Antiemetics in Children With Acute Gastroenteritis: A Meta-analysis Laura F. Niño-Serna, MD, MSc,a,b Jorge Acosta-Reyes, MD, MSc,c Areti-Angeliki Veroniki, PhD,d,e,f Ivan D. Florez, MD, MSca,g

CONTEXT: Several antiemetics have been used in children with acute gastroenteritis. However, abstract there is still controversy over their use. OBJECTIVE: To determine the effectiveness and safety of antiemetics for controlling vomiting in children with acute gastroenteritis. DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Latin America and the Caribbean Literature on Health Sciences, and gray literature, until December 2018. STUDY SELECTION: We selected randomized clinical trials comparing metoclopramide, ondansetron, domperidone, dexamethasone, dimenhydrinate, and granisetron. DATA EXTRACTION: Two reviewers independently screened abstracts and full texts, extracted the data, and assessed the risk of bias. We performed pairwise and network meta-analysis using the random-effects model. RESULTS: Twenty-four studies were included (3482 children). Ondansetron revealed the largest effect in comparison to placebo for cessation of vomiting (odds ratio = 0.28 [95% credible interval = 0.16 to 0.46]; quality of evidence: high) and for hospitalization (odds ratio = 2.93 [95% credible interval = 1.69 to 6.18]; quality of evidence: moderate). Ondansetron was the only intervention that reduced the need for intravenous rehydration and the number of vomiting episodes. When considering side effects, dimenhydrinate was the only intervention that was worse than placebo. LIMITATIONS: Most treatment comparisons had low- or very low–quality evidence, because of risk of biases and imprecise estimates. CONCLUSIONS: Ondansetron is the only intervention that revealed an effect on the cessation of vomiting, on preventing hospitalizations, and in reducing the need for intravenous rehydration. Ondansetron was also considered a safe intervention.

aDepartment of Pediatrics, University of Antioquia, Medellín, Colombia; bHospital Pablo Tobón Uribe, Medellín, Colombia; cDepartment of Public Health, Universidad del Norte, Barranquilla, Colombia; dDepartment of Primary Education, School of Education, University of Ioannina, Ioannina, Greece; eLi Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Canada; fDepartment of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, London, United Kingdom; and gDepartment of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada

Dr Niño-Serna conceptualized and designed the study, performed the data collection, evidence synthesis, and quality-of-evidence assessment, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Acosta-Reyes performed the data collection, evidence synthesis, and quality-of-evidence assessment and critically reviewed the manuscript as submitted; Dr Veroniki performed the statistical analyses, drafted the initial manuscript, and critically reviewed the manuscript as submitted; Dr Florez conceptualized and designed the study, performed the evidence synthesis and quality-of-evidence assessment, drafted the initial manuscript, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

To cite: Niño-Serna LF, Acosta-Reyes J, Veroniki A, et al. Antiemetics in Children With Acute Gastroenteritis: A Meta-analysis. Pediatrics. 2020;145(4):e20193260

