Antiemetics for reducing vomiting related to acute
gastroenteritis in children and adolescents (Review)
Alhashimi D, Alhashimi H, Fedorowicz Z
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2006, Issue 3 Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .
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SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 01. Baseline characteristics 24hr preceding the study (Ramsook 2002) Table 02. Proportion of patients without vomiting (Ramsook 2002) Table 03. Admission rate including the number requiring intravenous fluids (Ramsook 2002) Table 04. Participants with no vomiting 0-24hr (Cubeddu 1997) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Antiemetics for reducing vomiting related to acute
gastroenteritis in children and adolescents (Review)

Alhashimi D, Alhashimi H, Fedorowicz Z
This record should be cited as:
Alhashimi D, Alhashimi H, Fedorowicz Z. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents.
Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD005506. DOI: 10.1002/14651858.CD005506.pub2.
This version first published online: 19 July 2006 in Issue 3, 2006.
Date of most recent substantive amendment: 23 March 2006
Vomiting caused by acute gastroenteritis is very common in children and adolescents. Treatment of vomiting in children can be
problematic and the use of antiemetics remains a controversial issue. There have been concerns expressed about apparently unacceptable
levels of side effects such as sedation and extrapyramidal reactions, which are associated with some of the earlier generation of antiemetics.
To assess the effectiveness of antiemetics on gastroenteritis induced vomiting in children and adolescents.
Search strategy
We searched the Cochrane Central register of Controlled Trials (CENTRAL), which includes the Cochrane Upper Gastrointestinal and
Pancreatic Diseases Group Trials Register (searched 28 July 2005), MEDLINE (1966 to July 2005) and EMBASE (1980 to July 2005).
Published abstracts from conference proceedings from the United European Gastroenterology Week and Digestive Disease Week were
handsearched. Members of the Cochrane UGPD Group were contacted for details of any ongoing or relevant unpublished clinical
Selection criteria
Randomised controlled trials comparing antiemetics and/or placebo in children and adolescents, under the age of 18, with vomiting
due to gastroenteritis.
Data collection and analysis
Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse
effects data was collected from the studies.
Main results
Two trials involving 181 participants were included. Although no data were available for the precise time to cessation of vomiting (the
primary outcome specified in the protocol for this review), one trial reported that the proportion of patients without vomiting over
a 24 hour period was higher in the ondansetron and metoclopramide groups than placebo. In the second trial, ondansetron ensured
complete anti-emesis for 8/12 (67%) patients within the first 4 hours and in 7/12 (58%) patients in the first 24 hr period. A few
secondary outcomes were reported in the included trials.
Authors’ conclusions
The small number of included trials provided some, albeit weak and unreliable, evidence which appeared to favor the use of ondansetron
and metoclopramide over placebo to reduce the number of episodes of vomiting due to gastroenteritis in children. The increased
incidence of diarrhea noted with both ondansetron and metoclopramide was considered to be as a result of retention of fluids and
toxins that would otherwise have been eliminated through the process of vomiting.
Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
and integrates the act of vomiting, is located close to other cen-ters which regulate respiration, vasomotor, and other autonomic Epidemiology
functions and that may play an additional role in vomiting.
Stimuli are received by the vomiting centre from the gastrointesti- Acute gastroenteritis is the leading cause of vomiting in children nal tract, from other parts of the body and the chemoreceptor trig- under three years of age and is a very common reason for chil- ger zone (Feldman 1989). In turn, the vomiting centre stimulates dren and adolescents attending emergency departments. Although the salivation center, respiratory center, and the pharyngeal, gas- vomiting is a fairly frequent occurrence in the younger child, it tro-intestinal and abdominal muscles, which then leads to vomit- tends to be less prevalent in older children (Taylor 1999). Vomit- ing is usually accompanied by diarrhea and each year in the United The chemoreceptor trigger zone (CTZ) may receive stimuli from States over 200,000 children aged less than five years require ad- bacterial toxins or from metabolic abnormalities that occur with mission for treatment of dehydration secondary to gastroenteritis uremia, but it cannot independently mediate the act of vomiting (Herikstad 2002). There is a similar pattern in the UK, with acute (Brunton 1996). Instead impulses from the CTZ are relayed to gastroenteritis in children under five years accounting for 20% of the vomiting center, which coordinates the various physiological General Practitioner consultations and resulting in 24,000 hospi- tal admissions annually (Flake 2004).
