Variables Associated With Intravenous Rehydration and Hospitalization in Children With Acute Gastroenteritis: A Secondary Analysis of 2 Randomized Clinical Trials

Key Points

Question  What clinical features are associated with intravenous rehydration and hospitalization in children with acute gastroenteritis?

Findings  In this secondary analysis of 2 randomized clinical trials with 1846 children, independent variables associated with intravenous rehydration included a higher clinical dehydration score, care in the US relative to Canada, greater frequency and duration of vomiting, prior intravenous rehydration, and lack of oral ondansetron. A higher clinical dehydration score, care in the US, greater frequency of vomiting, and lack of oral ondansetron were associated with hospitalization.

Meaning  These findings suggest that oral ondansetron may support oral rehydration therapy to reduce intravenous rehydration and the hospitalization of children with gastroenteritis.

Importance  Despite guidelines endorsing oral rehydration therapy, intravenous fluids are commonly administered to children with acute gastroenteritis in high-income countries.

Objective  To identify factors associated with intravenous fluid administration and hospitalization in children with acute gastroenteritis.

Design, Setting, and Participants  This study is a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) probiotic trials. Participants include children aged 3 to 48 months with 3 or more watery stools in 24 hours between November 5, 2013, and April 7, 2017, for the PERC study and July 8, 2014, and June 23, 2017, for the PECARN Study. Children were from 16 pediatric emergency departments throughout Canada (6) and the US (10). Data were analyzed from November 2, 2018, to March 16, 2021.

Exposures  Sex, age, preceding health care visit, distance between home and hospital, country (US vs Canada), frequency and duration of vomiting and diarrhea, presence of fever, Clinical Dehydration Scale score, oral ondansetron followed by oral rehydration therapy, and infectious agent.

Main Outcomes and Measures  Intravenous fluid administration and hospitalization.

Results  This secondary analysis of 2 randomized clinical trials included 1846 children (mean [SD] age, 19.1 [11.4] months; 1007 boys [54.6%]), of whom 534 of 1846 (28.9%) received oral ondansetron, 240 of 1846 (13.0%) received intravenous rehydration, and 67 of 1846 (3.6%) were hospitalized. The following were independently associated with intravenous rehydration: higher Clinical Dehydration Scale score (mild to moderate vs none, odds ratio [OR], 8.73; 95% CI, 5.81-13.13; and severe vs none, OR, 34.15; 95% CI, 13.45-86.73); country (US vs Canada, OR, 6.76; 95% CI, 3.15-14.49); prior health care visit with intravenous fluids (OR, 4.55; 95% CI, 1.32-15.72); and frequency of vomiting (per 5 episodes, OR, 1.66; 95% CI, 1.39-1.99). The following were independently associated with hospitalization: higher Clinical Dehydration Scale score (mild to moderate vs none, OR, 11.10; 95% CI, 5.05-24.38; and severe vs none, OR, 23.55; 95% CI, 7.09-78.25) and country (US vs Canada, OR, 3.37; 95% CI, 1.36-8.40). Oral ondansetron was associated with reduced odds of intravenous rehydration (OR, 0.21; 95% CI, 0.13-0.32) and hospitalization (OR, 0.44; 95% CI, 0.21-0.89).

Conclusions and Relevance  Intravenous rehydration and hospitalization were associated with clinical evidence of dehydration and lack of an oral ondansetron-supported oral rehydration period. Strategies focusing on oral ondansetron administration followed by oral rehydration therapy in children with dehydration may reduce the reliance on intravenous rehydration and hospitalization.

