Treatment Fidelity in 94 Randomized Controlled Trials of Physical Rehabilitation in the ICU: A Scoping Review.

OBJECTIVES: Recent reviews demonstrated discordant effects of ICU-based physical rehabilitation on physical function. These inconsistencies may be related to differences in treatment fidelity-the extent to which a protocol is delivered as planned. Before evaluating the association of fidelity with outcomes, we must first understand the extent of treatment fidelity reporting in ICU-based physical rehabilitation randomized controlled trials (RCTs). DATA SOURCES: Six electronic databases from inception to December 2022. STUDY SELECTION: We included RCTs enrolling adults or children admitted to the ICU, if greater than or equal to 50% were invasively mechanically ventilated greater than 24 hours, and underwent an ICU-based physical rehabilitation intervention, with no limitation to comparators or outcomes. DATA EXTRACTION: We screened and extracted data independently and in duplicate, with a third reviewer as needed. Extracted data included study characteristics, treatment descriptions, and the presence of National Institutes of Health Behaviour Change Consortium (NIH-BCC) treatment fidelity tool components. Treatment fidelity scores were calculated as the proportion of reported (numerator) out of total NIH-BCC components (denominator). We calculated scores across studies and by treatment group (intervention vs. comparator). We used linear regression to assess for a time trend in study treatment fidelity scores. DATA SYNTHESIS: Of 20,433 citations, 94 studies met inclusion criteria. Authors reported a median (first-third quartiles) of 19% (14-26%) of treatment fidelity components across studies. Intervention group scores were higher than comparator groups (24% [19-33%] vs. 14% [5-24%], p < 0.01). We found a mean increase in study treatment fidelity scores by 0.7% (0.3 points) per year. CONCLUSIONS: Only 19% of treatment fidelity components were reported across studies, with comparator groups more poorly reported. Future research could investigate ways to optimize treatment fidelity reporting and determine characteristics associated with treatment fidelity conduct in ICU-based physical rehabilitation RCTs.

Pharmacological agents for procedural sedation and analgesia in the emergency department and intensive care unit: a systematic review and network meta-analysis of randomised trials.

BACKGROUND: We aimed to evaluate the comparative effectiveness and safety of various i.v. pharmacologic agents used for procedural sedation and analgesia (PSA) in the emergency department (ED) and ICU. We performed a systematic review and network meta-analysis to enable direct and indirect comparisons between available medications. METHODS: We searched Medline, EMBASE, Cochrane, and PubMed from inception to 2 March 2023 for RCTs comparing two or more procedural sedation and analgesia medications in all patients (adults and children >30 days of age) requiring emergent procedures in the ED or ICU. We focused on the outcomes of sedation recovery time, patient satisfaction, and adverse events (AEs). We performed frequentist random-effects model network meta-analysis and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty in estimates. RESULTS: We included 82 RCTs (8105 patients, 78 conducted in the ED and four in the ICU) of which 52 studies included adults, 23 included children, and seven included both. Compared with midazolam-opioids, recovery time was shorter with propofol (mean difference 16.3 min, 95% confidence interval [CI] 8.4-24.3 fewer minutes; high certainty), and patient satisfaction was better with ketamine-propofol (mean difference 1.5 points, 95% CI 0.3-2.6 points, high certainty). Regarding AEs, compared with midazolam-opioids, respiratory AEs were less frequent with ketamine (relative risk [RR] 0.55, 95% CI 0.32-0.96; high certainty), gastrointestinal AEs were more common with ketamine-midazolam (RR 3.08, 95% CI 1.15-8.27; high certainty), and neurological AEs were more common with ketamine-propofol (RR 3.68, 95% CI 1.08-12.53; high certainty). CONCLUSION: When considering procedural sedation and analgesia in the ED and ICU, compared with midazolam-opioids, sedation recovery time is shorter with propofol, patient satisfaction is better with ketamine-propofol, and respiratory adverse events are less common with ketamine.

Ketamine sedation in the intensive care unit: a survey of Canadian intensivists.

