Assessment of Usefulness of Randomized Control Trials in Child Health Research Published in 2007 and 2017.

OBJECTIVE: To examine how clinical usefulness in pediatric research with randomized controlled trials (RCTs) has changed over a 10-year period via a research usefulness tool composed of unique clinical usefulness criteria. STUDY DESIGN: We leveraged a pre-existing sample of child health RCTs published in 2007, used by our team in a previous study. Using the same methods, a research librarian executed a literature search in the Cochrane Central Register of Controlled Trials for the 2017 cohort. We included the first 300 eligible citations from the randomly ordered list for each year, creating two cohorts of 300 publications each, 1 in 2007 and 1 in 2017. Each publication was analyzed and data regarding primary and secondary outcomes, as well as 11 unique criteria of clinical usefulness, were extracted. Each publication was then graded using a tool created by our research team. After quality review, statistical analysis was then performed. RESULTS: Six hundred pediatric RCT publications were included in this review. The mean score increased from 6.07 in 2007 to 9.20 in 2017 (P < .001). Usefulness factors that saw the largest increase in reporting were context placement, funding statements, and conflict of interest statements, while patient centeredness, value for money, and raw data availability remained infrequently reported. CONCLUSION: Our results demonstrate that clinical usefulness of pediatric research improved over this 10-year period, but there are still areas that need a great deal of improvement in order to maximize clinical usefulness and reduce research waste.

A Decade of Efforts to Add Value to Child Health Research Practices.

OBJECTIVE: To identify practices that add value to improve the design, conduct, and reporting of child health research and reduce research waste. STUDY DESIGN: In order to categorize the contributions of members of Standards for Research (StaR) in Child Health network, we developed a novel Child Health Improving Research Practices (CHIRP) framework comprised of 5 domains meant to counteract avoidable child health research waste and improve quality: 1) address research questions relevant to children, their families, clinicians, and researchers; 2) apply appropriate research design, conduct and analysis; 3) ensure efficient research oversight and regulation; 4) Provide accessible research protocols and reports; and 5) develop unbiased and usable research reports, including 17 responsible research practice recommendations. All child health research relevant publications by the 48 original StaR standards' authors over the last decade were identified, and main topic areas were categorized using this framework. RESULTS: A total of 247 publications were included in the final sample: 100 publications (41%) in domain 1 (3 recommendations), 77 publications (31%) in domain 2 (3), 35 publications (14%) in domain 3 (4), 20 publications (8%) in domain 4 (4), and 15 publications (6%) in domain 5 (3). We identified readily implementable "responsible" research practices to counter child health research waste and improve quality, especially in the areas of patients and families' engagement throughout the research process, developing Core Outcome Sets, and addressing ethics and regulatory oversight issues. CONCLUSION: While most of the practices are readily implementable, increased awareness of methodological issues and wider guideline uptake is needed to improve child health research. The CHIRP Framework can be used to guide responsible research practices that add value to child health research.

Large Pediatric Randomized Clinical Trials in ClinicalTrials.gov.

BACKGROUND: Large, randomized controlled trials (RCTs) are essential in answering pivotal questions in child health. METHODS: We created a bird's eye view of all large, noncluster, nonvaccine pediatric RCTs with ≥1000 participants registered in ClinicalTrials.gov (last search January 9, 2020). We analyzed the funding sources, countries, outcomes, publication status, and correlation with the pediatric global burden of disease (GBD) for eligible trials. RESULTS: We identified 247 large, nonvaccine, noncluster pediatric RCTs. Only 17 mega-trials with ≥5000 participants existed. Industry funding was involved in only 52 (21%) and exclusively funded 47 (19%) trials. Participants were from high-income countries (HICs) in 100 (40%) trials, from lower-middle-income countries (LMICs) in 122 (49%) trials, and from both HICs and LMICs in 19 (8%) trials; 6 trials did not report participants' country location. Of trials conducted in LMIC, 43% of investigators were from HICs. Of non-LMIC participants trials (HIC or HIC and LMIC), 39% were multicountry trials versus 11% of exclusively LMIC participants trials. Few trials (18%; 44 of 247) targeted mortality as an outcome. 35% (58 of 164) of the trials completed ≥12 months were unpublished at the time of our assessment. The number of trials per disease category correlated well with pediatric GBD overall (ρ = 0.76) and in LMICs (ρ = 0.69), but not in HICs (ρ = 0.29). CONCLUSIONS: Incentivization of investigator collaborations across diverse country settings, timely publication of results of large pediatric RCTs, and alignment with the pediatric GBD are of pivotal importance to ultimately improve child health globally.