Trial Registration  ClinicalTrials.gov Identifiers: NCT01853124 (PERC) and NCT01773967 (PECARN)

Acute gastroenteritis (AGE) accounts for nearly 500 000 deaths in children younger than 5 years annually.¹ Although AGE is generally a mild, self-limited condition in high-income countries, it accounts for almost 1.7 million emergency department (ED) visits² and 60 000 hospitalizations annually in the US.³ Guidelines uniformly support oral rehydration therapy (ORT), reserving intravenous rehydration for children with severe dehydration.^4-6 Unfortunately, clinical dehydration scales have variable accuracy,⁷ and most overestimate dehydration severity in high-income countries.⁸ These challenges, combined with the presence of vomiting, the need to minimize ED length of stay, and caregiver expectations,⁹ often lead to intravenous rehydration use.¹⁰

Intravenous rehydration has potentially deleterious effects. Children rate intravenous insertion as one of the most painful aspects of hospital care,¹¹ influencing future reactions to painful events.¹² Compared with ORT, intravenous rehydration is associated with phlebitis, longer hospital stays, and major adverse events,^13,14 and is one of the risk factors most strongly associated with ED revisits, presumably because it reinforces the decision to seek ED care and reduces the educational focus on ORT.¹⁵ Although quality improvement initiatives have been able to reduce intravenous rehydration rates, in many institutions, use remains frequent.^14,16 Thus, a better understanding of the factors associated with intravenous rehydration is needed to identify approaches to mitigate use.

Reducing unnecessary hospitalizations is also a priority given cost considerations. In 2010, the Agency for Healthcare Research and Quality estimated that the cost of preventable pediatric hospitalizations for AGE in the US was nearly $150 million dollars.¹⁷ Although rotavirus vaccination has reduced AGE hospitalizations by 36% globally,¹⁸ this enormous burden continues.¹⁹ Furthermore, there is considerable variation in hospitalization rates for AGE, and nonobjective measures of dehydration may be an important driver.²⁰

To address these issues, we conducted a secondary analysis of 2 large simultaneously collected data sets. Our objective was to explore factors associated with intravenous rehydration and hospitalization in children with AGE in the US and Canada.

This study was a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) Probiotic Regimen for Outpatient Gastroenteritis Utility of Treatment (PROGUT) (trial protocol available in Supplement 1)^21,22 and Pediatric Emergency Care Applied Research Network (PECARN) (trial protocol available in Supplement 2)^23,24 randomized clinical trials of probiotics in children with AGE-associated diarrhea. Research assistants at each site obtained written informed consent from the children’s parents. Participants were enrolled between November 5, 2013, and June 23, 2017, in 1 of 16 EDs, 6 in the PERC trial and 10 in the PECARN trial. Research ethics board approval was obtained at each site. The manuscript analysis plan for the present study is available in Supplement 3. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Eligible children were aged 3 to 48 months and had 3 or more watery stools reported in the preceding 24 hours. Exclusion criteria were prior enrollment in the study, hematochezia, bilious emesis, chronic gastrointestinal disease, structural heart disease, indwelling vascular access line, immunotherapy or history of immunodeficiency, inability to be contacted for daily follow-up while symptomatic, supplemental probiotic use in the preceding 14 days, clinical instability (eg, hypovolemic shock), family member with an indwelling vascular access line, or being immunocompromised.^22,23 The main distinctions between the 2 studies were maximal symptom duration before enrollment (72 hours in the PERC trial and 7 days in the PECARN trial) and different investigational probiotic products. In addition, the PERC trial excluded children with pancreatic dysfunction, oral or gastrointestinal surgery within the preceding 7 days, and known soy hypersensitivity. Participants lost to follow-up in the primary clinical trials were eligible for inclusion in this analysis if intravenous fluid administration status was known. The protocols for both trials recommended ORT supported by ondansetron as needed but did not specify criteria for intravenous rehydration or hospitalization.

The primary outcomes, evaluated at the index visit, were (1) intravenous rehydration, defined as any crystalloid administered through a peripheral intravenous line for the purposes of rehydration; and (2) hospitalization, defined as admission to an inpatient unit outside the ED. We also collected demographic characteristics, frequency of vomiting and diarrhea in the 24 hours pre-ED visit, previous health care visit for the same illness, duration of illness, fever during the current illness (temperature ≥38.0 °C at home or in the ED, adjusted to rectal temperature by adding 1.1 °C to the axillary or 0.6 °C to the oral temperature²⁵) or tactile temperature (PECARN), oral ondansetron, trial of ORT, intravenous fluid administration, and ED disposition. Children who received oral ondansetron within 30 minutes of ordering intravenous rehydration were not classified as having received oral ondansetron to promote ORT.