PURPOSE: We sought to understand the beliefs and practices of Canadian intensivists regarding their use of ketamine as a sedative in critically ill patients and to gauge their interest in a randomized controlled trial (RCT) examining its use in the intensive care unit (ICU). METHODS: We designed and validated an electronic self-administered survey examining the use of ketamine as a sedative infusion for ICU patients. We surveyed 400 physician members of the Canadian Critical Care Society (CCCS) via email between February and April 2022 and sent three reminders at two-week intervals. The survey was redistributed in January 2023 to improve the response rate. RESULTS: We received 87/400 (22%) completed questionnaires. Most respondents reported they rarely use ketamine as a continuous infusion for sedation or analgesia in the ICU (52/87, 58%). Physicians reported the following conditions would make them more likely to use ketamine: asthma exacerbation (73/87, 82%), tolerance to opioids (68/87, 77%), status epilepticus (44/87, 50%), and severe acute respiratory distress syndrome (33/87, 38%). Concern for side-effects that limited respondents' use of ketamine include adverse psychotropic effects (61/87, 69%) and delirium (47/87, 53%). The majority of respondents agreed there is need for an RCT to evaluate ketamine as a sedative infusion in the ICU (62/87, 71%). CONCLUSION: This survey of Canadian intensivists illustrates that use of ketamine as a continuous infusion for sedation is limited, and is at least partly driven by concerns of adverse psychotropic effects. Canadian physicians endorse the need for a trial investigating the safety and efficacy of ketamine as a sedative for critically ill patients.

RéSUMé: OBJECTIF: Nous avons cherché à comprendre les croyances et les pratiques des intensivistes pratiquant au Canada concernant leur utilisation de la kétamine comme sédatif chez la patientèle gravement malade et à évaluer leur intérêt pour une étude randomisée contrôlée (ERC) examinant son utilisation à l'unité de soins intensifs (USI). MéTHODE: Nous avons mis au point et validé un sondage électronique auto-administré examinant l'utilisation de la kétamine comme perfusion sédative pour les patient·es aux soins intensifs. Nous avons envoyé le sondage à 400 médecins membres de la Société canadienne de soins intensifs (SCCC) par courriel entre février et avril 2022 et envoyé trois rappels à intervalles de deux semaines. Le sondage a été redistribué en janvier 2023 afin d'améliorer le taux de réponse. RéSULTATS: Nous avons reçu 87 questionnaires remplis sur 400 (22 %). La plupart des personnes répondantes ont déclaré qu'elles utilisaient rarement la kétamine en perfusion continue pour la sédation ou l'analgésie à l'USI (52/87, 58 %). Les médecins ont déclaré que les conditions suivantes les rendraient plus susceptibles d'utiliser de la kétamine : une exacerbation de l'asthme (73/87, 82 %), une tolérance aux opioïdes (68/87, 77 %), un état de mal épileptique (44/87, 50 %) et un syndrome de détresse respiratoire aigu (33/87, 38 %). Les inquiétudes quant aux effets secondaires qui ont limité l'utilisation de la kétamine par les répondant·es comprennent les effets psychotropes indésirables (61/87, 69 %) et le delirium (47/87, 53 %). La majorité des personnes répondantes étaient d'accord qu'une ERC est nécessaire pour évaluer la kétamine en tant que perfusion sédative à l'USI (62/87, 71 %). CONCLUSION: Cette enquête menée auprès d'intensivistes au Canada montre que l'utilisation de la kétamine comme perfusion continue pour la sédation est limitée, au moins en partie en raison d'inquiétudes liées aux effets psychotropes indésirables. Les médecins pratiquant au Canada reconnaissent la nécessité d'une étude sur l'innocuité et l'efficacité de la kétamine comme sédatif pour la patientèle gravement malade.

Levetiracetam Versus Phenytoin or Fosphenytoin for Second-Line Treatment of Pediatric Status Epilepticus: A Meta-Analysis.

OBJECTIVE: To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus. DATA SOURCES: We searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Two reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials. DATA EXTRACTION AND SYNTHESIS: Independently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively. RESULTS: We identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69). CONCLUSIONS: The efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.

Gender and Authorship in Pediatric Critical Care Randomized Control Trials.

