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Ondansetron for children with gastro-enteritis


Ondansetron is a serotonin receptor antagonist which has been authorised for use as an anti-emetic in the context of chemotherapy (from an age of 6 months) and radiotherapy (in adults). It has also been authorised for the prevention and treatment of postoperative nausea and vomiting. For several years now, the syrup has also been prescribed off-label for children who vomit due to acute gastro-enteritis. A systematic review has shown that a single dose administered in primary care reduces the vomiting, as well as the need for intravenous rehydration and hospitalisation. Adverse effects after a single dose are rare.

What is Ge-Bu’s opinion?
  • Children with gastro-enteritis, in whom vomiting is a major concern and in whom the vomiting hampers fluid uptake, could be treated with a single dose of ondansetron in primary care. 
  • Research has shown that a single dose of odansetron reduces the vomiting, though the quality of the evidence is poor to moderate. 
  • It is possible that this treatment can prevent hospitalisation in a number of cases. 
  • Ondansetron is not a therapy for dehydration due to gastro-enteritis.
  • No relevant adverse effects have been documented after a single dose of ondansetron. 

In recent years, ondansetron has been prescribed off-label for children with gastro-enteritis and vomiting. This is partly the result of the lack of evidence for the effectiveness of domperidone and the occurrence of extrapyramidal adverse effects when metoclopramide is used in children.1,2 The Paediatric Drug Formulary, published by the Dutch Paediatric Pharmacotherapy Expertise Network (NKFK), mentions acute gastro-enteritis with vomiting in children as an off-label indication for ondansetron.3 The recommended dosage of the syrup (0.8 mg/mL) is 0.1 mg per kilogram body weight for each dose, with a maximum of 3 times a day at intervals of at least 4 hours.3 Until recently, the lack of sound research meant that it was unclear whether treating nausea and vomiting in children with gastro-enteritis offered clinically relevant benefits. A Dutch randomised trial and a recent meta-analysis of the use of a single dose of ondansetron in acute viral gastro-enteritis have shown that ondansetron increases the chances of ending the vomiting. Ondansetron thus appears to reduce the need for intravenous rehydration and hospitalisation.4,5 However, the quality of the evidence was poor to moderate. 

Mechanism of action

Ondansetron is a selective 5HT3 (serotonin) receptor antagonist. It blocks 5-HT3 receptors in the gastrointestinal tract and in the autonomous and central nervous systems. This combination of peripheral and central effects probably suppresses the gag reflex due to serotonin. One major source of serotonin release is that of intestinal cells damaged by cytostatics, causing activation of the vomiting centre through stimulation by 5-HT3. Ondansetron has been authorised to counteract nausea and vomiting due to cytotoxic chemotherapy (from an age of 6 months) and radiotherapy (in adults).6


Outcome measures

Since ondansetron is effective for the treatment of vomiting during chemotherapy and in the context of anaesthesia, researchers have investigated whether it is also effective as a treatment for vomiting due to gastro-enteritis. The main goal with anaesthesia and chemotherapy is patient comfort. In the case of gastro-enteritis, preventing dehydration is a major goal. The literature mentions the following outcome measures for effectiveness:

  • stopping the vomiting 
  • need for hospitalisation
  • need for intravenous rehydration.

Effectiveness against vomiting

Dutch randomised trial

This randomised trial (RCT), which took place at out-of-hours primary care centres, included 194 of the 1061 children screened (aged 6 months to 6 years). Only 175 of them were included in the intention-to-treat analysis. The most common reason to exclude children (395) was that the risk of dehydration was deemed to be minor. Parents provided diaries or were interviewed by telephone about the course of the gastro-enteritis, including vomiting. Complete data were available for 77 of the 87 children who had been given a single oral dose of ondansetron (syrup, 0.1 mg/kg), and for 77 of the 88 children offered care as usual (CAU). CAU consisted of the treatment recommended in the Dutch College of General Practitioners’ clinical practice guideline on nausea and vomiting.7 In the ondansetron group, 15 children continued to vomit, compared to 33 in the CAU group. The odds ratio for continued vomiting during the 4 hours after administration was 0.37 (95% confidence interval [CI] 0.20 to 0.72) for ondansetron versus CAU.4 The number needed to treat (NNT) was 4.

Systematic review and meta-analysis

This meta-analysis included 13 randomised studies, comprising a total of 2146 patients. These studies assessed the effectiveness of ondansetron (oral or intravenous) compared to placebo in children younger than 18 years who were vomiting and were clinically suspected to have acute gastro-enteritis. Nine of the studies reported vomiting cessation within 8 hours as the primary outcome measure. Of the 873 children given ondansetron, 714 stopped vomiting, while of the 875 children given placebo, 566 stopped vomiting. The relative risk of vomiting cessation in the 8 hours after administration was 1.41 (95% CI 1.19 to 1.68) for ondansetron compared to placebo.5 This corresponds to an NNT of 4.

