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: −4.8%; 95% confidence interval [CI], −9.7% 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: −12.9%; 95% CI, −18.0% to −7.8%). 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.

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,1113  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.

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.

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.

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.

Close modal

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 “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 <−3 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.

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.

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 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 dehydration, a repeat in-person reassessment in 24 hours was required.

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 

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 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).

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).

TABLE 1

Baseline Clinical Characteristics of Participants by Treatment Group

Ondansetron, n = 462Placebo, 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 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) 
Ondansetron, n = 462Placebo, 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 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.

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) 
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) 

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 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).

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.

FIGURE 2

Impact of age in 6-month increments on the primary outcome. IVF, intravenous fluid.

FIGURE 2

Impact of age in 6-month increments on the primary outcome. IVF, intravenous fluid.

Close modal
TABLE 4

A Priori Specified Subgroup Analysis of the Primary Outcome

nOndansetron, 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 
nOndansetron, 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.

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 911).

FIGURE 3

Number of vomiting episodes during the 4 hours after study drug administration.

FIGURE 3

Number of vomiting episodes during the 4 hours after study drug administration.

Close modal

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).

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 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 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 ondansetron use barriers in LMIC settings are needed.

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.

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.

This work was presented at the annual meeting of the Pediatric Academic Societies; April 24, 2019, to May 1, 2019; Baltimore, MD.

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.

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.

This trial has been registered at www.clinicaltrials.gov (identifier NCT01870648).

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.

     
  • 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

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 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:
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.int/pmnch/media/press_materials/fs/fs_mdg4_childmortality/en/#targetText=Most%20of%20the%2025%2C000%20children%per%201000%20in%20industrialized%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 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

Competing Interests

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.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data