Rapid normalization of vitamin D deficiency in PICU (VITdALIZE-KIDS): study protocol for a phase III, multicenter randomized controlled trial.

BACKGROUND: The rate of vitamin D deficiency (VDD) in critically ill children worldwide has been estimated at 50%. These children are at risk of multiple organ dysfunction, chronic morbidity, and decreased health related quality of life (HRQL). Pediatric and adult ICU clinical trials suggest that VDD is associated with worse clinical outcomes, although data from supplementation trials are limited and inconclusive. Our group's phase II multicenter dose evaluation pilot study established the efficacy and safety of an enteral weight-based cholecalciferol loading dose to rapidly restore vitamin D levels in critically ill children. METHODS: Our aim is to evaluate the impact of this dosing regimen on clinical outcomes. VITdALIZE-KIDS is a pragmatic, phase III, multicenter, double-blind RCT aiming to randomize 766 critically ill children from Canadian PICUs. Participants are randomized using a 1:1 scheme to receive a single dose at enrollment of enteral cholecalciferol (10,000 IU/kg, max 400,000 IU) or placebo. Eligibility criteria include critically ill children aged newborn (> 37 weeks corrected gestational age) to < 18 years who have blood total 25-hydroxyvitamin D < 50 nmol/L. The primary objective is to determine if rapid normalization of vitamin D status improves HRQL at 28 days following enrollment. The secondary objective is to evaluate the impact of rapid normalization of vitamin D status on multiple organ dysfunction. The study includes additional tertiary outcomes including functional status, HRQL and mortality at hospital discharge and 90 days, PICU and hospital length of stay, and adverse events related to vitamin D toxicity. Additionally, we are performing comprehensive vitamin D speciation and non-targeted metabolite profiling as part of a sub-study for the first 100 participants from whom an enrollment and at least one post-intervention blood and urine sample were obtained. DISCUSSION: The VITdALIZE-KIDS trial is the first phase III, multicenter trial to evaluate whether rapid normalization of vitamin D status could represent a simple, inexpensive, and safe means of improving outcomes following pediatric critical illness. Recruitment was initiated in June 2019 and is expected to continue to March 2026. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03742505. Study first submitted on November 12, 2018 https://clinicaltrials.gov/study/NCT03742505.

An Equity, Diversity, and Inclusion glossary for sociodemographic determinants of health within critical care medicine.

PURPOSE: Equity, Diversity, and Inclusion (EDI) initiatives within critical care research are limited by a lack of resources and inconsistent and rapidly changing language. The Canadian Critical Care Trials Group (CCCTG) is committed to modelling EDI for the critical care community through its programming, communications, protocols, and policies. The objective of developing the EDI glossary of sociodemographic determinants of health described here was to provide a resource for critical care professionals to support broader equity initiatives and to promote education and awareness about inclusive language. METHODS: Through literature review, we identified EDI-related sociodemographic determinants of health, defined as sociodemographic factors that are associated with disparities in health care and health outcomes, with a focus on critical care medicine. For each sociodemographic determinant of health, we identified umbrella terms (defined as domains) and subterms/constructs that are related to these domains. We designed the glossary collaboratively with the CCCTG EDI working group, patient and family partnerships committee, and executive committee, which included diverse knowledge users such as researchers, clinicians, and patient and family partners. RESULTS: We report on 12 sociodemographic determinants of health domains including age, sex, gender, sexuality, race and ethnicity, income, education, employment status, marital status, language, disability, and migration status. Each domain (e.g., sex) contains relevant subterms such as male, female, intersex. For each domain, we provide examples of disparities in health care and health outcomes with a focus on critical care medicine. CONCLUSIONS: This EDI glossary of sociodemographic determinants of health serves as a nonexhaustive resource that may be referenced by critical care researchers, research coordinators, clinicians, and patient and family partners. The glossary is an essential step to raising awareness about inclusive terminology and to fostering and advancing equity in critical care medicine.

