A comparison of alternative ranking methods in two-stage clinical trials with multiple interventions: An application to the anxiolysis for laceration repair in children trial.

BACKGROUND/AIMS: Multi-arm, multi-stage trials frequently include a standard care to which all interventions are compared. This may increase costs and hinders comparisons among the experimental arms. Furthermore, the standard care may not be evident, particularly when there is a large variation in standard practice. Thus, we aimed to develop an adaptive clinical trial that drops ineffective interventions following an interim analysis before selecting the best intervention at the final stage without requiring a standard care. METHODS: We used Bayesian methods to develop a multi-arm, two-stage adaptive trial and evaluated two different methods for ranking interventions, the probability that each intervention was optimal (Pbest) and using the surface under the cumulative ranking curve (SUCRA), at both the interim and final analysis. The proposed trial design determines the maximum sample size for each intervention using the Average Length Criteria. The interim analysis takes place at approximately half the pre-specified maximum sample size and aims to drop interventions for futility if either Pbest or the SUCRA is below a pre-specified threshold. The final analysis compares all remaining interventions at the maximum sample size to conclude superiority based on either Pbest or the SUCRA. The two ranking methods were compared across 12 scenarios that vary the number of interventions and the assumed differences between the interventions. The thresholds for futility and superiority were chosen to control type 1 error, and then the predictive power and expected sample size were evaluated across scenarios. A trial comparing three interventions that aim to reduce anxiety for children undergoing a laceration repair in the emergency department was then designed, known as the Anxiolysis for Laceration Repair in Children Trial (ALICE) trial. RESULTS: As the number of interventions increases, the SUCRA results in a higher predictive power compared with Pbest. Using Pbest results in a lower expected sample size when there is an effective intervention. Using the Average Length Criterion, the ALICE trial has a maximum sample size for each arm of 100 patients. This sample size results in a 86% and 85% predictive power using Pbest and the SUCRA, respectively. Thus, we chose Pbest as the ranking method for the ALICE trial. CONCLUSION: Bayesian ranking methods can be used in multi-arm, multi-stage trials with no clear control intervention. When more interventions are included, the SUCRA results in a higher power than Pbest. Future work should consider whether other ranking methods may also be relevant for clinical trial design.

Balanced crystalloids (RInger's lactate) versus normal Saline in adults with diabetic Ketoacidosis in the Emergency Department (BRISK-ED): a pilot randomised controlled trial.

BACKGROUND: Current diabetic ketoacidosis (DKA) treatment guidelines recommend using normal saline (NS); however, NS may delay DKA resolution by causing more hyperchloremic metabolic acidosis compared with balanced crystalloids. This study's objective was to determine the feasibility of a future multicentred randomised controlled trial (RCT) comparing intravenous Ringer's lactate (RL) with NS in managing ED patients with DKA. METHODS: We conducted a parallel-arm, triple-blind, pilot RCT of adults (≥18 years) with DKA at a Canadian academic tertiary care ED. The primary feasibility outcome was recruitment rate (target ≥41.3% of eligible participants over the 1-year study period); the primary efficacy outcome was time elapsed from ED presentation to DKA resolution. The superiority margin for a clinically significant difference was chosen to be a 40% time reduction to DKA resolution. We also assessed the need to break allocation concealment and loss to follow-up. Patients with clinical suspicion for DKA were screened for inclusion and enrolled patients were randomised 1:1 to receive RL or NS. Patients, clinicians and outcome assessors were blinded to allocation. RESULTS: We enrolled 52 (25 RL, 27 NS) of 60 eligible patients (86.7%), exceeding our target recruitment rate. There were more patients in the NS group with type 1 diabetes, and more patients in the RL group had an admission co-diagnosis in addition to DKA. For the 44 participants with confirmed laboratory evidence of resolution, median (IQR) time to DKA resolution for RL versus NS was 15.7 (10.4-18.8) and 12.7 (7.9-19.2) hours, respectively. There were no cases where blinding was broken, and there was no loss to follow-up. CONCLUSIONS: This pilot trial demonstrated our protocol's feasibility by exceeding our target recruitment rate. Our results may be used to inform future multicentre trials to compare the safety and efficacy of RL and NS in managing DKA in the ED. TRIAL REGISTRATION NUMBER: NCT04926740.

Pharmacologic Procedural Distress Management During Laceration Repair in Children: A Systematic Review.

