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• To improve your knowledge of the management of gastroenteritis in children
• To gain insight into the recent literature on the use of ondansetron to treat gastroenteritis in children
• To reflect on your own practice when treating children with gastroenteritis
In the UK, the use of antiemetics in children with gastroenteritis is not standardised. The antiemetic ondansetron is often administered, in clinical practice, to children presenting with gastroenteritis. However, it is not listed in the British National Formulary for Children for use in gastroenteritis and it is not included in the National Institute for Health and Care Excellence algorithm for the management of gastroenteritis in children under 5 years.
This article discusses the findings of a literature review of the outcomes of ondansetron use in children with gastroenteritis in the emergency department. The article concludes that ondansetron appears to be a beneficial and useful adjunct to the treatment of gastroenteritis in children.
Emergency Nurse. doi: 10.7748/en.2021.e2069
Peer reviewThis article has been subject to external double-blind peer review and checked for plagiarism using automated software
Correspondenceelizabeth.lloydmartin@wlv.ac.uk
Conflict of interestNone declared
Lloyd-Martin E (2021) Outcomes of ondansetron use in children with gastroenteritis in the emergency department: a literature review. Emergency Nurse. doi: 10.7748/en.2021.e2069
Published online: 23 March 2021
Gastroenteritis, which should be suspected if there is a sudden change in stool consistency to loose or watery stools (that is, diarrhoea) and/or a sudden onset of vomiting (National Institute for Health and Care Excellence (NICE) 2009), is extremely common in children and many children in the UK experience more than one episode a year (NICE 2009). Diarrhoea is potentially life-threatening, particularly in infants, since it can cause dehydration leading to hypovolaemic shock (Advanced Life Support Group 2016). Complications of diarrhoea include sepsis and malnutrition (Tomasik et al 2016).
Although gastroenteritis can often be managed at home, many parents and family carers seek advice from medical professionals (NICE 2009). In the UK, gastroenteritis in children under the age of 5 years is responsible for 20% of GP consultations (Elliott 2007). Vomiting, which is most often associated with acute gastroenteritis, is a major cause of paediatric presentations to the emergency department (ED) in developed countries (Romano et al 2019). Together, dehydration and gastroenteritis form one of five ambulatory care-sensitive conditions (ACSCs) that account for more than half the annual cost of emergency admissions for ACSCs in England (Tian et al 2012).
The NICE (2009) guideline for diagnosing and managing diarrhoea and vomiting caused by gastroenteritis in children under 5 years recommends treating a dehydrated child with oral rehydration therapy (ORT) by administering an oral rehydration solution (ORS). ORSs are readily available and can adequately and safely replace lost electrolytes. They contain an alkalinising agent to counteract acidosis and are simple to use in hospital and at home (British National Formulary for Children (BNFC) 2021a).
NICE (2009) does not mention antiemetics as part of the management of gastroenteritis in children under 5 years. The NICE 2009 guideline covers children under 5 years, but in clinical practice it is commonly applied in children of all ages.
The author has observed that, in clinical practice, healthcare professionals often depart from the NICE (2009) guideline and prescribe and administer the antiemetic ondansetron to treat gastroenteritis in children. Ondansetron features in the BNFC (2021b) but its indications do not include gastroenteritis. Despite several reviews of the NICE 2009 guideline (for example, NICE 2018), NICE does not advocate the use of ondansetron – nor of any other antiemetic – for managing gastroenteritis in children under the age of 5 years.
In the author’s experience, ondansetron is the antiemetic most commonly used in clinical practice to treat gastroenteritis in children, although the BNFC also features the antiemetics domperidone and cyclizine (neither of which is indicated for gastroenteritis).
Ondansetron is a 5HT3 receptor antagonist that blocks the receptors in the gastrointestinal tract (BNFC 2021b). Its precise mode of action in controlling nausea and vomiting is unknown (Electronic Medicines Compendium (EMC) 2020). Peak plasma concentration depends on whether ondansetron is administered orally or intravenously – peak plasma concentration is reached 1.5 hours after administration via the oral route and within 10 minutes of administration via the intravenous (IV) route (EMC 2020). Contraindications include cardiac arrhythmias (BNFC 2021b).