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 4, April 2020:e20193260 REVIEW ARTICLE Diarrheal diseases remain the third whereas dimenhydrinate revealed Search strategies were developed in cause of death among children a positive effect on vomiting duration. liaison with an experienced librarian ,5 years old, mostly in low- and Nevertheless, the authors did not (Supplemental Information). We used middle-income countries.1,2 Although compare antiemetics among them validated filters for identifying in high-income countries the disease and included only 7 studies. Later, pediatric articles and RCTs.7,12 No is rarely fatal, it is a leading cause of Carter et al10 performed a network language or publication status limits emergency department (ED) visits meta-analysis (NMA) including all the were used. We performed gray and hospitalizations.3 The American antiemetics for which there was literature searches through trial Academy of Pediatrics defines acute evidence at that time. The authors registries (www.clinicaltrials.gov and gastroenteritis as a diarrheal disease found that ondansetron was the best World Health Organization Clinical of rapid onset, with or without intervention to reduce vomiting, the Trials Registry Platform). additional symptoms and signs, such need for intravenous rehydration, and as nausea, vomiting, fever, or hospitalizations. However, some Eligibility Criteria 4 abdominal pain. Furthermore, acute concerns were raised because We included RCTs and quasi RCTs in fi diarrhea is de ned by the World ondansetron was associated with an which authors evaluated antiemetics Health Organization as the passage of increase of diarrhea. used for controlling vomiting in 3 or more loose or liquid stools per In the last decade, many randomized children with ADG. Our interventions , day for 3 or more days but 14 clinical trials (RCTs) comparing of interest were metoclopramide, 5 fi days. Both de nitions refer to the different antiemetics to placebo or ondansetron, domperidone, same disease: acute diarrhea and against each other have been dexamethasone, dimenhydrinate, gastroenteritis (ADG), that is, an published and have not been yet alizapride, and granisetron at any infectious episode of the synthesized. Specifically, new dose and presentation in children gastrointestinal tract. evidence from trials studying with ADG and vomiting. Researchers In addition to diarrhea, ADG dexamethasone, metoclopramide, had to compare any of the commonly presents with vomiting.5 domperidone, and ondansetron have interventions against them, a placebo, Vomiting is particularly challenging been available. To date, there is no conventional treatment with ORT, or for parents and health care systematic review or NMA comparing different doses or administration professionals because it can hinder all the currently available antiemetics routes of the same intervention and oral rehydration therapy (ORT), in children with ADG. Therefore, we had to report at least 1 of the worsen dehydration, and cause aimed to assess the relative outcomes of interest. hospitalizations.6 In most cases, ORT effectiveness and safety of can help to control vomiting. antiemetics in children with ADG Outcomes However, in some cases, vomiting is through direct and indirect Our primary outcomes were cessation severe and may affect the ORT comparisons using an NMA. of vomiting and hospitalization. The success. Therefore, some antiemetics secondary outcomes included the have been used to control vomiting in METHODS need for intravenous rehydration children with ADG. Nevertheless, (measured as the number of This systematic review was some clinical practice guidelines participants who required registered in the PROSPERO (CPGs) do not recommend intravenous rehydration during the International Prospective Register of antiemetics because some of them ED stay and up to 3 days after Systematic Reviews have shown significant side effects.4,7 discharge); revisit to the ED (CRD42016035236). This article In contrast, other CPGs8 recommend (measured as the number of complies with the recommendations ondansetron and have discouraged participants that revisited the ED up of the PRISMA (Preferred Reporting the use of other antiemetics because to 72 hours after discharge); number Items for Systematic Reviews and of lack of evidence. of vomiting (measured as the mean Meta-Analyses) extension for NMA.11 number of vomiting episodes during The evidence of antiemetics for ADG the observation period); and side was first synthesized by Fedorowicz Search Process effects. et al.9 In this review, ondansetron We searched Medline (Ovid), Embase revealed a significant effect on (Ovid), Cochrane Central Register of Regarding side effects, as a post hoc cessation of vomiting and the need Controlled Trials, Cumulative Index to analysis, we analyzed side effects for intravenous rehydration. Also, Nursing and Allied Health Literature, (any side effect reported by the metoclopramide was found to be and Latin America and the Caribbean authors) and diarrhea separately. We effective in reducing vomiting Literature on Health Sciences from separated the outcomes because episodes and hospital admissions, the inception to December 31, 2018. diarrhea was reported as

Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 NIÑO-SERNA et al a dichotomous (presence or absence Assessment of Risk of Bias in NMA Included Studies of diarrhea in the observation) and We performed an NMA to analyze continuous variable (mean number of We assessed, independently and in all the potential comparisons among diarrheal stools), with the latter being duplicate, all included studies for interventions for each outcome. An the most commonly reported. The their risk of bias (RoB) using NMA, also known as multiple- presence of diarrhea (dichotomous) a modified version of the Cochrane treatment comparisons or multiple- was analyzed along with the rest of RoB tool13 on the basis of the treatment meta-analysis, is a special the side effects, but it was not following criteria: sequence statistical technique that provides possible to combine with the generation, allocation concealment, a methodology to address the issue continuous data. Lastly, the blinding of participants, personal of having available many worsening of diarrhea has been and outcome assessors, completeness interventions for the same condition described as a major concern for of follow-up, selective outcome under study, mostly compared against the use of ondansetron in previous reporting, and other biases. For 9,10 4,7 a placebo but less or not compared systematic reviews and CPGs. each criterion, an RoB score was against each other.16 NMA takes Thus, we wanted to determine the assigned as “definitely low,” advantage of 2 statistical approaches. fi speci c effect on the number of stools “probably low,”“probably high,” or First, it takes advantage of the use beside the incidence of side effects to “definitely high” risk.14 of indirect comparisons: we can better inform further clinical Disagreements were resolved by estimate the effect of intervention decision-making. consensus, and a third reviewer A versus intervention B, indirectly Study Selection was involved (I.D.F) when consensus if both A and B have been compared was not reached. against an intervention C (usually Two reviewers (L.F.N.-S. and J.A.-R.) a placebo). Second, the combination performed independently and in Pairwise Meta-analysis of direct and indirect comparisons duplicate the screening of available allows researchers to obtain more titles and abstracts to assess their We performed a pairwise random- precise estimates (ie, narrower eligibility. Studies were retrieved in effects meta-analysis of each confidence intervals or credible full text if either one of the reviewers available direct comparison. intervals in the results).16 With considered them eligible. Potentially Treatment effects were estimated an NMA, we can obtain an effect eligible studies were reviewed, and using odds ratios (ORs) for estimate to determine the differences studies were included if both dichotomous outcomes and mean between any pair of interventions, reviewers agreed on their eligibility. differences (MDs) for continuous even if they have not been directly In case of disagreement, a third outcomes, along with their 95% compared, and summarize all reviewer (I.D.F.) resolved it. We tried credible intervals (CIs). We used the available evidence in one to contact authors of primary studies vague priors for all model parameters single study. during data extraction for missing and a common half-normal prior information. distribution for the between-study For each outcome and a connected SD (t∼N [0,1], t . 0) across all network of studies, we performed Data Extraction treatment comparisons per outcome, a Bayesian random-effects NMA if the We used a prespecified and piloted given that many treatment assumptions of between-study form to extract the data. Among the comparisons were informed by homogeneity, transitivity, and extracted data were study single studies (20). Heterogeneity incoherence across treatment characteristics (design, year, duration in pairwise meta-analysis for all the comparisons were judged to be of follow-up, sample size, setting); direct comparisons was quantified justifiable. Transitivity17 is the patient characteristics (age, impatient with the statistic for heterogeneity assumption that an indirect or outpatient, days of disease, in direct comparisons (I2) expressed comparison is a valid method to hydration status); intervention details as a percentage of variability that is compare 2 treatments because the (doses, administration forms); and due to true differences between studies are sufficiently similar in outcome results (number of events, studies rather than sampling error.15 important clinical and methodological mean and SD or SEs, per arm) at the All analyses were performed by using characteristics, or in other words, longest duration of follow-up. Two the Markov chain Monte Carlo they are similar in their distributions reviewers (L.F.N.-S. and J.A.-R.) method. A geometry plot was used to of effect modifiers.18 Incoherence independently and in duplicate present all the available direct (also called inconsistency) is defined conducted data extraction. When comparisons per outcome, in which as the statistical difference between consensus was not reached, a third each node represents one direct and indirect treatment reviewer was involved (I.D.F). intervention. effects.19