OBJECTIVES: To systematically appraise the literature on the relative effectiveness of pharmacologic procedural distress management agents for children undergoing laceration repair. METHODS: Six databases were searched in August 2021, and the search was updated in January 2023. We included completed randomized or quasi-randomized trials involving ( a ) children younger than 15 years undergoing laceration repair in the emergency department; ( b ) randomization to at least one anxiolytic, sedative, and/or analgesic agent versus any comparator agent or placebo; ( c ) efficacy of procedural distress management measured on any scale. Secondary outcomes were pain during the procedure, administration acceptance, sedation duration, additional sedation, length of stay, and stakeholder satisfaction. Cochrane Collaboration's risk-of-bias tool assessed individual studies. Ranges and proportions summarized results where applicable. RESULTS: Among 21 trials (n = 1621 participants), the most commonly studied anxiolytic agents were midazolam, ketamine, and N 2 O. Oral midazolam, oral ketamine, and N 2 O were found to reduce procedural distress more effectively than their comparators in 4, 3, and 2 studies, respectively. Eight studies comparing routes, doses, or volumes of administration of the same agent led to indeterminate results. Meta-analysis was not performed because of heterogeneity in comparators, routes, and outcome measures across studies. CONCLUSIONS: Based on procedural distress reduction, this study favors oral midazolam and oral ketamine. However, this finding should be interpreted with caution because of heterogeneous comparators across studies and minor conflicting results. An optimal agent for procedural distress management cannot be recommended based on the limited evidence. Future research should seek to identify the minimal, essential measures of patient distress during pharmacologic anxiolysis and/or sedation in laceration repair to guide future trials and reviews.

Factors Influencing Parental Decision-Making Regarding Analgesia for Children with Musculoskeletal Injury-Related Pain: A Qualitative Study.

OBJECTIVES: To explore and understand parental decision-making relating to acute pain management for their children presenting to the emergency department. STUDY DESIGN: This study employed one-on-one semistructured interviews. Parents of children with acute musculoskeletal injuries were recruited from 3 Canadian pediatric emergency departments. Interviews were conducted via telephone from June 2019 to March 2021. Verbatim transcription and thematic analyses occurred concurrently with data collection, supporting data saturation and theory development considerations. RESULTS: Twenty-seven interviews were completed. Five major themes regarding pain care emerged: (1) my child's comfort is a priority, (2) every situation is unique, (3) opioids only if necessary, (4) considerations when choosing opioids, and (5) pain research is important. Overall, parents were highly comfortable with their assessment of their child's pain. Participants' willingness to use opioid analgesia for their children was primarily dependent on perceptions of injury and pain severity. Opioid-averse and opioid-accepting families had similar considerations when making analgesic decisions but weighed risks and benefits differently. CONCLUSIONS: Parents assess and manage their children's pain globally and multimodally, with comfort being prioritized. For most parents, the desire to relieve their children's pain outweighed concerns of substance use disorder, misuse, and adverse events when making decisions about opioid analgesia for short-term use. These results can inform evidence-based family-centered approaches to co-decision-making of analgesic plans for children with acute pain.

Emergency department visits and hospital admissions for suicidal ideation, self-poisoning and self-harm among adolescents in Canada during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic had profound effects on the mental wellbeing of adolescents. We sought to evaluate pandemic-related changes in health care use for suicidal ideation, self-poisoning and self-harm. METHODS: We obtained data from the Canadian Institute for Health Information on emergency department visits and hospital admissions from April 2015 to March 2022 among adolescents aged 10-18 years in Canada. We calculated the quarterly percentage of emergency department visits and hospital admissions for a composite outcome comprising suicidal ideation, self-poisoning and self-harm relative to all-cause emergency department visits and hospital admissions. We used interrupted time-series methods to compare changes in levels and trends of these outcomes between the prepandemic (Apr. 1, 2015-Mar. 1, 2020) and pandemic (Apr. 1, 2020-Mar. 31, 2022) periods. RESULTS: The average quarterly percentage of emergency department visits for suicidal ideation, self-poisoning and self-harm relative to all-cause emergency department visits was 2.30% during the prepandemic period and 3.52% during the pandemic period. The level (0.08%, 95% confidence interval [CI] -0.79% to 0.95%) or trend (0.07% per quarter, 95% CI -0.14% to 0.28%) of this percentage did not change significantly between periods. The average quarterly percentage of hospital admissions for the composite outcome relative to all-cause admissions was 7.18% during the prepandemic period and 8.96% during the pandemic period. This percentage showed no significant change in level (-0.70%, 95% CI -1.90% to 0.50%), but did show a significantly increasing trend (0.36% per quarter; 95% 0.07% to 0.65%) during the pandemic versus prepandemic periods, specifically among females aged 10-14 years (0.76% per quarter, 95% CI 0.22% to 1.30%) and females aged 15-18 years (0.56% per quarter, 95% CI 0.31% to 0.81%). INTERPRETATION: The quarterly change in the percentage of hospital admissions for suicidal ideation, self-poisoning and self-harm increased among adolescent females in Canada during the first 2 years of the COVID-19 pandemic. This underscores the need to promote public health policies that mitigate the impact of the pandemic on adolescent mental health.