Hanif et al (2019) highlighted that the treatment of gastroenteritis in young children in the UK is controversial because the use of antiemetics is not standardised. Other authors (Fedorowicz et al 2011, Thompson et al 2016) agree that there appears to be a lack of consensus among clinicians about the indications for antiemetics to treat gastroenteritis in children. There is a considerable amount of recent research on the use of antiemetics – particularly ondansetron – to treat gastroenteritis in children, including by Danewa et al (2016), Freedman et al (2019a, 2019b), Hanif et al (2019) and Romano et al (2019).
• The treatment of gastroenteritis in young children in the UK is controversial because the use of antiemetics is not standardised
• The National Institute for Health and Care Excellence (NICE) does not advocate the use of antiemetics for managing gastroenteritis in children
• In clinical practice, healthcare professionals often administer the antiemetic ondansetron to treat gastroenteritis in children
• In recent studies, outcomes of ondansetron use to treat gastroenteritis in children included cessation or reduction of vomiting, reduced hospital admission rates, reduced need for intravenous therapy and increased tolerability of oral rehydration solutions
• NICE has noted an association between ondansetron and increased diarrhoea and considers that further evidence is required before the medicine can be added to its guideline recommendations
This literature review aims to contribute to this research area by reviewing recent studies and summarising their findings regarding the outcomes of ondansetron use in children with gastroenteritis in the ED.
The population, intervention, comparison and outcome (PICO) tool (Sackett et al 1996) was used to frame the review. The ‘population’ was children in the ED, the ‘intervention’ was the administration of ondansetron, and ‘comparison’ was placebo and/or ORS.
The Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Cochrane and MEDLINE were searched using four main search terms – ‘ondansetron’, ‘gastroenteritis’, ‘children’ and ‘emergency department’ – as well as alternative terms including ‘Zofran’, ‘vomiting’, ‘diarrhoea’, ‘diarrhea’, ‘nausea’, ‘child’, ‘paediatric’, ‘paediatrics’, ‘pediatric’, ‘pediatrics’, ‘infants’, ‘ED’, ‘casualty’, ‘accident and emergency’ and ‘A&E’. Different databases use different indexing terms and spellings (Coughlan et al 2013), so using a broad range of search terms ensures all pertinent studies are captured. Boolean operators were used, giving greater control over the search results (Coughlan et al 2013).
Table 1 summarises the search strategy and its rationale.
The search identified 110 articles. After removal of duplicates, 42 articles remained. These were screened by reading their title and abstract, which left 27 articles. These were assessed by reading their full text, which left 17 articles suitable for inclusion in the review. These articles are summarised in an appendix available at rcni.com/ondansetron-children
A data extraction table converting data into systematic categories was devised using a combination of models (Woodward and Webb 2000, Kudchadkar et al 2014). This ensured information was extracted systematically and comprehensively, giving clarity to the study interventions and providing a robust framework for identifying patterns across the data. A Critical Appraisal Skills Programme (2013) tool was used to critique the studies. This was followed by a thematic analysis of the data (Braun and Clarke 2014).
Seven main outcomes of ondansetron use in children with gastroenteritis in the ED, listed in Table 2, emerged from the review. These seven main outcomes emerged as clear and common themes from 16 of the 17 included studies. One study (Danewa et al 2016) did not discuss any of these seven main outcomes. Some studies reported different or additional outcomes. It would be remiss to conclude that the seven main outcomes arose solely from the use of ondansetron, since there may have been other contributing factors.
Gastroenteritis is a clinical diagnosis (Freedman et al 2013) and its severity can vary greatly. The definition of gastroenteritis was not consistent between the reviewed studies, so ondansetron was administered to participants who could have been in different clinical states. For example, in some studies ondansetron was only administered to participants presenting with mild-to-moderate dehydration. These variations may have influenced the outcomes.