OBJECTIVES: To examine the gender distribution of authorship of pediatric critical care randomized control trials. DATA SOURCES: The 415 randomized control trials in pediatric critical care published before 2019. STUDY SELECTION: We included all randomized control trials enrolling children in a PICU. We used PICUtrials.net, which uses comprehensive search strategies of multiple databases, to identify published randomized control trials. DATA EXTRACTION: We manually extracted the name and profession of each listed author from each publication and classified each author as male or female based on their name. RESULTS: We included 2,146 authors and were able to classify 1,888 (88%) as men or women. Overall, 38% of authors were women, this varied with the authorship position: 37% of first, 38% of middle, and 25% of last authors were women (p < 0.001). The three most common professions were physician (63%), nonclinician (11%), and nurse (6%)-of which 30%, 45%, and 97%, respectively, were women. The percentage of female authorship overall has increased from 28% in 1985-1989 to 39% in 2015-2018 (p for trend = 0.004). There were no significant differences in the characteristics of randomized control trials published with a female first or last author versus those with both male first and last authors with respect to the median number of children randomized (60 vs. 50; p = 0.41), multicentred trials (17% vs. 24%; p = 0.12), trials at low risk of bias (50% vs. 66%; p = 0.26), reporting any funding (55% vs. 51%; p = 0.66), or median number of citations per year (1.5 vs. 2.4; p = 0.09). CONCLUSIONS: Although increasing over time, the percentage of researchers publishing pediatric critical care randomized control trials who are women still lags behind the percentage clinicians who are women. Trials that female researchers publish are similar in characteristics and impact as male researchers. Further work should identify barriers to gender diversity and potential solutions in pediatric critical care research.

Research Collaboration in Pediatric Critical Care Randomized Controlled Trials: A Social Network Analysis of Coauthorship.

OBJECTIVES: Clinical research is a collaborative enterprise; researchers benefit from the expertise, experience, and resources of their collaborators. We sought to describe the extent and patterns of collaboration among pediatric critical care trialists, and to identify the most influential individuals, centers, and countries. DESIGN: Social network analysis of coauthorship. DATA SOURCES: Publications of pediatric critical care randomized controlled trials (1986-2018). DATA EXTRACTION: We manually extracted the names of all authors and their affiliations. We used productivity (number of randomized controlled trials), influence (number of citations), and four measures of prominence in the social network (degree, betweenness, closeness, and eigenvector centrality) to identify the most influential individuals. MEASUREMENTS AND MAIN RESULTS: From 415 randomized controlled trials in pediatric critical care, we identified 2,176 trialists from 377 centers in 43 countries. The coauthorship network is highly disconnected and dominated by a single large cluster of trialists publishing 142 (34%) of the randomized controlled trials. However, 119 (29%) of the randomized controlled trials were published by 28 smaller clusters-a median (interquartile range) of 3 (2-4) randomized controlled trials each. The remaining 154 (37%) randomized controlled trials were coauthored by researchers publishing a single randomized controlled trial each. This overall structure has remained constant with the publication of new randomized controlled trials over 33 years. The most influential trialists and centers varied according to the metric we used; only one trialist and three centers ranked in the top 10 for all measures of influence. Thirty-five of the 40 trialists (88%) ranking in the top 10 of any of the measures were from the United States, the United Kingdom, and Canada. CONCLUSIONS: Pediatric critical care has made considerable progress in the number of trialists and randomized controlled trials, but the research enterprise remains highly clustered and fragmented, particularly geographically. Efforts to further increase the quantity and quality of research in the field should include steps to increase the level and range of collaboration.

Stress Ulcer Prophylaxis in Critically Ill Children: A Multicenter Observational Study.