Optimal Dose of Intranasal Dexmedetomidine for Laceration Repair in Children: A Phase II Dose-Ranging Study.

STUDY OBJECTIVE: To determine the optimal sedative dose of intranasal dexmedetomidine for children undergoing laceration repair. METHODS: This dose-ranging study employing the Bayesian Continual Reassessment Method enrolled children aged 0 to 10 years with a single laceration (<5 cm), requiring single-layer closure, who received topical anesthetic. Children were administered 1, 2, 3, or 4 mcg/kg intranasal dexmedetomidine. The primary outcome was the proportion with adequate sedation (Pediatric Sedation State Scale score of 2 or 3 for ≥90% of the time from sterile preparation to tying of the last suture). Secondary outcomes included the Observational Scale of Behavior Distress-Revised (range: 0 [no distress] to 23.5 [maximal distress]), postprocedure length of stay, and adverse events. RESULTS: We enrolled 55 children (35/55 [64%] males; median [interquartile range {IQR}] age 4 [2, 6] years). At 1, 2, 3, and 4 mcg/kg intranasal dexmedetomidine, respectively, the proportion of participants "adequately" sedated was 1/3 (33%), 2/9 (22%), 13/21 (62%), and 12/21 (57%); the posterior mean (95% equitailed credible intervals) for the probability of adequate sedation was 0.38 (0.04, 0.82), 0.25 (0.05, 0.54), 0.61 (0.41, 0.80), and 0.57 (0.36, 0.76); the median (IQR) Observational Scale of Behavior Distress-Revised scores during suturing was 2.7 (0.3, 3), 0 (0, 3.8), 0.6 (0, 5), and 0 (0, 3.7); the median (IQR) postprocedure length of stay was 67 (60, 78), 76 (60, 100), 89 (76, 109), and 113 (76, 150) minutes. There was 1 adverse event, a decrease in oxygen saturation at 4 mcg/kg, which resolved with head repositioning. CONCLUSION: Despite limitations, such as our limited sample size and subjectivity in Pediatric Sedation State Scale scoring, sedation efficacy for 3 and 4 mcg/kg were similarly based on equitailed credible intervals suggesting either could be considered optimal.

Characterizing the Pain Experience of Children With Acute Gastroenteritis Based on Identified Pathogens.

OBJECTIVES: Pain is common with acute gastroenteritis (AGE) yet little is known about the severity associated with specific enteropathogens. We sought to explore the correlation of pain severity with specific enteropathogens in children with AGE. METHODS: Participants were prospectively recruited by the Alberta Provincial Pediatric EnTeric Infection TEam at 2 pediatric emergency departments (EDs) (December 2014-August 2018). Pain was measured (by child and/or caregiver) using the 11-point Verbal Numerical Rating Scale. RESULTS: We recruited 2686 participants; 46.8% (n = 1256) females, with median age 20.1 months (interquartile range 10.3, 45.3). The mean highest pain scores were 5.5 [standard deviation (SD) 3.0] and 4.2 (SD 2.9) in the 24 hours preceding the ED visit, and in the ED, respectively. Prior to ED visit, the mean highest pain scores with bacterial detection were 6.6 (SD 2.5), compared to 5.5 (SD 2.9) for single virus and 5.5 (SD 3.1) for negative stool tests. In the ED, the mean highest pain scores with bacterial detection were 5.5 (SD 2.7), compared to 4.1 (SD 2.9) for single virus and 4.2 (SD 3.0) for negative stool tests. Using multivariable modeling, factors associated with greater pain severity prior to ED visit included older age, fever, illness duration, number of diarrheal or vomiting episodes in the preceding 24 hours, and respiratory symptoms, but not enteropathogen type. CONCLUSION: Children with AGE experience significant pain, particularly when the episode is associated with the presence of a bacterial enteric pathogen. However, older age and fever appear to influence children's pain experiences more than etiologic pathogens.

Predictors of Adherence to Short-Course Probiotics Among Children with Gastroenteritis who are Enrolled in a Clinical Trial.