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 4, April 2020 3 In the absence of direct evidence for Our hypotheses were as follows: Summary and Certainty of the a given comparison, we indirectly the effect of the interventions Results estimated treatment effectiveness might be inferior with oral With the aim of optimizing results and safety. In the presence of both medication (versus intravenous) in interpretation and clinical . direct and indirect evidence, the NMA children with 4 episodes of applicability, we present a summary , provided a combined effect vomiting per hour (versus 4 using a novel approach that has been 20 estimate. A Bayesian hierarchical episodes) or when outcomes are previously described to summarize . model with vague priors adjusting for measured 12 hours after the results from NMA.35 We grouped the , correlation of multiarm trials was recruitment (versus 12 hours). interventions according to the fi fi tted. After discarding the rst magnitude of the effect in comparison 10 000 iterations, series of When 10 or more studies were to a placebo and the quality of 100 000 burn-in simulations with available for an outcome, we evidence (according to the GRADE thinning of 10 values were used to assessed small-study effects and approach). The different categories allow convergence. The model publication bias using the 24 (marked by different colors) are convergence was checked by visual comparison-adjusted funnel plot, displayed in Fig 1. Dark colors inspection of the evaluation of the which was used to inform the represent interventions with mixing of 2 chains. The analysis was Grading of Recommendations, moderate- to high-quality evidence performed in OpenBUGs (version Assessment, Development, and (high certainty on the results). Light 21 3.2.3). Evaluation (GRADE) assessment colors represent interventions with (see Rating the Confidence in the – Variables used for the assessment of very low to low-quality evidence Effect Estimates section below). We the transitivity assumption included (low certainty on the results). calculated the surface under the the mean number of vomiting before cumulative ranking (SUCRA) curve recruitment (fewer or .4 episodes values to rank the available RESULTS per hour), the follow-up time of treatments according to their efficacy, outcome measurement (less than and and we captured the uncertainty Selection, Characteristics, and RoB .12 hours), and the route of in the parameter values that of Studies administration (intravenous or oral). informed treatment rankings We identified 3196 titles from The statistical incoherence between calculating their corresponding 95% databases and 4 additional records the direct and indirect estimates was CI.25-27 We graphically depicted the through other sources. After assessed with both a global x2 test by SUCRA curve values for all outcomes removing duplicates, 1840 titles and using the random-effects design-by- in a rank-heat plot.28 abstracts were screened. Sixty-six treatment interaction model22 and studies were identified for full-text a local z test by using the loop- screening. We excluded 42 studies specific approach calculating the ratio fi Rating the Con dence in the Effect because of reasons presented in of OR.23 Estimates Supplemental Table 4 and included – We conducted meta-regression, Reviewers (L.F.N.-S. and J.A.-R.), in 24 RCTs36 59 enrolling 3482 children. sensitivity, and subgroup analyses pairs and independently, assessed In Supplemental Table 5, we describe to explore the potential sources of the quality of evidence for each the characteristics of included heterogeneity and incoherence. reported outcome according to studies. The flow diagram of the Meta-regression was performed by the GRADE approach.19 Any study selection is shown in Fig 2. The using the number of vomiting disagreement was resolved by eligible studies were conducted in 16 episodes before the recruitment a third reviewer (I.D.F.). We rated countries from 5 continents. The as the independent variable. Three confidence as high, moderate, low, or mean number of vomiting episodes sensitivity analyses were conducted very low. The direct comparisons before recruiting was 7.09 (SD = on the basis of the RoB, excluding assessment was based in 5 4.28) and the age of children across studies with (1) overall high RoB, categories: study limitations (RoB),29 the studies was 35.1 months (SD = (2) high RoB because of allocation imprecision,30 inconsistency,31 24.3; range: 5.2–120.6). The concealment, and (3) high RoB indirectness,32 and publication bias.33 interventions studied were because of incomplete outcome. For NMA, the approaches by Puhan metoclopramide, ondansetron, Lastly, we performed three et al19 and Brignardello-Petersen domperidone, dexamethasone, subgroup analyses for route et al34 were applied. These consider, dimenhydrinate, and granisetron, of administration, vomiting number in addition, the assessment of mostly compared against a placebo. before recruitment, and time of intransitivity and incoherence The search did not retrieve studies on follow-up for outcome measurement. criteria. alizapride. The network geometry

Downloaded from www.aappublications.org/news by guest on September 29, 2021 4 NIÑO-SERNA et al incoherence was found with the global assessment (P = .95). The loop- specific approach also revealed no statistically significant incoherence, but the high ratio of OR may suggest that some degree of incoherence exists (Supplemental Fig 6). Ondansetron was the best intervention measured with the SUCRA values (SUCRA = 1.0) (Supplemental Table 8). Forest plots and funnel plots are displayed in Supplemental Figs 7 and 8, respectively.