Vomiting is usually defined as a violent expulsion of gastric con- Treatment
tents through the mouth. The act of vomiting requires the coor- Vomiting associated with acute gastroenteritis is a distressing dinated contractions of the abdominal muscles coupled with a di- symptom for children and their parents. When faced with dis- minished esophageal sphincter pressure and esophageal dilatation, traught parents, pediatricians may find themselves compelled to with the stomach itself playing a somewhat passive role.
administer medication to stop children from vomiting. Treatment Dehydration, which is the decrease in total body water through of vomiting in children is a controversial issue. Although the Amer- a reduction in both the intracellular and extracellular fluid vol- ican Academy of Pediatrics stated in its position statement on the umes, is an important cause of morbidity in children with vom- management of acute gastroenteritis in young children that it did iting (AAP1996). The clinical manifestations of dehydration are not specifically evaluate the use of antiemetic drugs, it did confirm closely related to intravascular volume depletion which may lead that there was a consensus of opinion that antiemetic drugs are to complications including irreversible shock, intractable seizures, not recommended and that physicians should be aware of their Starvation caused by reduced caloric intake in children with vom- Antiemetic medications are known to alleviate vomiting by in- iting can lead to ketonemia, which in turn may lead to further hibiting the body’s chemoreceptor trigger zone (CTZ) or by a more direct action on the brain’s vomiting centre.
A wide range of medicines have been used as antiemetics inchildren. These medications include: dopamine (D2) antago- Gastroenteritis attributable to viruses or bacteria occurs in the U.K.
nists, serotonin or 5-hydroxytryptamine (5-HT3) antagonists, at a rate of 1.2 infections per person per year and is most common anticholinergic agents, antihistamines, benzodiazepines, corticos- in the autumn and winter (Taylor 1999). The incidence in other teroids, and cannabinoids (Brunton 1996).
developed countries is likely to be similar but may possibly be even Several studies have investigated the effectiveness of prochlor- higher in developing countries. The rotavirus, calcivirus, astro- perazine, promethazine hydrochloride, and metoclopramide as virus, reoviruses, and adenoviruses are most commonly implicated.
antiemetic medications. However, there have been concerns ex- Bacterial causes may include Staphylococcus aureus, Salmonella, pressed about some of the adverse effects, such as sedation and Bacillus cereus, or Clostridium perfringens. However, in develop- extrapyramidal reactions, that have been associated with some of ing countries, the rotavirus remains the most common cause of these medications. Quite surprisingly, very few of these reports re- vomiting in children under 3 years of age (Doan 2003).
late directly to children, and the frequencies of such adverse events Intestinal irritation caused by gastroenteritis appears to be the in pediatric populations are somewhat difficult to determine. The main stimulus for vomiting. As the virus invades the mucosal cells adverse effects of metoclopramide in young children have been of the upper gastrointestinal tract, it disrupts the normal sodium well documented and may include fatigue and such extrapyrami- and osmotic intracellular balance and intracellular fluids are lost dal phenomena as dystonia, dyskinesia, akathisia, opisthotonos, producing cellular fluid depletion. Paralysis of the bowel develops and oculogyric crises (Taylor 1999).
with resultant abdominal distension which induces further vom- Choosing between these therapeutic agents involves the careful consideration of a number of factors, including their effectiveness, Vomiting, from whatever cause, occurs because of the stimulation their side effect profiles and cost.
of the two centers located in the brain, the chemoreceptor triggerzone and the vomiting center. The vomiting center, which controls Rationale for a systematic review
Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Concerns have been expressed about the side effects of antiemetics • The primary outcome for this review was the time taken from prescribed to children with vomiting. Several randomised control the first administration of the treatment measure till cessation trials have investigated the effectiveness of different antiemetics but to the present time there has not been a systematic review of Secondary
the evidence for the effectiveness of these medicines.
We also considered the following secondary outcomes for thisreview.
• Parental satisfaction as assessed by questionnaire or interview • Number of subjects who had been admitted due to intractable The objective of this review was to provide reliable evidence regard- ing the clinical effectiveness and safety of antiemetics prescribedfor vomiting due to gastroenteritis by comparing clinical outcomes • Number of subjects who required intravenous fluids expressed as cessation of vomiting and the eventual resumption of • Time taken to reduction of episodes of vomiting oral rehydration therapy.
The following null hypothesis was tested: for gastroenteritis in- duced vomiting there is no difference in the time taken to achieve • Number of subjects resumed oral rehydration.
cessation of vomiting between patients taking antiemetics as com-pared to those who have received placebo or nothing.


See: Upper Gastrointestinal and Pancreatic Diseases Groupmethods used in reviews.
Types of studies
Searches were conducted on 28th July 2005 to identify allpublished and unpublished randomised controlled trials.
We only considered randomised controlled clinical trials in this There were no language or date restrictions in the electronic Types of participants
ELECTRONIC SEARCHESThe search strategy for this review was constructed by using a Studies which had recruited children and adolescents who were combination of MESH subject headings and textwords relating under the age of 18 and who presented with vomiting and a con- to the use of antiemetics for the treatment of gastroenteritis in firmed clinical diagnosis of gastroenteritis.
