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Ketamine is commonly used for procedural sedation and analgesia (PSA) in children. Evidence suggests it can be administered intranasally (IN). We sought to review the evidence for IN ketamine for PSA in children. We performed a systematic review of randomized trials of IN ketamine in PSA that reported any sedation-related outcome in children 0 to 19 years. Trials were identified through electronic searches of MEDLINE (1946-2016), EMBASE (1947-2016), Google Scholar (2016), CINAHL (1981-2016), The Cochrane Library (2016), Web of Science (2016), Scopus (2016), clinical trial registries, and conference proceedings (2000-2016) without language restrictions. The methodological qualities of studies and the overall quality of evidence were evaluated using the Cochrane Collaboration's Risk of Bias tool, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, respectively. The review included 7 studies (n = 264) of children ranging from 0 to 14 years. Heterogeneity in study design precluded meta-analysis. Most studies were associated with a low or unclear risk of bias and outcome-specific ratings for quality of evidence were low or very low. In four of seven studies, IN ketamine provided superior sedation to comparators and resulted in adequate sedation for 148/175 (85%) of participants. Vomiting was the most common adverse effect; reported by 9/91 (10%) of participants. IN ketamine administration is well tolerated and without serious adverse effects. Although most participants were deemed adequately sedated with IN ketamine, effectiveness of sedation with respect to superiority over comparators was inconsistent, precluding a recommendation for PSA in children.

Emergency department overcrowding has been associated with increased odds of hospital admission and mortality after discharge from the emergency department in predominantly adult cohorts. The objective of this study was to evaluate the association between crowding and the odds of several adverse outcomes among children seen at a pediatric emergency department. We conducted a retrospective cohort study involving all children visiting 8 Canadian pediatric emergency departments across 4 provinces between 2010 and 2014. We analyzed the association between mean departmental length of stay for each index visit and hospital admission within 7 days or death within 14 days of emergency department discharge, as well as hospital admission at index visit and return visits within 7 days, using mixed-effects logistic regression modelling. A total of 1 931 465 index visits occurred across study sites over the 5-year period, with little variation in index visit hospital admission or median length of stay. Hospital admission within 7 days of discharge and 14-day mortality were low across provinces (0.8%–1.5% and < 10 per 100 000 visits, respectively), and their association with mean departmental length of stay varied by triage categories and across sites but was not significant. There were increased odds of hospital admission at the index visit with increasing departmental crowding among visits triaged to Canadian Triage and Acuity Scale (CTAS) score 1–2 (odds ratios [ORs] ranged from 1.01 to 1.08) and return visits among patients with a CTAS score of 4–5 discharged at the index visit at some sites (ORs ranged from 1.00 to 1.06). Emergency department crowding was not significantly associated with hospital admission within 7 days of the emergency department visit or mortality in children. However, it was associated with increased hospital admission at the index visit for the sickest children, and with return visits to the emergency department for those less sick.

Bronchiolitis exerts a high burden on children, their families and the healthcare system. The Canadian Bronchiolitis Epinephrine Steroid Trial (CanBEST) assessed whether administering epinephrine alone, dexamethasone alone, or in combination (EpiDex) could reduce bronchiolitis-related hospitalizations among children less than 12 months of age compared to placebo. CanBEST demonstrated a statistically significant reduction in 7-day hospitalization risk with EpiDex in an unadjusted analysis but not after adjustment. To explore the probability that EpiDex results in a reduction in hospitalizations using Bayesian methods. Using prior distributions that represent varying levels of preexisting enthusiasm or skepticism, i.e., how confident or doubtful one is that EpiDex may reduce hospitalizations, and information about the treatment effect before data were collected, the posterior distribution of the relative risk of hospitalization compared to placebo was determined. The probability that the treatment effect is less than 1, 0.9, 0.8 and 0.6, indicating increasing reductions in hospitalization risk, are computed alongside 95% credible intervals. Combining a minimally informative prior distribution with the data from CanBEST provides comparable results to the original analysis. Unless strongly skeptical views about the effectiveness of EpiDex were considered, the 95% credible interval for the treatment effect lies below 1, indicating a reduction in hospitalizations. There is a 90% probability that EpiDex results in a clinically meaningful reduction in hospitalization of 10% even when incorporating skeptical views, with a 67% probability when considering strongly skeptical views. A Bayesian analysis demonstrates a high chance that EpiDex reduces hospitalization rates for bronchiolitis, although strongly skeptical individuals may require additional evidence to change practice. Clinical Trial registry name, registration number: Current Controlled Trials number, ISRCTN56745572.