RéSUMé: OBJECTIF: Les initiatives en matière d'équité, de diversité et d'inclusion (EDI) dans le cadre de la recherche en soins intensifs sont limitées à la fois par un manque de ressources et par un langage incohérent et évoluant rapidement. Le Groupe canadien de recherche en soins intensifs (CCCTG) s'est engagé à devenir un modèle en matière d'EDI pour la communauté des soins intensifs par le biais de ses programmes, de ses communications, de ses protocoles et de ses politiques. L'objectif de l'élaboration du glossaire pour les déterminants sociodémographiques de la santé respectant l'EDI décrit ici était de fournir une ressource aux professionnel·les des soins intensifs pour soutenir des initiatives d'équité plus larges et de promouvoir l'éducation et la sensibilisation au langage inclusif. MéTHODE: En procédant à l'examen de la littérature, nous avons identifié des déterminants sociodémographiques de la santé liés à l'EDI, définis comme des facteurs sociodémographiques associés à des disparités dans les soins de santé et les devenirs en santé, en mettant l'accent sur la médecine des soins intensifs. Pour chaque déterminant sociodémographique de la santé, nous avons identifié des termes génériques (définis comme des domaines) et des sous-termes/construits liés à ces domaines. Nous avons conçu le glossaire en collaboration avec le groupe de travail sur l'EDI du CCCTG, le comité des partenariats avec les patient·es et les familles et le comité exécutif, qui comprenait divers utilisateurs et utilisatrices des connaissances tels que des personnes impliquées dans la recherche ou en clinique ainsi que des partenaires issu·es de la patientèle et de leurs familles. RéSULTATS: Nous rendons compte de 12 domaines sociodémographiques pour les déterminants de la santé, notamment l'âge, le sexe, le genre, la sexualité, la race et l'origine ethnique, le revenu, l'éducation, la situation d'emploi, l'état matrimonial, la langue, le handicap et le statut migratoire. Chaque domaine (par exemple, le sexe) contient des sous-termes pertinents tels que masculin, féminin, intersexe. Pour chaque domaine, nous fournissons des exemples de disparités dans les soins de santé et les issues en matière de santé, en mettant l'accent sur la médecine des soins intensifs. CONCLUSION: Ce glossaire EDI des déterminants sociodémographiques de la santé sert de ressource non exhaustive qui peut être consultée par les équipes de recherche en soins intensifs, les coordonnateurs et coordonnatrices de recherche, les clinicien·nes et les patient·es ainsi que les familles. Ce glossaire est une étape essentielle pour sensibiliser à la terminologie inclusive et pour favoriser et faire progresser l'équité en médecine des soins intensifs.

Core socioDemographic data variables in ICU Trials (CoDe-IT): a protocol for generating core data variables using a Delphi consensus process.

INTRODUCTION: Sociodemographic variables influence health outcomes, either directly (ie, gender identity) or indirectly (eg, structural/systemic racism based on ethnoracial group). Identification of how sociodemographic variables can impact the health of critically ill adults is important to guide care and research design for this population. However, despite the growing recognition of the importance of collecting sociodemographic measures that influence health outcomes, insufficient and inconsistent data collection of sociodemographic variables persists in critical care studies. We aim to develop a set of core data variables (CoDaV) for social determinants of health specific to studies involving critically ill adults. METHODS AND ANALYSIS: We will conduct a scoping review to generate a list of possible sociodemographic measures to be used for round 1 of the modified Delphi processes. We will engage relevant knowledge users (previous intensive care unit patients and family members, critical care researchers, critical care clinicians and research co-ordinators) to participate in the modified Delphi consensus survey to identify the CoDaV. A final consensus meeting will be held with knowledge user representatives to discuss the final CoDaV, how each sociodemographic variable will be collected (eg, level of granularity) and how to disseminate the CoDaV for use in critical care studies. ETHICS AND DISSEMINATION: The University of Calgary conjoint health research ethics board has approved this study protocol (REB22-1648).

Barriers, Solutions, and Opportunities for Adapting Critical Care Clinical Trials in the COVID-19 Pandemic.

Importance: The COVID-19 pandemic created unprecedented challenges for clinical trials worldwide, threatening premature closure and trial integrity. Every phase of research operations was affected, often requiring modifications to protocol design and implementation. Objectives: To identify the barriers, solutions, and opportunities associated with continuing critical care trials that were interrupted during the pandemic, and to generate suggestions for future trials. Design, Setting, and Participants: This mixed-methods study performed an explanatory sequential analysis involving a self-administered electronic survey and focus groups of principal investigators (PIs) and project coordinators (PCs) conducting adult and pediatric individual-patient randomized trials of the Canadian Critical Care Trials Group during the COVID-19 pandemic. Eligible trials were actively enrolling patients on March 11, 2020. Data were analyzed between September 2023 and January 2024. Main Outcomes and Measures: Importance ratings of barriers to trial conduct and completion, solutions employed, opportunities arising, and suggested strategies for future trials. Quantitative data examining barriers were analyzed using descriptive statistics. Data addressing solutions, opportunities, and suggestions were analyzed by qualitative content analysis. Integration involved triangulation of data sources and perspectives about 13 trials, synthesized by an interprofessional team incorporating reflexivity and member-checking. Results: A total of 13 trials run by 29 PIs and PCs (100% participation rate) were included. The highest-rated barriers (on a 5-point scale) to ongoing conduct during the pandemic were decisions to pause all clinical research (mean [SD] score, 4.7 [0.8]), focus on COVID-19 studies (mean [SD] score, 4.6 [0.8]), and restricted family presence in hospitals (mean [SD] score, 4.1 [0.8]). Suggestions to enable trial progress and completion included providing scientific leadership, implementing technology for communication and data management, facilitating the informed consent process, adapting the protocol as necessary, fostering site engagement, initiating new sites, streamlining ethics and contract review, and designing nested studies. The pandemic necessitated new funding opportunities to sustain trial enrollment. It increased public awareness of critical illness and the importance of randomized trial evidence. Conclusions and Relevance: While underscoring the vital role of research in society and drawing the scientific community together with a common purpose, the pandemic signaled the need for innovation to ensure the rigor and completion of ongoing trials. Lessons learned to optimize research procedures will help to ensure a vibrant clinical trials enterprise in the future.