BACKGROUND: To improve our understanding of adherence to discharge medications in the ED and within research trials, we sought to quantify medication adherence and identify predictors thereof in children with acute gastroenteritis (AGE). METHODS: We conducted a secondary analysis of a randomized trial of twice daily probiotic for 5 days. The population included previously healthy children aged 3-47 months with AGE. The primary outcome was patient-reported adherence to the treatment regimen, defined a priori as having received >70% of the prescribed doses. Secondary outcomes included predictors of treatment adherence and concordance between patient-reported adherence and the returned medication sachet counts. RESULTS: After excluding participants with missing data on adherence, 760 participants were included in this analysis: 383 in the probiotic arm (50.4%); and 377 in the placebo arm (49.6%). Self-reported adherence was similar in both groups (77.0% in probiotic versus 80.3% in placebo). There was good agreement between self-reported adherence and sachet counts (87% within limits of agreement (-2.9 to 3.5 sachets) on the Bland-Altman plots). In the multivariable regression model, covariates associated with adherence were greater number of days of diarrhea post-emergency department visit, and the study site; covariates negatively associated with adherence were age 12-23 months, severe dehydration and greater total number of vomiting and diarrhea episodes after enrolment. CONCLUSIONS: Longer duration of diarrhea and study site were associated with higher probiotic adherence. Age 12-23 months, severe dehydration and greater number of vomiting and diarrhea episodes post enrolment negatively predicted treatment adherence.

Adolescent and Caregiver Perspectives on Living With a Limb Fracture: A Qualitative Study.

BACKGROUND: Fractures occur in up to half of children by age 16 years. After initial emergency care for a fracture, function is universally impaired in children, and impacts extend to the immediate family. Knowledge of expected functional limitations is key to providing proper discharge instructions and anticipatory guidance to families. OBJECTIVES: The primary objective of this study was to understand how changes in functional ability impact youth with fractures. METHODS: We conducted individual, semistructured interviews from June 2019 to November 2020 with adolescents and their caregivers 7 to 14 days following their initial visit to a pediatric emergency department. We used qualitative content analysis methodology; recruitment proceeded until thematic saturation was achieved. Coding and analysis were concurrent with recruitment and interviews. The interview script was modified in an iterative process, to reflect emerging themes. RESULTS: Twenty-nine interviews were completed. The most frequently affected functions were ( a ) showering and hygiene (requiring the most caregiver support), ( b ) sleep (due to pain and cast-related discomfort), and ( c ) exclusion from sports/activities. Many adolescents experienced disruptions to social activities and gatherings. Youth valued independence and took more time to complete tasks, regardless of inconvenience. Both adolescents and caregivers reported feelings of frustration from day-to-day impacts of the injury. Generally, caregivers' perspectives were in keeping with the experiences that adolescents described for themselves. Notable family impacts included "sibling burden," or conflicts that arose when a sibling had to take on extra chores/tasks. CONCLUSIONS: Overall, caregivers' perspectives were congruent with the self-described experiences of adolescents. Key messages for optimized discharge instructions include pain and sleep management, allowing extra time to complete tasks independently, considering impact on siblings, preparing for changes in activities and social dynamics, and normalizing frustration. These themes highlight an opportunity to better tailor discharge instructions for adolescents with fractures.

Pathogen-Specific Effects of Probiotics in Children With Acute Gastroenteritis Seeking Emergency Care: A Randomized Trial.

BACKGROUND: It is unknown if probiotics exert pathogen-specific effects in children with diarrhea secondary to acute gastroenteritis. METHODS: Analysis of patient-level data from 2 multicenter randomized, placebo controlled trials conducted in pediatric emergency departments in Canada and the United States. Participants were 3-48 months with >3 diarrheal episodes in the preceding 24 hours and were symptomatic for <72 hours and <7 days in the Canadian and US studies, respectively. Participants received either placebo or a probiotic preparation (Canada-Lactobacillus rhamnosus R0011/Lactobacillus helveticus R0052; US-L. rhamnosus GG). The primary outcome was post-intervention moderate-to-severe disease (ie, ≥9 on the Modified Vesikari Scale [MVS] score). RESULTS: Pathogens were identified in specimens from 59.3% of children (928/1565). No pathogen groups were less likely to experience an MVS score ≥9 based on treatment allocation (test for interaction = 0.35). No differences between groups were identified for adenovirus (adjusted relative risk [aRR]: 1.42; 95% confidence interval [CI]: .62, 3.23), norovirus (aRR: 0.98; 95% CI: .56, 1.74), rotavirus (aRR: 0.86; 95% CI: .43, 1.71) or bacteria (aRR: 1.19; 95% CI: .41, 3.43). At pathogen-group and among individual pathogens there were no differences in diarrhea duration or the total number of diarrheal stools between treatment groups, regardless of intervention allocation or among probiotic sub-groups. Among adenovirus-infected children, those administered the L. rhamnosus R0011/L. helveticus R0052 product experienced fewer diarrheal episodes (aRR: 0.65; 95% CI: .47, .90). CONCLUSIONS: Neither probiotic product resulted in less severe disease compared to placebo across a range of the most common etiologic pathogens. The preponderance of evidence does not support the notion that there are pathogen specific benefits associated with probiotic use in children with acute gastroenteritis. CLINICAL TRIALS REGISTRATION: NCT01773967 and NCT01853124.

