Oral Ondansetron Administration to Dehydrated Children in Pakistan: A Randomized Clinical Trial - American Academy of Pediatrics
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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
BACKGROUND: Ondansetron is an effective antiemetic employed to prevent vomiting in children abstract
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.
a WHAT’S KNOWN ON THIS SUBJECT: Ondansetron administration to dehydrated
Sections of Pediatric Emergency Medicine and Gastroenterology, Department of Pediatrics, Alberta Children’s children with gastroenteritis-associated vomiting in emergency departments in
Hospital and Alberta Children’s Hospital Research Institute and bSection of Pediatric Emergency Medicine, high-income countries reduces vomiting and intravenous rehydration. Although it
Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; cCentre of is ineffective among well-hydrated children, evidence of efficacy in dehydrated
Excellence in Women and Child Health, The Aga Khan University, Karachi, Pakistan; dOntario Child Health Support children in low- and middle-income countries is lacking.
Unit, SickKids Research Institute, Toronto, Ontario, Canada; and eCentre for Global Child Health, The Hospital for
WHAT THIS STUDY ADDS: Emergency department oral ondansetron administration
Sick Children, Toronto, Ontario, Canada
to dehydrated children with gastroenteritis-associated vomiting in Pakistan safely
reduces intravenous rehydration fluid administration and vomiting, and it should
This work was presented at the annual meeting of the Pediatric Academic Societies; April 24, 2019, be considered to promote oral rehydration therapy in this population.
to May 1, 2019; Baltimore, MD.
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
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PEDIATRICS Volume 144, number 6, December 2019:e20192161 ARTICLEGlobally, nearly 6 million children superiority trial (Fig 1) in the funded research officers 24 hours/
,5 years of age still die annually.1 emergency departments (EDs) of The day, 7 days/week. Eligible children
Despite advances in oral rehydration Aga Khan University Hospital for were aged 0.5 to 5.0 years, weighed
therapy (ORT) and treatment of Women and Children and The Aga $8.0 kg, and had $1 episode of
diarrhea, some 500 000 of these Khan University Hospital, Karachi, diarrhea (ie, a minimum of 1 loose or
deaths are due to acute Pakistan. Pediatric emergency liquid stool) and $1 vomiting episode
gastroenteritis (AGE).1 Important medicine trained physicians treat within the 4 hours preceding triage.13
contributors to diarrhea-related ∼10 000 and 5000 patients annually in As previously performed,13 we
mortality include limited access to each of these institutions, respectively. employed lower age and weight limits
services and the stagnated use of The study was approved by the ethics because infants ,6 months of age are
ORT,2,3 particularly in the presence of committees of The Aga Khan more likely to have alternative
vomiting. In Pakistan, 80% of those University and University of Calgary.
underlying etiologies (eg, urinary
who develop severe dehydration have
tract infection), and 8.0 kg
persistent vomiting, with a high Study Population corresponds to the weight at which
frequency in the first 6 hours of
Potentially eligible children were the smallest study dose (2 mg) can be
therapy.4 Although use of antiemetic
consecutively screened by study- administered. Participants had
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
FIGURE 1
Design and Setting 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
We performed a 2-center, randomized, hour emergency department observation period. The child was included in the primary analysis as
double-blind, placebo-controlled he received . 20 ml/kg of intravenous fluids and thus experienced the outcome of interest.
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2 FREEDMAN et al“some” dehydration quantified by child’s tongue, and the child was Should children deteriorate and
using the World Health Organization instructed to swallow 5 seconds develop “severe” dehydration, rapid
(WHO) dehydration tool,16,17 which later.13 Fifteen minutes after ODT intravenous rehydration was
requires the presence of $2 of the administration, ORT was initiated. administered.12,21 The need for
following: restlessness and/or Children who vomited $1 times hospitalization was determined by
irritability, sunken eyes, drinking during that interval received a repeat the treating physician. Postdischarge
eagerly and/or thirst, and skin pinch dose.13 Blinded individuals included care was in keeping with WHO
retracts slowly.16 the ED physicians, research officers, recommendations.16 Caregivers
families, patients, and on-site whose children were suitable for
Children with the following were
pharmacists. The placebo and active discharge were provided with a 2-day
excluded: severe dehydration, bloody
ODTs were of identical size, supply of ORS and were instructed to
or bilious vomiting, hypotension,18
appearance, taste, and smell.13 give as much fluid as the child desired
vomiting or diarrhea for .7 days,
to prevent dehydration. To reduce the
previous abdominal surgery, A prespecified computer-generated
likelihood of persistent diarrhea,
hypersensitivity to ondansetron or randomization list with associated kit
participants were also provided with
any serotonin receptor antagonist, numbers was sent from www.
