• 
• 

Three Part Question

In [an 18 month old girl with rotavirus gastroenteritis] does [the administration of antiemetic medication] [decrease vomiting and increase the likelihood that oral rehydration therapy will be successful]?

Clinical Scenario

An 18 month old female is brought to the emergency department by her mother. She has been suffering from repeated vomiting and diarrhoea for the past 24 hours. Over the past eight hours she has vomited approximately 12 times. The vomitus has not contained any bile or blood. The little girl appears mildly dehydrated. Her stool tests positive for rotavirus. You wonder whether administration of an antiemetic may lessen her symptoms and increase the likelihood that oral rehydration therapy will be successful.

Search Strategy

Medline 1966–July, 2004 using OVID interface
ondansetron OR promethazine OR metoclopramide OR antiemetics AND exp rotavirus infections OR exp Norwalk virus OR exp gastroenteritis OR exp enteritis OR exp transmissible gastroenteritis virus OR exp rotavirus
Limits: human, English language, all infant (birth to 23 months) or preschool child (2 to 5 years) or child (6 to 12 years).

Search Outcome

No systematic reviews. Seventy papers were identified, four of which were relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Reeves et al, 2002	107 children, age 1 month to 22 years who presented to an ED who had experienced at least three episodes of vomiting in the previous 24 hours thought to be secondary to an acute gastroenteritis and required intravenous fluids. Patients were excluded if they had received any antiemetic therapy within 72 hours of enrolment, had a history of hepatic disease or had diarrhoea lasting more than 7 days. Ondansetron 0.15 mg/kg IV was given as a single dose	Double blind RCT	Primary outcomes: frequency of vomiting episodes after drug administration, and the need for hospitalisation Secondary outcomes: duration of vomiting after drug administration, number and duration of diarrhoea symptoms, frequency of return visits to an urgent or emergency care centre, need for readministration of intravenous fluids, and need for later hospital admission	38 (70%) of the 54 patients in the group who received ondansetron and 27 (51%) in the group that received placebo had complete cessation of vomiting (p = 0.04) Fourteen patients (26%) who received ondansetron and 16 patients (30%) who received placebo were hospitalised (p>0.05)	The study was supported by a grant from Glaxo Wellcome Inc. who manufacture ondansetron No testing was done to determine the cause of gastroenteritis. In a subgroup analysis excluding patients who had serum CO2 <14 mEq/l or had previously received intravenous hydration, 3 of 43 (7.5%) patients who received ondansetron and 11 of 47 (23%) who received placebo required hospitalisation (p = 0.04)
Ramsook et al, 2002	145 children ages 6 months to 12 years who presented to an ED due to with or without diarrhoea thought be secondary to gastroenteritis and had vomited at least five times during the preceding 24 hours and had not received any antiemetics. Patients were excluded if they had any chronic illnesses, possible appendicitis, urinary tract infection, or, severe gastroenteritis requiring immediate intravenous fluid resuscitation. Ondansetron syrup was given every eight hours for up to two days. Children 6 months to 1 year of age were given 1.6 mg/dose, children 1 to 3 years of age were given 3.2 mg/dose and children 4 to 12 years of age were given 4 mg/dose. Oral rehydration was initiated 15 minutes after the first dose of ondansetron or placebo	Double blind RCT	Primary outcomes: frequency of emesis during the 48 hours after enrolment and rates of intravenous fluid administration Secondary outcomes: hospital admission rates and frequency of diarrhoea	The rank sum of vomiting episodes while in the ED was significantly lower in the group who received ondansetron (p = 0.001). During the 48 hours of follow up, the median number of episodes of vomiting were not significantly different in the two groups. A lower proportion of patients receiving ondansetron required intravenous fluids (p = 0.015). The admission rate was lower in the patients receiving ondansetron (p = 0.007) Children receiving ondansetron had significantly more diarrhoea in the 48 hour follow up period than did controls The children who received ondansetron were more likely to return to the ED than were controls (p = 0.047)	The study was supported in part by a grant from GlaxoWellcome Research and Development who manufacture ondansetron. The majority of children studied were less than 4 years of age No testing was done to determine the cause of gastroenteritis 120 children were available for follow up at 24 hours and 113 were available for follow up at 48 hours
Cubeddu et al, 1997	36 children ages 6 months to 8 years diagnosed with acute gastroenteritis with associated vomiting who had vomited twice within one hour. Patients were excluded if they were severely dehydrated, had a rectal temperature greater than 39°C, had experienced seizures, or had received any parenteral antiemetic medication in the six hours prior to the study. Ondansetron 0.3 mg/kg, metoclopramide 0.3 mg/kg, or sterile saline were given as a single IV infusion. Oral rehydration was commenced 30 minutes after treatment administration	Double blind RCT	Frequency of vomiting over the 24 hours after treatment	The number of vomiting episodes was significantly less in the children who received ondansetron (mean = 2) than in controls (mean = 5). There was no statistically significant difference between children treated with metoclopramide or placebo 58% of children who received ondansetron experienced no vomiting as compared to 17% of controls. There was no statistically significant difference between children treated with metoclopramide or placebo Over 24 hours, the number of treatment failures was significantly greater in the children treated placebo (33%) and metoclopramide (42%) than in children treated with ondansetron (17%) Children receiving both metoclopramide and ondansetron experienced more episodes of diarrhea than controls over the 24 hours study period (p = 0.013 and 0.004 respectively)	The study was supported by Glaxo Wellcome Research and Development who manufacture ondansetron. 47% of children enrolled had rotavirus enteritis, 11% had adenovirus enteritis, and 31% had bacterial enteritis. All 36 children completed the study. At entry, children in the placebo group were somewhat better hydrated and somewhat older than children in both treatment groups There was no difference in the number or type of adverse events in the three groups
Van Egan et al, 1979	60 children ages 2 to 6 years admitted to the hospital with acute gastroenteritis with vomiting. No exclusionary criteria were mentioned. A suppository containing placebo, 30 mg of domperidone, or 10 mg of metoclopramide was given at study entry and up to three more times as clinically warranted over the 24 hour study period	Double blind RCT	Primary outcome was severity of nausea, vomiting, anorexia, abdominal pain, and abdominal distension as rated on a four point Likert scale Secondary outcome was global rating of symptoms at 24 hours	Children receiving domperidone required fewer additional suppositories than children who received metoclopramide (p<0.05) or placebo (p<0.05) The time span between suppositories was longer in children receiving domperidone than children receiving metoclopramide (p<0.01) or placebo (p<0.05) Children treated with domperidone had significantly less nausea, vomiting, anorexia and abdominal pain than children treated with metoclopramide or placebo	No testing was done to determine the cause of gastroenteritis. All 60 children completed the trial No drug-related side effects were identified