Oral Ondansetron Administration in Children Seeking Emergency Department Care for Acute Gastroenteritis: A Patient-Level Propensity-Matched Analysis.

STUDY OBJECTIVE: This study aimed to explore oral ondansetron usage and impact on outcomes in clinical practice. METHODS: This observational study was a planned secondary analysis of 2 trials conducted in 10 US and 6 Canadian institutions between 2014 and 2017. Children 3 to 48 months old with gastroenteritis and ≥3 episodes of vomiting in the 24 hours preceding emergency department (ED) presentation were included. Oral ondansetron was administered at the discretion of the provider. The principal outcomes were intravenous fluid administration and hospitalization at the index visit and during the subsequent 72 hours and diarrhea and vomiting frequency during the 24 hours following the ED visit. RESULTS: In total, 794 children were included. The median age was 16.0 months (interquartile range 10.0 to 26.0), and 50.1% (398/794) received oral ondansetron. In propensity-adjusted analysis (n=528), children administered oral ondansetron were less likely to receive intravenous fluids at the index visit (adjusted odds ratio [aOR] 0.50; 95% confidence interval [CI] 0.29 to 0.88). There were no differences in the frequencies of intravenous fluid administration within the first 72 hours (aOR 0.65; 95% CI 0.39 to 1.10) or hospitalization at the index visit (aOR 0.31; 95% CI 0.09 to 1.10) or the subsequent 72 hours (aOR 0.52; 95% CI 0.21 to 1.28). Episodes of vomiting (aRR 0.86; 95% CI 0.63 to 1.19) and diarrhea (aRR 1.11; 95% CI 0.93 to 1.32) during the 24 hours following ED discharge also did not differ. CONCLUSION: Among preschool-aged children with gastroenteritis seeking ED care, oral ondansetron administration was associated with a reduction in index ED visit intravenous fluid administration; it was not associated with intravenous fluids administered within 72 hours, hospitalization, or vomiting and diarrhea in the 24 hours following discharge.

Derivation of the Pediatric Acute Gastroenteritis Risk Score to Predict Moderate-to-Severe Acute Gastroenteritis.

OBJECTIVES: Although most acute gastroenteritis (AGE) episodes in children rapidly self-resolve, some children go on to experience more significant and prolonged illness. We sought to develop a prognostic score to identify children at risk of experiencing moderate-to-severe disease after an index emergency department (ED) visit. METHODS: Data were collected from a cohort of children 3 to 48 months of age diagnosed with AGE in 16 North American pediatric EDs. Moderate-to-severe AGE was defined as a Modified Vesikari Scale (MVS) score ≥9 during the 14-day post-ED visit. A clinical prognostic model was derived using multivariable logistic regression and converted into a simple risk score. The model's accuracy was assessed for moderate-to-severe AGE and several secondary outcomes. RESULTS: After their index ED visit, 19% (336/1770) of participants developed moderate-to-severe AGE. Patient age, number of vomiting episodes, dehydration status, prior ED visits, and intravenous rehydration were associated with MVS ≥9 in multivariable regression. Calibration of the prognostic model was strong with a P value of 0.77 by the Hosmer-Lemenshow goodness-of-fit test, and discrimination was moderate with an area under the receiver operator characteristic curve of 0.68 (95% confidence interval [CI] 0.65-0.72). Similarly, the model was shown to have good calibration when fit to the secondary outcomes of subsequent ED revisit, intravenous rehydration, or hospitalization within 72 hours after the index visit. CONCLUSIONS: After external validation, this new risk score may provide clinicians with accurate prognostic insight into the likely disease course of children with AGE, informing disposition decisions, anticipatory guidance, and follow-up care.

Parental Perspectives on Children's Functional Experiences After Limb Fracture: A Qualitative Study.

