2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia.

RATIONALE: New evidence is available examining the use of corticosteroids in sepsis, acute respiratory distress syndrome (ARDS) and community-acquired pneumonia (CAP), warranting a focused update of the 2017 guideline on critical illness-related corticosteroid insufficiency. OBJECTIVES: To develop evidence-based recommendations for use of corticosteroids in hospitalized adults and children with sepsis, ARDS, and CAP. PANEL DESIGN: The 22-member panel included diverse representation from medicine, including adult and pediatric intensivists, pulmonologists, endocrinologists, nurses, pharmacists, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. We followed Society of Critical Care Medicine conflict of interest policies in all phases of the guideline development, including task force selection and voting. METHODS: After development of five focused Population, Intervention, Control, and Outcomes (PICO) questions, we conducted systematic reviews to identify the best available evidence addressing each question. We evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach and formulated recommendations using the evidence-to-decision framework. RESULTS: In response to the five PICOs, the panel issued four recommendations addressing the use of corticosteroids in patients with sepsis, ARDS, and CAP. These included a conditional recommendation to administer corticosteroids for patients with septic shock and critically ill patients with ARDS and a strong recommendation for use in hospitalized patients with severe CAP. The panel also recommended against high dose/short duration administration of corticosteroids for septic shock. In response to the final PICO regarding type of corticosteroid molecule in ARDS, the panel was unable to provide specific recommendations addressing corticosteroid molecule, dose, and duration of therapy, based on currently available evidence. CONCLUSIONS: The panel provided updated recommendations based on current evidence to inform clinicians, patients, and other stakeholders on the use of corticosteroids for sepsis, ARDS, and CAP.

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.

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.

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.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

The Association of Corticosteroids and Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-II Biomarker Risk Stratification With Mortality in Pediatric Septic Shock.

OBJECTIVES: Mortality risk stratification may identify a subset of children who benefit from or are harmed by corticosteroid administration. The Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-II score is a biomarker-based mortality risk stratification tool for pediatric sepsis. Our objective was to assess the association of corticosteroid administration with 28-day mortality within different levels of baseline mortality risk (PERSEVERE-II) in a cohort of children with septic shock. DESIGN: We performed a secondary analysis using prospectively collected data (January 2015 to December 2018). SETTING: PICUs in 13 tertiary care, academic centers in the United States. PATIENTS: Children with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed the association of corticosteroid administration within PERSEVERE-II risk score categories and 28-day mortality, ICU-free days, and maximum failed organs in children with septic shock. We analyzed a total of 461 patients (215 with corticosteroids exposure, 246 without corticosteroid exposure) with an average age of 7.1 years (interquartile range, 2.2-13.6 yr). In the subgroup of patients with a high PERSEVERE-II score, corticosteroid administration was associated with an increased adjusted risk of 28-day mortality (odds ratio [OR] 4.10 [95% CI 1.70-9.86]; p = 0.002), but not in the low risk group (OR 0.20 [95% CI 0.02-1.73]; p = 0.15). A significant interaction between PERSEVERE-II score and corticosteroids was seen for both secondary outcomes complicated course ( p = 0.01) and maximum failed organs ( p < 0.001). Corticosteroid exposure was associated with fewer ICU-free days ( p < 0.0001). CONCLUSIONS: In our multicenter observational study, corticosteroid administration was associated with increased mortality in a subgroup of children with a high PERSEVERE-II risk score.

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.

Reporting of Social Determinants of Health in Pediatric Sepsis Studies.

OBJECTIVE: Standardized, consistent reporting of social determinants of health (SDOH) in studies on children with sepsis would allow for: 1) understanding the association of SDOH with illness severity and outcomes, 2) comparing populations and extrapolating study results, and 3) identification of potentially modifiable socioeconomic factors for policy makers. We, therefore, sought to determine how frequently data on SDOH were reported, which factors were collected and how these factors were defined in studies of sepsis in children. DATA SOURCES AND SELECTION: We reviewed 106 articles (published between 2005 and 2020) utilized in a recent systematic review on physiologic criteria for pediatric sepsis. DATA EXTRACTION: Data were extracted by two reviewers on variables that fell within the World Health Organization's SDOH categories. DATA SYNTHESIS: SDOH were not the primary outcome in any of the included studies. Seventeen percent of articles (18/106) did not report on any SDOH, and a further 36.8% (39/106) only reported on gender/sex. Of the remaining 46.2% of articles, the most reported SDOH categories were preadmission nutritional status (35.8%, 38/106) and race/ethnicity (18.9%, 20/106). However, no two studies used the same definition of the variables reported within each of these categories. Six studies reported on socioeconomic status (3.8%, 6/106), including two from upper-middle-income and four from lower middle-income countries. Only three studies reported on parental education levels (2.8%, 3/106). No study reported on parental job security or structural conflict. CONCLUSIONS: We found overall low reporting of SDOH and marked variability in categorizations and definitions of SDOH variables. Consistent and standardized reporting of SDOH in pediatric sepsis studies is needed to understand the role these factors play in the development and severity of sepsis, to compare and extrapolate study results between settings and to implement policies aimed at improving socioeconomic conditions related to sepsis.