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. 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. 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). 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

There is uncertainty about which children with minor head injury need to undergo computed tomography (CT). We sought to prospectively validate the accuracy and potential for refinement of a previously derived decision rule, Canadian Assessment of Tomography for Childhood Head injury (CATCH), to guide CT use in children with minor head injury. This multicentre cohort study in 9 Canadian pediatric emergency departments prospectively enrolled children with blunt head trauma presenting with a Glasgow Coma Scale score of 13–15 and loss of consciousness, amnesia, disorientation, persistent vomiting or irritability. Phys icians completed standardized assessment forms before CT, including clinical predictors of the rule. The primary outcome was neurosurgical intervention and the secondary outcome was brain injury on CT. We calculated test characteristics of the rule and used recursive partitioning to further refine the rule. Of 4060 enrolled patients, 23 (0.6%) underwent neurosurgical intervention, and 197 (4.9%) had brain injury on CT. The original 7-item rule (CATCH) had sensitivities of 91.3% (95% confidence interval [CI] 72.0%–98.9%) for neurosurgical intervention and 97.5% (95% CI 94.2%–99.2%) for predicting brain injury. Adding “≥ 4 episodes of vomiting” resulted in a refined 8-item rule (CATCH2) with 100% (95% CI 85.2%–100%) sensitivity for neurosurgical intervention and 99.5% (95% CI 97.2%–100%) sensitivity for brain injury. Among children presenting to the emergency department with minor head injury, the CATCH2 rule was highly sensitive for identifying those children requiring neurosurgical intervention and those with any brain injury on CT. The CATCH2 rule should be further validated in an implementation study designed to assess its clinical impact.

IntroductionThe Canadian Bronchiolitis Epinephrine Steroid Trial (CanBEST) and the Bronchiolitis Severity Cohort (BSC) study enrolled infants with bronchiolitis during the first year of life. The CanBEST trial suggested that treatment of infants with a combined therapy of high-dose corticosteroids and nebulised epinephrine reduced the risk of admission to hospital. Our study aims to—(1) quantify the risk of developing asthma by age 5 and 10 years in children treated with high-dose corticosteroid and epinephrine for bronchiolitis during infancy, (2) identify risk factors associated with development of asthma in children with bronchiolitis during infancy, (3) develop asthma prediction models for children diagnosed with bronchiolitis during infancy.Methods and analysisWe propose a longitudinal cohort study in which we will link data from the CanBEST (ISRCTN56745572, post-results) and BSC study with routinely collected data from provincial health administrative databases. Our outcome is asthma incidence measured using a validated health administrative data algorithm. Primary exposure will be treatment with a combined therapy of high-dose corticosteroids and nebulised epinephrine for bronchiolitis. Covariates will include type of viral pathogen, disease severity, medication use, maternal, prenatal, postnatal and demographic factors and variables related to health service utilisation for acute lower respiratory tract infection. The risk associated with development of asthma in children treated with high-dose corticosteroid and epinephrine for bronchiolitis will be assessed using multivariable Cox proportional hazards regression models. Prediction models will be developed using multivariable logistic regression analysis and internally validated using a bootstrap approach.Ethics and disseminationOur study has been approved by the ethics board of all four participating sites of the CanBEST and BSC study. Finding of the study will be disseminated to the academic community and relevant stakeholders through conferences and peer-reviewed publications.