Intravenous rehydration

Systematic review and meta-analysis

Eight of the studies included in the meta-analysis reported intravenous rehydration during the stay at the emergency department as an endpoint. Of the 826 children who received ondansetron, 70 required intravenous rehydration, while of the 836 children receiving placebo, 163 required intravenous rehydration. The relative risk of intravenous rehydration during the stay at the emergency department was 0.44 (95% CI 0.34 to 0.57) after ondansetron compared to placebo.5 The NNT is 7.

Preventing hospitalisation

Dutch RCT

Complete data were available for 59 of the 87 children given ondansetron, and for 73 of the 88 children receiving CAU.7 In the ondansetron group, nine children were admitted to hospital, compared to 10 in the CAU group. The odds ratio for hospitalisation was 1.80 (95% CI 0.91 to 3.55) for ondansetron compared to CAU, a non-significant difference.4

Systematic review and meta-analysis

Five of the studies in the meta-analysis used hospitalisation within 8 hours after the start of treatment as an endpoint. Of the 411 children given a single oral or intravenous dose of ondansetron, 29 were admitted to hospital, while of the 412 children given placebo, 59 were admitted to hospital. The relative risk of hospitalisation within 8 hours after the start of treatment was 0.49 (0.32 to 0.75) for ondansetron compared to placebo.5 The NNT was 8.


 According to the studies discussed above, a single dose of ondansetron rarely causes adverse effects. As regards adverse effects like coughing and diarrhoea, no differences were found between the groups given placebo or ondansetron. Ondansetron is associated with a (rare) elevated risk of cardiac arrhythmias with prolonged QT interval on the ECG. This adverse effect is potentially fatal, as it results in an elevated risk of developing torsade de pointes (ventricular tachycardia). The occurrence of this adverse effect is restricted to children at increased risk and is dose-dependent. An elevated risk is found in children with heart failure, bradycardia, congenital long-QT syndrome or those using other QT prolonging medication. Prolonged QT interval was found in about 30% of the children given intravenous ondansetron at a paediatric intensive care unit.8 None of the studies of ondansetron in gastro-enteritis included making an ECG. 

The Dutch Paediatric Drug Formulary mentions that headache occurs in over 10% of patients, but this adverse effect was not mentioned in the studies discussed above.3 It should be noted that such a headache may well arise only after several doses. Most studies actually did not specifically assess adverse effects. Underreporting and incomplete reporting of adverse effects in studies among children is a well-known problem.9


Acute viral gastro-enteritis

Acute viral gastro-enteritis is a common condition and is characterised by diarrhoea. It often involves vomiting, nausea and fever. The incidence is high (13.6 per 1000 patients, based on GP registrations). The incidence peaks in young children aged 0 to 4 years (91.2 per 1000 patients aged 0 to 1 year and 45.7 per 1000 patients aged 2 to 4 years).7 Acute gastro-enteritis often occurs in clusters, for instance among children in day-care centres. Gastro-enteritis is usually self-limiting, but is often a reason to visit a GP or other doctor, including those at out-of-hours primary care. The main risk of gastro-enteritis is dehydration due to fluid loss caused by the diarrhoea.

Dehydration can be prevented by sufficient fluid intake. Hence it is useful to frequently offer fluids, and if there are signs of dehydration to give oral rehydration solution (ORS) or dilute apple juice.10

In addition to diarrhoea, fever and abdominal pain, vomiting is also a common feature. Vomiting can hamper fluid intake and is sometimes regarded as the main cause of failed oral rehydration therapy. This is usually not the case, however. The amount of fluid lost due to vomiting is limited. The bulk of fluid loss is caused by the diarrhoea.

Ondansetron reduces vomiting, but plays a minor role in preventing dehydration. This implies a certain risk. Carers may think that the child is doing much better, as it is vomiting less, whereas fluid losses through diarrhoea continue. It is therefore important to focus on signs of (severe) dehydration, such as further reduction of urine production and drowsiness. The main goal in treating gastro-enteritis is to ensure a state of adequate hydration.

Details of the studies discussed

Bonvanie et al4
Study name: KOOKING (Kosteneffectiviteit ondansetron bij kinderen met acute gastro-enteritis; cost-effectiveness of ondansetron in children with acute gastro-enteritis)
Design: multicentre randomised controlled trial in primary care
Inclusion criteria: children at risk of dehydration, aged 6 months to 6 years, with gastro-enteritis, who had vomited at least four times in the last 24 hours and at least once in the last hour
Main exclusion criteria: treatment with antiemetics in the previous 6 hours, underlying conditions like diabetes or kidney failure, or known hypersensitivity to 5HT3 receptor antagonists, prolonged QT interval
Intervention: two interventions were compared:

1.  Care as usual according to the guidelines of the Dutch College of General Practitioners, administering ORS
2.  Care as usual plus ondansetron oral (syrup 0.1 mg/kg), a second dose being given if vomiting occurs again within 15 minutes