Any studies in which patients were vomiting as a result of gen- Trials were identified by searching the following electronic eral anaesthesia or due to chemotherapy were excluded. In addi- databases - The Cochrane Central Register of Controlled tion, studies in which patients were suffering from surgical con- Trials - CENTRAL (which includes the Cochrane Upper ditions (for example, acute appendicitis/pelvic abscess, inflamma- Gastrointestinal and Pancreatic Diseases Group Trials Register) tory bowel disease), or systemic infections (such as urinary tract on The Cochrane Library (Issue 2 2005), MEDLINE (1966 to infections, pneumonia, meningitis), or metabolic conditions (dia- July 2005) and EMBASE (1980 to July 2005).
betes mellitus or any other previously diagnosed disorders, includ- To identify randomized controlled trials, the following search ing immunodeficiency) were excluded.
was combined with the Cochrane highly sensitive search strategy Types of intervention
phases one two and three, as contained in the CochraneReviewers’ Handbook 4.2.5 (Higgins 2005).
Active interventions
We considered any antiemetics administered orally, IV or as sup-
positories at any dosage, prescribed to terminate or reduce vomit- Control
Administration of placebo or nothing prescribed to terminate exp diarrhea, infantile/diarrhea.tw.
Types of outcome measures
Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
In addition members of the Cochrane UGPD Group and experts in the field were contacted and asked to provide details of any ongoing clinical trials and any relevant unpublished materials.
exp dopamine antagonists/(dopamin$ adj2 antagonists).tw.
Assessment of search results
The abstracts of studies resulting from the searches were independently assessed by two reviewers (DAH/ZF) and all irrelevant studies were excluded. Full copies of all relevant and potentially relevant studies, those appearing to meet the inclusion criteria, or for which there were insufficient data in the title and abstract to make a clear decision, were obtained. Studies not matching our inclusion criteria were excluded and their details and reasons for their exclusion were noted in the ’Characteristics tropisetron.tw.
exp anticholinergic agent/ Assessment of methodological quality
Each of the two reviewers then graded the selected studies separately and every study reporting a randomised controlled clinical trial was assessed using a simple contingency form. The criterion grading system described in the Cochrane Reviewers’ Handbook 4.2.5 (Higgins 2005) was followed. The gradings were compared and any inconsistencies between the reviewers in the interpretation of inclusion criteria and their significance to the selected studies were discussed and resolved.
The following parameters of methodological quality were assessed: • Randomisation: was graded as adequate (A), unclear (B), inadequate (C). Adequate (A) included any one of the following methods of randomisation: computer generated or table of random numbers, drawing of lots, coin-toss, shuffling cards or throw of a dice. Methods of randomisation utilising any of the following: case record number, date of birth or alternate numbers were judged as inadequate(C).
• Concealment of allocation: was graded as adequate (A), unclear (B), inadequate (C) or concealment not used (D).
Adequate (A) methods of allocation concealment included either central randomisation or sequentially numbered sealed opaque envelopes. This criterion was considered inadequate (C) if there was an open allocation sequence and the participants and trialists could foresee the upcoming assignment.
• Blinding of outcomes assessment: whether persons assessing the outcome of care were aware of which treatment the participantreceived, was graded as yes, no and unclear (detection bias).
• Handling of withdrawals and losses - if there was a clear Reference lists from trials selected by electronic searching were description given of the difference between the two groups of handsearched to identify further relevant trials. Published losses to follow up was graded as yes (A), unclear (B) and no abstracts from conference proceedings from the United European Gastroenterology Week (published in Gut) and Digestive DiseaseWeek (published in Gastroenterology) were handsearched.
Data collection
Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Study details and outcomes data from randomised controlled to bronchitis or ’other’. As over half of the participants in this clinical trials that met the inclusion criteria were collected using study were not suffering with gastroenteritis and the authors failed a form which was designed for this purpose, then entered into to provide any separate data for those children with vomiting in- the ’Characteristics of included studies’ table in RevMan 4.2.2 duced by gastroenteritis, this study is awaiting further assessment.
by each reviewer sequentially, and were automatically checked for We have written to the authors to try to obtain the missing data differences. Data was only included when there was agreement. All and, on the basis of any additional information we receive, this disagreements were discussed and resolved by consensus. Dunia Alhashimi (DAH) held the master copy.
The inclusion criteria in our protocol specified that the partici-pants should be children and adolescents up to the age of 18 years.
The following details were extracted.
Although the mean age of participants in the Reeves trial was 5.3 (1) Study methods: method of allocation, masking of participants years, this trial did include patients up to the age of 22 years, which and outcomes, exclusion of participants after randomisation and we considered are neither children nor adolescents (Reeves 2002).
