Multi-dose Oral Ondansetron for Pediatric Gastroenteritis: study Protocol for the multi-DOSE oral ondansetron for pediatric Acute GastroEnteritis (DOSE-AGE) pragmatic randomized controlled trial

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,(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

Dating of Bruises in Children: An Assessment of Physician Accuracy

Dating of Bruises in Methods. Children who presented to the emergency department of a children's hospital with accidental bruises of known age and origin had demographic data and information about their injury recorded. Historyblinded emergency pediatricians, other physicians, and trainees (fellows, residents, and medical students) independently examined the bruised area and recorded injury characteristics and age estimation and ranked characteristics that influenced their estimation. Results. Fifty children with accidental bruises were enrolled. Emergency pediatricians' accuracy of age estimation within 24 hours of actual age was 47.6%. Individual emergency pediatrician's accuracy ranged from 0% to 100%, and the interobserver reliability was poor ( ‫؍‬ ؊0.03). Accuracy within 24 hours of actual age was 29.4% for other physicians and 36.8% for trainees, which was similar to the emergency pediatricians. Observers reported using color primarily to estimate age, followed by tenderness and then swelling; however, none of these factors was significantly correlated with accuracy. Conclusions. Physician estimates of bruise age are highly inaccurate within 24 hours of the actual age of the injury. Large individual variability and poor interrater reliability also suggest that caution must be used when interpreting these estimates. This study supports earlier studies, urging extreme caution in estimating bruise age, even when such estimates are based on direct examination of the injured area. Pediatrics 2003;112:804 -807; children, bruising, abuse, emergency

A pragmatic randomized controlled trial of multi-dose oral ondansetron for pediatric gastroenteritis (the DOSE-AGE study): statistical analysis plan.

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

Innovative approaches to investigator-initiated, multicentre paediatric clinical trials in Canada

Data from clinical trials are needed to guide the safe and effective use of medicines in children. Clinical trials are challenging to design and implement in all populations, and children present additional considerations. Several regions including the UK, USA and Europe have established clinical trial infrastructure to capitalise on expertise and promote clinical trials enrolling children. Our objective is to describe the partnerships and operational considerations for the development of paediatric clinical trials infrastructure in Canada. We describe the design and conduct of four emergency room paediatric trials, with four separate sponsors, across four provinces in parallel. Operations discussed include multisite contract development, centralised risk-based data monitoring, ethical review and patient engagement. We conclude with lessons learnt, additional challenges and potential solutions to facilitate drug development for children in Canada

Quality of Reporting and Study Design of CKD Cohort Studies Assessing Mortality in the Elderly Before and After STROBE:A Systematic Review

BACKGROUND:The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement was published in October 2007 to improve quality of reporting of observational studies. The aim of this review was to assess the impact of the STROBE statement on observational study reporting and study design quality in the nephrology literature. STUDY DESIGN:Systematic literature review. SETTING & POPULATION:European and North American, Pre-dialysis Chronic Kidney Disease (CKD) cohort studies. SELECTION CRITERIA FOR STUDIES:Studies assessing the association between CKD and mortality in the elderly (>65 years) published from 1st January 2002 to 31st December 2013 were included, following systematic searching of MEDLINE & EMBASE. PREDICTOR:Time period before and after the publication of the STROBE statement. OUTCOME:Quality of study reporting using the STROBE statement and quality of study design using the Newcastle Ottawa Scale (NOS), Scottish Intercollegiate Guidelines Network (SIGN) and Critical Appraisal Skills Programme (CASP) tools. RESULTS:37 papers (11 Pre & 26 Post STROBE) were identified from 3621 potential articles. Only four of the 22 STROBE items and their sub-criteria (objectives reporting, choice of quantitative groups and description of and carrying out sensitivity analysis) showed improvements, with the majority of items showing little change between the period before and after publication of the STROBE statement. Pre- and post-period analysis revealed a Manuscript STROBE score increase (median score 77.8% (Inter-quartile range [IQR], 64.7-82.0) vs 83% (IQR, 78.4-84.9, p = 0.05). There was no change in quality of study design with identical median scores in the two periods for NOS (Manuscript NOS score 88.9), SIGN (Manuscript SIGN score 83.3) and CASP (Manuscript CASP score 91.7) tools. LIMITATIONS:Only 37 Studies from Europe and North America were included from one medical specialty. Assessment of study design largely reliant on good reporting. CONCLUSIONS:This study highlights continuing deficiencies in the reporting of STROBE items and their sub-criteria in cohort studies in nephrology. There was weak evidence of improvement in the overall reporting quality, with no improvement in methodological quality of CKD cohort studies between the period before and after publication of the STROBE statement