In the meta-regression analysis using the number of vomiting before recruitment as a covariate, a marginally significant coefficient was obtained (b = 0.24; CI = 0.01 to 0.48; on log OR scale) (Supplemental Table 9). In the subgroup analysis by route of administration, in comparison to the placebo, both oral (placebo versus ondansetron; OR = 0.34 [CI = 0.17 to 0.67]) and intravenous ondansetron (placebo versus ondansetron; OR = 0.21 [CI = 0.07 FIGURE 1 to 0.53]) were found to be effective Categories for summarizing results based on quality of the evidence and effect estimates. Inter- (Supplemental Table 10). In the ventions are categorized from the most effective to the least effective on the basis of the NMA effect estimates and the quality of the evidence for the comparison of the intervention versus placebo. subgroup analyses by severity of the episodes, only ondansetron was better than the placebo (placebo plots with the available direct all comparisons except for the versus ondansetron; OR = 0.32 comparisons for the 6 outcomes are placebo-dimenhydrinate comparison [CI = 0.18 to 0.56]), than shown in Fig 3. (I2 = 53.5%). Ondansetron was found domperidone (domperidone versus to be better than metoclopramide, ondansetron; OR = 0.34 [CI = 0.14 Among the included studies, 6 (25%) dexamethasone, and placebo in direct to 0.90]), and better than revealed concerns for high RoB due to meta-analyses. The remaining metoclopramide (metoclopramide allocation concealment and blinding treatment comparisons revealed no versus ondansetron: OR = 0.31 [CI = of participants and/or outcome statistical differences (Supplemental 0.1 to 0.83]) in the subgroup of ,4 assessors. Five studies had high RoB Table 7). episodes per hour. We found no because of incomplete outcome differences in the subgroup of .4 reporting and 5 studies because of In the NMA, we obtained 21 paired episodes per hour. In the subgroup inadequate sequence generation. The effect estimates. Ondansetron analysis by time of follow-up, RoB assessment is described in revealed the largest effect in ondansetron was similarly effective, Supplemental Table 6. comparison to the placebo (placebo although the effect was larger when versus ondansetron; OR = 0.28 [CI = follow-up was ,12 hours than when Cessation of Vomiting 0.16 to 0.46]) with a high quality of follow-up was .12 hours We conducted pairwise meta- evidence. Ondansetron was also (Supplemental Table 10). Three analyses in 10 direct comparisons better than metoclopramide sensitivity analyses based on the RoB (2627 patients) for cessation of (ondansetron versus were performed; ondansetron vomiting. According to the I2 result, metoclopramide; OR = 3.27 [CI = 1.20 maintained its effect across all the heterogeneity was low to medium in to 9.19]) (Supplemental Table 7). No analyses (Supplemental Table 11).

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 4, April 2020 5 14.5]) (Supplemental Table 15). In the subgroup of ,4 episodes of vomiting per hour, only ondansetron was more effective than the placebo (placebo versus ondansetron; OR = 2.06 [CI = 1.18 to 3.8]). We found no differences when vomiting frequency was .4 episodes per hour. Lastly, ondansetron revealed to be effective when follow-up was .12 hours after the intervention (placebo versus ondansetron; OR = 2.27 [CI = 1.08 to 5.55]) (Supplemental Table 15). Ondansetron maintained its effect across all the sensitivity analyses on the basis of different RoB criteria (Supplemental Table 16). In Fig 4, we display the league table with all the NMA effect estimates for both primary outcomes.

Secondary Outcomes We analyzed 10 comparisons (1544 patients) that measured the need for intravenous rehydration. In the pairwise meta-analysis, ondansetron FIGURE 2 was better than metoclopramide PRISMA flow diagram of study selection. For more information, visit www.prisma-statement.org. (ondansetron versus Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred Reporting metoclopramide; OR = 0.03 [CI = 0.00 Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med. 2009;6(7): e1000097. to 0.46]) and better than the placebo (placebo versus ondansetron; OR = 3.22 [CI = 2.02 to 5.43]) Hospitalization We found no incoherence with the (Supplemental Fig 12). In the NMA, global test (P = .21) or the loop- Thirteen studies provided ondansetron revealed the greatest fi information on hospitalization rates speci c approaches (Supplemental effect in comparison to the placebo (2008 patients). In the pairwise meta- Fig 9). The SUCRA values, forest plots, (placebo versus ondansetron; OR = analyses, ondansetron was better and funnel plot are displayed in 3.0 [CI = 1.9 to 5.1]; moderate than domperidone (domperidone Supplemental Table 13 and quality) (Supplemental Fig 13). versus ondansetron; OR = 2.72 [CI = Supplemental Figs 10 and 11, Ondansetron was also more effective respectively. 1.56 to 5.89]) and better than the than metoclopramide (ondansetron placebo (placebo versus ondansetron; versus metoclopramide; OR 0.02 [CI = In the meta-regression analysis using OR = 3.63 [CI = 1.16 to 21.3]). 0.00 to 0.48]; moderate quality) the number of vomiting episodes (Supplemental Table 17). The Heterogeneity was low in all the before recruitment as a covariate, we incoherence, SUCRA values, and comparisons except for the found no association (b = 20.04 [CI = funnel plot for the outcome need for domperidone-ondansetron 20.24 to 0.15]; on log OR scale) I2 intravenous rehydration are comparison ( = 65.9%). In the NMA, (Supplemental Table 14). In the displayed in Supplemental Fig 14, ondansetron was better than the subgroup analysis by route of Supplemental Table 18, and, placebo (placebo versus ondansetron; administration, the placebo compared Supplemental Fig 15, respectively. OR = 2.93 [CI = 1.69 to 6.18]) and to oral ondansetron was found also better than domperidone effective (placebo versus Seventeen studies reported the (domperidone versus ondansetron; ondansetron; OR = 3.29 [CI = 1.65 to number of vomiting episodes (2504 OR = 3.31 [CI = 1.21 to 15.8]). The 8.56]) in contrast to intravenous patients). In the direct meta-analysis, remaining comparisons revealed no ondansetron (placebo versus ondansetron was better than the differences (Supplemental Table 12). ondansetron; OR = 2.19 [CI = 0.44 to placebo (placebo versus ondansetron;