OBJECTIVE: To describe current stress ulcer prophylaxis practice in Canadian PICUs. DESIGN: Multicenter cohort study. We defined stress ulcer prophylaxis as the use of a proton-pump inhibitor, histamine-2 receptor antagonist, or sucralfate within the first 2 PICU days among children who had not been on these medications at home and had no evidence of gastrointestinal bleeding. SETTING: Seven PICUs in Canada. PATIENTS: Three hundred seventy-eight children requiring mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children were ventilated for a median (interquartile range) of 2 days (1-6 d) and stayed in the PICU for a median (interquartile range) of 4 days (2-10 d). The median (interquartile range) age was 1.3 years (0.3-6.7 yr). Seventy percent of all children received acid suppression during their PICU stay. One hundred sixty-seven (54%) of the 309 children eligible for stress ulcer prophylaxis received it. Histamine-2 receptor antagonists were the most frequently used class (66%), followed by proton-pump inhibitors (47%) and sucralfate (4%), and 20% received more than one class. Stress ulcer prophylaxis was continued on the PICU transfer orders for 34% of these children. Children who received prophylaxis were older and had a higher Pediatric Risk of Mortality III score, more often received nonsteroidal anti-inflammatory drugs and systemic corticosteroids and received less enteral nutrition. In multivariate analysis, age and invasive mechanical ventilation were independently associated with an increased likelihood of receiving stress ulcer prophylaxis and receiving feeds was independently associated with a decreased likelihood of receiving stress ulcer prophylaxis. Gastrointestinal bleeding was reported in 21 (6%) of 378 children; three (0.8%) were clinically important. Eighteen percent were treated for a new respiratory tract infection, and 1% developed Clostridium difficile-associated diarrhea. CONCLUSIONS: Stress ulcer prophylaxis is common in Canadian PICUs. Clinically important gastrointestinal bleeding and C. difficile-associated diarrhea are rare, and the utility of routine prophylaxis should be examined.

Occupational Therapy in the ICU: A Scoping Review of 221 Documents.

OBJECTIVES: Occupational therapists have specialized expertise to enable people to perform meaningful "occupations" that support health, well-being, and participation in life roles. Given the physical, cognitive, and psychologic disability experienced by ICU survivors, occupational therapists could play an important role in their recovery. We conducted a scoping review to determine the state of knowledge of interventions delivered by occupational therapists in adult ICU patients. DATA SOURCES: Eight electronic databases from inception to 05/2018. STUDY SELECTION: We included reports of adult patients receiving direct patient care from an occupational therapist in the ICU, all study designs, and quantitative and qualitative traditions. DATA EXTRACTION: Independently in duplicate, interprofessional team members screened titles, abstracts, and full texts and extracted report and intervention characteristics. From original research articles, we also extracted study design, number of patients, and primary outcomes. We resolved disagreements by consensus. DATA SYNTHESIS: Of 50,700 citations, 221 reports met inclusion criteria, 74 (79%) published after 2010, and 125 (56%) appeared in critical care journals. The three most commonly reported types of interventions were mobility (81%), physical rehabilitation (61%), and activities of daily living (31%). We identified 46 unique original research studies of occupational therapy interventions; the most common study research design was before-after studies (33%). CONCLUSIONS: The role of occupational therapists in ICU rehabilitation is not currently well established. Current interventions in the ICU are dominated by physical rehabilitation with a growing role in communication and delirium prevention and care. Given the diverse needs of ICU patients and the scope of occupational therapy, there could be an opportunities for occupational therapists to expand their role and spearhead original research investigating an enriched breadth of ICU interventions.

PICU-Based Rehabilitation and Outcomes Assessment: A Survey of Pediatric Critical Care Physicians.

OBJECTIVES: Characterize current practices for PICU-based rehabilitation, and physician perceptions and attitudes, barriers, resources, and outcome assessment in contemporary PICU settings. DESIGN: International, self-administered, quantitative, cross-sectional survey. SETTING: Online survey distributed from March 2017 to April 2017. PATIENTS OR SUBJECTS: Pediatric critical care physicians who subscribed to email distribution lists of the Pediatric Acute Lung Injury and Sepsis Investigators, the Pediatric Neurocritical Care Research Group, or the Prevalence of Acute Critical Neurological Disease in Children: A Global Epidemiological Assessment study group, and visitors to the World Federation of Pediatric Intensive and Critical Care Societies website. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 170 subjects who began the survey, 148 completed it. Of those who completed the optional respondent information, most reported working in an academic medical setting and were located in the United States. The main findings were 1) a large majority of PICU physicians reported working in institutions with no guidelines for PICU-based rehabilitation, but expressed interest in developing and implementing such guidelines; 2) despite this lack of guidelines, an overwhelming majority of respondents reported that their current practices would involve consultation of multiple rehabilitation services for each case example provided; 3) PICU physicians believed that additional research evidence is needed to determine efficacy and optimal implementation of PICU-based rehabilitation; 4) PICU physicians reported significant barriers to implementation of PICU-based rehabilitation across centers; and 5) low routine assessment of long-term functional outcomes of PICU patients, although some centers have developed multidisciplinary follow-up programs. CONCLUSIONS: Physicians lack PICU-based rehabilitation guidelines despite great interest and current practices involving a high degree of PICU-based rehabilitation consultation. Data are needed to identify best practices and necessary resources in the delivery of ICU-based multidisciplinary rehabilitation and long-term functional outcomes assessment to optimize recovery of children and families affected by critical illness.