Comment(s)

No study expressly answered the question as to whether antiemetics lessen the vomiting associated specifically with rotavirus gastroenteritis infection in children and increase the likelihood that oral rehydration therapy will be successful. In the one study in which the authors attempted to identify the cause of gastroenteritis (Cubeddu) approximately half of the enrolled children were suffering from rotavirus gastroenteritis. It is reasonable to assume that at least similar numbers of children in the other studies were suffering from rotavirus infection. In one study (Ramsook) oral ondansetron (1.6–4 mg/dose depending on the child's age) or placebo was administered in the emergency department and then every eight hours for up to two days. Compared to the controls, children that received ondansetron experienced less vomiting while they were in the emergency department, were less likely to require intravenous fluid therapy, and were less likely to be admitted to the hospital. In another study (Reeves) a single dose of intravenous ondansetron (0.15 mg/kg) or placebo was given in the emergency department. All of the children in this study also received intravenous fluids. The children who received ondansetron had significantly less vomiting in the emergency department than did the children who received placebo. Hospitalisation rates were comparable in the two groups; however when the authors excluded children who had a serum CO2 less than 14 mEq/l or had received intravenous fluids prior to their emergency room visit, those who received ondansetron were significantly less likely to be admitted to the hospital than were children who were treated with placebo. Cubeddu and colleagues showed that in children hospitalised with gastroenteritis, a single dose of intravenous ondansetron (0.3 mg/kg) decreased the frequency of vomiting over the subsequent 24 hours compared to a single dose of metoclopramide (0.3 mg/kg) or placebo. Van Egan and colleagues showed that in children hospitalised with gastroenteritis, 30 mg domperidone suppositories decreased the amount of vomiting compared 10 mg metoclopramide suppositories or placebo. In both of these two studies, metoclopramide was not superior to placebo. In these four studies comprising 358 patients, no serious side effects were associated with the administration of ondansetron, metoclopramide, or domperidone; however only 140 patients received ondansetron, 32 received metoclopramide, and 20 received domperidone, and follow up was limited to no more than seven days. In the study by Cubeddu and colleagues hospitalised children who received ondansetron or metoclopramide experienced more episodes of diarrhoea during the 24 hour study period than did children who received placebo. Similarly, in the study by Ramsook and colleagues, children who received ondansetron had significantly more diarrhoea during the 48 hour study period than did children who received placebo. In two of the studies (Ramsook, Cubeddu) children who received ondansetron experienced more diarrhoea than did children who received placebo.

Clinical Bottom Line

There is currently insufficient evidence to justify the use of oral or intravenous ondansetron in children suffering from acute viral gastroenteritis. A large, well constructed prospective study is needed to answer this question. Ondansetron given intravenously (0.15–0.3 mg/kg/dose) or orally (1.2–4 mg/dose given every eight hours) probably decreases vomiting in children suffering from viral gastroenteritis. Serious complications appear to occur in less than 1% of children given ondansetron, but studies in gastroenteritis are limited. Ondansetron given intravenously (a single dose of 0.15–0.3 mg/kg) or orally (1.2–4 mg/dose given every eight hours) may decrease the need for hospitalisation in children suffering from vomiting associated with acute viral gastroenteritis. Metoclopramide given intravenously or as a suppository does not decrease vomiting in children suffering from viral gastroenteritis.

References

1. Reeves JJ. Shannon MW, Fleisher GR. Ondansetron decreases vomiting associated with acute gastroenteritis: a randomized controlled trial. Pediatrics 2002;109:e62.
2. Ramsook C, Sahagun-Carreon I, Kozinetz CA. et al. A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med 2002;39:397–403.
3. Cubeddu LX, Trujillo LM. Talmaciu I. et al. Antiemetic activity of ondansetron in acute gastroenteritis. Aliment Pharmacol Ther 1997;11:185–96.
4. Van Egan M, Heck E, Dhondt F. et al. A double-blind comparison of domperidone and metoclopramide suppositories in the treatment of nausea and vomiting in children. Postgrad Med J 1979;55(suppl):36-9.