Effectiveness of dexmedetomidine on patient-centred outcomes in surgical patients: a systematic review and Bayesian meta-analysis.

BACKGROUND: Dexmedetomidine is increasingly used for surgical patients requiring general anaesthesia. However, its effectiveness on patient-centred outcomes remains uncertain. Our main objective was to evaluate the patient-centred effectiveness of intraoperative dexmedetomidine for adult patients requiring surgery under general anaesthesia. METHODS: We conducted a systematic search of MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL from inception to October 2023. Randomised controlled trials (RCTs) comparing intraoperative use of dexmedetomidine with placebo, opioid, or usual care in adult patients requiring surgery under general anaesthesia were included. Study selection, data extraction, and risk of bias assessment were performed by two reviewers independently. We synthesised data using a random-effects Bayesian regression framework to derive effect estimates and the probability of a clinically important effect. For continuous outcomes, we pooled instruments with similar constructs using standardised mean differences (SMDs) and converted SMDs and credible intervals (CrIs) to their original scale when appropriate. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our primary outcome was quality of recovery after surgery. To guide interpretation on the original scale, the Quality of Recovery-15 (QoR-15) instrument was used (range 0-150 points, minimally important difference [MID] of 6 points). RESULTS: We identified 49,069 citations, from which 44 RCTs involving 5904 participants were eligible. Intraoperative dexmedetomidine administration was associated with improvement in postoperative QoR-15 (mean difference 9, 95% CrI 4-14, n=21 RCTs, moderate certainty of evidence). We found 99% probability of any benefit and 88% probability of achieving the MID. There was a reduction in chronic pain incidence (odds ratio [OR] 0.42, 95% CrI 0.19-0.79, n=7 RCTs, low certainty of evidence). There was also increased risk of clinically significant hypotension (OR 1.98, 95% CrI 0.84-3.92, posterior probability of harm 94%, n=8 RCTs) and clinically significant bradycardia (OR 1.74, 95% CrI 0.93-3.34, posterior probability of harm 95%, n=10 RCTs), with very low certainty of evidence for both. There was limited evidence to inform other secondary patient-centred outcomes. CONCLUSIONS: Compared with placebo or standard of care, intraoperative dexmedetomidine likely results in meaningful improvement in the quality of recovery and chronic pain after surgery. However, it might increase clinically important bradycardia and hypotension. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023439896).

Impact of Legal Guardian Absence on Research Enrollment in the PICU.

OBJECTIVES: To identify the frequency of which a legal guardian is at the bedside of children admitted to the PICU that are eligible for research studies. DESIGN: A prospective, observational study. SETTING: Three tertiary Canadian PICUs. PATIENTS: Two hundred one patients were admitted to the PICU between September 2021 and March 2023 (site 1), from March 2019 to March 2020 and March 2022 to March 2023 (site 2), and from March 2019 to March 2020 and July 2020 to November 2021 (site 3). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At each center, the duration of consent encounters was recorded for patients eligible for research by documenting the length of each attempt (min). The frequency of parental presence at bedside and the ability for a guardian to make a decision were also recorded. Thirty-five percent of patients eligible for research did not have a legal guardian at the bedside on the first attempted consent encounter. Twenty-three percent of approached patients were not enrolled due to an inability for a consent decision to be made by the child's legal guardian or an inability to contact the guardian before discharge. CONCLUSIONS: The absence of legal guardians in the PICU poses a barrier to the enrollment of critically ill children in pertinent research studies and suggests that a model of deferred consent or implied consent would aid in the future of critical care research.

The response of Canada's clinical health research ecosystem to the COVID-19 pandemic.

BACKGROUND: The response of Canada's research community to the COVID-19 pandemic provides a unique opportunity to examine the country's clinical health research ecosystem. We sought to describe patterns of enrolment across Canadian Institutes of Health Research (CIHR)-funded studies on COVID-19. METHODS: We identified COVID-19 studies funded by the CIHR and that enrolled participants from Canadian acute care hospitals between January 2020 and April 2023. We collected information on study-and site-level variables from study leads, site investigators, and public domain sources. We described and evaluated factors associated with cumulative enrolment. RESULTS: We obtained information for 23 out of 26 (88%) eligible CIHR-funded studies (16 randomized controlled trials [RCTs] and 7 cohort studies). The 23 studies were managed by 12 Canadian and 3 international coordinating centres. Of 419 Canadian hospitals, 97 (23%) enrolled a total of 28 973 participants - 3876 in RCTs across 78 hospitals (median cumulative enrolment per hospital 30, interquartile range [IQR] 10-61), and 25 097 in cohort studies across 62 hospitals (median cumulative enrolment per hospital 158, IQR 6-348). Of 78 hospitals recruiting participants in RCTs, 13 (17%) enrolled 50% of all RCT participants, whereas 6 of 62 hospitals (9.7%) recruited 54% of participants in cohort studies. INTERPRETATION: A minority of Canadian hospitals enrolled the majority of participants in CIHR-funded studies on COVID-19. This analysis sheds light on the Canadian health research ecosystem and provides information for multiple key partners to consider ways to realize the full research potential of Canada's health systems.

