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.

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.

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.

Outcomes of pediatric fluid-refractory septic shock according to different vasoactive strategies: A systematic review and meta-analysis.

BACKGROUND: Hemodynamic support using vasoactive agents is a mainstay in the management of patients with pediatric Fluid-Refractory Septic Shock (FRSS). However, evidence supporting the appropriate choice of vasoactive agent is limited. This study aimed to perform a systematic review and meta-analysis on the effect of different first-line vasoactive strategies on mortality in pediatric FRSS. METHODS: MEDLINE, EMBASE, Scopus, CINAHL, Web of Science, the Cochrane Library, ClinicalTrials.gov, and the ISRCTN registry were searched up until December 2023. Randomized controlled trials and observational cohort studies reporting vasoactive agent-specific outcomes of children with FRSS were included. Mortality was assessed as primary outcome in studies on patients receiving dopamine, epinephrine, or norepinephrine as first-line. Random-effects meta-analyses were conducted. Prevalence ratio (PR) estimates were calculated between two drugs when was available in the same study. FINDINGS: Of the 26,284 identified articles, 13 were included, for a total of 997 children. Twelve studies included 748 patients receiving a single vasoactive agent. Of these, 361 received dopamine, 271 epinephrine, and 116 norepinephrine. Overall pooled mortality for patients receiving a single vasoactive was 12% (95% CI 6-21%) of which 11% (95% CI 3-36%) for patients receiving dopamine, 17% (95% CI 6-37%) for epinephrine, 7% (95% CI 1-48%) for norepinephrine. Four first-line dopamine (176 patients) and first-line epinephrine (142 patients): dopamine showed a tendency towards higher mortality (PR 1.38, 95% CI 0.81-2.38) and a significant higher need for mechanical ventilation (MV) (PR 1.12, 95% CI 1.02-1.22).InterpretationAmong children with FRSS receiving a single vasoactive agent, norepinephrine was associated with the lowest mortality rate. Comparing dopamine and epinephrine, patients receiving epinephrine needed less MV and showed a trend for lower mortality rate. Further research is needed to better delineate the first-line vasoactive agent in this population.

Sex differences in pediatric sepsis-a systematic review protocol.

BACKGROUND: Pediatric sepsis remains a leading cause of childhood morbidity and mortality worldwide. Despite advancements in modern medicine, it accounts for more than 3 million childhood deaths per year. Multiple studies have emphasized that sex and gender have an impact on the treatment and outcome of various diseases. Adult studies have revealed sex differences in pathophysiological responses to septic shock, as well as a possible protective effect of estrogens on critical illness. Sex-specific maturational and developmental differences in host immunology have been previously demonstrated for neonatal and pediatric age groups. At present, there are no studies assessing the impact of sex on outcomes of children with sepsis. METHODS: The goal of this study is to assess sex-specific differences in childhood sepsis survival outcomes. We will systematically assess associations of sex and gender with outcomes in pediatric sepsis in the literature by performing a systematic search of MEDLINE and Embase databases. We will include all English language randomized trials and cohort studies. The study population will include children > 37 weeks gestational age and < 18 years of age. Exposure will be sepsis, severe sepsis, and septic shock and the main comparison will be between male and female sex. The primary outcome will be hospital mortality. Secondary outcomes will be the pediatric intensive care unit and hospital length of stay. DISCUSSION: Results from this review are expected to provide important information on the association of sex with the outcomes of pediatric sepsis. If an association is noted, this study may serve as a foundation for further research evaluating the pathophysiological aspects as well as potential socioeconomic factors responsible for the clinically detected sex differences. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022315753.

Corticosteroids in Sepsis and Septic Shock: A Systematic Review, Pairwise, and Dose-Response Meta-Analysis.

OBJECTIVES: To perform a systematic review and meta-analysis to assess the efficacy and safety of corticosteroids in patients with sepsis. DATA SOURCES: We searched PubMed, Embase, and the Cochrane Library, up to January 10, 2023. STUDY SELECTION: We included randomized controlled trials (RCTs) comparing corticosteroids with placebo or standard care with sepsis. DATA EXTRACTION: The critical outcomes of interest included mortality, shock reversal, length of stay in the ICU, and adverse events. DATA ANALYSIS: We performed both a pairwise and dose-response meta-analysis to evaluate the effect of different corticosteroid doses on outcomes. We used Grading of Recommendations Assessment, Development and Evaluation to assess certainty in pooled estimates. DATA SYNTHESIS: We included 45 RCTs involving 9563 patients. Corticosteroids probably reduce short-term mortality (risk ratio [RR], 0.93; 95% CI, 0.88-0.99; moderate certainty) and increase shock reversal at 7 days (RR, 1.24; 95% CI, 1.11-1.38; high certainty). Corticosteroids may have no important effect on duration of ICU stay (mean difference, -0.6 fewer days; 95% CI, 1.48 fewer to 0.27 more; low certainty); however, probably increase the risk of hyperglycemia (RR, 1.13; 95% CI, 1.08-1.18; moderate certainty) and hypernatremia (RR, 1.64; 95% CI, 1.32-2.03; moderate certainty) and may increase the risk of neuromuscular weakness (RR, 1.21; 95% CI, 1.01-1.45; low certainty). The dose-response analysis showed a reduction in mortality with corticosteroids with optimal dosing of approximately 260 mg/d of hydrocortisone (RR, 0.90; 95% CI, 0.83-0.98) or equivalent. CONCLUSIONS: We found that corticosteroids may reduce mortality and increase shock reversal but they may also increase the risk of hyperglycemia, hypernatremia, and neuromuscular weakness. The dose-response analysis indicates optimal dosing is around 260 mg/d of hydrocortisone or equivalent.

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 trials (RCTs) and observational studies published by investigators in association with the Canadian Critical Care Trials Group (CCCTG). METHODS: 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: 120 publications (28 RCTs, 92 observational studies) enrolled 211,144 participants. Most (107/120, 89.2%) were multicenter studies, and 70% (84/120) were conducted exclusively in Canadian centers; 77.5% (93/120) studies enrolled adult participants, and 19.2% (23/120) 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 which 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 language proficiency, sexual orientation, disability or geography of participants. Of the studies reporting gender, women/girls comprised 42.3% participants (range 8.9 to 67.7%). Within 9 studies reporting race or ethnicity of 2950 participants, 59.7% were white, 8% South Asian, 7% Indigenous, 3% Asian, 1% Black, 14% unknown, and 6% 'Other'. CONCLUSIONS: Research publications from the CCCTG infrequently report important participant demographics, and diversity of research participants is disproportionate compared to Canadian societal demographics.

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.