Pediatrics
A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis*,**,*,*

https://doi.org/10.1067/mem.2002.122706Get rights and content

Abstract

Study Objective: Vomiting in children suffering from acute gastroenteritis interferes with the oral rehydration process and equally frustrates parents and health care providers. Adjuncts such as promethazine and metoclopramide are less than optimally effective and are associated with side effects. Ondansetron, a 5-HT3 receptor antagonist marketed as Zofran, is a safe and effective antiemetic used extensively in oncology and postoperative patients. We evaluate the effect of the antiemetic ondansetron versus placebo on the clinical outcome of patients with vomiting from gastroenteritis in a pediatric emergency department. Methods: This was a randomized, prospective, double-blind clinical trial in a university-affiliated children's hospital ED. Children between the ages of 6 months and 12 years who had vomited at least 5 times during the preceding 24 hours were randomized to receive either oral ondansetron or a taste- and color-matched placebo. Oral rehydration was commenced 15 minutes later at 5 mL/min per standard oral rehydration protocols. Patients were discharged after they voided and continued standard oral rehydration at home with the introduction of a bananas, rice, applesauce, and toast (BRAT) diet after the first 24 hours. Any patient requiring admission was considered a treatment failure, and no further doses were given. Discharged patients were given 5 additional doses to be used every 8 hours, and they were contacted by telephone 24 and 48 hours after discharge to record the number of episodes of vomiting and diarrhea. The parents were also required to complete a diary of the same information, which was mailed to the investigators for confirmation of the telephone data. Results: One hundred forty-five patients were enrolled, of whom 51% (n=74) were randomized to ondansetron. At baseline, age distribution, sex, and severity of illness did not differ between the ondansetron and placebo groups. During the observation period in the ED, the median number of episodes of vomiting was 0 in both groups, but the rank sum of vomiting episodes was significantly lower in the ondansetron group (P =.001). The number of episodes of emesis in the ED after enrollment ranged from 0 to 7 in the placebo group and 0 to 2 in the ondansetron group. During the 48 hours of follow-up, the median number of episodes of vomiting remained 0, with no statistically significant difference between the groups. There was no statistically significant difference in the rank sum of episodes of diarrhea in the ED between the groups (P =.622); however, during the next 48 hours, the patients in the ondansetron group had significantly more diarrhea than the placebo group. A lower proportion of patients receiving ondansetron compared with placebo required intravenous fluid therapy (P =.015). The admission rate was also lower in patients receiving ondansetron (P =.007). The revisit rate was higher in the ondansetron group compared with the placebo group (P =.047). Conclusion: Ondansetron was effective in reducing the emesis from gastroenteritis during the ED phase of oral rehydration and in lowering the rates of intravenous fluid administration and hospital admission. [Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D. A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med. April 2002;39:397-403.]

Introduction

Acute gastroenteritis is a common disease resulting in significant morbidity in young children. The recommended first-line treatment is oral rehydration, unless contraindications exist such as persistent vomiting, ileus, obtundation, shock, or impending shock.1 Oral rehydration has been proven safe and cost-effective and is the recommended first-line therapy for acute gastroenteritis by the American Academy of Pediatrics (AAP).2 Parents often become discouraged even with one episode of emesis during the rehydration phase, despite overall oral rehydration failure rates of 5% to 20%.3, 4, 5 Multiple drugs have been tried to assist oral rehydration, with varying degrees of success and complicating side effects. The use of promethazine (Phenergan) is widespread but has a failure rate of 31% and results in mild to moderate drowsiness in 71% of patients with gastroenteritis.6, 7 This interferes with the oral rehydration process and the assessment of lethargy. Promethazine is also associated with extrapyramidal side effects. Metoclopramide has also been tried, but low efficacy and the relatively high incidence of side effects, such as somnolence, nervousness, irritability, and dystonic reactions, have limited its use.8