The Pediatric Emergency Research Network: A Decade of Global Research Cooperation in Pediatric Emergency Care.

OBJECTIVES: The Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in pediatric emergency care to organize globally for the conduct of collaborative research across networks. METHODS: The Pediatric Emergency Research Network has grown from 5- to 8-member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed, and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children. RESULTS: Beginning as a pandemic response with a high-quality retrospective case-controlled study of H1N1 influenza risk factors, PERN research has progressed to multiple observational studies and ongoing global randomized controlled trials. As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current coronavirus disease 2019 pandemic. In light of the ongoing need for translation of research knowledge into equitable clinical practice and to promote health equity, PERN is committed to a coordinated international effort to increase the uptake of evidence-based management of common and treatable acute conditions in all emergency department settings. CONCLUSIONS: The Pediatric Emergency Research Network's successes with global research, measured by prospective observational and interventional studies, mean that the network can now move to improve its ability to promote the implementation of scientific advances into everyday clinical practice. Achieving this goal will involve focus in 4 areas: (1) expanding the capacity for global randomized controlled trials; (2) deepening the focus on implementation science; (3) increasing attention to healthcare disparities and their origins, with growing momentum toward equity; and (4) expanding PERN's global reach through addition of sites and networks from resource-restricted regions. Through these actions, PERN will be able to build on successes to face the challenges ahead and meet the needs of acutely ill and injured children throughout the world.

P value and Bayesian analysis in randomized-controlled trials in child health research published over 10 years, 2007 to 2017: a methodological review protocol.

BACKGROUND: There is an unresolved debate about the reliability of the interpretation of P value. Some investigators have suggested that an alternative Bayesian method is preferred in conducting health research. As randomized-controlled trials (RCTs) are important in generating research evidence, we decided to investigate the extent, if any, the inferential statistical framework in published RCTs in child health research have changed over 10 years. We aim to examine the change in P value and Bayesian analysis in RCTs in child health research papers published from 2007 to 2017. METHODS: We will search the Cochrane Central Register of Controlled Trials (Wiley) to identify relevant citations. We will leverage a pre-existing sample of child health RCTs published in 2007 (n=300) used in our previous study of reporting quality of pediatric RCTs. Using the same strategy and study selection methods, we will identify a comparable random sample of child health RCTs published in 2017 (n=300). Eligible studies will include RCTs in health research among individuals aged 21 years and below. One reviewer will select studies for inclusion and extract the data and another reviewer will verify these. Disagreements will be resolved by a discussion between reviewers or by involving another reviewer. We will perform a descriptive analysis of 2007 and 2017 samples and analyze the results using both the frequentist and Bayesian methods. We will present specific characteristics of the clinical trials from 2007 and 2017 in tabular and graphical forms. We will report the difference in the proportion of P value and Bayesian analysis between 2007 and 2017 to assess the 10-year change. Clustering around P values of significance, if observed, will be reported. DISCUSSION: This review will present the difference in the proportion of trials that reported on P value and Bayesian analysis between 2007 and 2017 to assess the 10-year change. The implications for future clinical research will be discussed and this research work will be published in a peer-reviewed journal. This review has the potential to help inform the need for a change in the methodological approach from the null hypothesis significance test to Bayesian methods. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework https://osf.io/aj2df.

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, <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.

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.

Pediatric information seeking behaviour, information needs, and information preferences of health care professionals in general emergency departments: Results from the Translating Emergency Knowledge for Kids (TREKK) Needs Assessment.