A baseline modified Vesikari Scale score was calculated based on symptoms reported at the index ED visit. The modified Vesikari Scale is a global gastroenteritis severity scale validated in our population. Scores range from 0 to 20 and are categorized as mild (0-8), moderate (9-10), or severe (≥11).^22,26 The number and duration of vomiting and diarrhea episodes were categorized according to the modified Vesikari Scale score cut-points.^22,26 Dehydration was assessed using the Clinical Dehydration Scale (CDS), a validated 4-item instrument with high interrater reliability (κ = 0.77).^7,27 The CDS includes an assessment of general appearance, eyes (eg, sunken), mucous membranes (eg, dry), and tears. Total scores range from 0 to 8 and are grouped to correspond to dehydration severity: none (0), mild to moderate (1-4), and severe (5-8).²⁷ The CDS scores were assigned by a trained research assistant at recruitment.

Stool specimens were requested from all participants for enteropathogen identification. Testing was performed using the Luminex xTAG Gastrointestinal Pathogen Panel (Luminex Corp)²⁸ that tests for viruses (adenovirus, norovirus, rotavirus), bacteria (Clostridioides difficile [formerly Clostridium] toxins A and B, enterotoxigenic Escherichia coli heat-labile toxin and heat-stable toxin, E coli O157, Salmonella, Shiga toxin-producing E coli, Shigella, Vibrio cholera, and Yersinia enterocolitica) and parasites (Cryptosporidium, Entamoeba histolytica, and Giardia). Specimens collected in the PERC study were also tested for adenovirus, astrovirus, norovirus, rotavirus, and sapovirus.²⁹ Results were unavailable at the time of disposition.

Demographic characteristics were combined from both trials and summarized with counts and percentages for categorical data and medians and interquartile ranges for continuous data. Bivariate analyses adjusted for site and multivariable analyses were used to explore the associations between outcome variables (ie, intravenous rehydration and hospitalization) and the following prespecified, biologically plausible covariates: sex, age in months using a priori determined groups (3 to <12 months, 12 to <24 months, 24 to <36 months, and 36 to <48 months), prior health care practitioner visit during the current illness, country, distance to hospital, infectious agent, duration of vomiting and diarrhea at the time of the index visit, frequency of vomiting and diarrheal episodes within 24 hours of the index visit, fever, ED CDS score, and oral ondansetron administration. Unadjusted bivariate and adjusted multivariable odds ratios (ORs) and 95% CIs were obtained from generalized mixed-effects logistic regression models that employed random intercepts and assumed a simple diagonal covariance structure to adjust for clinical center.

We fit additional multivariable models in order to estimate the adjusted association of infectious agents among the subset of participants from whom stool specimens were obtained. Infectious agents were categorized as negative vs isolated virus vs isolated bacteria vs virus and bacteria codetection vs parasites. In models assessing factors associated with hospitalization, the parasite category was excluded owing to an insufficient number of hospitalized participants. Children 24 months or younger in whom C difficile was detected were classified as negative given the high colonization rate and low likelihood of symptomatic causality. Finally, we fit additional multivariable models to explore the separate associations of prior health care visits with and without intravenous rehydration.

Data were analyzed using SAS/STAT software, version 9.4 (SAS Institute Inc). A type I error rate of .05 was used to reject the null hypothesis of no association. All P values were 2-tailed. Data analyses were conducted from November 2, 2018, to March 16, 2021.