Advancing Randomized Controlled Trials in Pediatric Critical Care: The Perspectives of Trialists.

OBJECTIVES: Clinical research is a complex scientific and social enterprise. Our objective was to identify strategies that pediatric critical care trialists consider acceptable, feasible, and effective to improve the design and conduct randomized controlled trials in pediatric critical care. DESIGN: Qualitative descriptive study using semistructured individual interviews. SUBJECTS: We interviewed 26 pediatric critical care researchers from seven countries who have published a randomized controlled trial (2005-2015). We used purposive sampling to achieve diversity regarding researcher characteristics and randomized controlled trial characteristics. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Most participants (24 [92%]) were from high-income countries, eight (31%) had published more than one randomized controlled trial, 17 (65%) had published a multicenter randomized controlled trial, and eight (31%) had published a multinational randomized controlled trial. An important theme was "building communities"-groups of individuals with similar interests, shared experiences, and common values, bound by professional and personal relationships. Participants described a sense of community as a source of motivation and encouragement and as a means to larger, more rigorous trials, increasing researcher and clinician engagement and maintaining enthusiasm. Strategies to build communities stressed in-person interactions (both professional and social), capable leadership, and trust. Another important theme was "getting started." Participants highlighted the importance of formal research training and high-quality experiential learning through collaboration on other's projects, guided by effective mentorship. Also important was "working within the system"-ensuring academic credit for a range of contributions, not only for the principal investigator role. The longitudinal notion of "building on success" was also underscored as a cross-cutting theme. CONCLUSIONS: Coordinated, deliberate actions to build community and ensure key training and practical experiences for new investigators may strengthen the research enterprise in pediatric critical care. These strategies, potentially in combination with other novel approaches, may vitalize clinical research in this field.

Beyond Survival: Pediatric Critical Care Interventional Trial Outcome Measure Preferences of Families and Healthcare Professionals.

OBJECTIVES: To identify, in addition to survival, preferred outcome measures of PICU family care providers and PICU healthcare professionals for interventional trials enrolling critically ill children, and to describe general attitudes of family care providers and healthcare professionals regarding research in the PICU. DESIGN: Cross-sectional survey examining subject experience with clinical research and personal preferences for outcome measures for a hypothetical interventional clinical trial. SETTING: PICUs within four academic children's hospitals in the United States and Canada. SUBJECTS: Two cohorts including family members of critically ill children in PICUs (family care providers) and multidisciplinary staff working in the PICUs (healthcare professionals). INTERVENTIONS: Administration of a short, deidentified survey. MEASUREMENTS: Demographic data were collated for the two subject groups. Participants were queried regarding their attitudes related to research conducted in the PICU. In addition to survival, each group was asked to identify their three most important outcomes for an investigation examining whether or not an intervention helps seriously ill children recover. MAIN RESULTS: Demographics for family care providers (n = 40) and healthcare professionals (n = 53) were similarly distributed. Female respondents (79.8%) predominated. Participants (98.9%) ascertained the importance of conducting research in the PICU, but significant challenges associated with this goal in the high stress PICU environment. Both quality of life and functioning after leaving the hospital were chosen as the most preferred outcome measure, with 77.5% of family care providers and 84.9% of healthcare professionals indicating this choice. Duration of organ dysfunction was identified by 70.0% of family care providers and 40.7% of healthcare professionals as the second most preferred outcome measure. CONCLUSIONS: In addition to survival, long-term quality of life/functional status and duration of organ dysfunction represent important interventional trial outcome measures for both families of critically ill children, as well as the multidisciplinary team who provides critical care.