Background There are limited treatment options that clinicians can provide to children presenting to emergency departments with vomiting secondary to acute gastroenteritis. Based on evidence of effectiveness and safety, clinicians now routinely administer ondansetron in the emergency department to promote oral rehydration therapy success. However, clinicians are also increasingly providing multiple doses of ondansetron for home use, creating unquantified cost and health system resource use implications without any evidence to support this expanding practice. Methods/design DOSE-AGE is a randomized, placebo-controlled, double-blinded, six-center, pragmatic clinical trial being conducted in six Canadian pediatric emergency departments (EDs). In September 2019 the study began recruiting children aged 6 months to 18 years with a minimum of three episodes of vomiting in the 24 h preceding enrollment, <72 h of gastroenteritis symptoms and who were administered a dose of ondansetron during their ED visit. We are recruiting 1030 children (1:1 allocation via an internet-based, third-party, randomization service) to receive a 48-h supply (i.e., six doses) of ondansetron oral solution or placebo, administered on an as-needed basis. All participants, caregivers and outcome assessors will be blinded to group assignment. Outcome data will be collected by surveys administered to caregivers 24, 48 and 168 h following enrollment. The primary outcome is the development of moderate-to-severe gastroenteritis in the 7 days following the ED visit as measured by a validated clinical score (the Modified Vesikari Scale). Secondary outcomes include duration and frequency of vomiting and diarrhea, proportions of children experiencing unscheduled health care visits and intravenous rehydration, caregiver satisfaction with treatment and safety. A preplanned economic evaluation will be conducted alongside the trial. Discussion Definitive data are lacking to guide the clinical use of post-ED visit multidose ondansetron in children with acute gastroenteritis. Usage is increasing, despite the absence of supportive evidence. The incumbent additional costs associated with use, and potential side effects such as diarrhea and repeat visits, create an urgent need to evaluate the effect and safety of multiple doses of ondansetron in children focusing on post-emergency department visit and patient-centered outcomes. Trial Registration ClinicalTrials.gov : NCT03851835 . Registered on 22 February 2019.

Background Acute gastroenteritis is a leading cause of emergency department visits and hospitalizations among children in North America. Oral-rehydration therapy is recommended for children with mild-to-moderate dehydration, but children who present with vomiting are frequently offered intravenous rehydration in the emergency department (ED). Recent studies have demonstrated that the anti-emetic ondansetron can reduce vomiting, intravenous rehydration, and hospitalization when administered in the ED to children with dehydration. However, there is little evidence of additional benefit from prescribing ondansetron beyond the initial ED dose. Moreover, repeat dosing may increase the frequency of diarrhea. Despite the lack of evidence and potential adverse side effects, many physicians across North America provide multiple doses of ondansetron to be taken following ED disposition. Thus, the Multi-Dose Oral Ondansetron for Pediatric Gastroenteritis (DOSE-AGE) trial will evaluate the effectiveness of prescribing multiple doses of ondansetron to treat acute gastroenteritis-associated vomiting. This article specifies the statistical analysis plan (SAP) for the DOSE-AGE trial and was submitted before the outcomes of the study were available for analysis. Methods/design The DOSE-AGE study is a phase III, 6-center, placebo-controlled, double-blind, parallel design randomized controlled trial designed to determine whether participants who are prescribed multiple doses of oral ondansetron to administer, as needed, following their ED visit have a lower incidence of experiencing moderate-to-severe gastroenteritis, as measured by the Modified Vesikari Scale score, compared with a placebo. To assess safety, the DOSE-AGE trial will investigate the frequency and maximum number of diarrheal episodes following ED disposition, and the occurrence of palpitations, pre-syncope/syncope, chest pain, arrhythmias, and serious adverse events. For the secondary outcomes, the DOSE-AGE trial will investigate the individual elements of the Modified Vesikari Scale score and caregiver satisfaction with the therapy. Discussion The DOSE-AGE trial will provide evidence on the effectiveness of multiple doses of oral ondansetron, taken as needed, following an initial ED dose in children with acute gastroenteritis-associated vomiting. The data from the DOSE-AGE trial will be analyzed using this SAP. This will reduce the risk of producing data-driven results and bias in our reported outcomes. The DOSE-AGE study was registered on ClinicalTrials.gov on February 22, 2019. Trial registration ClinicalTrials.gov NCT03851835 . Registered on 22 February 2019.