Of the 1857 participants randomized in the parent trials, we analyzed the results from 1846 children (mean [SD] age, 19.1 [11.4] months; 1007 boys [54.6%]) (Figure 1). Table 1 and Table 2 summarize demographic features. A total of 240 of 1846 participants (13.0%) received intravenous rehydration at the index ED visit, and 67 of 1846 (3.6%) were hospitalized. Oral ondansetron to promote ORT was administered to 534 of 1846 participants (28.9%): 166 of 876 (18.9%) in Canada and 368 of 970 (37.9%) in the US. When 3 or more vomiting episodes were reported, oral ondansetron was administered to 408 of 892 participants (45.7%): 141 of 428 (32.9%) in Canada and 267 of 464 (57.5%) in the US.

In bivariate analysis adjusted for site (Table 1), variables associated with intravenous rehydration included location of care in the US (167 of 970 [17.2%]); fever (161 of 981 [16.4%]); isolated virus (144 of 810 [17.8%]); parasites (4 of 19 [21.1%]); mild, moderate, or severe dehydration using the CDS score (mild or moderate, 157 of 681 [23.1%]; severe, 27 of 40 [67.5%]); prolonged and more frequent vomiting (≥48 hours, prolonged, 101 of 504 [20.0%]; per 5-episode increase [more frequent] OR, 1.65; 95% CI, 1.44-1.89); more frequent diarrheal episodes (unadjusted OR, 1.41; 95% CI, 1.24-1.61 per 5-episode increase); prior health care visit with intravenous rehydration (11 of 16 [68.8%]); and increased distance between home and the ED (unadjusted OR, 1.11; 95% CI, 1.02-1.19). Oral ondansetron followed by ORT was associated with lower odds of intravenous rehydration (OR, 0.43; 95% CI, 0.31-0.61).

In the multivariable model, independent variables associated with intravenous rehydration (Figure 2) were CDS scores indicative of mild to moderate (OR, 8.73; 95% CI, 5.81-13.13) and severe (OR, 34.15; 95% CI, 13.45-86.73) dehydration, care in the US (OR, 6.76; 95% CI, 3.15-14.49; relative to Canada), detection of an isolated virus (OR, 1.80; 95% CI, 1.16-2.79; relative to negative), greater number of vomiting episodes (OR, 1.66; 95% CI, 1.39-1.99 per 5-episode increase) and duration of vomiting (OR, 2.53; 95% CI, 1.39-4.61 for ≥48 hours relative to no vomiting), and prior health care visit (OR, 1.82; 95% CI, 1.20-2.77), particularly with intravenous rehydration (OR, 4.55; 95% CI, 1.32-15.72). Oral ondansetron was associated with lower odds of intravenous rehydration (OR, 0.21; 95% CI, 0.13-0.32).

In bivariate analysis adjusted for site (Table 2), the variables associated with hospitalization included increased distance to the ED (US, OR, 1.23; 95% CI, 1.12-1.36), detection of an isolated viral enteropathogen (OR, 2.89; 95% CI, 1.58-5.31), evidence of dehydration on the CDS score (severe, OR, 53.45; 95% CI, 19.10-149.57), prolonged duration of vomiting (≥48 hours, OR, 3.21; 95% CI, 1.37-7.56), greater frequency of diarrheal (OR, 1.67 per 5-episode increase; 95% CI, 1.39-2.01) and vomiting episodes (OR, 1.50 per 5-episode increase; 95% CI, 1.25-1.81), prior health care practitioner visit (yes, with rehydration, OR, 10.26; 95% CI, 3.11-33.86), and presence of a fever (OR, 1.93; 95% CI, 1.14-3.28). Oral ondansetron followed by ORT was associated with lower odds of hospitalization (OR, 0.47; 95% CI, 0.25-0.89).

In the multivariable model, independent variables associated with hospitalization (Figure 3) included CDS scores indicative of mild to moderate (OR, 11.10; 95% CI, 5.05-24.38; P < .001) and severe (OR, 23.55; 95% CI, 7.09-78.25; P < .001) dehydration, care in the US (OR, 3.37; 95% CI, 1.36-8.40 relative to Canada; P = .009), and greater number of vomiting (OR, 1.41; 95% CI, 1.13-1.77 per 5-episode increase; P = .003) and diarrhea (OR, 1.34; 95% CI, 1.07-1.68 per 5-episode increase; P = .01) episodes. Administration of oral ondansetron was associated with a lower odds of hospitalization (OR, 0.44; 95% CI, 0.21-0.89; P = .02).