BACKGROUND: Fractures are a common childhood injury. Although the pain associated with fractures is well described, the related functional impact is less understood. When a child's function is impaired, his or her ability to participate in day-to-day life is restricted. Eighty percent of children with fractures experience compromise in daily function. An in-depth understanding of function can guide emergency department (ED) providers' discharge instructions. OBJECTIVES: Our aim was to report caregivers' perspectives of the functional impact of limb fractures on their children's day-to-day life activities. METHODS: We performed a qualitative study using interviews of caregivers of children (aged 5 to 11 years) who received care for acute, nonoperative long bone fractures in a pediatric ED. Audio-recorded, semistructured telephone interviews were completed 7 to 14 days after the ED visit. Interviews were primarily open ended, including questions targeting areas of function from existing pediatric fracture literature. Qualitative analysis was completed using content analysis. RESULTS: Twenty-five interviews were included in the final analysis. Most of the children were diagnosed with upper extremity fractures, and most participants were mothers. All parents reported a change in their child's function. The most commonly affected areas were sleep, activities of daily living, and play. Play was either self-limited by the child or restricted by the parent. Pain was worse in the first days after discharge. Many children struggled emotionally with functional limitations. All children required help from their parents to perform daily tasks; this required adaptive strategies such as planning, changes to household routine, and missed work. Key concerns from parents included regression in the child's independence and fracture healing and complications. CONCLUSIONS: Function is universally impaired in young children with fractures, significantly affecting family life after discharge. Discharge conversations with families should include pain management, changes to activities of daily living, family routines and play, and expectations for fracture healing.

Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis.

BACKGROUND: Gastroenteritis accounts for approximately 1.7 million visits to the emergency department (ED) by children in the United States every year. Data to determine whether the use of probiotics improves outcomes in these children are lacking. METHODS: We conducted a randomized, double-blind trial involving 886 children 3 to 48 months of age with gastroenteritis who presented to six pediatric EDs in Canada. Participants received a 5-day course of a combination probiotic product containing Lactobacillus rhamnosus R0011 and L. helveticus R0052, at a dose of 4.0×109 colony-forming units twice daily or placebo. The primary outcome was moderate-to-severe gastroenteritis, which was defined according to a post-enrollment modified Vesikari scale symptom score of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease). Secondary outcomes included the duration of diarrhea and vomiting, the percentage of children who had unscheduled physician visits, and the presence or absence of adverse events. RESULTS: Moderate-to-severe gastroenteritis within 14 days after enrollment occurred in 108 of 414 participants (26.1%) who were assigned to probiotics and 102 of 413 participants (24.7%) who were assigned to placebo (odds ratio, 1.06; 95% confidence interval [CI], 0.77 to 1.46; P=0.72). After adjustment for trial site, age, detection of rotavirus in stool, and frequency of diarrhea and vomiting before enrollment, trial-group assignment did not predict moderate-to-severe gastroenteritis (odds ratio, 1.06; 95% CI, 0.76 to 1.49; P=0.74). There were no significant differences between the probiotic group and the placebo group in the median duration of diarrhea (52.5 hours [interquartile range, 18.3 to 95.8] and 55.5 hours [interquartile range, 20.2 to 102.3], respectively; P=0.31) or vomiting (17.7 hours [interquartile range, 0 to 58.6] and 18.7 hours [interquartile range, 0 to 51.6], P=0.18), the percentages of participants with unscheduled visits to a health care provider (30.2% and 26.6%; odds ratio, 1.19; 95% CI, 0.87 to 1.62; P=0.27), and the percentage of participants who reported an adverse event (34.8% and 38.7%; odds ratio, 0.83; 95% CI, 0.62 to 1.11; P=0.21). CONCLUSIONS: In children who presented to the emergency department with gastroenteritis, twice-daily administration of a combined L. rhamnosus-L. helveticus probiotic did not prevent the development of moderate-to-severe gastroenteritis within 14 days after enrollment. (Funded by the Canadian Institutes of Health Research and others; PROGUT ClinicalTrials.gov number, NCT01853124 .).

Association Between Diarrhea Duration and Severity and Probiotic Efficacy in Children With Acute Gastroenteritis.