Clonidine for sedation in the critically ill: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis investigates the efficacy and safety of clonidine as a sedative in critically ill patients requiring invasive mechanical ventilation. METHODS: We performed a comprehensive search of MEDLINE, EMBASE, CINAHL and the Cochrane trial registry. We identified RCTs that compared clonidine to any non-clonidine regimen in critically ill patients, excluding neonates, requiring mechanical ventilation. The GRADE method was used to assess certainty of evidence. RESULTS: We included eight RCTs (n = 642 patients). In seven of the trials clonidine was used for adjunctive rather than stand-alone sedation. There was no difference in the duration of mechanical ventilation (mean difference (MD) 0.05 days, 95% confidence interval (CI) = -0.65 to 0.75, I 2 = 86%, moderate certainty), ICU mortality (relative risk (RR) 0.98, 95% CI = 0.51 to 1.90, I 2 = 0%, low certainty), or ICU length of stay (MD 0.04 days, 95% CI = -0.46 to 0.53, I 2 = 16%, moderate certainty), with clonidine. There was a significant reduction in the total dose of narcotics (standard mean difference (SMD) -0.26, 95% CI = -0.50 to -0.02, I 2 = 0%, moderate certainty) with clonidine use. Clonidine was associated with increased incidence of clinically significant hypotension (RR 3.11, 95% CI = 1.64 to 5.87, I 2 = 0%, moderate certainty). CONCLUSIONS: Until further RCTs are performed, data remains insufficient to support the routine use of clonidine as a sedative in the mechanically ventilated population. Clonidine may act as a narcotic-sparing agent, albeit with an increased risk of clinically significant hypotension.

High-Quality Randomized Controlled Trials in Pediatric Critical Care: A Survey of Barriers and Facilitators.

OBJECTIVES: High-quality, adequately powered, randomized controlled trials are needed to inform the care of critically ill children. Unfortunately, such evidence is not always available. Our objective was to identify barriers and facilitators of conducting high-quality randomized controlled trials in pediatric critical care, from the perspective of trialists in this field. DESIGN: Self-administered online survey. Respondents rated the importance of barriers and effectiveness of facilitators on seven-point scales. SETTING: Authors of 294 pediatric critical care randomized controlled trials (published 1986 to June 2015). SUBJECTS: One hundred sixteen researchers from 25 countries participated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Respondents reported a median (Q1, Q3) of 21 years (15, 26 yr) of experience and 41 (36%) had authored more than one randomized controlled trial. More survey respondents, compared with nonrespondents, had published more than one trial (35% vs 26%; p = 0.002) and their trials were more often cited (median citations/yr, 2.4 vs 1.5; p < 0.001). Of the barriers listed, the five most important were primarily related to lack of funding. The five facilitators perceived as most effective were protected time for research, ability to recruit participants 24 hours per day/7 days per week, conducting randomized controlled trials in collaboration with a research network, funding from government agencies specifically for randomized controlled trials in critically ill children, and academic department support for conducting randomized controlled trials. Respondent experience and country income level were associated with differences in importance ratings for eight of 41 barriers. There were fewer such differences for facilitators. CONCLUSIONS: Lack of funding and time are major barriers to conducting pediatric critical care randomized controlled trials worldwide. Although barriers varied among country income levels, the facilitators of such trials were more consistent. In addition to increased funding, respondents identified other strategies such as research networks that are within the purview of the pediatric critical care research community, to facilitate the conduct of rigorous randomized controlled trials.

Primary Outcome Measures in Pediatric Septic Shock Trials: A Systematic Review.