Four studies (Golshekan et al 2013, Danewa et al 2016, Freedman et al 2019a, 2019b) used the World Health Organization (WHO) (2005) dehydration tool to classify dehydration but most other studies did not provide details of how dehydration had been classified, which could have introduced bias and variance in the findings.
None of the studies used the NICE (2009) guideline for diagnosing and managing diarrhoea and vomiting caused by gastroenteritis in children under 5 years to aid diagnosis, which would have given more consistency. The NICE (2009) guideline includes a table describing dehydration, which highlights ‘red flag’ symptoms and signs such as appearing unwell or deteriorating, altered responsiveness, sunken eyes, tachycardia, tachypnoea and reduced skin turgor. However, the NICE (2009) guideline is only applicable in England and Wales and none of the reviewed studies was undertaken in England and/or Wales.
Eight studies (listed in Table 2) concluded that use of ondansetron led to a cessation or reduction of vomiting. While this is a positive finding, it is perhaps unsurprising given that ondansetron is an antiemetic. The remaining nine studies did not mention the effect of ondansetron use on vomiting.
The eight studies demonstrated a cessation or reduction of vomiting despite variations in population size, participant age and study design. For example, Cheng (2011) had 466 participants while Freedman et al (2015) had 4,444. In paediatric studies, because of the population’s vulnerability, obtaining a large sample is not always possible (Bragadóttir 2000). Studies with a large number of participants are more powerful than studies with a small number of participants (Fletcher 2008), which increases the confidence that their findings can be extrapolated to a wider population.
Study designs varied, with a mixture of randomised controlled trials (RCTs), systematic reviews and retrospective studies. RCTs are best used when evaluating the effectiveness of an intervention (Evans 2007), particularly if they are multicentre (Bowling 2009). Freedman et al (2019a, 2019b) were double-centre RCTs. Evans (2007) argued that a well conducted RCT, whether single-centre or multicentre, produces results with a low risk of error or bias which can provide valid evidence of the effectiveness of the intervention being investigated.
Two of the included systematic reviews (Freedman et al 2015, Tomasik et al 2016) only considered RCTs. Cheng (2011) carried out a literature review that examined three RCTs but did not discuss the selection process, which is a limitation and may have introduced an element of bias. Furthermore, Cheng (2011) did not establish whether there was blinding in the RCTs reviewed.
The cessation or reduction of vomiting seen with ondansetron use is an important outcome, since vomiting can be one of the main concerns of parents because of general discomfort, visual distress and the risk of dehydration (Flake et al 2004).
Eight studies (listed in Table 2) concluded that the use of ondansetron reduced hospital admission rates. Not having to be admitted to hospital is likely to have psychological benefits for parents and children (Power et al 2020) and financial benefits for the NHS (Tian et al 2012). Freedman et al (2014), who conducted a retrospective observational analysis, concluded that there was no change in hospital admission rates but reported a reduction in re-attendance rates. The outcome of reduced hospital admission rates was unaffected by differences in participant age, population size, study design and inclusion criteria, which supports the validity of the finding.
Three of the eight studies that reported reduced hospital admission rates were RCTs or systematic reviews of RCTs (Cheng 2011, Fedorowicz et al 2011, Tomasik et al 2016) and three were cohort studies (Mullarkey et al 2013, Marzuillo et al 2016, McLaren et al 2016). Compared with RCTs, cohort studies have a disadvantage in that data analysis produces a ‘cohort effect’. This refers to the fact that each group or cohort experiences different study conditions (Bowling 2009) and that there is therefore a lack of consistency in participants’ experiences. Furthermore, cohort studies cannot exclude confounding factors that may contribute to or affect the findings.
Five of the eight studies that reported reduced hospital admission rates also found that ondansetron was effective in the cessation or reduction of vomiting, which could partly explain the reduced hospital admission rates.