a 2-week supply of 20-mg zinc tablets
personal or family history of randomize.net via password-
to be administered daily for 14
prolonged QT syndrome, taking protected files to the research
days.22 Caregivers were instructed to
a medication listed as causing pharmacist who prepared, packed,
initiate zinc therapy a minimum of
torsades de pointes (https:// and shipped all drug kits. At
30 minutes after study drug
crediblemeds.org/index.php/login/ enrollment, www.randomize.net
administration.
dlcheck:), previously enrolled in the randomly selected a kit number from
study, and those for whom follow-up the remaining kits containing the
would not be possible. We excluded Data
assigned treatment. Each kit
children whose weight for height was contained two 4-mg ondansetron or Data were collected by research
,23 z scores of the median WHO placebo ODTs (cut in half if needed to officers. During the 4-hour study
growth standards because children provide a 2-mg dose) including 1 observation period, the following
with malnutrition are at greater risk extra dose in case a repeat dose was were recorded every 60 minutes: oral
of electrolyte abnormalities.19 required. If the extra dose was intake, intravenous fluids, and
Guardians of all participants provided vomited, no additional medications episodes of vomiting, diarrhea, and
written informed consent. were provided. urination. We placed urine collection
bags on children who could not
Allocation urinate into measurement containers.
Study Interventions
Children were randomly assigned to Stool was quantified by weighing
Aside from study interventions,
receive a single ondansetron or diapers for infants and toddlers and
participants received therapy in
placebo oral disintegrating tablet the use of collection devices for
keeping with WHO recommendations.
(ODT; both provided in-kind by children who were toilet trained.
Concomitant medication
GlaxoSmithKline, Inc, Philadelphia, Although the WHO tool was employed
administration was at the discretion
PA) in a 1:1 ratio, stratified by age to assess dehydration regarding
of the clinical team. The protocol
(,18 and $18 months) and study eligibility, we employed the clinical
emphasized a targeted weight-based
center by using variable block sizes of dehydration scale (CDS) score23,24 to
ORT protocol during the 4-hour
4 and 6. Use of an Internet-based perform repeat dehydration
observation period and caregiver
randomization service facilitated assessments during ED monitoring
education regarding oral rehydration
allocation concealment. The study because the CDS allows for a better
solution (ORS) administration.
team was unaware of block sizes. quantification of dehydration and
Breastfeeding continued ad lib in
thus is better suited to serve as
As is commonly performed in clinical addition to giving WHO ORS. If the
a covariate during analysis.
practice20 and trials,13 doses were child vomited, caregivers waited
weight based: 8 to 15 kg received 10 minutes and then resumed giving Participants were reassessed
a dose of 2 mg; .15 kg received ORS more slowly. Children whose 24 hours after discharge at their
a dose of 4 mg. Within the dose range dehydration, assessed by using the home or the enrolling institution. If
of 0.13 to 0.26 mg/kg, higher doses of WHO tool, had resolved were there were no signs of dehydration
ondansetron are not superior to discharged; those with some and vomiting and diarrhea had
lower doses nor are they associated dehydration after 4 hours had ORT resolved, 48- and 72-hour follow-up
with increased side effects.21 The treatment repeated for another was done by telephone. For children
ODT was placed on the top of each 4 hours with food administration. with ongoing symptoms or signs of
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PEDIATRICS Volume 144, number 6, December 2019 3dehydration, a repeat in-person 90% power to detect an absolute investigators was that the probability
reassessment in 24 hours was between-group difference of 10% in of intravenous rehydration among