The Diversity of Research Participants in Randomized Controlled Trials and Observational Studies Conducted by the Canadian Critical Care Trials Group.

Rationale: Women, older individuals, and racial and ethnic minority groups are often underrepresented in research studies. Objectives: We evaluated the demographics and diversity of participants enrolled in randomized controlled trials (RCTs) and observational studies published by investigators in association with the Canadian Critical Care Trials Group. Methods: We performed quantitative content analysis of peer-reviewed RCTs and observational studies from December 1994 to December 2022. For each publication, we extracted participant demographic variables, including sex, gender, age, race or ethnicity, sexual orientation, pregnancy status, language proficiency, income/financial status, housing, education, disability, and geography. Results: A total of 120 publications (28 RCTs, 92 observational studies) included 211,144 enrolled participants. Most (107 of 120; 89.2%) were multicenter studies, and 70% (84 of 120) were conducted exclusively in Canadian centers; 77.5% (93 of 120) studies enrolled adult participants, and 19.2% (23 of 120) enrolled pediatric participants. All studies reported participant mean or median age, 118 (98.3%) reported binary sex or gender, and 9 (7.5%) reported race or ethnicity. No justification was provided in 35 studies that listed pregnancy as an exclusion. There was infrequent reporting of housing (n = 4), employment (n = 2), income (n = 2), and education (n = 1). No studies reported the language proficiency, sexual orientation, disability, or geography of participants. Of the studies reporting gender, women and/or girls comprised 42.3% participants (range, 8.9-67.7%). Within nine studies reporting race or ethnicity of 2,950 participants, 59.7% were White, 8% South Asian, 7% Indigenous, 3% Asian, 1% Black, 14% unknown, and 6% "other." Conclusions: Research publications from the Canadian Critical Care Trials Group infrequently report important participant demographics, and diversity of research participants is disproportionate compared with Canadian societal demographics.

Childhood autoimmune hemolytic anemia: A scoping review.

BACKGROUND AND OBJECTIVE: Autoimmune hemolytic anemia (AIHA) is a rare but important cause of morbidity in pediatric hematology patients. Given its rarity, there is little high-quality evidence on which to base the investigation and management of pediatric AIHA. This scoping review aims to summarize the current evidence and highlight key gaps to inform future studies. METHODS: This review searched MEDLINE and the Cochrane CENTRAL Trials Register from 2000 to November 03, 2023. Experimental and observational studies reporting AIHA diagnostic criteria, laboratory workup, or treatment/management in populations with at least 20% of patients ≤18 years were included. RESULTS: Forty-three studies were included, with no randomized controlled trials identified. AIHA diagnostic criteria, diagnostic tests, and treatments were highly variable. First-line treatment approaches include corticosteroids, intravenous immunoglobulin, or both. Approaches to AIHA resistance to first-line therapy were widely variable between studies, but most commonly included rituximab and/or cyclosporine. CONCLUSIONS: We identify a heterogenous group of observational studies into this complex, immune-mediated disorder. Standardized definitions and classifications are needed to guide collaborative efforts needed to study this rare disease. The work done by the CEREVANCE group provides an important paradigm for future studies.

Measuring continuing medical education conference impact and attendee experience: a scoping review.

Objectives: The aim was to comprehensively identify published research evaluating continuing medical education conferences, to search for validated tools and perform a content analysis to identify the relevant domains for conference evaluation. Methods: We used scoping review methodology and searched MEDLINE® for relevant English or French literature published between 2008 and 2022 (last search June 3, 2022). Original research (including randomized controlled trials, non-randomized studies, cohort, mixed-methods, qualitative studies, and editorial pieces) where investigators described impact, experience, or motivations related to conference attendance were eligible. Citations were assessed in triplicate, and data extracted in duplicate. Results: Eighty-three studies were included, 69 (83%) of which were surveys or interview based, with the majority conducted at the end of or following conference conclusion. Of the 74 tools identified, only one was validated and was narrowly focused on a specific conference component. A total of 620 items were extracted and categorized into 4 a priori suggested domains (engagement-networking, education-learning, impact, scholarship), and an additional 4 identified through content analysis (value-satisfaction, logistics, equity-diversity-inclusivity, career influences). Time trends were evident, including the absence of items related to equity-diversity-inclusivity prior to 2019, and a focus on logistics, particularly technology and virtual conferences, since 2020. Conclusions: This study identified 8 major domains relevant for continuing medical education conference evaluation. This work is of immediate value to individuals and organizations seeking to either design or evaluate a conference and represents a critical step in the development of a standardized tool for conference evaluation.

Reporting of social determinants of health in randomized controlled trials conducted in the pediatric intensive care unit.