The majority of children requiring emergency care are treated in general emergency departments (EDs) with variable levels of pediatric care expertise. The goal of the Translating Emergency Knowledge for Kids (TREKK) initiative is to implement the latest research in pediatric emergency medicine in general EDs to reduce clinical variation. OBJECTIVES: To determine national pediatric information needs, seeking behaviours, and preferences of health care professionals working in general EDs. METHODS: An electronic cross-sectional survey was conducted with health care professionals in 32 Canadian general EDs. Data were collected in the EDs using the iPad and in-person data collectors. RESULTS: Total of 1,471 surveys were completed (57.1% response rate). Health care professionals sought information on children's health care by talking to colleagues (n=1,208, 82.1%), visiting specific medical/health websites (n=994, 67.7%), and professional development opportunities (n=941, 64.4%). Preferred child health resources included protocols and accepted treatments for common conditions (n=969, 68%), clinical pathways and practice guidelines (n=951, 66%), and evidence-based information on new diagnoses and treatments (n=866, 61%). Additional pediatric clinical information is needed about multisystem trauma (n=693, 49%), severe head injury (n=615, 43%), and meningitis (n=559, 39%). Health care professionals preferred to receive child health information through professional development opportunities (n=1,131, 80%) and printed summaries (n=885, 63%). CONCLUSION: By understanding health care professionals' information seeking behaviour, information needs, and information preferences, knowledge synthesis and knowledge translation initiatives can be targeted to improve pediatric emergency care. The findings from this study will inform the following two phases of the TREKK initiative to bridge the research-practice gap in Canadian general EDs.

Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial.

BACKGROUND: The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for 'point of care' management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. DESIGN/METHODS: We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma--the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis--the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process evaluation to assess the implementation strategy and an economic analysis to evaluate implementation costs and benefits. DISCUSSION: This study will contribute to the body of evidence supporting effective strategies for clinical pathway implementation, and ultimately reducing the research to practice gaps by operationalizing best evidence care recommendations through effective use of clinical pathways. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01815710.

Do health care institutions value research? A mixed methods study of barriers and facilitators to methodological rigor in pediatric randomized trials.

BACKGROUND: Pediatric randomized controlled trials (RCTs) are susceptible to a high risk of bias. We examined the barriers and facilitators that pediatric trialists face in the design and conduct of unbiased trials. METHODS: We used a mixed methods design, with semi-structured interviews building upon the results of a quantitative survey. We surveyed Canadian (n=253) and international (n=600) pediatric trialists regarding their knowledge and awareness of bias and their perceived barriers and facilitators in conducting clinical trials. We then interviewed 13 participants from different subspecialties and geographic locations to gain a more detailed description of how their experiences and attitudes towards research interacted with trial design and conduct. RESULTS: The survey response rate was 23.0% (186/807). 68.1% of respondents agreed that bias is a problem in pediatric RCTs and 72.0% felt that there is sufficient evidence to support changing some aspects of how trials are conducted. Knowledge related to bias was variable, with inconsistent awareness of study design features that may introduce bias into a study. Interview participants highlighted a lack of formal training in research methods, a negative research culture, and the pragmatics of trial conduct as barriers. Facilitators included contact with knowledgeable and supportive colleagues and infrastructure for research. CONCLUSIONS: A lack of awareness of bias and negative attitudes towards research present significant barriers in terms of conducting methodologically rigorous pediatric RCTs. Knowledge translation efforts must focus on these issues to ensure the relevance and validity of trial results.

Cost-effectiveness of epinephrine and dexamethasone in children with bronchiolitis.