required. the risk of receiving $20 mL/kg over children administered the placebo
4 hours of an isotonic fluid for the was higher than the 17% previously
Study Outcomes purpose of rehydration within reported by the International Study
The primary outcome was 72 hours of random assignment (risk Group on Reduced-Osmolarity ORS26
intravenous rehydration defined as ratio: 0.67) at a baseline risk of 30% because all study participants have
the administration of $20 mL/kg (under the assumption of a 2-sided some dehydration. On the basis of
over 4 hours of an isotonic fluid for 5% level of significance) and a lack of local expert opinion, sample size
the purpose of rehydration within primary outcome ascertainment of calculations employed a minimally
72 hours of random assignment. This 5%. The consensus among clinically important difference of
outcome was selected because we
sought to include only those who had
an intravenous line inserted for TABLE 1 Baseline Clinical Characteristics of Participants by Treatment Group
hydration purposes. It excludes those Ondansetron, n = 462 Placebo, n = 456
who received only maintenance fluids Age, mo 18 (12–30) 18 (12–29)
and those who had the intravenous Male 271 (58.7) 279 (61.2)
line inserted for medication Wt, kg 10.0 (8.6–12.0) 10.0 (8.6–12.0)
administration, while capturing those Chronic medical conditions 0 5 (1.1)
who received brief bolus fluid 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)
therapy or greater-than-maintenance Vomit episodes in past 24 h 4 (3–6) 4 (3–6)
fluids for several hours. The 72-hour Vomiting duration, d 1 (1–2) 1 (1–2)
time frame balances the potential Maximal diarrheal episodes per 24-h period 4 (2–6) 3 (2–6)
benefits and side effects of Diarrheal episodes in past 24 h 3 (2–5) 3 (2–5)
ondansetron. Diarrhea duration, d 1 (1–2) 1 (1–2)
Fevera 122 (26.4) 104 (22.8)
Secondary outcomes identified Previous ED visit, current illness 60 (13.0) 62 (13.6)
a priori were the (1) presence and (2) Previous intravenous rehydration, current illness 20 (4.3) 25 (5.5)
Previous hospitalization, current illness 4 (0.9) 6 (1.3)
frequency of vomiting during the 4- Medications administered, past 24 hb
hour observation period, (3) Antacids
hospitalization for .24 hours defined Omeprazole and/or ranitidine 4 (0.9) 4 (0.9)
as the interval from ED arrival to Antipyretics 51 (11.0) 46 (10.1)
hospital discharge, (4) volume of ORS Acetaminophen 45 (9.7) 44 (9.6)
Ibuprofen 6 (1.3) 6 (1.3)
consumed during the 4-hour Antibiotics and/or antihelminthics 69 (14.9) 60 (13.2)
observation period, (5) presence of Azithromycin and/or clarithromycin 1 (0.2) 0 (0)
some dehydration at any time after Amoxicillin and/or ampicillin 1 (0.2) 1 (0.2)
discharge up to the 72-hour follow-up Cefixime and/or cefotaxime/ceftriaxone 31 (6.7) 25 (5.5)
assessment, and (6) number of Diloxanide and/or mebendazole 6 (1.3) 10 (2.2)
Metronidazole 41 (8.9) 36 (7.9)
diarrheal (ie, loose or liquid) stools Other 8 (1.7) 3 (0.7)
during the 72 hours after random Antiemetics 97 (21.0) 86 (18.9)
assignment. The composite outcome Dimenhydrinate 32 (6.9) 31 (6.8)
of treatment failure includes Domperidone 76 (16.5) 63 (13.8)
intravenous rehydration, nasogastric Metoclopramide 1 (0.2) 4 (0.9)
Antihistamines and/or anticholinergics
rehydration for .24 hours, or death Cetirizine, clemastine, cyclizine, and/or 9 (1.9) 10 (2.2)
within 72 hours. Nasogastric diphenhydramine
rehydration was included in our Nutrition
composite outcome measure because Zinc 10 (2.2) 14 (3.1)
it is preferred to intravenous Probiotics
Saccharomyces boulardii and/or Lactobacilus 13 (2.8) 14 (3.1)
rehydration as second-line aicdophilus
rehydration treatment, after ORT, in Rotavirus vaccine received 201 (43.5) 193 (42.3)
numerous guidelines.25 Exclusively breastfed 14 (3.0) 9 (2.0)
CDS score23 2 (2–3) 2 (2–3)
Statistical Analysis 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
The planned sample size of 868 temperatures by adding 1.1°C and 0.6°C, respectively.27
patients was estimated to provide b Some children received .1 medication in the past 24 h.