Eight studies (listed in Table 2) found that ondansetron reduced the need for intravenous (IV) fluid therapy, thus lowering the risks associated with IV therapy and alleviating parents’ concerns about IV therapy. The benefits of not requiring IV fluid therapy are extensive. The NICE guideline (2020) on IV fluid therapy in children and young people in hospital includes an extensive list of considerations, including assessment, monitoring (notably of electrolyte plasma concentration), fluid resuscitation and routine maintenance. Reducing or removing the need for this invasive intervention would benefit patients and families as well as service providers.
Although the eight studies had different primary outcomes, all of them reached the conclusion that ondansetron reduced the need for IV fluid therapy. However, definitions of gastroenteritis varied, as did the point at which participants were assessed to establish whether the ORT regimen had been successful. The studies also had different population sizes, ranging from 73 (Schnadower et al 2015) to 4,444 (Freedman et al 2015), and different designs, such as double-blind RCT (Freedman et al 2019a, 2019b) and retrospective study (Mullarkey et al 2013).
Nine studies (listed in Table 2) concluded that the use of ondansetron had a positive effect on ORT in that it increased the tolerability of ORSs. Participants’ ages ranged from 1 to 10 years in Golshekan et al (2013) to ‘less than 18 years’ in Zanon et al (2013) and designs varied as well, yet the outcome was the same, which supports its validity.
Tomasik et al (2016) included ten double-blind RCTs in their review, which strengthens the credibility of findings and reduces bias (Miller and Stewart 2011). However, Tomasik et al (2016) reported that blinding in the reviewed studies was unclear, which may be considered a limitation.
The individual benefits of each treatment may be enhanced, and harm reduced, when ondansetron and an ORS are administered together. Increased tolerability of ORSs when used with ondansetron could, for example, alleviate concerns about dehydration due to diarrhoea. Freedman et al (2011b) argued that ORT administration in the ED is not an intervention that adds value, since ORT can be administered at home by family carers. Mullarkey et al (2013) described ondansetron as a ‘useful adjunct’ to ORT but also argued that ORT does not represent an optimal use of resources in the ED, since it can be administered at home.
Of the six studies that discussed the effect of ondansetron use on ED re-attendance rates, three concluded that ondansetron use had no effect on re-attendance rates (Golshekan et al 2013, Freedman et al 2015, Tomasik et al 2016). These three studies were RCTs and two involved double blinding, which increases the credibility of the findings. In a double-blind RCT, neither the healthcare professionals nor the patients are aware of the treatment assignment. Double-blind RCTs are considered the pinnacle of study designs (Misra 2012).
Sample sizes ranged from 176 (Golshekan et al 2013) to 4,444 (Freedman et al 2015). Small sample sizes are associated with concerns about the reliability and validity of findings. Participant age appeared to have no effect on this outcome, since Golshekan et al (2013) included children aged between 1 and 10 years and Freedman et al (2015) and Tomasik et al (2016) included children up to 15 years.
One further study (Freedman et al 2014) reported a reduction in ED re-attendance rates. Two further studies (Freedman et al 2011b, McLaren et al 2016) reported an increase in ED re-attendance rates, which may be regarded as a negative outcome, as it suggests that treatment was unsuccessful. Increased re-attendance rates counteract the benefits of reduced admission rates. Freedman et al (2011b), was multicentred but was also, like McLaren et al (2016), a cohort study, which has the disadvantages discussed above.
Three studies discussed the effect of ondansetron on the number of participants’ stools, two of which concluded that ondansetron compounded the increased number of stools (diarrhoea) typically seen in gastroenteritis (Freedman et al 2013, 2015) and one that ondansetron did not affect the number of stools (Tomasik et al 2016). The association between ondansetron and increased diarrhoea was noted by NICE in its 2018 surveillance review of the 2009 guideline (NICE 2018) as a reason for not adding ondansetron to its guideline recommendations. NICE (2018) explained that further evidence in this area was required before the guideline could be changed. However, diarrhoea is not listed as a side effect of ondansetron in the BNFC (2021b), whereas constipation is. There is clearly inconsistency here.