As it was not clear from the text how many of the participants were (2) Participants: country of origin, sample size, age, sex, inclusion over the age of 18 years ,we have written to the trialists asking for clarification as to how many of the participants fall outside our (3) Intervention: type of antiemetic; dose, frequency and route.
inclusion criteria of 18 years of age. This trial is awaiting further assessment pending a reply from the trialists. The Van Eygen trial (5) Outcomes: any primary and secondary outcomes which had did not include any of our primary or secondary outcomes and was been specified a priori in the ’types of outcomes measures’ section therefore excluded from further assessment (Van Eygen 1979).
of the protocol.
(6) Adverse effects: any adverse effects related to any clinically Even though the two remaining studies (Ramsook 2002; Cubeddu diagnosed hypersensitivity or other adverse reactions or side effects 1997) did not address the primary outcomes specified in the pro- tocol for this review and therefore did not totally match our inclu- This information was used to help us assess heterogeneity and the sion criteria, it was considered that their inclusion and the report- ing of their results, some of which matched our secondary out- Data synthesis
comes, might help to provide some evidence towards answering Due to significant clinical heterogeneity and the paucity of data this research question. (see table of ’Characteristics of Included in the few included studies, we were unable to do a meta-analysis Studies’ and ’What’s new’ ).
of the extracted data and therefore only provide a descriptive Summary of trial details
summary of results of the individual trials.
The study by Ramsook et al was a randomized double blind clin- Sensitivity analyses
ical trial conducted in the emergency department of a university- There were insufficient included studies in this systematic review affiliated hospital in Texas, USA (Ramsook 2002). The partici- and therefore no attempt was made to conduct a sensitivity pants comprised 145 children (82 males, 63 females), who were aged between six months and 12 years. The baseline characteristicsof age, sex distribution and episodes of vomiting were similar inboth the intervention and placebo groups.
Eligibility for the study required participants to have a clinicallyconfirmed diagnosis of gastroenteritis, at least five episodes of Finding the trials
vomiting with or without diarrhea, and to have not received any The search strategy identified 2443 references (the Cochrane Li- antiemetics in the preceding 24 hrs. The presence of any serious brary =644, MEDLINE = 628, EMBASE = 1171). After exam- underlying chronic systemic conditions or the necessity for im- ination of the titles and abstracts of these references, all but six mediate rehydration resulted in the automatic exclusion of any studies were eliminated and excluded from further review. Full text copies of the six remaining studies were obtained and subjected to Baseline data showed that 37 (50%) of the patients in the on- dansetron and 40 (56.33%) in the placebo group had up to 10 The Ginsberg study was a non randomised controlled trial and episodes of vomiting in the preceding 24 hours (Table 01). In it was withdrawn from further review (Ginsburg 1980). The De- addition, 37 (50%) patients in the ondansetron group and 31 bray trial was translated from French into English and was then (43.66%) in the placebo group had more than 10 episodes of vom- assessed against the inclusion criteria specified for this review (De- bray 1990). The participants in this trial included children and Randomization was to oral ondansetron (74) or taste and colour infants vomiting from either bacterial or viral infectious diseases, matched placebo (71). The patients received ondansetron 1.6mg of which less than half (49%) had vomiting attributable to gas- for those aged six months to one year, 3.2mg aged one to three troenteritis whereas the remaining participants were vomiting due years and 4mg aged four to 12 years, or placebo eight hourly. Each Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
received a total of six doses of the ondansetron or placebo of which episode was defined as an expulsion of stomach contents and was a single dose was taken in the emergency department followed recorded as a single vomit or retch or any number of continuous by an additional five doses taken eight hourly for up to 48 hours vomits and/or retches with a minimum one minute interval sepa- rating each episode. Retching was defined as an attempt to vomit Oral rehydration therapy, consisting of unflavored Pedialyte, was that was not productive of any stomach contents.
started 15 minutes after the first dose of ondansetron or placebo Participants were excluded if they had severe dehydration, seizures, was administered in the emergency room. Patients were only dis- significantly elevated rectal temperatures, had received any par- charged after they were able to successfully tolerate oral fluids and enteral antiemetic medication in the six hours previously or were after successful rehydration. At the end of the 24 hour period, all diagnosed with a parasite-induced gastroenteritis.
the patients were progressively weaned onto a diet consisting ofbananas, rice, applesauce and toast (BRAT). A total of 13 patients Three groups of 12 children in each group were randomised to with persistent vomiting who had received intravenous fluids and either ondansetron hydrochloride dihydrate (0.3mg/kg), meto- refused oral fluids were admitted and classified as treatment fail- clopramide hydrochloride (0.3mg/kg), or sterile saline solution (placebo) administered as a single intravenous dose. Oral rehy- dration, consisting of a solution of sodium, potassium, citrate Out of 74 patients who were enrolled in the trial, one patient who and glucose, was started 30 minutes after administration of either developed a rash after the first dose was withdrawn, seven were antiemetic or control and continued at 30 minute intervals for lost to follow up and two were eventually admitted. Only 64 out up to four hours. No food was permitted during this rehydration of the 73 patients completed the 24-hour follow up. A total of 62 period but it was gradually introduced based on the individual patients completed the trial at 48 hours.
status of the patient (i.e. their level of hydration, the presence or absence of retching and/or diarrhea).