INTRODUCTION: It is unclear whether the alleged efficacy of probiotics in childhood acute gastroenteritis depends on the duration and severity of symptoms before treatment. METHODS: Preplanned secondary analysis of 2 randomized placebo-controlled trials in children 3-48 months of age was conducted in 16 emergency departments in North America evaluating the efficacy of 2 probiotic products (Lactobacillus rhamnosus GG and a combination probiotic: L. rhamnosus and L. helveticus). Participants were categorized in severity groups according to the duration (<24, 24-<72, and ≥72 hours) and the frequency of diarrhea episodes in the 24 hours (≤3, 4-5, and ≥6) before presentation. We used regression models to assess the interaction between pretreatment diarrhea severity groups and treatment arm (probiotic or placebo) in the presence of moderate-to-severe gastroenteritis (Modified Vesikari Scale score ≥9). Secondary outcomes included diarrhea frequency and duration, unscheduled healthcare provider visits, and hospitalization. RESULTS: A total of 1,770 children were included, and 882 (50%) received a probiotic. The development of moderate-to-severe gastroenteritis symptoms after the initiation of treatment did not differ between groups (probiotic-18.4% [162/882] vs placebo-18.3% [162/888]; risk ratio 1.00; 95% confidence interval 0.87, 1.16; P = 0.95). There was no evidence of interaction between baseline severity and treatment (P = 0.61) for the primary or any of the secondary outcomes: diarrhea duration (P = 0.88), maximum diarrheal episodes in a 24-hour period (P = 0.87), unscheduled healthcare visits (P = 0.21), and hospitalization (P = 0.87). DISCUSSION: In children 3-48 months with acute gastroenteritis, the lack of effect of probiotics is not explained by the duration of symptoms or frequency of diarrheal episodes before presentation.

Characterizing Pain in Children with Acute Gastroenteritis Who Present for Emergency Care.

OBJECTIVE: To characterize the pain experienced by children with acute gastroenteritis (AGE) in the 24 hours before emergency department (ED) presentation. Secondary objectives included characterizing ED pain, discharge recommendations, overall analgesic use, and factors that influenced analgesic use and pain severity. STUDY DESIGN: A prospective cohort was recruited from 2 pediatric EDs (December 2014 to September 2017). Eligibility criteria included <18 years of age, AGE (≥3 episodes of diarrhea or vomiting in the previous 24 hours), and symptom duration <7 days at presentation. RESULTS: We recruited 2136 patients, median age 20.8 months (IQR 10.4, 47.4) and 45.8% (979/2136) female. In the 24 hours before enrollment, most caregivers reported moderate (28.6% [610/2136, 95% CI 26.7-30.5]) or severe (46.2% [986/2136, CI 44.0-48.3]) pain for their child. In the ED, they reported moderate (31.1% [664/2136, 95% CI 29.1-33.1]) or severe ([26.7% [571/2136, 95% CI 24.9-28.7]) pain; analgesia was provided to 21.2% (452/2131). The most common analgesics used in the ED were acetaminophen and ibuprofen. At discharge, these were also most commonly recommended. Factors associated with greater analgesia use in the ED were high pain scores during the index visit, having a primary care physician, earlier presentation to emergency care, fewer diarrheal episodes, presence of fever, and hospitalization at index visit. CONCLUSIONS: Most caregivers of children presenting to the ED with AGE reported moderate or severe pain, both before and during their visit. Future research should focus on the development of effective, safe, and timely pain management plans.

A Bayesian response-adaptive dose-finding and comparative effectiveness trial.

BACKGROUND/AIMS: Combinations of treatments that have already received regulatory approval can offer additional benefit over Each of the treatments individually. However, trials of these combinations are lower priority than those that develop novel therapies, which can restrict funding, timelines and patient availability. This article develops a novel trial design to facilitate the evaluation of New combination therapies. This trial design combines elements of phase II and phase III trials to reduce the burden of evaluating combination therapies, while also maintaining a feasible sample size. This design was developed for a randomised trial that compares the properties of three combination doses of ketamine and dexmedetomidine, given intranasally, to ketamine delivered intravenously for children undergoing a closed reduction for a fracture or dislocation. METHODS: This trial design uses response-adaptive randomisation to evaluate different dose combinations and increase the information collected for successful novel drug combinations. The design then uses Bayesian dose-response modelling to undertake a comparative effectiveness analysis for the most successful dose combination against a relevant comparator. We used simulation methods determine the thresholds for adapting the trial and making conclusions. We also used simulations to evaluate the probability of selecting the dose combination with the highest true effectiveness the operating characteristics of the design and its Bayesian predictive power. RESULTS: With 410 participants, five interim updates of the randomisation ratio and a probability of effectiveness of 0.93, 0.88 and 0.83 for the three dose combinations, we have an 83% chance of randomising the largest number of patients to the drug with the highest probability of effectiveness. Based on this adaptive randomisation procedure, the comparative effectiveness analysis has a type I error of less than 5% and a 93% chance of correcting concluding non-inferiority, when the probability of effectiveness for the optimal combination therapy is 0.9. In this case, the trial has a greater than 77% chance of meeting its dual aims of dose-finding and comparative effectiveness. Finally, the Bayesian predictive power of the trial is over 90%. CONCLUSIONS: By simultaneously determining the optimal dose and collecting data on the relative effectiveness of an intervention, we can minimise administrative burden and recruitment time for a trial. This will minimise the time required to get effective, safe combination therapies to patients quickly. The proposed trial has high potential to meet the dual study objectives within a feasible overall sample size.