Operationalizing Appropriate Sepsis Definitions in Children Worldwide: Considerations for the Pediatric Sepsis Definition Taskforce.

Sepsis is a leading cause of global mortality in children, yet definitions for pediatric sepsis are outdated and lack global applicability and validity. In adults, the Sepsis-3 Definition Taskforce queried databases from high-income countries to develop and validate the criteria. The merit of this definition has been widely acknowledged; however, important considerations about less-resourced and more diverse settings pose challenges to its use globally. To improve applicability and relevance globally, the Pediatric Sepsis Definition Taskforce sought to develop a conceptual framework and rationale of the critical aspects and context-specific factors that must be considered for the optimal operationalization of future pediatric sepsis definitions. It is important to address challenges in developing a set of pediatric sepsis criteria which capture manifestations of illnesses with vastly different etiologies and underlying mechanisms. Ideal criteria need to be unambiguous, and capable of adapting to the different contexts in which children with suspected infections are present around the globe. Additionally, criteria need to facilitate early recognition and timely escalation of treatment to prevent progression and limit life-threatening organ dysfunction. To address these challenges, locally adaptable solutions are required, which permit individualized care based on available resources and the pretest probability of sepsis. This should facilitate affordable diagnostics which support risk stratification and prediction of likely treatment responses, and solutions for locally relevant outcome measures. For this purpose, global collaborative databases need to be established, using minimum variable datasets from routinely collected data. In summary, a "Think globally, act locally" approach is required.

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.

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.

Criteria for Pediatric Sepsis-A Systematic Review and Meta-Analysis by the Pediatric Sepsis Definition Taskforce.

OBJECTIVE: To determine the associations of demographic, clinical, laboratory, organ dysfunction, and illness severity variable values with: 1) sepsis, severe sepsis, or septic shock in children with infection and 2) multiple organ dysfunction or death in children with sepsis, severe sepsis, or septic shock. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2004, and November 16, 2020. STUDY SELECTION: Case-control studies, cohort studies, and randomized controlled trials in children greater than or equal to 37-week-old postconception to 18 years with suspected or confirmed infection, which included the terms "sepsis," "septicemia," or "septic shock" in the title or abstract. DATA EXTRACTION: Study characteristics, patient demographics, clinical signs or interventions, laboratory values, organ dysfunction measures, and illness severity scores were extracted from eligible articles. Random-effects meta-analysis was performed. DATA SYNTHESIS: One hundred and six studies met eligibility criteria of which 81 were included in the meta-analysis. Sixteen studies (9,629 patients) provided data for the sepsis, severe sepsis, or septic shock outcome and 71 studies (154,674 patients) for the mortality outcome. In children with infection, decreased level of consciousness and higher Pediatric Risk of Mortality scores were associated with sepsis/severe sepsis. In children with sepsis/severe sepsis/septic shock, chronic conditions, oncologic diagnosis, use of vasoactive/inotropic agents, mechanical ventilation, serum lactate, platelet count, fibrinogen, procalcitonin, multi-organ dysfunction syndrome, Pediatric Logistic Organ Dysfunction score, Pediatric Index of Mortality-3, and Pediatric Risk of Mortality score each demonstrated significant and consistent associations with mortality. Pooled mortality rates varied among high-, upper middle-, and lower middle-income countries for patients with sepsis, severe sepsis, and septic shock (p < 0.0001). CONCLUSIONS: Strong associations of several markers of organ dysfunction with the outcomes of interest among infected and septic children support their inclusion in the data validation phase of the Pediatric Sepsis Definition Taskforce.

Balanced Versus Unbalanced Fluid in Critically Ill Children: Systematic Review and Meta-Analysis.