Introduction: The influence of social determinants of health (SDOH) on access to care and outcomes for critically ill children remains an understudied area with a paucity of high-quality data. Recent publications have highlighted the importance of incorporating SDOH considerations into research but the frequency with which this occurs in pediatric intensive care unit (PICU) research is unclear. Our objective was to determine the frequency and categories of SDOH variables reported and how these variables were defined in published PICU randomized controlled trials (RCTs). Methods: We searched Medline, Embase, Lilacs, and Central from inception to Dec 2022. Inclusion criteria were randomized controlled trials of any intervention on children or their families in a PICU. Data related to study demographics and nine WHO SDOH categories were extracted, and descriptive statistics and qualitative data generated. Results: 586 unique RCTs were included. Studies had a median sample size of 60 patients (IQR 40-106) with 73.0% of studies including ≤100 patients and 41.1% including ≤50 patients. A total of 181 (181/586, 30.9%) studies reported ≥1 SDOH variable of which 163 (163/586, 27.8%) reported them by randomization group. The most frequently reported categories were food insecurity (100/586, 17.1%) and social inclusion and non-discrimination (73/586, 12.5%). Twenty-five of 57 studies (43.9%) investigating feeding or nutrition and 11 of 82 (13.4%) assessing mechanical ventilation reported baseline nutritional assessments. Forty-one studies investigated interventions in children with asthma or bronchiolitis of which six reported on smoking in the home (6/41, 14.6%). Discussion: Reporting of relevant SDOH variables occurs infrequently in PICU RCTs. In addition, when available, categorizations and definitions of SDOH vary considerably between studies. Standardization of SDOH variable collection along with consistent minimal reporting requirements for PICU RCT publications is needed.

A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (ICU) and associated with worse clinical course. Trials in adult ICU demonstrate rapid restoration of vitamin D status using an enteral loading dose is safe and may improve outcomes. There have been no published trials of rapid normalization of VDD in the pediatric ICU. METHODS: We conducted a multicenter placebo-controlled phase II pilot feasibility randomized clinical trial from 2016 to 2017. We randomized 67 critically ill children with VDD from ICUs in Canada, Chile and Austria using a 2:1 randomization ratio to receive a loading dose of enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or placebo. Participants, care givers, and outcomes assessors were blinded. The primary objective was to determine whether the loading dose normalized vitamin D status (25(OH)D > 75 nmol/L). Secondary objectives were to evaluate for adverse events and assess the feasibility of a phase III trial. RESULTS: Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary analyses (40 treatment, 19 placebo). Thirty-one/38 (81.6%) participants in the treatment arm achieved a plasma 25(OH)D concentration > 75 nmol/L versus 1/18 (5.6%) the placebo arm. The mean 25(OH)D concentration in the treatment arm was 125.9 nmol/L (SD 63.4). There was no evidence of vitamin D toxicity and no major drug or safety protocol violations. The accrual rate was 3.4 patients/month, supporting feasibility of a larger trial. A day 7 blood sample was collected for 84% of patients. A survey administered to 40 participating families showed that health-related quality of life (HRQL) was the most important outcome for families for the main trial (30, 75%). CONCLUSIONS: A single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children with VDD, but with significant variability in 25(OH)D concentrations. We established that a phase III multicentre trial is feasible. Using an outcome collected after hospital discharge (HRQL) will require strategies to minimize loss-to-follow-up. CLINICALTRIALS: gov NCT02452762 Registered 25/05/2015.

Inhaled nitrous oxide for painful procedures in children and youth: a systematic review and meta-analysis.

OBJECTIVES: The objective of this study was to synthesize indication-based evidence for N2O for distress and pain in children. STUDY DESIGN: We included trials of N2O in participants 0-21 years, reporting distress or pain for emergency department procedures. The primary outcome was procedural distress. Where meta-analysis was not possible, we used Tricco et al.'s classification of "neutral" (p ≥ 0.05), "favorable," or "unfavorable" (p < 0.05, supporting N2O or comparator, respectively). We used the Cochrane Collaboration's Risk of Bias tool and the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate risk of bias and quality of evidence, respectively. RESULTS: We included 30 trials. For pain using the Visual Analog Scale (0-100 mm) during IV insertion, 70% N2O (delta:-16.5; 95%CI:-28.6 to -4.4; p = 0.008; three trials; I2 = 0%) and 50% N2O plus eutectic mixture of local anesthetics (EMLA) (delta:-1.2; 95%CI:-2.1 to -0.3; p = 0.007; two trials; I2 = 43%) were superior to EMLA. 50% N2O was not superior to EMLA (delta:-0.4; 95%CI:-1.2 to 0.3; p = 0.26; two trials; I2 = 15%). For distress and pain during laceration repair, N2O was "favorable" versus each of SC lidocaine, oxygen, and oral midazolam but "neutral" versus IV ketamine (five trials). For distress and pain during fracture reduction (three trials), N2O was "neutral" versus each of IM meperidine plus promethazine, regional anesthesia, and IV ketamine plus midazolam. For distress and pain during lumbar puncture (one trial), N2O was "favorable" versus oxygen. For distress and pain during urethral catheterization (one trial), N2O was "neutral" versus oral midazolam. For pain during intramuscular injection (one trial), N2O plus EMLA was "favorable" versus N2O and EMLA alone. Common adverse effects of N2O included nausea (4.4%), agitation (3.7%), and vomiting (3.6%) AEs were less frequent with N2O alone (278/1147 (24.2%)) versus N2O plus midazolam (48/52 (92.3%)) and N2O plus fentanyl (123/201 (61.2%)). CONCLUSIONS: There is sufficient evidence to recommend N2O plus topical anesthetic for IV insertion and laceration repair. Adverse effects are greater when combined with other sedating agents.

