Introduction
Evidence from randomized controlled trials (RCTs) is required to guide treatment of critically ill children. There are fewer RCTs in pediatrics when compared to adult medicine; in reviews of RCTs published in general and specialist medical journals only 14% of trials enrolled exclusively children [
1,
2]. Moreover, while the methodological quality of pediatric RCTs appears to be improving, 37 to 59% were still at high risk of bias [
3‐
5]. Finally, the focus of published pediatric RCTs may not align with the frequency or importance of the conditions seen in clinical practice. For example, in pediatric primary care there is discordance between the conditions studied and the frequency seen in clinical practice: 23% of Cochrane systematic reviews relevant to pediatrics focused on asthma, which represents 3 to 5% of children’s primary care visits [
6].
The extent of these challenges in pediatric critical care has not previously been examined. An example from critical care is the Surviving Sepsis Campaign’s International Guidelines for Management of Severe Sepsis and Septic Shock [
7]. These guidelines highlight the limited quality of evidence available in pediatric critical care to support clinical decision-making. The consensus committee was able to make 76 recommendations for adults, but only 22 pediatric-specific recommendations. Not only are there fewer pediatric recommendations, but the quality of the evidence informing these pediatric recommendations is lower; 3 (14%) of the pediatric recommendations were supported by high/moderate evidence as compared to 41 (54%) of those for adults.
To effectively apply the results of pediatric critical care RCTs, it is imperative that clinicians can easily and efficiently find these publications. However, clinicians are not typically trained to conduct the complex literature searches required to find pediatric RCTs; even a highly specific search strategy yielded only 56% of citations relevant to children [
8]. Challenges in locating relevant pediatric RCTs are likely to increase as the number of adult RCTs increases faster than the number of pediatric RCTs in both general medical journals (4.7 RCTs per year vs. 0.4 RCTs per year) and in specialist journals (91 RCTs per year vs. 17 RCTs per year) [
1,
2]. There also are few tools, resources or reviews to help clinicians quickly access or identify the available RCTs in pediatric critical care.
A scoping review systematically maps a broad and diverse body of research evidence [
9]. We conducted this scoping review to systematically identify and describe RCTs in pediatric critical care and make them readily accessible to clinicians and researchers.
Discussion
Scoping reviews can be used ‘to examine the extent, range, and nature of research activity; to determine the value for undertaking a full systematic review; to summarize and disseminate research findings; and to identify research gaps in the existing literature’ [
16]. In this scoping review we found 248 pediatric critical care RCTs, from 31 countries, published in 7 languages over 28 years. The majority of these RCTs were single-centered, focused on intermediate or surrogate outcomes and were small in sample size. Important aspects of their methodology and reporting remain less than optimal. As part of this review we have created a publicly accessible online database of these trials including key methodological features and links to the original reports [
17].
There are gaps in the body of pediatric critical care RCT research. For example, rehabilitation and the needs of parents coping with their child’s illness are relevant for almost all critically ill children, yet there are only two trials focusing on each of these. Similarly, pharmacological interventions were studied in the majority of RCTs; although 27% of RCTs studied devices, there were no trials focused on renal replacement therapy or extracorporal membrane oxygenation. Pediatric critical care clinicians, researchers and decision-makers can use the results of this review as part of a process to evaluate unmet needs and set research priorities, both in terms of the focus and design of additional RCTs and other research designs. There are also important limitations to the reporting of these trials; for example, only two-thirds reported the primary outcome and less than half reported the planned sample size or the funding source.
When compared to the findings of a random sample of 300 pediatric RCTs published in 2007, pediatric critical care RCTs were less frequently multicentered (18% vs. 35%), randomized fewer children (median 49 vs. 83), and had a lower proportion assessed as having a low risk of bias (4% vs. 8%) [
5]. Pediatric critical care RCTs are also smaller and less common than adult critical care RCTs. A systematic review of adult critical care RCTs with clinical or economic primary outcomes published in 16 prominent journals included 127 RCTs published between 2007 and 2012 [
18]. We identified 79 pediatric RCTs over the same time period. Compared to these adult RCTs, pediatric RCTs randomized fewer participants (mean 109 vs. 519), and were less frequently multicentered (18% vs. 60%). Another systematic review of RCTs evaluating nutritional interventions in critically ill adults included 207 RCTs randomizing a mean of 112 adults in the period 1980 to 2008 [
19]. Using similar criteria, we found 17 trials randomizing a mean of 48 children in the same time period.