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4 FREEDMAN et al10%. Because of delays in data entry RESULTS Primary Outcome
and concerns about completeness, an Among 918 randomly assigned The administration of $20 mL/kg
additional 50 patients were recruited. children (median age, 18.0 over 4 hours of an intravenous
Full outcome data were not available [interquartile range (IQR), 12.0–30.0] rehydration solution within 72 hours
until the final analysis. All children months) recruited between June 5, of random assignment occurred in
randomly assigned were included in 2014, and December 12, 2017 (Fig 1), 14.7% (68 of 462) vs 19.5% (89 of
the primary and secondary analyses. 462 were assigned to ondansetron 456) of those in the ondansetron and
Analyses were undertaken by and 456 to placebo. Baseline placebo groups, respectively (odds
intention-to-treat principles. The characteristics (Table 1), laboratory ratio [OR]: 0.71; 95% CI, 0.50 to 1.00;
proportion of children receiving parameters (Supplemental Table 5), difference: 4.8%; 95% CI, 0.0% to
intravenous rehydration by 72 hours and cointerventions (Table 2) were 9.7%; Table 3). Employing
was analyzed by using a Mantel- similar between groups. The a multivariable logistic regression
Haenszel test, stratified by clinical intervention or placebo medication model fitted with the treatment group
center and age. Prespecified subgroup was vomited by 3.5% (16 of 462) and and adjusted for the administration of
analyses based on subject age, 3.7% (17/456) of those in the other antiemetics, antibiotics, and
duration of illness, and baseline ondansetron and placebo groups, zinc before random assignment
diarrhea and vomiting frequency in respectively. Primary outcome data (Supplemental Tables 7 and 8) and
the preceding 24 hours were were available for 100% (918 of the number of vomiting episodes in
conducted. Secondary analysis of the 918) of study participants; 72-hour the preceding 24 hours yielded an OR
primary outcome employed follow-up was completed for 99.9% of 0.70 (95% CI, 0.49 to 1.00) in favor
a multivariable logistic regression (917 of 918; Supplemental Table 6). of the ondansetron treatment arm.
model fitted with treatment group Overall, 20.9% (192 of 918) of Antibiotic administration (OR: 1.75;
and baseline covariates (ie, children had an intravenous cannula 95% CI, 1.08 to 2.84) and the number
antiemetic, antibiotics, zinc inserted during the study period of vomit episodes in the preceding
administration before random (placebo: 105 of 456 [23.0%]; 24 hours (OR: 1.12; 95% CI, 1.06 to
assignment, and the number of ondansetron: 87 of 462 [18.8%]; OR: 1.19 per episode) were also
vomiting episodes in 24 hours before 0.77; 95% confidence interval [CI], associated with intravenous
random assignment), which 0.56 to 1.07). rehydration (Supplemental Tables 7
potentially predict intravenous
rehydration and were associated with
the outcome. TABLE 2 ED and Discharge Cointerventions
Ondansetron Placebo
The Mantel-Haenszel test, stratified (n = 462), n (%) (n = 456), n (%)
by clinical center, was used to analyze Antacid in the ED 10 (2.2) 26 (5.7)
the secondary outcomes of vomiting Omeprazole 10 (2.2) 25 (5.5)
(yes or no), hospitalization, presence Ranitidine 0 (0) 1 (0.2)
of some dehydration recurring within Antibiotic in the ED 114 (24.7) 99 (21.7)
72 hours, and treatment failure. The Amoxicillin 5 (1.1) 1 (0.2)
Azithromycin 5 (1.1) 12 (2.6)
van Elteren test, stratified by clinical Cefixime 28 (6.1) 18 (3.9)
center, was used for the continuous Ceftriaxone 38 (8.2) 39 (8.6)
variables of vomiting frequency, Ciprofloxacin 20 (4.3) 10 (2.2)
volume of ORS consumed, and Metronidazole 22 (4.8) 24 (5.3)
diarrheal stool frequency. 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)
Because missing baseline values were Antiemetic in the ED 168 (36.4) 180 (39.5)
Dimenhydrinate 1 (0.2) 2 (0.4)
present in ,1% of cases, imputation Domperidone 154 (33.3) 157 (34.4)
was not required. A Bonferroni Ondansetron 18 (3.9) 28 (6.1)
correction was used to correct for Metoclopramide 1 (0.2) 1 (0.2)
multiple comparisons, and adjusted P Antihistamine in the ED
values are reported. The analysis plan Cetirizine 5 (1.1) 3 (0.7)
Antipyretic in the ED 82 (17.7) 69 (15.1)
was prespecified in the protocol and Acetaminophen 59 (12.8) 52 (11.4)
was performed with SPSS version Ibuprofen 25 (5.4) 18 (3.9)
22.0 (IBM SPSS Statistics, IBM Other in the ED
Corporation) and SAS version 9.4 Saccharomyces boulardii 119 (25.8) 117 (25.7)
(SAS Institute, Inc, Cary, NC). Zinc 84 (18.2) 73 (16.0)
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PEDIATRICS Volume 144, number 6, December 2019 5TABLE 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.