Out of 71 patients who entered the trial, four were lost to followup, 11 were admitted and only 56 completed the 24-hour follow Treatment failures were defined as patients who had experienced up. There were a further five losses to follow up at 48 hours. A two vomiting episodes in any 90 minute period 1-8 hours after the total of 51 patients successfully completed the trial at 48 hours.
administration of the intervention, or had three episodes during Although the trialists recorded the proportion of participants with- the hour following the end of administration of the study treat- out vomiting during the emergency department stay, and the first 24-hour and second 24-hour period, they did not provide the pre- In this study, treatment failures at 0-4hrs included four (33%) who cise time to cessation of vomiting which was the primary outcome had received placebo, two (17%) metoclopramide and one (8%) specified for this systematic review.
who had received ondansetron. And at 0-24 hrs; four (33%) who The only secondary outcomes specified for this review and in- received placebo, five (42%) metoclopramide and two (17%) who cluded in this trial were the rates of intravenous fluid administra- had received ondansetron. Treatment failures accounted for 50% tion, and admission for each group. The trial did not include any assessment of parental satisfaction.
The only adverse effects reported in this trial were the frequency This trial produced no data for the exact time to cessation of vomiting and therefore did not address the primary outcome of thisreview. Although the trial provided no explicit data for the precise The Cubeddu study was a randomized double-blind placebo-con- time taken for a reduction in the number of episodes of vomiting trolled clinical trial conducted in a children’s hospital in Venezuela (which was one of our secondary outcomes), it did indicate the (Cubeddu 1997). All 36 participants (21 males, 15 females) aged number of vomiting episodes experienced by the participants over six months to eight years were hospitalised for a minimum period of 24 hours during the course of the trial. They were only enrolled Neither any revisit or readmission data nor any assessments of in the trial if they had been diagnosed with acute gastroenteritis parental satisfaction were reported. All participants were orally which was confirmed by a positive stool analysis for adenovirus or rehydrated and none of them received any intravenous fluids.
rotavirus. All but two of the participants had positive stool cultures Adverse events were noted in all treatment groups which included for rotavirus, adenovirus or bacteria.
episodes of diarrhea, general drowsiness, a cough which was expe- The participants in the groups were comparable for gender and rienced by a few of the patients in both groups and tremor expe- food intake but were not balanced for age, height, weight and rienced by one patient in the metoclopramide group.
degree of hydration.
The inclusion criteria specified for this study required participantsto have had at least two vomiting episodes (either spontaneous Further details of these trials can be found in the table ’Charac- or oral-rehydration induced) within one hour, where a vomiting Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
the initial observation period in the emergency department andwere followed up for up to 48 hrs, whereas the Cubeddu study The Ramsook study was a well conducted clinical trial in which was completed in 24 hours, after which all the participants were the intervention (oral ondansetron) and control (placebo) groups discharged and received no further care.
were assigned before the experiment through the use of standardrandom number allocation tables (Ramsook 2002). The medica- Hospitalisation of all the participants in the Cubeddu study en- tions were blinded, randomized, and packaged by a pharmacy. As- sured they were more closely observed and that data collection signment to either the oral ondansetron (strawberry flavour) inter- was more likely to be complete (Cubeddu 1997). Conversely a vention or the taste and colour matched placebo was carried out greater reliance was placed on the participants and their carers in by the pharmacy research section according to the predetermined the study by Ramsook (Ramsook 2002). These participants were randomization procedure. The randomization code was locked asked to complete a diary recording the number of episodes of away and was only broken and revealed to the assessors at the vomiting and diarrhea in the 24 hour follow up period. Although conclusion of the trial. Triple blinding was achieved in this trial the patients were contacted by telephone 24 and 48 hours after as neither the trialists, the emergency department staff, patients discharge, compliance with medication, oral rehydration and the and carers nor the outcomes assessors were aware of the treatment BRAT diet guidelines could not be assured. The parents were re- assignment in this study. Randomization and allocation conceal- quired to complete a diary which was then mailed to the trialists ment were both graded as adequate (A).
to confirm the data which had previously been obtained over the The authors followed the intention-to-treat principle and pre- telephone. The trialists did indicate that 10-15% of patients were sented a Trial Randomisation Flow diagram which comprehen- lost to follow up of telephone and mail-in diary.
sively charted the path of all the participants through the study,and all patients lost to the trial were accounted for satisfactorily.