RéSUMé: OBJECTIFS: Synthétiser les données probantes fondées sur l'indication pour le N2O pour la détresse et la douleur chez les enfants. Plan d'étude : Nous avons inclus des essais de N2O chez des participants âgés de 0 à 21 ans, signalant une détresse ou une douleur pour les procédures des services d'urgence. Le critère de jugement principal était la détresse procédurale. Lorsqu'une méta-analyse n'était pas possible, nous avons utilisé la classification de Tricco et al. "neutre" (p>0,05), "favorable" ou "défavorable" (p<0,05, en faveur de la N2O ou du comparateur, respectivement). Nous avons utilisé l'outil risque de biais de la Collaboration Cochrane et le système Grading of Recommendations Assessment, Development, and Evaluation pour évaluer respectivement le risque de biais et la qualité des preuves. RéSULTATS: Nous avons inclus 30 essais. Pour la douleur sur l'échelle visuelle analogique (0-100 mm) pendant l'insertion IV, 70 % de N2O (delta : -16,5 ; IC à 95% : -28,6 à -4,4 ; p = 0,008 ; trois essais ; I2 = 0 %) et 50 % de N2O plus un mélange eutectique d'anesthésiques locaux (EMLA) (delta : -1,2 ; IC à 95 % : -2,1 à -0,3 ; p = 0,007 ; deux essais ; I2 = 43 %) étaient supérieurs à l'EMLA. La N2O à 50 % n'était pas supérieure à l'EMLA (delta : -0,4 ; IC à 95 % : -1,2 à 0,3 ; p = 0,26 ; deux essais ; I2 = 15 %). En ce qui concerne la détresse et la douleur pendant la réparation des lacérations, le N2O était "favorable" par rapport à la lidocaïne SC, à l'oxygène et au midazolam oral, mais "neutre" par rapport à la kétamine IV (cinq essais). Pour la détresse et la douleur pendant la réduction des fractures (trois essais), le N2O était « neutre ¼ par rapport à la mépéridine IM plus prométhazine, l'anesthésie régionale et la kétamine IV plus midazolam. Pour la détresse et la douleur lors de la ponction lombaire (un essai), le N2O était "favorable" par rapport à l'oxygène. Pour la détresse et la douleur pendant le cathétérisme urétral (un essai), N2O était "neutre" par rapport au midazolam oral. Pour la douleur pendant l'injection intramusculaire (un essai), le N2O plus EMLA était « favorable ¼ par rapport au N2O et à l'EMLA seuls. Les effets indésirables les plus fréquents de la N2O étaient les nausées (4,4 %), l'agitation (3,7 %) et les vomissements (3,6 %). Les EI étaient moins fréquents avec la N2O seule (278/1147 (24,2 %)) par rapport au N2O plus midazolam (48/52 (92,3 %)) et le N2O plus fentanyl (123/201 (61,2 %)). CONCLUSIONS: Il existe suffisamment de preuves pour recommander le N2O plus un anesthésique topique pour l'insertion intraveineuse et la réparation des lacérations. Les effets indésirables sont plus importants lorsqu'ils sont combinés avec d'autres agents sédatifs.

Addressing health care inequities in Canadian critical care through inclusive science: a pilot tool for standardized data collection.

PURPOSE: Sociodemographic risks contributing to health inequities are often inadequately captured and reported in critical care studies. To address the lack of standardized terms and definitions, we sought to develop a practical and convenient resource of questions and response options for collecting sociodemographic variables for critical care research. SOURCE: To identify domains and variables that impact health equity, we searched: 1) PubMed for critical care randomized trials (2010 to 2021); 2) high-impact critical care and general medicine journals for special issues relating to equity; and 3) governmental and nongovernmental resources. PRINCIPAL FINDINGS: We identified 23 domains associated with health equity, including pronouns, age, sex, gender identity, sexual orientation, race and ethnicity, visible minorities, language, household income, marital/relationship status, education, disabilities, immigrant and refugee status, employment, primary care access, expanded health insurance, internet access, housing security, food security, dependents, religion, and postal code. For each domain we provided standardized questions and response options; for 13/23 domains, we included more than one version of the question and response categories. CONCLUSION: We developed a standardized, practical, and convenient demographic data collection tool for critical care research studies. Questions and response options can be adapted by researchers for inclusion in individual study questionnaires or case report forms.