OBJECTIVE: Using data from the Canadian Bronchiolitis Epinephrine Steroid Trial we assessed the cost-effectiveness of treatments with epinephrine and dexamethasone for infants between 6 weeks and 12 months of age with bronchiolitis. METHODS: An economic evaluation was conducted from both the societal and health care system perspectives including all costs during 22 days after enrollment. The effectiveness of therapy was measured by the duration of symptoms of feeding problems, sleeping problems, coughing, and noisy breathing. Comparators were nebulized epinephrine plus oral dexamethasone, nebulized epinephrine alone, oral dexamethasone alone, and no active treatment. Uncertainty around estimates was assessed through nonparametric bootstrapping. RESULTS: The combination of nebulized epinephrine plus oral dexamethasone was dominant over the other 3 comparators in that it was both the most effective and least costly. Average societal costs were $1115 (95% credible interval [CI]: 919-1325) for the combination therapy, $1210 (95% CI: 1004-1441) for no active treatment, $1322 (95% CI: 1093-1571) for epinephrine alone, and $1360 (95% CI: 1124-1624) for dexamethasone alone. The average time to curtailment of all symptoms was 12.1 days (95% CI: 11-13) for the combination therapy, 12.7 days (95% CI: 12-13) for no active treatment, 13.0 days (95% CI: 12-14) for epinephrine alone, and 12.6 days (95% CI: 12-13) for dexamethasone alone. CONCLUSION: Treating infants with bronchiolitis with a combination of nebulized epinephrine plus oral dexamethasone is the most cost-effective treatment option, because it is the most effective in controlling symptoms and is associated with the least costs.

Risk of bias versus quality assessment of randomised controlled trials: cross sectional study.

OBJECTIVES: To evaluate the risk of bias tool, introduced by the Cochrane Collaboration for assessing the internal validity of randomised trials, for inter-rater agreement, concurrent validity compared with the Jadad scale and Schulz approach to allocation concealment, and the relation between risk of bias and effect estimates. DESIGN: Cross sectional study. Study sample 163 trials in children. MAIN OUTCOME MEASURES: Inter-rater agreement between reviewers assessing trials using the risk of bias tool (weighted kappa), time to apply the risk of bias tool compared with other approaches to quality assessment (paired t test), degree of correlation for overall risk compared with overall quality scores (Kendall's tau statistic), and magnitude of effect estimates for studies classified as being at high, unclear, or low risk of bias (metaregression). RESULTS: Inter-rater agreement on individual domains of the risk of bias tool ranged from slight (kappa=0.13) to substantial (kappa=0.74). The mean time to complete the risk of bias tool was significantly longer than for the Jadad scale and Schulz approach, individually or combined (8.8 minutes (SD 2.2) per study v 2.0 (SD 0.8), P<0.001). There was low correlation between risk of bias overall compared with the Jadad scores (P=0.395) and Schulz approach (P=0.064). Effect sizes differed between studies assessed as being at high or unclear risk of bias (0.52) compared with those at low risk (0.23). CONCLUSIONS: Inter-rater agreement varied across domains of the risk of bias tool. Generally, agreement was poorer for those items that required more judgment. There was low correlation between assessments of overall risk of bias and two common approaches to quality assessment: the Jadad scale and Schulz approach to allocation concealment. Overall risk of bias as assessed by the risk of bias tool differentiated effect estimates, with more conservative estimates for studies at low risk.

The influence of display and statistical factors on the interpretation of metaanalysis results by physicians.

OBJECTIVE: The objective of this study was to determine the extent to which various factors affect the interpretation of metaanalytic results by physicians. STUDY DESIGN: A sample of 120 physicians, selected from The Royal College of Physicians and Surgeons of Canada (RCPSC), was randomly assigned to 1 of 6 groups (n = 20) created from a combination of 3 summary measures and 2 levels of disease severity. The intervention consisted of a written scenario and 4 individual displays of metaanalyses (M-A), each followed by questions related to the interpretation of results of M-A. Two final questions examined statistical familiarity/proficiency with the summary measures used. DATA ANALYSIS: Analyses of variance examined main effects and interactions among 4 factors: summary measure, disease severity, effect size, and statistical consistency of the studies comprising the metaanalysis. Two outcomes were examined: interpretation of the treatment effect and confidence in the interpretation of the treatment effect. PRINCIPAL FINDINGS: Physicians were more likely to favor treatment when the results of the primary randomized, controlled trials (RCTs) were statistically homogeneous (P = 0.001) and when the overall effect size was large (P = 0.001). Also, physicians were more likely to be confident when the results were homogeneous (P = 0.001) and when effect size was large (P = 0.000). Interactions also revealed that the effect of statistical consistency of contributing to RCTs was greatest when data were presented as risk difference for treatment outcome (P = 0.026) and when effect size was small (P = 0.000). CONCLUSIONS: The interpretation of metaanalytic displays is influenced by the overall effect size of M-A, the statistical consistency of the contributing RCTs, and interactions of these factors with display factors.