OBJECTIVES: The ideal crystalloid fluid bolus therapy for fluid resuscitation in children remains unclear, but pediatric data are limited. Administration of 0.9% saline has been associated with hyperchloremic metabolic acidosis and acute kidney injury. The primary objective of this systematic review was to compare the effect of balanced versus unbalanced fluid bolus therapy on the mean change in serum bicarbonate or pH within 24 hours in critically ill children. DATA SOURCES: We searched MEDLINE including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, CENTRAL Trials Registry of the Cochrane Collaboration, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform. STUDY SELECTION: Using the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols guidelines, we retrieved all controlled trials and observational cohort studies comparing balanced and unbalanced resuscitative fluids in critically ill children. The primary outcome was the change in serum bicarbonate or blood pH. Secondary outcomes included the prevalence of hyperchloremia, acute kidney injury, renal replacement therapy, and mortality. DATA EXTRACTION: Study screening, inclusion, data extraction, and risk of bias assessments were performed independently by two authors. DATA SYNTHESIS: Among 481 references identified, 13 met inclusion criteria. In the meta-analysis of three randomized controlled trials with a population of 162 patients, we found a greater mean change in serum bicarbonate level (pooled estimate 1.60 mmol/L; 95% CI, 0.04-3.16; p = 0.04) and pH level (pooled mean difference 0.03; 95% CI, 0.00-0.06; p = 0.03) after 4-12 hours of rehydration with balanced versus unbalanced fluids. No differences were found in chloride serum level, acute kidney injury, renal replacement therapy, or mortality. CONCLUSIONS: Our systematic review found some evidence of improvement in blood pH and bicarbonate values in critically ill children after 4-12 hours of fluid bolus therapy with balanced fluid compared with the unbalanced fluid. However, a randomized controlled trial is needed to establish whether these findings have an impact on clinical outcomes before recommendations can be generated.

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.

Prevalence of Acute Rehabilitation for Kids in the PICU: A Canadian Multicenter Point Prevalence Study.

OBJECTIVES: To evaluate mobilization practices, barriers, and mobility-related adverse events in Canadian PICUs. DESIGN: National 2-day point prevalence study. SETTING: Thirteen PICUs across Canada. PATIENTS: Children with a minimum 72-hour PICU length of stay on the allocated study day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes of interest were the prevalence and nature of mobilization activities, rehabilitation resources, adverse events, and factors associated with out-of-bed mobility and therapist-provided mobility. Two PICUs (15%) had early mobilization practice guidelines, and one PICU (8%) reported a formal process for engaging families in the mobilization of patients. The prevalence of mobilization was 110 of 137 patient-days (80%). The commonest activity was out-of-bed mobility (87/137; 64% patient-days); there was no active mobilization on 46 patient-days (34%). Therapists provided mobility on 33% of patient-days. Mobility was most commonly facilitated by nurses (74% events) and family (49% events). Family participation was strongly associated with out-of-bed mobility (odds ratio 6.4; p = 0.001). Intubated, mechanically ventilated patients were mobilized out-of-bed on 18 of 50 patient-days (36%). However, the presence of an endotracheal tube, vasoactive infusions, and age greater than or equal to 3 years were independently associated with not being mobilized out-of-bed. Barriers were reported on 58 of 137 patient-days (42%), and adverse events occurred in 22 of 387 mobility events (6%). CONCLUSIONS: Mobilization is common and safe, and the majority of children in Canadian PICUs are being mobilized out-of-bed, even when mechanically ventilated. Family engagement in PICU-based rehabilitation is increasing. This study provides encouraging evidence that common barriers can be overcome in order to safely mobilize children in PICUs.

Parental Understanding of Research Consent Forms in the PICU: A Pilot Study.

OBJECTIVES: To describe legal guardians' understanding of key concepts in a research consent form presented within 24 hours of their child's admission to the PICU and to explore legal guardians' opinions of the format (language, length) of the consent form and the overall consent process. DESIGN: Single-center, exploratory pilot study. SETTING: PICU at a tertiary-care hospital in Canada. SUBJECTS: Forty-one English- and French-speaking legal guardians of children less than 18 years old, who had been admitted to the PICU within the past 24 hours and were expected to stay at least 48 hours, between October 2018 and February 2019. INTERVENTIONS: The consent form from a previous PICU trial was given and explained to legal guardians within 24 hours of their child's admission to the PICU. MEASUREMENTS AND MAIN RESULTS: Legal guardians' understanding of key concepts in the consent form was evaluated using a questionnaire the day after the form was explained, and opinions were collected verbally and using an additional survey. The median number of questions answered incorrectly was three of seven (interquartile range = 2-4). Participants best understood the topic of the study (5% incorrect), but 80% of participants were unable to recall a single risk. The median rating of the language in the form was five of five (very easy to understand; interquartile range = 4-5), and 88% of participants said it was a reasonable length. CONCLUSIONS: Despite positive opinions of the consent form, most legal guardians did not understand all key components of the consent information provided to them orally and in writing within 24 hours of their child's PICU admission. Future studies are required to determine barriers to understanding and explore alternative approaches to obtaining consent in this setting.