In this planned secondary analysis of the PERC and PECARN trials of oral probiotics in children with AGE-associated diarrhea, we identified independent variables associated with intravenous rehydration and hospitalization. Significant variables included more severe dehydration, care in the US, greater travel distance to the ED, and more vomiting episodes in the 24 hours preceding the ED visit. Oral ondansetron followed by ORT reduced the odds of receiving intravenous rehydration and hospitalization, underlying its importance in the majority of children with AGE.^4,6,30 These findings can inform quality improvement initiatives to improve outcomes in at-risk children.

After adjustment for clinical characteristics, intravenous rehydration and hospitalization rates were much higher in the US. This finding is most likely explained by a previously characterized difference in willingness to initiate ORT as first-line therapy in children with moderate dehydration between emergency providers in Canada (76% willing) and the US (46% willing).³¹ Differences between Canada and the US, such as perception of medicolegal risks, training, hospital budgets, and parental expectations, have been highlighted as possible explanations to explain greater use of diagnostic imaging in US EDs.³² Some of these explanations may apply to intravenous rehydration and hospitalization. For example, the parents of young children in the US, when given the opportunity to make an informed decision, often opt for intravenous over ORT.⁹ Despite country differences, there was no association of site with outcomes. The study protocols standardized the treatment strategies and focused on the promotion of ORT, supported by ondansetron, as required. We did not explore variation in care over time, but as no major changes occurred in the recommended care of children with AGE,⁵ there is no reason to believe there was any variation in care over time.

The proportion of children receiving intravenous rehydration in our study was lower than reported in large retrospective studies (n = 3508 [13%] in Canada³³ and n = 30 519 [26%] in the US¹⁶). Although it is encouraging to see lower overall numbers, it should be noted that a leading driver of intravenous rehydration, vomiting,³⁴ was absent in 30% of our participants, with 51% having fewer than 3 episodes. This may have explained the low proportion of participants that received ondansetron in our study (28.9%), as ondansetron is indicated for dehydration and frequent and recent vomiting. Importantly, among participants who received intravenous rehydration, 89% were not severely dehydrated, suggesting that intravenous rehydration may be overused in pediatric EDs.

Our results are consistent with evidence that frequent vomiting is associated with intravenous rehydration.³⁴ Although gastroenteritis severity is often characterized by the frequency and duration of diarrhea, our multivariable models showed that dehydration severity, quantified using the CDS, was more strongly associated with both intravenous rehydration and hospitalization. Although this association makes intuitive sense, clinical and laboratory assessments of dehydration in children are inaccurate.⁷ Cognitive bias may partly explain the strong association between higher CDS scores and intravenous rehydration. Sunken eyes and dry mucous membranes are both components of the CDS and have long been held as useful clinical signs of dehydration.³⁵ Clinical identification of these factors may have driven intravenous rehydration, because subjective clinical measures often overestimate the degree of dehydration,³⁶ leading to potentially unnecessary intravenous rehydration. Thus, in high-income countries, otherwise healthy children, even those with high CDS scores, in the absence of circulatory compromise should initially undergo a trial of ORT.

One approach to reduce the use of intravenous rehydration is oral ondansetron followed by a trial of ORT.³⁷ Although clinical trials have consistently demonstrated benefit, database studies, which lack detailed clinical characteristics and timelines, have reported less positive results.³⁸ Our study, which included timelines related to ondansetron administration, route, and timing of orders for intravenous rehydration, enabled us to ensure that oral ondansetron was administered a minimum of 30 minutes before the order for intravenous rehydration, thereby ensuring it was given and followed by ORT. This is an important concept, as one can reach incorrect conclusions when such an approach is not incorporated into analyses, because in some settings, oral ondansetron and intravenous rehydration are ordered simultaneously. Our finding associating oral ondansetron with a reduction in intravenous rehydration and hospitalization suggest that strategies promoting the appropriate use of oral ondansetron in children with AGE and nonsevere dehydration are crucial to accruing its benefits.³⁹