OBJECTIVE: To evaluate all published pediatric randomized controlled trials of patients with septic shock from any cause to examine the outcome measures used, the strengths and limitations of these measurements and whether the trial outcomes met feasibility criteria. DATA SOURCES: We used a previously published database of pediatric critical care randomized controlled trials (PICUtrials.net) derived from searches of MEDLINE, EMBASE, LILACS, and CENTRAL. STUDY SELECTION: We included randomized controlled trials of interventions to children admitted to a PICU with septic or dengue hemorrhagic shock which were published in English. DATA EXTRACTION: Study characteristics and outcomes were retrieved by two independent reviewers with disagreement being resolved by a third reviewer. We defined feasibility as 1) recruitment of at least 90% of the targeted sample size and agreement of the observed outcome rate in the control group with the rate used for the sample size calculation to within 10% or 2) finding of a statistically significant difference in an interim or final analysis. DATA SYNTHESIS: Nineteen of 321 identified articles were selected for review. Fourteen of 19 studies (74%) provided an a priori definition of their primary outcome measure in their "Methods section." Mortality rate was the most commonly reported primary outcome (8/14; 57%), followed by duration of shock (4/14; 29%) followed by organ failure (1/14; 7%). Only three of 19 included trials met feasibility criteria. CONCLUSIONS: Our review found that use of mortality alone as a primary outcome in pediatric septic shock trials was associated with significant limitations and that long-term patient-centered outcomes were not used in this setting. Composite outcomes incorporating mortality and long-term outcomes should be explored for use in future pediatric septic shock trials.

The Impact of Clinical Trials Conducted by Research Networks in Pediatric Critical Care.

OBJECTIVES: Research networks in adult and neonatal critical care have demonstrated collaborative and successful execution of clinical trials. Such networks appear to have been relatively recently established in the field of pediatric critical care. The objective of this study was to evaluate the productivity and impact of randomized controlled trials conducted by pediatric critical care research networks, compared with nonnetwork trials. DATA SOURCES, STUDY SELECTION, AND DATA ABSTRACTION: We searched multiple online databases including MEDLINE, reference lists of randomized controlled trials, and relevant systematic reviews. Independent pairs of reviewers identified published randomized controlled trials administering any intervention to children in a PICU and abstracted data. A research network was defined as a formal consortium or collaborative research group established for the purpose of conducting clinical research. Data were independently abstracted in duplicate. MAIN RESULTS: There were 288 pediatric critical care randomized controlled trials published in English between 1986 and July 2015, of which 15 randomized controlled trials (5.2%) were conducted by a total of five research networks. Network randomized controlled trials were more often multicentered, multinational, and larger in size (p < 0.001), compared with nonnetwork randomized controlled trials. Accordingly, their trials took longer to complete (median, 36 vs 21 mo; p < 0.001). Early stopping occurred in 46.7% of network randomized controlled trials (46.7%) and 27% of nonnetwork randomized controlled trials (p = 0.14), most commonly for futility. None of the network, but 45% of the nonnetwork trials found a significant difference in their primary outcome (p < 0.001). Network trials were more frequently cited (median, 6 vs 2 citations per year) and published in higher impact journals (median impact factor, 21.8 vs 3; p < 0.001). CONCLUSIONS: Research networks have conducted a minority of randomized controlled trials in pediatric critical care. They infrequently demonstrate significant differences in their primary outcomes. Despite this, network trials are cited more frequently and appear to have greater impact. There are important lessons to learn from both individual researchers as well as research networks that may guide the successful conduct of collaborative, high-quality randomized controlled trials in critically ill children.

Stress ulcer prophylaxis in critical illness: a Canadian survey.

PURPOSE: Stress ulcer prophylaxis (SUP) using histamine-2-receptor antagonists has been a standard of care in intensive care units (ICUs) for four decades. Proton pump inhibitors (PPIs) are increasingly used despite apparently lower background rates of gastrointestinal bleeding and growing concerns about PPI-associated complications. Our objective was to understand the views and prescribing habits amongst Canadian physicians regarding SUP in the ICU and to gauge interest in a future randomized-controlled trial (RCT). METHODS: We created a short self-administered survey about SUP for critically ill adults, evaluated its clinical sensibility, and pilot tested the instrument. We surveyed all physician members of the Canadian Critical Care Trials Group (CCCTG) by e-mail and sent reminders three and five weeks later. RESULTS: We received 94 of 111 (85%) surveys from the validated respondent pool between May and June, 2015. Respondents reported use of SUP most commonly in patients 1) receiving invasive mechanical ventilation (62, 66%), 2) expected to be ventilated for ≥ two days (25, 27%), or 3) receiving mechanical ventilation but nil per os (NPO) (20, 21%). Stress ulcer prophylaxis is discontinued when patients no longer receive mechanical ventilation (75%), no longer are NPO (22%), or are discharged from the ICU (19%). Stress ulcer prophylaxis involves PPIs in 68% of centres. Most respondents endorsed the need for a large rigorous RCT of PPI vs placebo to understand the risks and benefits of this practice. CONCLUSIONS: Stress ulcer prophylaxis is reportedly used primarily for the duration of mechanical ventilation. The CCCTG physicians believe that a placebo-controlled RCT is needed to evaluate the effectiveness and safety of contemporary SUP with PPIs.