This trial was supported in part by a grant from Glaxo Wellcome The primary outcome specified in the protocol for this review was In the Cubeddu study it was stated that the participants were ran- the time taken from the administration of the treatment measure domly assigned to interventions and control, but the method used until cessation of vomiting. None of the included trials provided to achieve randomisation was not mentioned by the trialists and any data addressing this outcome but some of the secondary out- therefore this criterion was graded as (B) unclear (Cubeddu 1997).
The trialists confirmed that blinding of investigators was achievedthrough the preparation of the study medication by a pharmacist not involved in patient care and therefore the allocation conceal- Primary outcome: time to cessation of vomiting
ment in this study was graded as (A) adequate. There was no in- This report did indicate that the number of participants who re- dication from the study details if persons assessing the outcomes ceived ondansetron and had no vomiting was greater than those of care were blinded to which treatment the participants received who received placebo during the emergency department stay and (detection bias), and thus this criterion was graded as unclear.
during the first and second 24-hour period (Table 02). However The report was fairly explicit about the losses due to ’treatment it was not explicit about the precise time to cessation of vomiting failures’ and was graded as (A) clear.
in each person in each group during the study period.
It was stated that two of the authors of this trial obtained funding Secondary outcomes: Admission and revisit rate, intravenous rehy-
drationTwo participants in the placebo and 11 in the ondansetron group There were a number of differences in the conduct of the two who had persistent vomiting, or refused oral rehydration, or were administered intravenous fluids were subsequently admitted (Ta- • All patients in the Cubeddu study were hospitalised for 24 ble 03). Although no exact data were made available, the trialists hours, whereas in the Ramsook study any patient who was hos- confirmed that a smaller proportion of patients in the ondansetron pitalised was considered a treatment failure and took no further group compared with placebo required intravenous fluid ther- apy. The revisit rate was higher in the ondansetron group (4/74;5.41%), two for persistent vomiting and two for persistent diar- • In the Cubeddu study, a diagnosis of either bacterial or viral rhea, compared with the placebo group (0/71) P=.047.
gastroenteritis was confirmed by stool analysis, the diagnosis in This trial did not include any assessment of parental satisfaction.
Ramsook was less clear with the clinical definition of gastroen- Side effects:
teritis as “the presence of vomiting with or without diarrhea”.
Apart from diarrhea the only other side effect reported in this trial • The studies were conducted over different time periods. In the was the development of a macular rash in one patient who had Ramsook study, the patients were discharged to home care after Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
effects, appeared to indicate that other than diarrhea all of the Primary outcome: time to cessation of vomiting
drugs were reasonably well tolerated.
Although this report did not provide the precise time to cessation This review included two trials which were industry funded and of vomiting for participants in any of the groups, it did indicate provided some weak and unreliable evidence regarding the clini- that the proportion of patients experiencing no vomiting in the cal effectiveness and safety of antiemetics prescribed for children time period 0-24 hours was higher in the ondansetron group 7/12 (58%) than placebo 2/12 (17%) and 4/12 (33%) in the metoclo-pramide group P= .039 (Table 04).
Ondansetron ensured complete anti-emesis for 8/12 (67%) pa- A U T H O R S ’ C O N C L U S I O N S
tients within the first 4 hours and in 7/12 (58%) patients in thefirst 24 hr period.
Implications for practice
Secondary outcomes: Admission and revisit rate, intravenous rehy-
It appears that ondansetron may reduce the amount of acute vom- iting as well as reducing the number of children who required Intravenous fluid therapy for diarrhea induced fluid loss was given intravenous rehydration, and admission for acute gastroenteritis.
to 3 (25%) patients in the ondansetron group and to 1 (8%) in However this conclusion is only based on two studies. In addition, the metoclopramide group during the first 24 hour period after participants in the ondansetron group did have more diarrhoea than in the placebo group, but the amount is likely not clinically No data was available for either admission beyond the study period significant. The two included trials reported on two possible routes or revisit rates. The trialists did not include any data on assessment of administration for two antiemetics; either oral or intravenous ondansetron or intravenous metoclopramide. It is conceivable that Side effects:
in the presence of persistent vomiting the intravenous single dose Adverse events were noted in all treatment groups. All patients in of ondansetron, if available, may offer some advantages over the the study experienced at least one episode of diarrhea but compared oral route particularly in that the intravenous route is most likely with placebo there were significantly more episodes of diarrhea in to obviate any further irritation to the gastric mucosa.
the ondansetron (P= .013) and metoclopramide (P= .004) groupsin the first 24 hours although there was no significant difference Implications for research
In view of the likelihood of a higher incidence of gastroenteritis Other side effects included general drowsiness in 90% of the pa- in developing countries the importance of further research into tients, a cough experienced by a few patients in both groups and the effectiveness and cost effectiveness of antiemetics cannot be tremor by one patient in the metoclopramide group.
underestimated, particularly if this may lead to a reduction in thefrequency with which costly intravenous fluids and hospitalisationare required.