Downloaded from www.aappublications.org/news by guest on September 29, 2021 6 NIÑO-SERNA et al FIGURE 3 NMA plots. A, Vomit cessation. B, Hospitalization. C, Revisit to the ED. D, Intravenous rehydration. E, Number of vomits. F, Side effects. The nodes are proportional to the number of patients included in the corresponding treatments, and the edges are weighted according to the number of studies in the comparisons.

MD = 1.46 [CI = 0.74 to 2.63]) and ondansetron (I2 = 89.1%), placebo ondansetron; MD = 1.48 [CI = 0.81 to granisetron was more effective than versus domperidone (I2 = 80.6%), 2.62]; very low quality). No the placebo (placebo versus and placebo versus dimenhydrinate incoherence was found with the granisetron; MD = 0.60 [CI = 0.11 to (I2 = 43.4%) (Supplemental global or the local assessment (P = 1.09]) (Supplemental Fig 16). Table 19). In the NMA, only .99) (Supplemental Fig 17). The Heterogeneity was low except for the ondansetron was more effective than SUCRA values, forest plots of NMA, comparisons of the placebo versus the placebo (placebo versus and funnel plot for number of

FIGURE 4 League table. Results are presented as OR and their corresponding 95% CI. The table should be read from left to right. For vomiting cessation, an OR .1 favors cessation of vomiting. For hospitalization, an OR ,1 favors fewer hospitalizations. Significant results are marked with an asterisk. The colors represent the certainty of evidence: dark green: high; light green: moderate; light yellow: low; and light red: very low.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 4, April 2020 7 vomiting episodes are displayed in Supplemental Table 20 and Supplemental Figs 18 and 19, respectively.

Twelve studies had information about the revisiting (1763 patients). In the pairwise meta-analysis, the placebo was better than granisetron (placebo versus granisetron; OR = 0.31 [CI = 0.09 to 0.87]) (Supplemental Fig 20). In the NMA, none of the interventions revealed differences to the placebo (Supplemental Table 21; Supplemental Fig 21). The incoherence, SUCRA values, and funnel plot for revisiting are displayed in Supplemental Fig 22, Supplemental Table 22, and Supplemental Fig 23, respectively.

