Ondansetron (Zofran) for Pediatric Gastroenteritis

Tomasik E, Ziółkowska E, Kołodziej M, Szajewska H. Systematic review with metaanalysis: ondansetron for vomiting in children with acute gastroenteritis. Aliment Pharmacol Ther. 2016;44(5):438-46.

Study Population: Patients ranging from 3 months old to 15 years old presenting with vomiting due to acute gastroenteritis

Cessation of vomiting, hospitalization rate, need for intravenous rehydration, and return visits

Medication adverse events

Gastroenteritis is a common disease in children that presents predominantly with vomiting and diarrhea. According to the Center for Disease Control and Prevention (CDC), it accounts for 220,000 hospitalizations in the United States.1 Vomiting and diarrhea, in combination with decreased oral intake, can lead to dehydration. Ondansetron (an antiemetic) has been increasingly used in the pediatric population to help reduce the vomiting and hopefully decrease the risk for dehydration in the child.

This review is an update of a previous evidence-based review published on TheNNT.com.2 The most recent systematic review on ondansetron use in pediatric gastroenteritis was published in 2016.3 This systematic review included 10 RCTs enrolling 1215 patients diagnosed with gastroenteritis in aggregate with ages ranging from 3 months old to 15 years old. Two of the ten trials were carried out in hospitalized patients. The remaining eight trials were conducted in emergency departments (EDs). The trials took place in India, Iran, Thailand, Turkey, Venezuela, and the USA. The trials included children with vomiting due to acute gastroenteritis who were randomized to ondansetron (administered orally or intravenously), placebo or no intervention. The primary outcome of the meta-analysis was cessation of vomiting within one hour of drug administration. The secondary outcomes included treatment success beyond one hour, hospitalization rates, return visits, need for intravenous hydration, and medication side effects.

Ondansetron significantly decreased the chance of vomiting within 1 hour from start of treatment. (Relative risk [RR]: 1.49, 95% CI, 1.17 to 1.89, absolute risk difference [ARD]: 25%, Number-Needed-To Treat [NNT]: 4; Quality of evidence: Moderate). However, the difference was not statistically significant after 4, 24, or 48 hours. Ondansetron also reduced the risk of hospitalization at the index visit (RR: 0.53, 95%Cl, 0.29 to 0.97; ARD: 6.7%; NNT: 15; Quality of evidence: High), and the need for IV hydration (RR: 0.45, 95% CI, 0.31 to 0.63; ARD: 19.2%; NNT: 5; Quality of evidence: High). Ondansetron did not reduce the rate of ED return visits.

Adverse Events: Nine of the ten trials reported medication side effects but the reported side effects where minor and transient (cough, abdominal distention, rash, and diarrhea). No meta-analysis was performed on the harm endpoint due to the small number of events.3

A recent randomized, double blinded, placebo-controlled trial published in 2019 examined the efficacy of ondansetron in dehydrated children 6 months to 60 months with diarrhea and at least one episode of vomiting in Pakistan (n=918).4 In this trial, the number of children requiring intravenous hydration did not reach statistical significance (primary outcome, OR: 0.71, 95% Cl, 0.5 to 1.0), therefore ondansetron did not reduce the rates of IV rehydration among dehydrated children enrolled in this trial. However, a secondary outcome (cessation of vomiting during the observation period [4 hours]) showed a significant decrease in the rate of vomiting (OR: 0.43, 95% Cl, 0.31 to 0.61). Another randomized controlled trial (n=626) conducted by the same authors studied the impact of ondansetron on IV rehydration requirement (primary outcome) specifically in non-dehydrated children suffering from vomiting. This trial concluded that ondansetron did not reduce the need for IV rehydration in non-dehydrated children.5

A recent network meta-analysis published in 2020 also demonstrated the effectiveness of ondansetron. This meta-analysis included 24 studies and evaluated various antiemetics, in 3482 children across 16 different countries in five continents.6 The network meta-analysis showed ondansetron was the only antiemetic effective for cessation of vomiting compared to placebo (OR 0.28, 95% CI, 0.16 to 0.46, high quality evidence). It also proved to be effective in decreasing hospitalizations (OR 0.34, 95% CI, 0.16 to 0.59) and decreasing need for IV hydration (OR 0.33, 95% CI, 0.19 to 0.52) compared to placebo. Of note, in this meta-analysis the side effects of ondansetron did not differ from placebo. In this network meta-analysis, a subgroup analysis based on the severity of illness showed that ondansetron was less effective when vomiting was severe (>4 episodes of vomiting per hour).

The systematic review deemed the quality of evidence moderate to high. While there was substantial heterogeneity in the data regarding ondansetron for the endpoint of cessation of vomiting, there was little heterogeneity in the data pertaining to decreased hospitalizations and need for IV hydration.3

It must be noted that the United States Food and Drug Administration (FDA) has issued a warning on prolonged QT (and potential Torsade de Pointes) associated with ondansetron use.7 The FDA warning states that patients with previous history of underlying heart conditions, such as congenital long QT syndrome, those who are predisposed to low levels of potassium and magnesium in the blood, and those taking other medications that lead to QT prolongation are at higher risk of such adverse events. However, the frequency and severity of this adverse event is unknown. It is also important to note that vomiting and diarrhea can cause electrolyte imbalance, cardiac stress, and increased blood pressure. These effects are important to note in the context of the FDA warnings of increased QT prolongation and potential Torsades with ondansetron. None of the trials included in the systematic review reported any cardiac effects, apparent arrhythmia events, or unexplained sudden deaths.3

The 2014 European Society of Pediatric Gastroenterology, Hepatology, and Nutrition guidelines recommend the following: “Ondansetron at the dosages used in the available studies administered orally or intravenously, may be effective in young children with vomiting related to acute gastroenteritis.8 Before a final recommendation is made, a clearance on safety in children is need.” (Strong recommendation, low-quality evidence). This guideline also states, “There is no evidence to support the use of other antiemetics” (strong recommendation, low-quality evidence).

The American Academy of Pediatrics guidelines do not recommend antiemetics in acute gastroenteritis since the vomiting is believed to be self-limiting and usually corrected with rehydration.9 However, these guidelines were released in 1996 before most studies included in the meta-analysis were published. Lastly, the FDA document on indications for the use of ondansetron only lists severe vomiting resulting from chemotherapy or radiation therapy, and post-operative nausea or vomiting.10

In summary, in children presenting with vomiting due to acute gastroenteritis, oral or intravenous administration of ondansetron decreases the rate of vomiting within one hour of presentation, reduces the risk of hospitalization, but may not reduce the need for intravenous hydration. We have assigned a color recommendation of GREEN (Benefit > Harm) to this treatment.

See theNNT.com's previous reviews of this topic:
Ondansetron (Zofran) for Pediatric and Adolescent Gastroenteritis, April 28, 2012

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

June 16, 2020