Future research should also focus on outcomes that are of relevanceto patients and thus the time to cessation of vomiting rather than Whilst recognising the methodological limitations of the two stud- a reduction in the number of episodes of vomiting as outcomes ies, the incompleteness of their data, the likelihood of publication would appear to be more appropriate.
bias and the comparative unreliability of the evidence, we have stillchosen to include them but advise caution in the interpretation oftheir results. We expect that, with a response from the trialists in P O T E N T I A L C O N F L I C T O F
either of the studies which are awaiting assessment, we will be able I N T E R E S T
to add to and improve on the rather distinct lack of data availablefor the planned outcomes specified in the protocol of this review.
There are no financial conflicts of interest and the reviewers declarethat they do not have any associations with any parties who may The AAP guidelines (AAP1996), published almost 10 years ago, have vested interests in the results of this review.
stated that there was a consensus of opinion that antiemetics werenot needed for the management of vomiting due to gastroenteritisin children. It was thus somewhat disappointing to see a lack of A C K N O W L E D G E M E N T S
robust clinical trials to either support or refute this opinion andboth of these included trials provide little or no direct evidence to The reviewers would like to thank Janet Lilleyman, the Review support the necessity of any immediate changes to that guidance.
Group Coordinator of the Cochrane UGPD Group, for her sup- The AAP guidelines did also warn that clinicians should be aware port throughout this review . We also are very grateful to Iris Gor- of certain potential, but unspecified, adverse effects associated with don for her tireless effort in developing the search terms and strat- antiemetics, yet both of these studies, whilst reporting some side egy and running the searches for this review. Madame Ricks of the Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
British School of Bahrain also very kindly undertook the transla-tion of the French study into English for which we are extremelygrateful.
External sources of support
Internal sources of support
References to studies included in this review
Brunton 1996
Cubeddu 1997 {published data only}
Brunton LL. Agents affecting gastrointestinal water flux and motil- Cubeddu LX, Trujillo LM, Talmaciu I, Gonzalez V, Guariguata J, ity; emesis and anti emetics; bile acids and pancreatic enzymes. In: Seijas J, Miller IA, Paska, et al. Antiemetic activity of ondansetron Goodman, Gilman editor(s). The Pharmacological Basis of Therapeu- in acute gastroenteritis. Alimentary Pharmacology and Therapeutics tics. 9th Edition. New York: McGraw-Hill, 1996:928–932.
Doan 2003
Ramsook 2002 {published data only}
Doan LT, Okitsu S, Nishio O, Pham DT, Nguyen DH, Ushijima H.
Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D.
Epidemiological features of rotavirus infection among hospitalised A randomized clinical trial comparing oral Ondansetron with placebo children with gastroenteritis in Ho Chi Minh City, Vietnam. J Med in children with vomiting from acute gastroenteritis. Annals of Emer- Virol 2003;69:588–94.
gency Medicine 2002;39(4):397–403.
Feldman 1989
Feldman M. Nausea and Vomiting. In: SleisengerMH, FordtranJS References to studies excluded from this review
editor(s). Gastrointestinal Disease:Pathophysiology, Diagnosis, Manage- Ginsburg 1980
ment. 4th Edition. Philadelphia: Saunders, 1989:222–226.
Ginsburg CM, Clahsen J. Evaluation of trimethobenzamide hy-drochloride (Tigan) suppositories for treatment of nausea and vom- Flake 2004
iting in children. Journal of Pediatrics 1980;96(4):767–9.
Flake ZA, Scalley RD, Bailey AG. Practical Selection of Antiemetics.
American Family Physician 2004;69(5):1171.
Van Eygen 1979
Van Eygen M, Dhondt F, Heck E, Ameryckx L, Van Ravensteyn H.
Friedman 1998
A double blind comparison of domperidone and metoclopramide Friedman LS, Isselbacher KJ. Nausea, Vomiting, and Indigestion.
suppositories in the treatment of nausea and vomiting in children.
In: FauciAS, BraunwaldE, IsselbacherKJ, et al. editor(s). Harrison’s Postgraduate Medical Journal 1979;55(Suppl 1):36–9.
Principles of Internal Medicine. 14th Edition. New York: McGraw-Hill, 1998:230–232.
References to studies awaiting assessment
Herikstad 2002
Debray 1990
Herikstad H, Yang S, Van Gilder TJ ET AL. A population - based Debray H, Guihard J, Peyramond D, Tron P. Treatment of vomit- estimate of the burden of diarrhoeal illness in the United States: ing in infants and children induced by acute infectious pathology.
FoodNet. Epidemiol Infect 2002;129(1):9–17.