In 12 studies, the authors reported side effects (1816 children, 5 treatments). In 4 studies, the authors reported that no side effects were found. In the NMA, dimenhydrinate was the only intervention that revealed significantly more side effects than the placebo, including somnolence, sleepiness, sedation, and drowsiness (placebo versus dimenhydrinate; OR = 0.14 [CI = 0.01 to 0.7]; very low quality) (Supplemental Table 23; Supplemental Figs 24 and 25). The FIGURE 5 incoherence analyses, SUCRA values, Summary of results for all outcomes. NMA results are sorted on the basis of GRADE certainty of evidence for the comparisons of active treatments versus placebo for all outcomes (see the and funnel plot for side effects are Methods section and Fig 1 for more details about the categories). Effect estimates are presented in displayed in Supplemental Fig 26, the last column as OR (for dichotomous outcomes, such as cessation of vomiting, hospitalization, intravenous rehydration, revisit to the ED, and side effects) or MD (for continuous outcomes such as Supplemental Table 24, and a Supplemental Fig 27, respectively. vomiting number and diarrheal episodes) and their corresponding 95% CI. NMA estimates: OR (95% CI). b NMA estimates: MD (95% CI). Regarding diarrhea, domperidone revealed a reduction of the number of Supplemental Fig 31, respectively. A as the “best intervention.” The best stools in comparison to ondansetron rank-heat plot summarizing the intervention category means that, in the pairwise meta-analysis ranking statistic across all with high certainty, ondansetron was (domperidone versus ondansetron; interventions and outcomes is better than placebo and also better 2 2 2 MD = 1.25 [CI = 1.34 to 1.15]) displayed in Supplemental Fig 32. than at least one of the other (Supplemental Fig 28) and in the interventions. For cessation of NMA (dimenhydrinate versus In Fig 5, we summarize the results on vomiting and the need for ondansetron; MD = 22.04 [CI = 23.9 the basis of the effect estimates and intravenous rehydration, ondansetron to 20.05]; very low quality) quality of the evidence. With high (Supplemental Fig 29; Supplemental certainty, we found that for cessation was also better than metoclopramide Table 25). The incoherence, SUCRA of vomiting, hospitalization (Fig 4 and Supplemental Table 17, values, and funnel plot for diarrhea prevention and the need for respectively); for hospitalization, it are displayed in Supplemental Fig 30, intravenous rehydration, ondansetron was also better than domperidone Supplemental Table 26, and was the only intervention categorized (Fig 4).

Downloaded from www.aappublications.org/news by guest on September 29, 2021 8 NIÑO-SERNA et al For the same outcomes, the antiemetics. Although these results but in most of the cases, it will not be remaining interventions were suggest that ondansetron should be clinically significant. categorized as “similar to placebo” or administered orally and that its effect as “may be similar to placebo.” The seems to be lower when vomiting is Antiemetics use in children with ADG similar to placebo category means severe, these findings should be has been controversial. CPGs from organizations such as the World that, with high certainty, studied further. 5 metoclopramide, domperidone, Health Organization, the National Our study is the first NMA that Institute for Health and Care dexamethasone, granisetron, and 7 includes all the currently available Excellence, and the American dimenhydrinate were no different 4 from the placebo. The category may antiemetics used in children with Academy of Pediatrics do not be similar to placebo means that ADG. A previous NMA included only recommend their use. Conversely, the these interventions, with low 11 studies and studied only European Society for Pediatric certainty, seem to be similar to the ondansetron, metoclopramide, Gastroenterology, Hepatology, and 10 8 placebo. Lastly, ondansetron was granisetron, and dexamethasone. In Nutrition CPGs recommend considered similar to the placebo, contrast, we included 24 studies with ondansetron. This disagreement may with high certainty, for side effects additional evidence from be due to the lack of updated CPGs in and as may be similar to placebo, dimenhydrinate and ondansetron. We the former organizations that did not with low certainty, for causing also applied advanced statistical consider recent evidence. Therefore, diarrhea (Fig 5) techniques to explore causes of our results may be crucial for future heterogeneity and incoherence, and CPG updates. we assessed the quality of the Our study has several strengths. We DISCUSSION evidence with GRADE. A previous conducted a comprehensive Cochrane review9 also summarized In this systematic review and NMA, systematic review including all the all the available evidence but only we evaluated available antiemetics available evidence regardless of the performed direct comparisons and for controlling vomiting in children language and publication status of the therefore did not study differences with ADG. Moderate to high quality of studies. Our review is based on among interventions. Despite the evidence indicates that ondansetron statistical analyses that considered differences between our work and is the best intervention for cessation both NMA effect estimates and previous reviews, we all concluded of vomiting, preventing probability rankings, including that ondansetron is most likely the hospitalization, and the need for subgroup, sensitivity, and meta- best intervention. Nevertheless, we intravenous rehydration. There is no regression analyses. This allowed us can now be more confident in these evidence to support the use of to explore possible effect modifiers results because we provide updated domperidone, dimenhydrinate, and prove the robustness of our evidence, include more studies and metoclopramide, alizapride, or results. We used the GRADE to interventions, and provide more granisetron for the cessation of appraise the quality of evidence and precise effect estimates (narrower vomiting and preventing provided a straightforward CIs), all of which reduce uncertainty hospitalizations because they were presentation of our findings (Fig 5), around the results. classified as similar or may be similar which summarizes in a single to placebo in all the effectiveness resource the relative performance of We found that dimenhydrinate was outcomes. each intervention per outcome, the only intervention inferior to the categorized by the certainty on the placebo in terms of safety. Regarding Interestingly, in our subgroup evidence. Lastly, we followed diarrhea, all the interventions analyses, we found that the effect of Cochrane13 and International Society revealed no statistically significant ondansetron seems to be larger when for Pharmacoeconomics and differences against the placebo. used orally (rather than Outcomes Research Ondansetron has been previously intravenously) in children with a low recommendations for developing , associated with an increase in number of vomiting episodes ( 4 a rigorous NMA.60 episodes per hour) and when the diarrheal episodes. In our results, we hospitalization outcome was found that ondansetron increases However, our study is not free of measured after 12 hours. Meta- diarrhea in comparison to limitations. The evidence in most regression revealed a significant dimenhydrinate but not in treatment comparisons is of low or coefficient in cessation of vomiting, comparison to the placebo. very low quality. This is the result of meaning that the larger the number Ondansetron may have a slight the presence of a significant RoB and of vomiting episodes before impact on the number of stools that imprecise estimates. The latter is recruitment, the lower the effects of require monitoring in some children, explained by the lack of enough