Pilot Randomized Trials in Pediatric Critical Care: A Systematic Review.

OBJECTIVES: Pilot trials are smaller randomized controlled trials conducted to inform the design and assess the feasibility of a large-scale trials. The objectives of this systematic review were to describe pilot trials in pediatric critical care, their conclusions about the clinical implications of the results, and the need for future research and to determine the frequency of large follow-up trials. DATA SOURCES: The Evidence in Pediatric Intensive Care database (http://epicc.mcmaster.ca), a comprehensive repository of published pediatric critical care randomized controlled trials and the World Health Organization's Clinical Trials Registry Platform. STUDY SELECTION: Randomized controlled trials described in the publication as "pilot," "feasibility," "proof-of-concept," "exploratory," "phase 2," "vanguard," or "preliminary." DATA EXTRACTION: Pairs of reviewers screened studies for eligibility and abstracted data independently. DATA SYNTHESIS: We found 32 pilot trials (12.2% of all pediatric critical care randomized controlled trials) published before July 2014, varying in size from 6 to 165 children. Pilot trials were significantly smaller than those not described as pilots, but other key characteristics were not significantly different. The authors of 16 publications (48.4%) included explicit and specific conclusions about the design or feasibility of larger trials based on the results of the pilot trial. In 20 publications (64.5%), the authors made conclusions about clinical efficacy based on results of the pilot trial. Four of the 32 pilot trials (12.9%) led to larger trials, two of which have been published. CONCLUSIONS: Published pilot trials in pediatric critical care often focus on clinical outcomes. They uncommonly report explicit feasibility outcomes, criteria for success, or rationale for the pilot sample size. These pilot trials infrequently lead to larger trials. Understanding and addressing the reasons for this are key to the success of pediatric critical care research.

Making decisions about medications in critically ill children: a survey of Canadian pediatric critical care clinicians.

OBJECTIVE: Changing clinician practice in pediatric critical care is often difficult. Tailored knowledge translation interventions may be more effective than other types of interventions. To inform the design of tailored interventions, the primary objective of this survey was to describe the importance of specific factors that influence physicians and pharmacists when they make decisions about medications in critically ill children. DESIGN: In this postal survey, respondents used 7-point scales to rate the importance of specific factors that influence their decisions in the following scenarios: corticosteroids for shock, intensive insulin therapy, stress ulcer prophylaxis, surfactant for acute respiratory distress syndrome, and sedation interruption. We used generalized estimating equations to examine the association between the importance of specific factors influencing decision making and the scenario and respondents' practice, views, and demographics. SETTING: Canadian PICUs. PARTICIPANTS: One hundred and seventeen physicians and pharmacists practicing in 18 PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The response rate was 61%. The three factors reported to most strongly influence clinician decision making overall were: severity of illness (mean [SD] 5.8 [1.8]), physiologic rationale (5.2 [1.3]), and adverse effects (5.1 [1.9]). Factors least likely to influence decision making were drug costs (2.0 [1.5]), unit policies (2.9 [1.9]), and non-critical care randomized controlled trials (3.1 [1.9]). The relative importance of 8 of the 10 factors varied significantly among the five scenarios: only randomized controlled trials in critically ill children and other clinical research did not vary. Clinician characteristics associated with the greatest difference in importance ratings were: frequent use of the intervention in that scenario (seven factors), profession (five factors), and respondents' assessment of the quality of evidence (five factors). CONCLUSIONS: The relative importance of many factors that clinicians consider when making decisions about medications varies by demographics, and depends on the clinical problem. This variability should be considered in quality improvement and knowledge translation interventions in this setting.