Data initiatives supporting critical care research and quality improvement in Canada: an environmental scan and narrative review.

PURPOSE: Collection and analysis of health data are crucial to achieving high-quality clinical care, research, and quality improvement. This review explores existing hospital, regional, provincial and national data platforms in Canada to identify gaps and barriers, and recommend improvements for data science. SOURCE: The Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group undertook an environmental survey using list-identified names and keywords in PubMed and the grey literature, from the Canadian context. Findings were grouped into sections, corresponding to geography, purpose, and patient sub-group initiatives, using a narrative qualitative approach. Emerging themes, impressions, and recommendations towards improving data initiatives were generated. PRINCIPAL FINDINGS: In Canada, the Canadian Institute for Health Information Discharge Abstract Database contains high-level clinical data on every adult and child discharged from acute care facilities; however, it does not contain data from Quebec, critical care-specific severity of illness risk-adjustment scores, physiologic data, or data pertaining to medication use. Provincially mandated critical care platforms in four provinces contain more granular data, and can be used to risk adjust and link to within-province data sets; however, no inter-provincial collaborative mechanism exists. There is very limited infrastructure to collect and link biological samples from critically ill patients nationally. Comprehensive international clinical data sets may inform future Canadian initiatives. CONCLUSION: Clinical and biological data collection among critically ill patients in Canada is not sufficiently coordinated, and lags behind other jurisdictions. An integrated and inclusive critical care data platform is a key clinical and scientific priority in Canada.

Crowdsourcing the Citation Screening Process for Systematic Reviews: Validation Study.

BACKGROUND: Systematic reviews (SRs) are often cited as the highest level of evidence available as they involve the identification and synthesis of published studies on a topic. Unfortunately, it is increasingly challenging for small teams to complete SR procedures in a reasonable time period, given the exponential rise in the volume of primary literature. Crowdsourcing has been postulated as a potential solution. OBJECTIVE: The feasibility objective of this study was to determine whether a crowd would be willing to perform and complete abstract and full text screening. The validation objective was to assess the quality of the crowd's work, including retention of eligible citations (sensitivity) and work performed for the investigative team, defined as the percentage of citations excluded by the crowd. METHODS: We performed a prospective study evaluating crowdsourcing essential components of an SR, including abstract screening, document retrieval, and full text assessment. Using CrowdScreenSR citation screening software, 2323 articles from 6 SRs were available to an online crowd. Citations excluded by less than or equal to 75% of the crowd were moved forward for full text assessment. For the validation component, performance of the crowd was compared with citation review through the accepted, gold standard, trained expert approach. RESULTS: Of 312 potential crowd members, 117 (37.5%) commenced abstract screening and 71 (22.8%) completed the minimum requirement of 50 citation assessments. The majority of participants were undergraduate or medical students (192/312, 61.5%). The crowd screened 16,988 abstracts (median: 8 per citation; interquartile range [IQR] 7-8), and all citations achieved the minimum of 4 assessments after a median of 42 days (IQR 26-67). Crowd members retrieved 83.5% (774/927) of the articles that progressed to the full text phase. A total of 7604 full text assessments were completed (median: 7 per citation; IQR 3-11). Citations from all but 1 review achieved the minimum of 4 assessments after a median of 36 days (IQR 24-70), with 1 review remaining incomplete after 3 months. When complete crowd member agreement at both levels was required for exclusion, sensitivity was 100% (95% CI 97.9-100) and work performed was calculated at 68.3% (95% CI 66.4-70.1). Using the predefined alternative 75% exclusion threshold, sensitivity remained 100% and work performed increased to 72.9% (95% CI 71.0-74.6; P<.001). Finally, when a simple majority threshold was considered, sensitivity decreased marginally to 98.9% (95% CI 96.0-99.7; P=.25) and work performed increased substantially to 80.4% (95% CI 78.7-82.0; P<.001). CONCLUSIONS: Crowdsourcing of citation screening for SRs is feasible and has reasonable sensitivity and specificity. By expediting the screening process, crowdsourcing could permit the investigative team to focus on more complex SR tasks. Future directions should focus on developing a user-friendly online platform that allows research teams to crowdsource their reviews.