Unscheduled revisit rates for children with AGE range from 7% to 18%^15,38,40 and are associated with absence of a primary care provider, higher serum bicarbonate,⁴⁰ greater frequency of vomiting and diarrhea,¹⁵ and administration of intravenous rehydration in the ED.¹⁵ Similarly, we found that prior ED visits, particularly those associated with intravenous rehydration, were associated with intravenous rehydration at the enrollment ED visit. These findings highlight the importance of administering intravenous rehydration based on presenting clinical features rather than previous therapies. This approach is important because caregivers of children who received intravenous rehydration are less likely to comply with ORT recommendations.⁴¹

Consistent with previous reports,^38,42,43 the proportion of children with AGE admitted to the hospital was low (3.6%). Our data suggest that hospitalization was associated with more severe dehydration and care in the US. The latter association may reflect previously published differences in health care resource utilization between Canada and the US in children with AGE.³¹ Although we did not quantify volume of oral fluids consumed or fluid losses in the ED, a higher CDS score is independently associated with ORT failure,⁴⁴ which may have influenced the decision for hospitalization. Consistent with previous reports,^45,46 we found oral ondansetron to be associated with a lower odds of hospitalization, most likely through the reduction in intravenous rehydration. Thus, promoting oral ondansetron and a trial of ORT in the ED for children with nonsevere dehydration may decrease the risk of intravenous rehydration and demonstrate a strategy that caregivers can continue post–ED discharge.

Our study has several limitations. We enrolled children presenting to tertiary care pediatric centers in high-income countries, and only a small proportion were severely dehydrated. Although baseline characteristics, such as socioeconomic status, would have helped generalize our findings, we unfortunately did not collect this information in both studies in a manner that could be integrated into a joint analysis. Therefore, our results may not be applicable to children presenting for care in rural or low-resource settings where geographic, economic, and etiologic factors may influence the need for intravenous rehydration. As this was a secondary analysis, our data may not be generalizable to patients outside the trial’s eligibility criteria. Furthermore, we were unable to ascertain the role of other potential risk factors, including insurance status, provider experience, or the ability of the child and caregiver to perform ORT. The 2 trials were conducted in countries with different populations and health care systems. An important protocol difference that could have affected results was maximal symptom duration prior to enrollment between PERC (72 hours) and PECARN (7 days). For this reason, country and duration of gastrointestinal symptoms at the index visit were included in the models to address these potential limitations. Finally, we did not describe parental expectations, a potentially influential factor in clinical decision-making. Evidence suggests that parental expectations often contradict clinical practice guidelines and reflect a preference for intravenous rehydration.^9,41

In this study of children with AGE and minimal dehydration, independent variables associated with intravenous rehydration and hospitalization included greater dehydration, care in the US, greater travel distance to the ED, and more vomiting episodes in the 24 hours preceding the ED visit. Oral ondansetron followed by ORT was associated with a lower odds of both intravenous rehydration and hospitalization. Cost- and time-saving strategies focused on promoting successful integration of ORT and oral ondansetron into ED care for most children with AGE have the potential to reduce intravenous rehydration and hospitalizations rates.

Accepted for Publication: February 26, 2021.

Published: April 19, 2021. doi:10.1001/jamanetworkopen.2021.6433

Correction: This article was corrected on June 7, 2021, to add the missing middle initial “I.” to author Phillip Tarr’s name in the byilne.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Poonai N et al. JAMA Network Open.

Corresponding Author: Naveen Poonai, MSc, MD, Schulich School of Medicine & Dentistry, 800 Commissioners Rd E, London, Ontario, N6A 2V5, Canada (naveen.poonai@lhsc.on.ca).

Author Contributions: Dr Poonai had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Poonai, Schnadower, Tarr, O'Connell, Freedman.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Poonai, Tarr, Mahajan, Freedman.