and 8). There was no evidence of fewer vomiting episodes in the Adverse Events
interaction between treatment ondansetron group (P , .001; No serious adverse events or
group and age (Fig 2), presence Table 3) but no difference in the admissions to the step-down units or
of $3 diarrheal stools in the volume of oral fluids consumed ICUs were reported. Reported
preceding 24 hours, or presence of during the observation period. The adverse events were similar between
$3 vomits in the preceding 24 hours proportion of children hospitalized groups (Supplemental Table 11).
(Table 4, Supplemental Tables 9 .24 hours and that had some
and 10). dehydration develop at any time up
to 72 hours after discharge did not DISCUSSION
Secondary Outcomes differ between groups. The number of In this 2-center trial, young children
Overall, 13.2% (61 of 462) of diarrheal stools during the 72-hour with some dehydration were less
children in the ondansetron group follow-up period and the median likely to receive intravenous
vomited during the 4-hour volume of diarrhea during the 4-hour rehydration if they received
observation period compared with observation period were similar ondansetron compared with children
26.1% (119 of 456) in the placebo between groups. Primary and who received the placebo. This effect
group (OR: 0.43; 95% CI, 0.31 to 0.61; secondary outcomes were similar at stems from the reduction in vomiting
difference: 12.9%; 95% CI: 7.8% to both study sites (Supplemental associated with ondansetron
18.0%; Table 3, Fig 3). There were Tables 9–11). administration. These results are
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6 FREEDMAN et alFIGURE 2
Impact of age in 6-month increments on the primary outcome. IVF, intravenous fluid.
important because .500 000 It is important to consider our results effective antiemetic. Although the
children continue to die each year in the context of the companion study absolute reduction in intravenous
from AGE,1 and most deaths in LMICs that included 626 children without rehydration use was lower than
could be prevented by the use of dehydration in which the authors anticipated, the reduction was
known and cost-effective identified no benefits associated with significant, and the number needed to
interventions.28 The evidence from ondansetron administration.15 treat is 21. The benefits are
this study has the potential to lead to Participants in the current study were symptomatically meaningful with the
further evaluations in more rural older, had more frequent vomiting, number needed to treat to prevent
contexts where a disproportionate and higher CDS scores. They were vomiting being 8. Because these
number of children die.29 thus more likely to benefit from an benefits are in keeping with findings
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.
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PEDIATRICS Volume 144, number 6, December 2019 7educational 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
FIGURE 3 may reflect the propensity of
Number of vomiting episodes during the 4 hours after study drug administration.
antibiotics to cause diarrhea in
exposed children.38
from high-income countries where In Delhi, India,17 25% of children
the absolute reductions in vomiting with some dehydration who were Although we had intended to conduct
and intravenous rehydration are 25% administered the placebo received stool microbial analyses, because of
and 19%, respectively,30 ondansetron intravenous fluids compared with an insufficient number of specimens
use may be considered to promote 14% of children who were submitted, this objective was not
ORT success in children similar to administered ondansetron (relative completed. Although not different
those enrolled in our study. risk: 0.56). Benefits attributed to between groups, the extensive
ondansetron administration included coadministration of antiemetics such
The lower than anticipated expedited resolution of dehydration, as domperidone was not anticipated.