Adverse Events Related to Emergency Department Care: A Systematic Review

<div><p>Objective</p><p>To systematically review the literature regarding the prevalence, preventability, severity and types of adverse events (AE) in the Emergency Department (ED).</p><p>Methods</p><p>We systematically searched major bibliographic databases, relevant journals and conference proceedings, and completed reference reviews of primary articles. Observational studies (cohort and case-control), quasi-experimental (e.g. before/after) studies and randomized controlled trials, were considered for inclusion if they examined a broad demographic group reflecting a significant proportion of ED patients and described the proportion of AE. Studies conducted outside of the ED setting, those examining only a subpopulation of patients (e.g. a specific entrance complaint or receiving a specific intervention), or examining only adverse drug events, were excluded. Two independent reviewers assessed study eligibility, completed data extraction, and assessed study quality with the Newcastle Ottawa Scale.</p><p>Results</p><p>Our search identified 11,624 citations. Ten articles, representing eight observational studies, were included. Methodological quality was low to moderate with weaknesses in study group comparability, follow-up, and outcome ascertainment and reporting. There was substantial variation in the proportion of patients with AE related to ED care, ranging from 0.16% (n = 9308) to 6.0% (n = 399). Similarly, the reported preventability of AE ranged from 36% (n = 250) to 71% (n = 24). The most common types of events were related to management (3 studies), diagnosis (2 studies) and medication (2 studies).</p><p>Conclusions</p><p>The variability in findings and lack of high quality studies on AE in the high risk ED setting highlights the need for research in this area. Further studies with rigorous, standardized outcome assessment and reporting are required.</p></div

Summary of Quality Assessments.

1<p>Maximum of 4 stars for: representativeness of the exposed cohort; selection of the non-exposed cohort; ascertainment of exposure; and demonstration that outcome of interest was not present at start of study.</p>2<p>Maximum of 2 stars for: comparability of cohorts on the basis of the design or analysis.</p>3<p>Maximum of 3 stars for: assessment of outcome; was follow-up long enough for outcome to occur; and adequacy of follow-up of cohorts.</p><p>NR not reported.</p

PRISMA Diagram.

<p>PRISMA Diagram.</p

How Safe Are Common Analgesics for the Treatment of Acute Pain for Children? A Systematic Review

Background. Fear of adverse events and occurrence of side effects are commonly cited by families and physicians as obstructive to appropriate use of pain medication in children. We examined evidence comparing the safety profiles of three groups of oral medications, acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, to manage acute nonsurgical pain in children (ud_less_than18 years) treated in ambulatory settings. Methods. A comprehensive search was performed to July 2015, including review of national data registries. Two reviewers screened articles for inclusion, assessed methodological quality, and extracted data. Risks (incidence rates) were pooled using a random effects model. Results. Forty-four studies were included; 23 reported on adverse events. Based on limited current evidence, acetaminophen, ibuprofen, and opioids have similar nausea and vomiting profiles. Opioids have the greatest risk of central nervous system adverse events. Dual therapy with a nonopioid/opioid combination resulted in a lower risk of adverse events than opioids alone. Conclusions. Ibuprofen and acetaminophen have similar reported adverse effects and notably less adverse events than opioids. Dual therapy with a nonopioid/opioid combination confers a protective effect for adverse events over opioids alone. This research highlights challenges in assessing medication safety, including lack of more detailed information in registry data, and inconsistent reporting in trials.Peer Reviewe