RéSUMé: OBJECTIF: Les risques sociodémographiques qui contribuent aux inégalités en matière de santé sont souvent mal saisis et rapportés dans les études de soins intensifs. Pour remédier au manque de termes et de définitions normalisés, nous avons cherché à élaborer une ressource à la fois pratique et utile de questions et d'options de réponse pour le recueil des variables sociodémographiques pour la recherche en soins intensifs. SOURCES: Pour identifier les domaines et les variables qui ont une incidence sur l'équité en santé, nous avons effectué des recherches dans : 1) PubMed, pour en extraire les études randomisées en soins intensifs (2010 à 2021); 2) des revues de soins intensifs et de médecine générale à impact élevé pour identifier les numéros spéciaux liés à l'équité; et 3) les ressources gouvernementales et non gouvernementales. CONSTATATIONS PRINCIPALES: Nous avons identifié 23 domaines associés à l'équité en santé, y compris les pronoms, l'âge, le sexe, l'identité de genre, l'orientation sexuelle, la race et l'origine ethnique, les minorités visibles, la langue, le revenu du ménage, l'état matrimonial / relationnel, l'éducation, les handicaps, le statut d'immigrant·e et de réfugié·e, l'emploi, l'accès aux soins primaires, l'assurance maladie élargie, l'accès à l'internet, la sécurité du logement, la sécurité alimentaire, les personnes à charge, la religion et le code postal. Pour chaque domaine, nous avons fourni des questions et des options de réponse normalisées; pour 13/23 domaines, nous avons inclus plus d'une version des catégories de questions et réponses. CONCLUSION: Nous avons mis au point un outil de collecte de données démographiques normalisé, pratique et utile pour la recherche en soins intensifs. Les options de questions et de réponses peuvent être adaptées par les chercheuses et chercheurs pour être incluses dans des questionnaires d'étude individuels ou des formulaires de présentation de cas.

Defining Pediatric Chronic Critical Illness: A Scoping Review.

OBJECTIVES: Children with chronic critical illness (CCI) are hypothesized to be a high-risk patient population with persistent multiple organ dysfunction and functional morbidities resulting in recurrent or prolonged critical care; however, it is unclear how CCI should be defined. The aim of this scoping review was to evaluate the existing literature for case definitions of pediatric CCI and case definitions of prolonged PICU admission and to explore the methodologies used to derive these definitions. DATA SOURCES: Four electronic databases (Ovid Medline, Embase, CINAHL, and Web of Science) from inception to March 3, 2021. STUDY SELECTION: We included studies that provided a specific case definition for CCI or prolonged PICU admission. Crowdsourcing was used to screen citations independently and in duplicate. A machine-learning algorithm was developed and validated using 6,284 citations assessed in duplicate by trained crowd reviewers. A hybrid of crowdsourcing and machine-learning methods was used to complete the remaining citation screening. DATA EXTRACTION: We extracted details of case definitions, study demographics, participant characteristics, and outcomes assessed. DATA SYNTHESIS: Sixty-seven studies were included. Twelve studies (18%) provided a definition for CCI that included concepts of PICU length of stay (n = 12), medical complexity or chronic conditions (n = 9), recurrent admissions (n = 9), technology dependence (n = 5), and uncertain prognosis (n = 1). Definitions were commonly referenced from another source (n = 6) or opinion-based (n = 5). The remaining 55 studies (82%) provided a definition for prolonged PICU admission, most frequently greater than or equal to 14 (n = 11) or greater than or equal to 28 days (n = 10). Most of these definitions were derived by investigator opinion (n = 24) or statistical method (n = 18). CONCLUSIONS: Pediatric CCI has been variably defined with regard to the concepts of patient complexity and chronicity of critical illness. A consensus definition is needed to advance this emerging and important area of pediatric critical care research.

Pediatric refractory immune thrombocytopenia: A systematic review.

Pediatric immune thrombocytopenia (ITP) is an acquired disorder associated with autoimmune destruction and impairment of platelet production in children. Some children exhibit poor or transient response to ITP-directed treatments and are referred to as having refractory ITP (rITP). There is currently no consensus on the definition of rITP, nor evidence-based treatment guidelines for patients with rITP. After a survey of pediatric ITP experts demonstrated lack of consensus on pediatric rITP, we pursued a systematic review to examine the reported clinical phenotypes and treatment outcomes in pediatric rITP. The search identified 253 relevant manuscripts; following review, 11 studies proposed a definition for pediatric rITP with no consensus amongst them. Most definitions included suboptimal response to medical management, while some outlined specific platelet thresholds to define this suboptimal response. Common attributes identified in this study should be used to propose a comprehensive definition, which will facilitate outcome comparisons of future rITP studies.

Assent in Pediatric Critical Care Research: A Cross-Sectional Stakeholder Survey of Canadian Research Ethics Boards, Research Coordinators, Pediatric Critical Care Researchers, and Nurses.