Primary endpoint(s) and duration: number of children vomiting in the first 4 hours after randomisation
Intended number of participants and power: 220 children were needed to be able to show a difference on the primary endpoint with an alpha of 5%, with 90% power, assuming a 10% loss to follow-up
Randomisation: 1:1 ratio, using a web-based, interactive computer system, stratified for age and severity of dehydration
Blinding: children, parents and treatment providers were not blinded for the treatment, while the statistician was. Children, parents and treatment providers were unaware of the primary endpoint
Population analysed: intention-to-treat (missing values being supplemented based on prediction obtained with a multivariate imputation model)
Number of patients included: 194 of the 1061 children screened were randomised, 97 in each group; in the intention-to-treat population, 88 received CAU and 87 CAU plus ondansetron 
Trial registration: Dutch Trial Register NL4700 and NL5830 (combining data from the pilot study [NL4700] and the actual trial [NL5830])
Funding: ZonMw (Netherlands Organisation for Health Research and Development)
Conflicts of interest: none reported
Fugetto et al5
Type of study: systematic literature review and meta-analysis
Outcome measure: vomiting cessation within 8 hours after medication
Inclusion criteria: randomised controlled trials comparing the use of ondansetron (oral or intravenous) with placebo in children younger than 18 years with vomiting and clinically suspected acute gastro-enteritis
Number of trials analysed: 13
Number of patients included: 2146
Trial registration: PROSPERO CRD42019134580
Funding: none
Conflicts of interest: none reported

  1. Geneesmiddeleninformatiebank. DHPC Domperidon (Joint Marketing Authorisation Holders), College ter Beoordeling van Geneesmiddelen (CBG), Utrecht, 2021. Available from: https://www.cbg-meb.nl/binaries/college-ter-beoordeling-van-geneesmiddelen/documenten/brieven/2019/06/25/dhpc-domperidon/190625+DHPC+Domperidon.pdf. Accessed 23 December 2021 
  2. Heads of Medicine Agencies. Primperan (and others) Metoclopramide: Rapporteurs Public Paediatric Assessment Report for paediatric studies. Available from: http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Paediatric_Regulation/Assessment_Reports/Article_45_work-sharing/Metoclopramid_Art.45_PdAR_Update.pdf. Accessed 23 December 2021
  3. Kinderformularium. Het Nederlands Kenniscentrum voor Farmacotherapie bij Kinderen (NKFK), Den Haag, 2021. Available from: https://kinderformularium.nl/geneesmiddel/30/ondansetron. Accessed 23 December 2021
  4. Bonvanie IJ, Weghorst AA, Holtman GA, Russchen HA, Fickweiler F, Verkade HJ, et al. Oral ondansetron for paediatric gastroenteritis in primary care: a randomised controlled trial. Br J Gen Pract. 2021 Sep 30;71(711):e728-e735. doi: 10.3399/BJGP.2021.0211. 
  5. Fugetto F, Filice E, Biagi C, Pierantoni L, Gori D, Lanari M. Single-dose of ondansetron for vomiting in children and adolescents with acute gastroenteritis-an updated systematic review and meta-analysis. Eur J Pediatr. 2020 Jul;179(7):1007-1016. doi: 10.1007/s00431-020-03653-0. 
  6. Geneesmiddeleninformatiebank. College ter Beoordeling van Geneesmiddelen (CBG), Utrecht, 2021. Available from: https://www.geneesmiddeleninformatiebank.nl/smpc/h19922_smpc.pdf. Accessed 23 December 2021
  7. NHG-Behandelrichtlijn Misselijkheid en braken. Version August 2016. Nederlands Huisartsen Genootschap (NHG), Utrecht, 2021. Available from: https://richtlijnen.nhg.org/behandelrichtlijnen/misselijkheid-en-braken. Accessed 23 December 2021
  8. Trivedi S, Schiltz B, Kanipakam R, Bos JM, Ackerman MJ, Ouellette Y. Effect of Ondansetron on QT Interval in Patients Cared for in the PICU. Pediatr Crit Care Med. 2016 Jul;17(7):e317-23. doi: 10.1097/PCC.0000000000000776. 
  9. Prins TJ, Rollema C, van Roon E, de Vries TW. Improved quality of reporting safety data of medication in paediatric randomised controlled trials. Arch Dis Child. 2021 Oct;106(10):1010-1014. doi: 10.1136/archdischild-2020-321197. 
  10. Freedman SB, Willan AR, Boutis K, Schuh S. Effect of Dilute Apple Juice and Preferred Fluids vs Electrolyte Maintenance Solution on Treatment Failure Among Children With Mild Gastroenteritis: A Randomized Clinical Trial. JAMA. 2016 May 10;315(18):1966-74. doi: 10.1001/jama.2016.5352.

Authors

  • Frank A. Verhoog
  • Tjalling W. de Vries, dr