A randomized trial of a single dose of oral dexamethasone for mild croup.

BACKGROUND: The benefits of dexamethasone treatment for moderate-to-severe croup are well established. However, most children with croup have mild symptoms, and it is unknown whether they would derive the same degree of benefit from dexamethasone treatment as children with more severe disease. METHODS: We conducted a double-blind trial at four pediatric emergency departments in which 720 children with mild croup were randomly assigned to receive one oral dose of either dexamethasone (0.6 mg per kilogram of body weight) or placebo. The children had mild croup, as defined by a score of < or =2 on the croup scoring system of Westley et al. The primary outcome was a return to a medical care provider for croup within seven days after treatment. The secondary outcome was the presence of ongoing symptoms of croup on days 1, 2, and 3 after treatment. Other outcomes included economic costs, hours of sleep lost by the child, and stress on the part of the parent in relation to the child's illness. RESULTS: Baseline clinical characteristics were similar in the two groups. Return to medical care was significantly lower in the dexamethasone group (7.3 percent vs. 15.3 percent, P<0.001). In the dexamethasone group, there was quicker resolution of croup symptoms (P=0.003), less lost sleep (P<0.001), and less stress on the part of the parent (P<0.001). CONCLUSIONS: For children with mild croup, dexamethasone is an effective treatment that results in consistent and small but important clinical and economic benefits. Although the long-term effects of this treatment are not known, our data support the use of dexamethasone in most, if not all, children with croup.

Evidence-based prescribing of antibiotics for children: role of socioeconomic status and physician characteristics.

BACKGROUND: Evidence-based guidelines for antibiotic use are well established, but nonadherence to these guidelines continues. This study was undertaken to determine child, household and physician factors predictive of nonadherence to evidence-based antibiotic prescribing in children. METHODS: The prescription and health care records of 20 000 Manitoba children were assessed for 2 criteria of nonadherence to evidence-based antibiotic prescribing during the period from fiscal year 1996 (April 1996 to March 1997) to fiscal year 2000: receipt of an antibiotic for a viral respiratory tract infection (VRTI) and initial use of a second-line agent for acute otitis media, pharyngitis, pneumonia, urinary tract infection or cellulitis. The likelihood of nonadherence to evidence-based prescribing, according to child demographic characteristics, physician factors (specialty and place of training) and household income, was determined from hierarchical linear modelling. Child visits were nested within physicians, and the most parsimonious model was selected at p < 0.05. RESULTS: During the study period, 45% of physician visits for VRTI resulted in an antibiotic prescription, and 20% of antibiotic prescriptions were for second-line antibiotics. Relative to general practitioners, the odds ratio for antibiotic prescription for a VRTI was 0.51 (95% confidence interval [CI] 0.42-0.62) for pediatricians and 1.58 (95% CI 1.03-2.42) for other specialists. The likelihood that an antibiotic would be prescribed for a VRTI was 0.99 for each successive 10,000 Canadian dollars increase in household income. Pediatricians and other specialists were more likely than general practitioners to prescribe second-line antibiotics for initial therapy. Both criteria for nonadherence to evidence-based prescribing were 40% less likely among physicians trained in Canada or the United States than among physicians trained elsewhere. INTERPRETATION: The links that we identified between nonadherence to evidence-based antibiotic prescribing in children and physician specialty and location of training suggest opportunities for intervention. The independent effect of household income indicates that parents also have an important role.