Emesis is a complicated process involving several anatomic regions, receptors, and neurotransmitters. Stimulation of these vomiting regions is mediated by neurotransmitters such as serotonin, dopamine, opiates, choline, and histamines, and the blocking of these receptors is presumed to be the mechanism of existing antiemetics. Serotonin receptor subtypes (ie, 5-HT3) receptors are found in high concentration in both the peripheral and central nervous system, especially the chemoreceptor trigger zone (CTZ). More than 80% of the total body 5-HT is contained in the enterochromaffin cells of the gastrointestinal mucosa in the area of the vagal afferent nerves.9 Vomiting in gastroenteritis probably results from gut mucosal damage induced by viral or bacterial pathogens, triggering the release of serotonin from enterochromaffin cells that act through receptors on the vagal afferent nerves. These nerves stimulate the vomiting center and the CTZ to induce emesis similar to chemotherapy-induced damage to the gut mucosa. In addition, metabolism of cytotoxic drugs may produce metabolites that directly stimulate the CTZ, thereby causing delayed emesis, and it is possible that similar metabolites are produced in gastroenteritis.10

Ondansetron, a selective 5-HT3 receptor antagonist marketed as Zofran, is a safe and effective antiemetic used extensively in oncology and postoperative patients.11, 12, 13, 14 Ondansetron was first synthesized in 1983 and became available for clinical use in 1991.15 It is completely and rapidly absorbed from the gastrointestinal tract after oral administration, with the drug being first detected in plasma 30 minutes after administration of an oral dose but with the time to peak concentration in adults being 1.7 to 2.2 hours.16 As a result of first-pass metabolism, its bioavailability is only approximately 60%, compared with ondansetron given by intravenous infusion over a 15-minute period.16 Hepatic oxidative metabolism accounts for more than 95% of ondansetron clearance, and it does not accumulate with repeated oral administration. The cerebral 5-HT3 receptor binding site of ondansetron is the area postrema, which contains the CTZ. Ondansetron also acts peripherally in the upper gastrointestinal tract, where it blocks 5-HT3 receptors on vagal afferent nerve terminals.10 The use of ondansetron in acute gastroenteritis was first reported by Cubeddu et al,17 who used a single intravenous dose and compared its effect with metoclopramide and placebo in the ensuing 24 hours. In the ondansetron group, the frequency of emesis was lower, and a larger proportion had no emesis in the subsequent 24 hours.

In the randomized, controlled trial described here, we studied the role of oral ondansetron in patients presenting to a pediatric emergency department with acute gastroenteritis. We report the effect of oral ondansetron on clinical outcomes including frequency of vomiting, oral rehydration, and hospital admission.

Section snippets

Materials and methods

This was a randomized, controlled trial designed to test the hypothesis that the administration of oral ondansetron to patients with acute gastroenteritis leads to a clinically relevant reduction in vomiting (emesis) and rates of intravenous fluid administration. The primary outcome measures were the frequency of emesis during the 48-hour period after enrollment and the rates of intravenous fluid administration. The secondary outcomes were admission rates and the frequency of diarrhea.

A true

Results

A total of 145 patients were recruited into the study; 74 were randomized to ondansetron and 71 to placebo. At baseline, age distribution, sex, and severity of illness, as measured by the number of episodes of vomiting in the 24 hours before enrollment, were similar between the ondansetron and placebo groups (Table 1).

. Baseline characteristics of participants.

CharacteristicOndansetron Group, n (%)Placebo Group, n (%)
Age
6 mo to 1 y8 (10.82)6 (8.45)
1-4 y42 (56.76)43 (60.56)
4-12 y24 (32.43)22

Discussion

In this randomized, double-blinded, clinical trial, ondansetron did not reduce the overall frequency of and proportion of patients with vomiting, except during the ED period. The most likely explanation is that the patients enrolled in the study were not sufficiently ill (only ≥5 episodes of vomiting in the preceding 24 hours). In addition, patients with mild gastroenteritis often have their peak of vomiting on the first day of the illness. This may explain why both the treatment and placebo

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    *

    Author contributions are provided at the end of this article.

    **

    Supported in part by a grant from GlaxoWellcome Research and Development.

    *

    Address for reprints: Chris Ramsook, MD, 910 Labrocita Canyon, La Luz, NM 88337.

    *

    Author contributions: CR and DM-S conceived the study, designed the trial, and obtained funding from GlaxoWellcome. CR, DM-S, and IS-C undertook recruitment, data collection, and supervision of the project. CAK provided statistical advice on design, sample size estimation, and analyzed the data. CR drafted the manuscript, and all authors contributed substantially to its revision. CR takes responsibility for the paper as a whole.

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