A comparative study of alizapride versus metopimazine. Annales de Higgins 2005
Pediatrie 1990;37(10):683–7.
Higgins JPT, Green S editors. Cochrane Handbook for Systematic Re- Reeves 2002
views of Interventions 4.2.5 In: The Cochrane Library, Issue 3. Chich- Additional references
ester, UK: John Wiley & Sons, Ltd, 2005.
Taylor 1999
Nazarian LF, Berman JH, Brown G, Margolis PA, Matson DO, Mc- Taylor AT. Nausea and Vomiting. In: DiPiroJT, TalbertRL, YeeGl, Clung J, et al. Practice Parameter: The Management of Acute Gas- et al. editor(s). Pharmacotherapy, A Pathophysiologic Approach. 4th troenteritis in Young Children. Pediatrics 1996;97:424–35.
Edition. Stanford CT: Appleton & Lange, 1999:586–596.
Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies
Cubeddu 1997
A randomised double blind placebo-controlled parallel group study. Method of randomisation not specified.
A single IV dose of Ondansetron (0.3mg/kg) or metoclopramide (0.3mg/kg) or placebo( sterile saline) Primary outcome: a single vomit or retch or any number of continuous vomits and/or retches Treatment failures at 0-4hrs: four (33%) placebo, two (17%) metoclopramide and one (8%) ondansetron.
At 0-24hrs: four (33%) placebo, five (42%) metoclopramide and two (17%) ondansetron.
This study was supported by Glaxo Wellcome Research and Development Ramsook 2002
A prospective double blind randomised study. Random allocation tables were used to assign treatment orplacebo.Treatment was blinded randomised and packaged by a pharmacy.
Children between the ages of 6 months and 12 years Oral Ondansetron 2mL( 1.6mg) for ages 6 months to I yr, 4mL (3.2mg) aged 1-3yrs, and 5mL (4mg) aged 4-12 (all 8 hourly) or placebo. Oral rehydration was started 15 mins after the initial dose at 5mL/min accordingto standard accepted protocols.
Primary outcomes: frequency of vomiting during the 48hour period after enrollment and rates of intravenousfluid administration.
Secondary outcomes: admission rates and frequency of diarrhea.
One patient who developed a rash was withdrawn after the first dose. A total of 13 patients, who had receivedintravenous fluids, had persistent vomiting and who had to be subsequently admitted, were classified astreatment failures.
Study funding was obtained from Glaxo Wellcome.
Characteristics of excluded studies
This was a non randomised controlled study.
No outcomes matching those specified in the protocol of this review.
Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Table 01. Baseline characteristics 24hr preceding the study (Ramsook 2002)
Emesis episodes
Ondansetron group
Placebo group
Table 02. Proportion of patients without vomiting (Ramsook 2002)
Time period
Ondansetron group
Placebo Group
Table 03. Admission rate including the number requiring intravenous fluids (Ramsook 2002)
Ondansetron Group
Placebo Group
Table 04. Participants with no vomiting 0-24hr (Cubeddu 1997)
Placebo (n=12)
Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents Contribution of author(s)
Dunia Alhashimi(DAH) and Zbys Fedorowicz (ZF) were responsible for:Designing the reviewCo-ordinating the reviewPerforming previous work that was the foundation of current study.
(DAH) (ZF)and Hakima Alhashimi (HAH) were responsible for:Data collection for the reviewScreening the search resultsScreening retrieved papers against inclusion criteriaAppraising quality of papersAbstracting data from papersObtaining and screening data on unpublished studiesEntering data into RevManAnalysis of data Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Interpretation of dataWriting the review.
(ZF) and (DAH) were responsible for:Organising retrieval of papersWriting to authors of papers for additional informationProviding additional data about papers.
(DAH) conceived the idea for the review and is the guarantor for the review.
Issue protocol first published
Review first published
Date of most recent amendment
Date of most recent
What’s New
In view of the absence of any trials addressing the primary outcome of this review, ’thetime taken from the first administration of treatment measure to cessation of vomiting“, wereport only on the outcomes presented in the two included trials, which specifically referto some of the secondary outcomes specified in the protocol of this review. Two trials areawaiting assessment and if data relevant to the outcomes of this review become available wewill update the review accordingly.
Date new studies sought but
none found
Date new studies found but not
yet included/excluded
Date new studies found and
Date authors’ conclusions
section amended
Contact address
Dr Dunia AlhashimiPaediatric Emergency PhysicianPaediatricsSalmaniya Medical ComplexBox 12ManamaBAHRAINE-mail: drdunia@gmail.comTel: +973 39888245Fax: +973 17596658 Cochrane Library number
Editorial group
Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Editorial group code
Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents (Review)
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

Source: http://www.rt.ae/cochrane/Article_04_Alhashimi_Review_published.pdf

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