What is the role of antiemetics for children with acute gastroenteritis in the developing world?

¹Flinders University, Adelaide, Australia
² Gastroenterology and Neural Development Units Institute of Child Health and Great Ormond Street Hospital, London

Date posted: 8th January 2008

The World Health Organization has produced guidelines for the management of common illnesses in hospitals with limited resources. This series reviews the scientific evidence behind WHO's recommendations. The WHO guidelines, and more reviews are available at
http://www.who.int/child-adolescent-health/publications/CHILD_HEALTH/PB.htm

This review addresses the question: : What is the role of antiemetics for children with acute gastroenteritis in the developing world?

The WHO Pocketbook of Hospital Care for Children recommends that “ anti-emetics should not be given to young children with acute or persistent diarrhoea or dysentery: they do not prevent dehydration or improve nutritional status and some have dangerous, sometimes fatal, side-effects. (Pocketbook chapter 5, page 110). 

Introduction:

Gastroenteritis is a particularly common paediatric illness. Rotavirus is the most common cause of severe gastroenteritis and accounts for an estimated 139 million episodes worldwide each year in children under 5 years of age. Annually, 25 million clinic visits and 2 million hospitalizations can be attributed to rotavirus gastroenteritis. Rotavirus is responsible for nearly half a million deaths per year.  Children in developing countries account for 82% of these deaths.[1]
Vomiting limits the success of oral rehydration in acute gastroenteritis leading to an increased need for prolonged emergency department stays, hospitalization and use of intravenous rehydration. Antiemetics therefore have significant potential to lessen the burden of gastroenteritis for both the patient and the health care system. In general the use of antiemetics in children with gastroenteritis has been limited by concerns of adverse effects such as sedation and extra pyramidal effects.
If there is to be a role for antiemetics in acute gastroenteritis in the developing world then there must be evidence to suggest that these medications are effective, have a clinically acceptable adverse effect profile and are cost effective.

Methodology

To address this question relevant articles were identified using a search of the MEDLINE database from 1970 to August 2007 using key words developing countr*, child*, antiemetic* and gastroenteritis as well as the Clinical Queries filter. A total of 1127 potentially relevant publications were identified. The Clinical Queries filter limited the number of articles to 142. The abstracts for all of these articles were read as well as the entire article if there was any doubt about the relevance of the publication. Only cohort studies or randomized controlled trials were accepted for review. A total of six relevant trials were identified as well as one Cochrane Review. All of the trials included were level 1b. Protocols for treatment of gastroenteritis in children published by the US Centers for Disease Control and the American Academy of Pediatrics were also reviewed.  