We found that pediatric RCTs are generally small, single-centered, and primarily measured short-term laboratory and physiological outcomes. This raises two important issues for clinicians, researchers and funding agencies to consider. The first question is whether or not the small sample size matters: were these studies able to definitively answer the question posed? This is unclear for many trials included in this review as 57% did not report the planned sample size. The second question is did these trials use appropriate outcome measures? Trials focusing on surrogate or intermediate outcomes can be used to inform the design and conduct of future studies using patient-important outcomes or when a trial with patient-important outcomes is not feasible [
20]. Further research should focus on assessing if these RCTs lead to subsequent trials focusing on patient-important outcomes or if the outcomes used are indeed appropriate surrogates for more patient-important outcomes [
21]. If many trials are indeed too small to generate clear results, further research needs to be done to identify the barriers to conducting larger trials and methods to overcome this limitation. A previous mixed-methods study of pediatric trialists identified a lack of research training, negative research culture and logistical challenges as barriers to conducting methodologically rigorous pediatric RCTs [
22]. One important factor we identified is certainly feasibility, as 27 trials in this review (11% of all trials, 22% of those reporting an
a priori sample size) were stopped early for reasons such as enrollment challenges or futility.
Strengths include the comprehensive search strategy to identify relevant trials and incorporation of trials published in any language. For each study we assessed the clinical and methodological features, and the completeness and transparency of reporting. We have also made publicly available data from the included trials and links to the full-text publications [
17]. This is updated quarterly. The public availability of the results of this scoping review increases the ability of clinicians and pediatric critical care researchers to easily access pre-appraised, relevant RCTs. Finally, by synthesizing the methodological features of, and identifying gaps in, the body of pediatric critical care research, it will allow researchers and funding agencies to prioritize trial designs to fill the gaps we identify in the conditions studied, trial methods, interventions, and the outcomes assessed.
This scoping review has some limitations. The relevance of this review to clinicians in some resource-limited areas may be limited, as a priori, we excluded trials that were conducted in settings where mechanical ventilation was not available. We limited this review to RCTs conducted in a pediatric ICU and acknowledge that that some trials conducted in other populations such as critically ill adults or neonates, or in other settings such as prehospital, the emergency department, or the operating room may also inform the care of children in the ICU. Our objective in this review was to identify and describe pediatric critical care RCTs. Other research designs are also relevant to pediatric critical care practice, but are beyond the scope of a single review to include all the potentially relevant research. To focus on trials most likely to inform clinical practice and to improve the feasibility of this review we also excluded individual patient crossover trials.
Acknowledgments
We thank Alonso Carrasco, Rita Chan, France Clarke, Cynthia Cupido, Ian Hanney, Atsushi Kawano, Harry Kawano, Norma Marchetti, Madison Zhang, Dave Zorko and Nicole Zytaruk for their assistance with this review and with non-English studies.
Funding
This study was funded by the Canadian Institutes of Health Research. The funding body had no role in the writing of the manuscript or in the decision to submit the manuscript for publication. Mark Duffett holds a Fellowship and Deborah J Cook holds a Research Chair,both from the Canadian Institutes of Health.
Competing interests
The authors have no competing financial or nonfinancial interests with this study.
Authors’ contributions
MD conceived of and coordinated this study, participated in its design and data collection, performed the analysis, and drafted the manuscript. KC participated in the design, data collection and helped to draft the manuscript. LH participated in the design, data collection and helped to draft the manuscript. KM participated in the design, data collection and helped to draft the manuscript. LT participated in the design, provided statistical expertise and helped to draft the manuscript. DC participated in the design, data collection and helped to draft the manuscript. All authors read and approved the final manuscript.