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 4, April 2020 9 evidence from direct comparisons makers may consider ondansetron ACKNOWLEDGMENT among the interventions given that as the standard of therapy and We thank Jesenia Avendaño, a health most of the evidence comes from facilitate the decision-making sciences librarian, for her assistance comparisons against placebo. process about what interventions in the design of the search strategy. Our results may be beneficial for should be funded in health fi clinicians, researchers, guideline bene t plans or for reimbursement developers, and decision-makers. policies. ABBREVIATIONS Clinicians count with updated ADG: acute diarrhea and evidence to support the use of gastroenteritis ondansetron, which is the only CI: credible interval intervention with moderate- to CONCLUSIONS CPG: clinical practice guideline high-quality evidence that supports Ondansetron is the only ED: emergency department its use in children with ADG and intervention that, with moderate to GRADE: Grading of vomiting. Considering the amount high certainty, showed an effect on Recommendations, of evidence and its quality, when cessation of vomiting, Assessment, Development, designing new trials, researchers hospitalization prevention, and the and Evaluation should consider comparing new need for intravenous rehydration. I2: statistic for heterogeneity in alternatives against ondansetron There is no evidence to support the direct comparisons rather than against a placebo. use of metoclopramide, MD: mean difference Guideline developers may use dimenhydrinate, domperidone, NMA: network meta-analysis our results for future CPG updates. alizapride, and dexamethasone in OR: odds ratio CPGs that have not recommended these patients. Ondansetron was ORT: oral rehydration therapy antiemetics may want to consider found to be a safe intervention, RCT: randomized clinical trial ondansetron as an alternative in whereas dimenhydrinate was the RoB: risk of bias children at risk for failure of oral only intervention that produced SUCRA: surface under the rehydration and to prevent more side effects than the cumulative ranking hospitalization. Finally, decision- placebo.

This trial has been registered with the PROSPERO International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/PROSPERO) (identifier CRD42016035236). DOI: https://doi.org/10.1542/peds.2019-3260 Accepted for publication Jan 22, 2020 Address correspondence to Ivan D. Florez, MD, MSc, Department of Pediatrics, Hospital Universitario San Vicente Fundación, Pabellón Infantil, Calle 64 N°51 D - 154; Medellín, Colombia. E-mail: ivan.fl[email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 12 NIÑO-SERNA et al Antiemetics in Children With Acute Gastroenteritis: A Meta-analysis Laura F. Niño-Serna, Jorge Acosta-Reyes, Areti-Angeliki Veroniki and Ivan D. Florez Pediatrics originally published online March 4, 2020;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2020/03/02/peds.2 019-3260 References This article cites 53 articles, 7 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2020/03/02/peds.2 019-3260#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Emergency Medicine http://www.aappublications.org/cgi/collection/emergency_medicine_ sub Evidence-Based Medicine http://www.aappublications.org/cgi/collection/evidence-based_medic ine_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 29, 2021 Antiemetics in Children With Acute Gastroenteritis: A Meta-analysis Laura F. Niño-Serna, Jorge Acosta-Reyes, Areti-Angeliki Veroniki and Ivan D. Florez Pediatrics originally published online March 4, 2020;

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