Results

A randomized double blind trial comparing domperidone, metaclopramide and placebo suppositories was conducted by Van Eygen et al.[2] Sixty children admitted to hospital with vomiting associated with gastroenteritis were evaluated. The study drug was given at the start of the trial and then up to 3 more times in the subsequent 24 hours. No adverse events are reported in the 24 hour period of the study. Those in the domperidone group were less likely to require further doses (P=0.055 compared with metaclopramide, P<0.05 compared with placebo). Domperidone was statistically better at reducing nausea, vomiting, anorexia and abdominal pain compared to placebo (P≤ 0.05 or better). In this small study no adverse events were identified within the 24 hour study period.
Cubbedu et al.[3] compared IV ondansetron, IV metaclopramide and placebo in a small study double blind randomized controlled trial. Thirty six children aged 6 months to 8 years with vomiting associated with gastroenteritis were enrolled. Those treated with ondansetron had fewer episodes of emesis in first 24 hours (P=0.048) compared to placebo and were more likely to have no episodes of emesis over 24 hours (P=0.039). No statistically significant benefit to metaclopramide was demonstrated. More diarrhea was seen in the treatment groups when compared to placebo (P=0.013 for ondansetron and p=0.004 for metaclopramide). Adverse events reported included drowsiness (>90% of patients in all groups), cough (25% in ondansetron group and 8% in metaclopramide group) and tremor seen in one patient treated with metaclopramide.
Reeves et al.[4] conducted a randomized double blind control trial looking at the efficacy of IV ondansetron for the treatment of gastroenteritis associated vomiting in 107 children aged 1 month to 22 years. Children enrolled in this study were assessed as needing IV fluids suggesting either a significant degree of dehydration or significant vomiting. However, the criteria for this clinical decision were not defined. Those treated with IV ondansetron were more likely to cease vomiting (70% vs. 51%, P= 0.04), and slightly less likely to be admitted to hospital (30% vs. 26%, P=NS). No significant adverse events were reported during the study period. Unfortunately the treatment and placebo groups were somewhat different at the start of the trial. The treatment group tended to be younger and had lower serum CO2 levels suggesting more severe disease in this group.
In a double blind, randomized controlled trial by Ramscook et al.[5] oral liquid ondansetron was evaluated in 145 children aged 6 months to 12 years who had vomited at least 5 times during 24 hours preceding presentation to ED. After discharge from ED participants were given 5 further doses to be taken 8 hourly at home. Those who received ondansetron were more likely to have no episodes of vomiting (87% vs. 65%, P=0.04) and more likely to have few episodes of vomiting (0.18 vs. 0.83, P=0.01) during the ED stay. However, the effect of reduced vomiting was not maintained beyond the ED stay. Those who received ondansetron were less likely to need IVT (P=0.015) and less likely to be admitted (p=0.007). Interestingly those in the treatment group had a higher rate of representation to ED rate (5.41% vs. 0%, P=0.047) and had more episodes of diarrhea during the first 24 hours of the study (4.70 vs. 1.37, P=0.02). The only adverse event reported was a macular rash in one patient within 30 minutes of ondansetron administration.
Freedman et al.[6]conducted a double blind randomized control trial of a single dose of oral dissolvable ondansetron in 215 children aged 6 months to 10 years with vomiting, diarrhea and dehydration. Those who received ondansetron were less likely to vomit (14% vs. 35%, RR 0.40, 95% CI 0.26-0.61), tended to vomit less often (0.18 episodes/child vs. 0.65, P<0.001) and have greater oral intake (239 ml vs. 196 ml, P=0.001). Both the treatment and placebo groups had similar rates of hospitalization (4% vs. 5%, P=1.0). No significant adverse events during the 7 days following ondansetron were identified. However, the treatment group did have more episodes of diarrhea during oral rehydration (1.4 vs. 0.5, P<0.001).
In a double blind randomized control trial of 137 children ages 6 months to 12 years presenting to the emergency department Stork et al.[7]compared IV dexamethasone and ondansetron to placebo. Admission rates were decreased for both dexamethasone (14%) and ondansetron (4%) compared to placebo (21%). The difference was statistically significant for ondansetron compared to placebo (RR=0.21, 95% CI of 0.05 to 0.81). All participants in this study received IV fluids making it difficult to generalize the results to outpatient settings where IV fluids are not available or feasible. Interestingly, the study ended prematurely because of increased number of patients who had already received antiemetics as outpatients precluding identification of previously untreated patients. No side effects were identified but it was not clear how this was assessed.
A recent Cochrane Review assessed three studies[3],[5],[6] looking for evidence of effectiveness of antiemetics for vomiting associated with gastroenteritis in children and adolescents.[8]The conclusion drawn from this review is that “ondansetron may reduce the amount of acute vomiting as well as reducing the number of children who required intravenous hydration and admission for acute gastroenteritis”. The authors note that participants treated with ondansetron did have more diarrhea than controls but felt that the difference was not clinically significant.
The American Academy of Pediatrics endorses the US Centers for Disease Control position of discouraging the use of antiemetics in gastroenteritis by stating that “reliance on pharmacologic agents shifts the therapeutic focus away from appropriate fluid, electrolyte, and nutritional therapy, [and] can result in adverse events”.[9],[1]

Discussion

In general the use of antiemetics in paediatric gastroenteritis has been avoided due to concerns about central nervous system side effects from medications such as domperidone and metaclopramide. Recently there has been increased interest in the role of ondansetron in gastroenteritis. Ondansetron is a 5-HT3-receptor antagonist that has a favourable side effect profile and has now been showed to be more effective than metaclopramide or dexamethasone. Freedman et al.[6] showed that a single dose of oral ondansetron in the ED can effectively decrease vomiting and improve the success of oral rehydration. The only adverse event identified in this study was an increase in diarrhea in the treatment group. So far this study provides the only evidence that a relatively safe, easy and effective treatment option exists for vomiting secondary to acute gastroenteritis exists in paediatrics. However, at an estimated cost of $35 USD per 4 mg tablet this is unlikely to be a realistic option in developing countries.

Summary

At this time there is some evidence that antiemetics may be safe and effective in gastroenteritis but there is still insufficient evidence that there is a significant cost benefit to their use in developing countries.

Table 1: Clinical trials investigating antiemetics in acute viral gastroenteritis
Please click here to view full size

References