intravenous rehydration rate likely reduced vomiting, and greater Although a more restrictive approach
relates to the baseline frequency of satisfaction.17 Thus, our findings, to concomitant medication use could
vomiting, which was lower than supported by previous LMIC work17 have been employed, we focused on
anticipated. The median frequency of and evidence from high-income conducting a pragmatic real-world
vomiting in the preceding 24 hours countries,10 lead to the conclusion trial.39 Although, in theory,
was only 4; other reports have that despite being of borderline concomitant antiemetic use could
exceeded 9.13,31 The connection statistical significance,32 it is highly have influenced the outcomes of the
between ondansetron benefits and likely that ondansetron study because this was a randomized
vomiting frequency is highlighted by administration to children with clinical trial, it is unlikely to have
our multivariable regression model dehydration is beneficial in resource- altered the effect of the intervention.
that retained vomiting frequency as poor settings. Identification of an Moreover, we incorporated this
an independent predictor of effective antiemetic in this setting is covariate in regression models to
treatment failure. Although it is also important because although further minimize any impact it may
possible that concomitant antiemetic domperidone has been revealed to be have had. It should be noted that
administration (ie, domperidone) ineffective at treating gastroenteritis- dehydration assessment using clinical
may have played a role, authors of associated vomiting,7,8 it is routinely scores is suboptimal.40 Although
most studies have found it to be employed in LMICs. This is likely concerns have been raised regarding
ineffective.7,8 Additionally, it may be because of the propensity for self- use of the WHO dehydration tool,41 in
that in this academic tertiary care medication in LMICs,33 the desire to keeping with local standards of care,
center, there was greater adherence treat vomiting in children with we used it to determine eligibility.
to guidelines with an emphasis on dehydration, and the widespread34 The CDS score23,24 was used to assess
ORT, and the use of higher belief that domperidone is dehydration as an outcome because,
thresholds for intravenous effective.8,35 Because both unlike the WHO tool, it can be
rehydration may be in routine use ondansetron and domperidone are employed as a quantitative tool.
than in earlier reports. readily available in Pakistan, Future studies investigating
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8 FREEDMAN et alondansetron use barriers in LMIC ACKNOWLEDGMENTS
settings are needed.
ABBREVIATIONS
We thank the extended study team AGE: acute gastroenteritis
based at the Alberta Children’s CDS: clinical dehydrationscale
CONCLUSIONS Hospital, Calgary, Alberta, Canada, CI: confidence interval
Among children with gastroenteritis- and the team based in Karachi, ED: emergency department
associated vomiting and dehydration, Pakistan. We also thank our funders: IQR: interquartile range
oral ondansetron administration (1) the Thrasher Research Fund LMIC: low- and middle-income
reduces vomiting and intravenous (award 10025), (2) Bill and Melinda country
rehydration use. These findings Gates Foundation (grant ODT: oral disintegrating tablet
should be replicated in a larger OPP1058793), and (3) Alberta OR: odds ratio
multicenter trial, and if successful, Children’s Hospital Foundation. ORS: oral rehydration solution
ondansetron use should be We also thank GlaxoSmithKline, Inc, ORT: oral rehydration therapy
considered to promote ORT success for supplying the study drug and WHO: World Health Organization
among dehydrated children in LMICs. placebo.
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.
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PEDIATRICS Volume 144, number 6, December 2019 11Oral Ondansetron Administration to Dehydrated Children in Pakistan: A
Randomized Clinical Trial
Stephen B. Freedman, Sajid B. Soofi, Andrew R. Willan, Sarah Williamson-Urquhart,
Emaduddin Siddiqui, Jianling Xie, Fady Dawoud and Zulfiqar A. Bhutta
Pediatrics 2019;144;
DOI: 10.1542/peds.2019-2161 originally published online November 6, 2019;
Updated Information & including high resolution figures, can be found at:
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Downloaded from www.aappublications.org/news by guest on February 1, 2021Oral Ondansetron Administration to Dehydrated Children in Pakistan: A
Randomized Clinical Trial
Stephen B. Freedman, Sajid B. Soofi, Andrew R. Willan, Sarah Williamson-Urquhart,
Emaduddin Siddiqui, Jianling Xie, Fady Dawoud and Zulfiqar A. Bhutta
Pediatrics 2019;144;
DOI: 10.1542/peds.2019-2161 originally published online November 6, 2019;
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