Seven studies discussed the fact that ondansetron can cause additional diarrhoea (Cheng 2011, Freedman et al 2013, Golshekan et al 2013, Pelc et al 2014, Schnadower et al 2015, Freedman et al 2015, McLaren et al 2016). These seven studies had a vast range of population sizes, from 68 in Pelc et al (2014) to 12,478 in Freedman et al (2013). One single participant in Freedman et al (2013) would have contributed 0.008% to the findings; one participant in Pelc et al (2014) would have contributed 1.47% to the findings and therefore would have had a much greater influence on the findings. Schnadower et al (2015) gave an overview of four studies but did not discuss their inclusion criteria, which creates a potential for bias.
The survey conducted by Pelc et al (2014) attracted 68 responses, which was estimated to represent 54% of the expected response rate (a precise response rate could not be calculated because the total number of potential responders was not known). Although this is a low response rate, Rindfuss et al (2015) argued that a low response rate in itself should not be considered a potential source of bias, but that researchers should test for the presence of bias by considering the specific content under analysis.
Three studies (Freedman et al 2011b, Mullarkey et al 2013, Tomasik et al 2016) addressed the cost implications of using ondansetron to treat gastroenteritis in children in the ED and concluded that ondansetron is a cost-effective treatment. Tomasik et al (2016) suggested that using ondansetron was cost-effective, not in itself but in relation to the reduced need for IV fluid therapy. Mullarkey et al (2013) did not undertake a formal cost-benefit or cost-effectiveness analysis, which raises doubts about the validity of their finding.
The limitations of this literature review were as follows:
• The grey literature was not searched beyond NICE guidelines. Considering the grey literature is a strategy advocated when conducting a literature review, as there is often unpublished evidence on the topic (Adams et al 2016). The grey literature may have provided further insight into the reasons why the use of ondansetron is not recommended by NICE (2009) and why ondansetron is not indicated for the treatment of gastroenteritis in the BNFC (2021b), as well as into the rationale for, and approach to, the use of ondansetron in clinical practice locally.
• The studies did not address the implications of the pharmacokinetics of ondansetron. The timing of ondansetron administration and time spent in the ED were not measured, which could have affected the outcome of increased tolerability of ORSs.
• Six studies had been undertaken by various teams led by Freedman. Personal views developed from previous findings could have influenced each subsequent study and introduced bias. Conversely, accumulated knowledge and experience could have enhanced the method, design and/or analysis of subsequent studies. Freedman et al’s findings on the effect of ondansetron use on ED re-attendance rates changed from increase re-attendance rates (Freedman et al 2011b) to reduced re-attendance rates (Freedman et al 2014) and to no effect on re-attendance rates (Freedman et al 2015).
• None of the studies had been undertaken in the UK. Seven studies had been undertaken in Canada and/or the US, five in European countries other than the UK, and four in the Middle East or Asia – the remaining study was a global study undertaken in several different countries. There may be national or regional cultural differences that affect the use of ondansetron and different outcomes may emerge in different countries or regions.
The antiemetic ondansetron is not listed in the BNFC for the treatment of gastroenteritis and the use of antiemetics is not recommended by NICE for managing gastroenteritis in children under the age of 5 years. However, a literature review of 17 recent studies suggests that ondansetron can have positive effects when used to treat children with gastroenteritis in the ED. In some studies, ondansetron appeared to lead to a cessation or reduction of vomiting; reduce hospital admission rates; reduce the need for IV fluid therapy; and improve the tolerability of ORSs – potentially making ondansetron a useful adjunct to ORT. The reviewed studies were inconsistent in their definitions of gastroenteritis and classification of dehydration and there were wide variations in study design, population size and participant age. While these variations may have affected findings, this could also demonstrate that ondansetron has consistent positive effects regardless of patients’ condition, level of dehydration or age.
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