guidelines for the Management of
Common Childhood Illnesses, 2nd ed.
Geneva, Switzerland: World Health
Organization Press; 2013:125–146
17. Danewa AS, Shah D, Batra P,
Bhattacharya SK, Gupta P. Oral
ondansetron in management of
dehydrating diarrhea with vomiting in
children aged 3 months to 5 years:
a randomized controlled trial. J Pediatr.
2016;169:105–109.e3
18. Kleinman ME, Chameides L,
Schexnayder SM, et al. Part 14:
pediatric advanced life support: 2010
American Heart Association Guidelines
for Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care.
Circulation. 2010;122(18 suppl 3):
S876–S908
19. Freedman SB, Uleryk E, Rumantir M,
Finkelstein Y. Ondansetron and the risk
of cardiac arrhythmias: a systematic
review and postmarketing analysis. Ann
Emerg Med. 2014;64(1):19–25.e6
20. Cheng A. Emergency department use of
oral ondansetron for acute
gastroenteritis-related vomiting in
infants and children. Paediatr Child
Health. 2011;16(3):177–182
21. Freedman SB, Powell EC, Nava-Ocampo
AA, Finkelstein Y. Ondansetron dosing in
pediatric gastroenteritis: a prospective
cohort, dose-response study. Paediatr
Drugs. 2010;12(6):405–410
22. Lazzerini M, Wanzira H. Oral zinc for
treating diarrhoea in children.
Cochrane Database Syst Rev. 2016;12:
CD005436
23. Friedman JN, Goldman RD, Srivastava R,
Parkin PC. Development of a clinical
dehydration scale for use in children
between 1 and 36 months of age.
J Pediatr. 2004;145(2):201–207
24. Tam RK, Wong H, Plint A, Lepage N, Filler
G. Comparison of clinical and
biochemical markers of dehydration
with the clinical dehydration scale in
children: a case comparison trial. BMC
Pediatr. 2014;14:149
25. Lo Vecchio A, Dias JA, Berkley JA, et al.
Comparison of recommendations in
clinical practice guidelines for acute
gastroenteritis in children. J Pediatr
Gastroenterol Nutr. 2016;63(2):226–235
26. International Study Group on Reduced-
Osmolarity ORS Solutions. Multicentre
evaluation of reduced-osmolarity oral
rehydration salts solution. Lancet. 1995;
345(8945):282–285
27. Alpern ER, Henretig FM. Fever. In:
Fleisher GR, Ludwig S, Henretig FM, eds.
Textbook of Pediatric Emergency
Medicine, 5th ed. Philadelphia, PA:
Lippincott Williams and Wilkins; 2006:
295–306
28. World Health Organization. Child
mortality: Millennium Development Goal
(MDG) 4. Available at: https://www.who.i
nt/pmnch/media/press_materials/fs/
fs_mdg4_childmortality/en/#targetTe
xt=Most%20of%20the%2025%2C000%
20children%per%201000%20in%20indu
strialized%20countries. Accessed
August 24, 2019
29. Van de Poel E, O’Donnell O, Van
Doorslaer E. What explains the rural-
urban gap in infant mortality:
household or community
characteristics? Demography. 2009;
46(4):827–850
30. Tomasik E, Ziółkowska E, Kołodziej M,
Szajewska H. Systematic review with
meta-analysis: ondansetron for
10 FREEDMAN et al
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

11. vomiting in children with acute
gastroenteritis. Aliment Pharmacol
Ther. 2016;44(5):438–446
31. 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(1):22–29.e6
32. Hackshaw A, Kirkwood A. Interpreting
and reporting clinical trials with
results of borderline significance. BMJ.
2011;343:d3340
33. Aziz MM, Masood I, Yousaf M, et al.
Pattern of medication selling and self-
medication practices: a study from
Punjab, Pakistan. PLoS One. 2018;13(3):
e0194240
34. Pfeil N, Uhlig U, Kostev K, et al.
Antiemetic medications in children with
presumed infectious gastroenteritis--
pharmacoepidemiology in Europe and
Northern America. J Pediatr. 2008;
153(5):659–662, 662–e3
35. Kita F, Hinotsu S, Yorifuji T, et al.
Domperidone with ORT in the treatment
of pediatric acute gastroenteritis in
Japan: a multicenter, randomized
controlled trial. Asia Pac J Public
Health. 2015;27(2):NP174-NP183
36. Thompson CN, Phan MV, Hoang NV, et al.
A prospective multi-center
observational study of children
hospitalized with diarrhea in Ho Chi
Minh City, Vietnam. Am J Trop Med Hyg.
2015;92(5):1045–1052
37. Zellweger RM, Carrique-Mas J,
Limmathurotsakul D, et al; Southeast
Asia Antimicrobial Resistance Network.
A current perspective on antimicrobial
resistance in Southeast Asia.
J Antimicrob Chemother. 2017;72(11):
2963–2972
38. Barbut F, Meynard JL. Managing
antibiotic associated diarrhoea. BMJ.
2002;324(7350):1345–1346
39. Ford I, Norrie J. Pragmatic trials. N Engl
J Med. 2016;375(5):454–463
40. Freedman SB, Vandermeer B, Milne A,
Hartling L; Pediatric Emergency
Research Canada Gastroenteritis Study
Group. Diagnosing clinically significant
dehydration in children with acute
gastroenteritis using noninvasive
methods: a meta-analysis. J Pediatr.
2015;166(4):908–916–e6
41. Pomorska D, Dziechciarz P, Mduma E,
et al. Comparison of three dehydration
scales showed that they were of limited
or no value for assessing small
children with acute diarrhoea. Acta
Paediatr. 2018;107(7):1283–1287
PEDIATRICS Volume 144, number 6, December 2019 11
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

12. DOI: 10.1542/peds.2019-2161 originally published online November 6, 2019;
2019;144;
Pediatrics
Emaduddin Siddiqui, Jianling Xie, Fady Dawoud and Zulfiqar A. Bhutta
Stephen B. Freedman, Sajid B. Soofi, Andrew R. Willan, Sarah Williamson-Urquhart,
Randomized Clinical Trial
Oral Ondansetron Administration to Dehydrated Children in Pakistan: A
Services
Updated Information &
http://pediatrics.aappublications.org/content/144/6/e20192161
including high resolution figures, can be found at:
References
http://pediatrics.aappublications.org/content/144/6/e20192161#BIBL
This article cites 36 articles, 6 of which you can access for free at:
Subspecialty Collections
sub
http://www.aappublications.org/cgi/collection/emergency_medicine_
Emergency Medicine
following collection(s):
This article, along with others on similar topics, appears in the
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtml
in its entirety can be found online at:
Information about reproducing this article in parts (figures, tables) or
Reprints
http://www.aappublications.org/site/misc/reprints.xhtml
Information about ordering reprints can be found online:
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from

13. DOI: 10.1542/peds.2019-2161 originally published online November 6, 2019;
2019;144;
Pediatrics
Emaduddin Siddiqui, Jianling Xie, Fady Dawoud and Zulfiqar A. Bhutta
Stephen B. Freedman, Sajid B. Soofi, Andrew R. Willan, Sarah Williamson-Urquhart,
Randomized Clinical Trial
Oral Ondansetron Administration to Dehydrated Children in Pakistan: A
http://pediatrics.aappublications.org/content/144/6/e20192161
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
http://pediatrics.aappublications.org/content/suppl/2019/11/05/peds.2019-2161.DCSupplemental
Data Supplement at:
by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2019
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
at Indonesia:AAP Sponsored on March 1, 2021
www.aappublications.org/news
Downloaded from