OBJECTIVES: Survey of four stakeholder groups involved in defining and obtaining assent for research in Canadian PICUs to better understand their perspectives and perceived barriers to assent. DESIGN: Cross-sectional survey. SETTING: Fourteen tertiary-care pediatric hospitals in Canada. PARTICIPANTS: Research Ethics Board Chairs, pediatric critical care nurses, research coordinators, and researchers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 193 participants responded. Thirty-seven percent (59/159) thought it was "Never/Almost Never" (59/159, 37%) feasible to obtain assent during the first 48 hours of PICU admission, and 112 of 170 (66%) indicated there are unique barriers to assent at the time of enrollment in PICU studies. Asking children for assent was most frequently rated as Important/Very Important for interviews/focus groups with the child (138/180, 77%), blood sample collection with a needle poke for research (137/178, 77%), and studies involving genetic testing with results communicated to the child/legal guardian (134/180, 74%). In two scenarios where a child and legal guardian disagreed about study participation, most respondents indicated that whether the child should still be enrolled would depend on the patient's age (34-36%), and/or the risk of the study (24-28%). There was a lack of consensus over how the assent process should be operationalized, and when and for how long children should be followed to seek assent for ongoing study participation. Most stakeholders (117/158, 74%) thought that children should have the opportunity to decide if their samples could stay in a biobank once they are old enough to do so. CONCLUSIONS: There was an overall lack of consensus on the feasibility of, and challenges associated with, obtaining assent at the time of study enrollment and on how key aspects of the assent process should be operationalized in the PICU. This highlights the need for guidelines to clarify the assent process in pediatric critical care research.

"We Aren't Meant to Go Through the Hardest Parts of Our Lives Alone": Family Experience With Restricted PICU Presence During the COVID-19 Pandemic.

CONTEXT: PICUs across Canada restricted family presence (RFP) in response to the COVID-19 pandemic from allowing two or more family members to often only one family member at the bedside. The objective of this study was to describe the experiences and impact of RFP on families of critically ill children to inform future policy and practice. HYPOTHESIS: RFP policies negatively impacted families of PICU patients and caused moral distress. METHODS AND MODELS: National, cross-sectional, online, self-administered survey. Family members of children admitted to a Canadian PICU between March 2020 and February 2021 were invited to complete the survey. RFP-attributable distress was measured with a modified distress thermometer (0-10). Closed-ended questions were reported with descriptive statistics and multivariable linear regression assessed factors associated with RFP-attributable distress. Open-ended questions were analyzed using inductive content analysis. RESULTS: Of 250 respondents who experienced RFP, 124 (49.6%) were restricted to one family member at the bedside. The median amount of distress that families attributed to RFP policies was 6 (range: 0-10). Families described isolation, removal of supports, and perception of trauma related to RFP. Most families (183, 73.2%) felt that policies were enforced in a way that made them feel valued by PICU clinicians, which was associated with less RFP-attributable distress. Differential impact was seen where families with lower household income indicated higher RFP-attributable distress score (2.35; 95% CI, 0.53-4.17; p = 0.03). Most respondents suggested that future policies should allow at least two family members at the bedside. INTERPRETATIONS AND CONCLUSIONS: Families of children admitted to PICUs during the COVID-19 pandemic described increased distress, trauma, and removal of supports due to RFP policies. Vulnerable families showed an increased odds of higher distress. Healthcare professionals played an important role in mitigating distress. Allowance of at least two family members at the bedside should be considered for future policy.

Operationalization of assent for research participation in pre-adolescent children: a scoping review.

BACKGROUND: Seeking assent from children for participation in medical research is an ethical imperative of numerous institutions globally. However, none of these organizations provide specific guidance on the criteria or process to be used when obtaining assent. The primary objective of this scoping review was to determine the descriptions of assent discussed in the literature and the reported criteria used for seeking assent for research participation in pre-adolescent children. METHODS: Medline and Embase databases were searched until November 2020 using the term "assent" in the title or abstract. Inclusion criteria were (1) studies enrolling children which specifically described operationalization of the assent process and (2) studies of the assent process which provided a description of assent. Data collected included participant information, patient criteria for seeking assent, guidelines referenced, description of assent reported, how assent was obtained and assent information presented, and reported assent rate. For qualitative articles focusing on the assent process, important themes were identified. RESULTS: A total of 116 articles were included of which 79 (68.9%) operationalized assent and 57 studies (%) described the assent process. The most commonly reported criterion used to determine the ability of a child to assent was age (35.4%, 28/79). The reported minimal age for obtaining pediatric assent varied considerably across and within jurisdictions (5-13 years; median 7.5 years, IQR 7.0, 9.75). Cognitive ability was reported as a criterion for obtaining assent in 5.1% (4/79) of studies. Assent rates were only reported in 17.7% (14/79) of citations and ranged from 32.0 to 100%. Analysis of the 57 studies describing the assent process identified several themes, including age thresholds, assessment of capacity, variable knowledge of pediatric assent and parental roles. CONCLUSION: We found significant variation in criteria used for assessment of patient capacity, delivery of information used to obtain assent and documentation of the assent process. While we acknowledge that individual children, settings and jurisdictions may require different approaches to obtaining assent, there should be agreement on important principles to be followed with resulting common guidance on assessing capacity, delivering information and documentation of the assent process for publication.