Clinical Suspicion and Language Translation in the Pediatric Emergency Department.

ABSTRACT: Elucidating a medical history and gaining patient consent and buy-in are difficult in any teenager presenting to a North American pediatric emergency department, but especially so when they present with limited English fluency. Translators can make this process easier, but both limited availability and impreciseness in translation can reduce their utility. We describe 2 teenage females who presented to our pediatric emergency department within 48 hours with similar presentations but no obvious organic cause or examination findings to suggest a specific diagnosis. We demonstrate how complex language translation issues in these adolescents contributed to prolonged diagnoses and advocate for independent interpreters to be available on first presentation to hospital.

A two-centre survey of caregiver perspectives on opioid use for children's acute pain management.

BACKGROUND: Given the current opioid crisis, caregivers have mounting fears regarding the use of opioid medication in their children. We aimed to determine caregivers' a) willingness to accept, b) reasons for refusing, and c) past experiences with opioids. METHODS: A novel electronic survey of caregivers of children aged 4 to 16 years who had an acute musculoskeletal injury and presented to two Canadian paediatric emergency departments (ED) (March to November 2017). Primary outcome was caregiver willingness to accept opioids for moderate pain for their children. RESULTS: Five hundred and seventeen caregivers participated; mean age was 40.9 (SD 7.1) years with 70.0% (362/517) mothers. Children included 62.2% (321/516) males with a mean age of 10.0 (SD 3.6) years. 49.6% of caregivers (254/512) reported willingness to accept opioids for ongoing moderate pain in the ED, while 37.1% (190/512) were 'unsure'; 33.2% (170/512) of caregivers would accept opioids for at-home use, but 45.5% (233/512) were 'unsure'. Caregivers' primary concerns were side effects, overdose, addiction, and masking of diagnosis. Caregiver fear of addiction (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.01 to 1.25) and side effects (OR 1.25, 95% CI 1.11 to 1.42) affected willingness to accept opioids in the emergency department; fears of addiction (OR 1.19, 95% CI 1.07 to 1.32), and overdose (OR 1.15, 95% CI 1.04 to 1.27) affected willingness to accept opioids for at-home use. CONCLUSIONS: Only half of the caregivers would accept opioids for moderate pain, despite ongoing pain following nonopioid analgesics. Caregivers' fears of addiction, side effects, overdose, and masking diagnosis may have influenced their responses. These findings are a first step in understanding caregiver analgesic decision making.

Hyoscine butylbromide versus acetaminophen for nonspecific colicky abdominal pain in children: a randomized controlled trial.

BACKGROUND: Less than two-thirds of children with abdominal pain in the emergency department receive analgesia. We sought to determine whether hyoscine butylbromide was superior to acetaminophen for children with nonspecific colicky abdominal pain. METHODS: We randomly allocated children aged 8-17 years with nonspecific colicky abdominal pain who presented to the pediatric emergency department of London Health Sciences Centre, London, Ontario to receive hyoscine butylbromide, 10 mg given orally, or acetaminophen, 15 mg/kg given orally (maximum 975 mg). We considered the minimal clinically important difference for the primary outcome (self-reported pain at 80 min) to be 13 mm on a 100 mm visual analogue scale. Secondary outcomes included administration of rescue analgesia, adverse effects and pain score less than 30 mm at 80 minutes. RESULTS: A total of 236 participants (120 in the hyoscine butylbromide group and 116 in the acetaminophen group) were included in the trial. The mean visual analogue scale scores at 80 minutes were 29 mm (standard deviation [SD] 26 mm) and 30 mm (SD 29 mm) with hyoscine butylbromide and acetaminophen, respectively (adjusted difference 1, 95% confidence interval -7 to 7). Rescue analgesia was administered to 4 participants (3.3%) in the hyoscine butylbromide group and 1 participant (0.9%) in the acetaminophen groups (p = 0.2). We found no significant differences in rates of adverse effects between hyoscine butylbromide (32/116 [27.6%]) and acetaminophen (28/115 [24.3]) (p = 0.5); no serious adverse effects were observed. The proportion with a pain score less than 30 mm at 80 minutes was 66 (55.0%) with hyoscine butylbromide and 63 (54.3%) with acetaminophen (p = 0.9). INTERPRETATION: Hyoscine butylbromide was not superior to acetaminophen in this setting. Both agents were associated with clinically important pain reduction, and either can be considered for children presenting to the emergency department with nonspecific colicky abdominal pain. Trial registration: Clinicaltrials.gov, no. NCT02582307.