Critical revision of the manuscript for important intellectual content: Poonai, Powell, Schnadower, Casper, Roskind, Olsen, Tarr, Rogers, Schuh, Hurley, Gouin, Vance, Farion, Sapien, O'Connell, Levine, Bhatt, Freedman.

Statistical analysis: Casper, Olsen.

Obtained funding: Schnadower, Tarr, Freedman.

Administrative, technical, or material support: Schnadower, Casper, Olsen, Freedman.

Supervision: Poonai, Freedman.

Conflict of Interest Disclosures: Dr Freedman reported receiving nonfinancial support from Lallemand Health Solutions, the Provincial Laboratory for Public Health, Luminex Corporation, and Copan Italia, and receiving grants from the Canadian Institutes for Health Research and Alberta Children’s Hospital Foundation. Dr Freedman reported providing consulting services to RedHill Biopharma LTD and Takeda Pharmaceutical Company during the conduct of the study. Dr Powell reported receiving grants from the National Institute of Child Health and Human Development (NICHD) via subcontract and grants from the National Institutes of Health (NIH) via subcontract outside the submitted work. Dr Schnadower reported receiving research grants from NIH/NICHD and nonfinancial support from iHealth Inc during the conduct of the study. Dr Casper reported receiving grants from the NICHD and from the Health Resources and Services Administration (HRSA) during the conduct of the study. Dr Roskind reported receiving grants from the NICHD during the conduct of the study. Dr Olsen reported receiving grants from the NICHD during the conduct of the study. Dr Tarr reported receiving grants from Washington University and the NIH during the conduct of the study. Dr Mahajan reported receiving grants from the NICHD during the conduct of the study. Dr Vance reported receiving grants from the NICHD and the NIH during the conduct of the study. Dr Sapien reported receiving grants from the NIH during the conduct of the study and from the HRSA outside the submitted work. Dr O'Connell reported receiving grants from the NIH during the conduct of the study. Dr Bhatt reported receiving grants from the NIH during the conduct of the study.

Funding/Support: This work was supported in part by grants 286384 and 325412 from the Canadian Institutes of Health Research (Dr Freedman), the Alberta Children’s Hospital Foundation’s Professorship in Child Health and Wellness (Dr Freedman), a grant from the Alberta Children’s Hospital Foundation to the Pediatric Emergency Medicine Research Associates’ Program, Calgary Laboratory Services (in kind), Provincial Laboratory for Public Health–Alberta Public Laboratories, Luminex Corporation, and Copan Italia. This study was supported in part by grant R01HD071915 from the NICHD (Dr Schnadower) and the Richard and Barbara Ruddy Endowed Chair in Emergency Medicine at Cincinnati Children's Hospital Medical Center (Dr Schnadower). The Pediatric Emergency Care Applied Research Network (PECARN) was supported by the HRSA of the US Department of Health and Human Services (HHS) and the Emergency Medical Services for Children program through the following grants: DCC-University of Utah (U03MC00008), GLEMSCRN-Nationwide Children’s Hospital (U03MC00003), HOMERUN-Cincinnati Children’s Hospital Medical Center (U03MC22684), PEMNEWS-Columbia University Medical Center (U03MC00007), PRIME-University of California at Davis Medical Center (U03MC00001), SW NODE-University of Arizona Health Sciences Center (U03MC28845), WBCARN-Children’s National Medical Center (U03MC00006), and CHaMP-Medical College of Wisconsin (H3MC26201).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Disclaimer: Dr Powell is an Assistant Editor at JAMA Network Open. She was not involved in the editorial review of or decision to publish this article.

Meeting Presentations: This study was presented as a poster at the Canadian Paediatric Society; June 7, 2019, Toronto, Ontario; as an oral presentation at the Canadian Association of Emergency Physicians; May 29, 2019, Halifax, Nova Scotia; and as a poster presentation at the Pediatric Academic Societies, April 27, 2019; Baltimore, Maryland.

Data Sharing Statement: See Supplement 4.

Additional Information: All PERC and PECARN members who fulfilled authorship criteria are listed as coauthors.