Ondansetron improves outcomes when administered in emergency departments to children with acute gastroenteritis-associated vomiting. It is commonly prescribed at discharge to reduce symptoms, but evidence to support this practice is limited. We conducted a double-blind, randomized superiority trial involving children 6 months to less than 18 years of age with acute gastroenteritis-associated vomiting in six pediatric emergency departments. Caregivers were provided with six doses of oral ondansetron or placebo to administer in response to ongoing vomiting during the first 48 hours after enrollment. The primary outcome was moderate-to-severe gastroenteritis, defined by a score of 9 or higher on the modified Vesikari scale (scores range from 0 to 20, with higher scores indicating greater severity), during the 7 days after enrollment. Secondary outcomes included the presence of vomiting, the duration of vomiting (defined as the time from enrollment to the last vomiting episode), the number of vomiting episodes within 48 hours after enrollment, unscheduled physician visits within 7 days after enrollment, and receipt of intravenous fluids. A total of 1030 children underwent randomization. Moderate-to-severe gastroenteritis occurred in 5.1% (23 of 452 participants for whom data were available) in the ondansetron group and 12.5% (55 of 441) in the placebo group (unadjusted risk difference, -7.4 percentage points; 95% confidence interval [CI], -11.2 to -3.7). After adjustment for site, weight, and missing data, ondansetron was associated with a lower risk of moderate-to-severe gastroenteritis than placebo (adjusted odds ratio, 0.50; 95% CI, 0.40 to 0.60). Although we did not observe any meaningful difference between the groups in the presence or median duration of vomiting, the total number of vomiting episodes within 48 hours after enrollment was lower with ondansetron than with placebo (adjusted rate ratio, 0.76; 95% CI, 0.67 to 0.87). The percentage of children who had unscheduled health care visits and the percentage who received intravenous fluids after enrollment did not differ substantially between the groups. The incidence of adverse events also did not differ meaningfully between the groups (odds ratio, 0.99; 95% CI, 0.61 to 1.61). Among children with gastroenteritis-associated vomiting, the provision of ondansetron after an emergency department visit led to lower risk of moderate-to-severe gastroenteritis during the subsequent 7 days than the provision of placebo. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT03851835.).

There is controversy about which children with minor head injury need to undergo computed tomography (CT). We aimed to develop a highly sensitive clinical decision rule for the use of CT in children with minor head injury. For this multicentre cohort study, we enrolled consecutive children with blunt head trauma presenting with a score of 13–15 on the Glasgow Coma Scale and loss of consciousness, amnesia, disorientation, persistent vomiting or irritability. For each child, staff in the emergency department completed a standardized assessment form before any CT. The main outcomes were need for neurologic intervention and presence of brain injury as determined by CT. We developed a decision rule by using recursive partitioning to combine variables that were both reliable and strongly associated with the outcome measures and thus to find the best combinations of predictor variables that were highly sensitive for detecting the outcome measures with maximal specificity. Among the 3866 patients enrolled (mean age 9.2 years), 95 (2.5%) had a score of 13 on the Glasgow Coma Scale, 282 (7.3%) had a score of 14, and 3489 (90.2%) had a score of 15. CT revealed that 159 (4.1%) had a brain injury, and 24 (0.6%) underwent neurologic intervention. We derived a decision rule for CT of the head consisting of four high-risk factors (failure to reach score of 15 on the Glasgow coma scale within two hours, suspicion of open skull fracture, worsening headache and irritability) and three additional medium-risk factors (large, boggy hematoma of the scalp; signs of basal skull fracture; dangerous mechanism of injury). The high-risk factors were 100.0% sensitive (95% CI 86.2%–100.0%) for predicting the need for neurologic intervention and would require that 30.2% of patients undergo CT. The medium-risk factors resulted in 98.1% sensitivity (95% CI 94.6%–99.4%) for the prediction of brain injury by CT and would require that 52.0% of patients undergo CT. The decision rule developed in this study identifies children at two levels of risk. Once the decision rule has been prospectively validated, it has the potential to standardize and improve the use of CT for children with minor head injury.