Adjudication of a primary trial outcome: Results of a calibration exercise and protocol for a large international trial.

Background: Ascertainment of the severity of the primary outcome of upper gastrointestinal (GI) bleeding is integral to stress ulcer prophylaxis trials. This protocol outlines the adjudication process for GI bleeding events in an international trial comparing pantoprazole to placebo in critically ill patients (REVISE: Re-Evaluating the Inhibition of Stress Erosions). The primary objective of the adjudication process is to assess episodes submitted by participating sites to determine which fulfil the definition of the primary efficacy outcome of clinically important upper GI bleeding. Secondary objectives are to categorize the bleeding severity if deemed not clinically important, and adjudicate the bleeding site, timing, investigations, and treatments. Methods: Research coordinators follow patients daily for any suspected clinically important upper GI bleeding, and submit case report forms, doctors' and nurses' notes, laboratory, imaging, and procedural reports to the methods center. An international central adjudication committee reflecting diverse specialty backgrounds conducted an initial calibration exercise to delineate the scope of the adjudication process, review components of the definition, and agree on how each criterion will be considered fulfilled. Henceforth, bleeding events will be stratified by study drug, and randomly assigned to adjudicator pairs (blinded to treatment allocation, and study center). Results: Crude agreement, chance-corrected agreement, or chance-independent agreement if data have a skewed distribution will be calculated. Conclusions: Focusing on consistency and accuracy, central independent blinded duplicate adjudication of suspected clinically important upper GI bleeding events will determine which events fulfil the definition of the primary efficacy outcome for this stress ulcer prophylaxis trial. Registration: NCT03374800 (REVISE: Re-Evaluating the Inhibition of Stress Erosions).

Proton pump inhibitors for gastrointestinal bleeding prophylaxis in critically ill patients: A systematic review protocol.

BACKGROUND: Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for preventing upper gastrointestinal bleeding in critically ill patients. However, concerns have arisen about the possible harms of using PPIs, including potentially increased risk of pneumonia, Clostridioides difficile infection, and more seriously, an increased risk of death in the most severely ill patients. Triggered by the REVISE trial, which is a forthcoming large randomized trial comparing pantoprazole to placebo in invasively mechanically ventilated patients, we will conduct this systematic review to evaluate the efficacy and safety of PPIs versus no prophylaxis for critically ill patients. METHODS: We will systematically search randomized trials that compared gastrointestinal bleeding prophylaxis with PPIs versus placebo or no prophylaxis in adults in the intensive care unit (ICU). Pairs of reviewers will independently screen the literature, and for those eligible trials, extract data and assess risk of bias. We will perform meta-analyses using a random-effects model, and calculate relative risks for dichotomous outcomes and mean differences for continuous outcomes, and the associated 95% confidence intervals. We will conduct subgroup analysis to explore whether the impact of PPIs on mortality differs in more and less severely ill patients. We will assess certainty of evidence using the GRADE approach. DISCUSSION: This systematic review will provide the most up-to-date evidence regarding the merits and limitations of stress ulcer prophylaxis with PPIs in critically ill patients in contemporary practice.

Implementation of an audit and feedback module targeting low-value clinical practices in a provincial trauma quality assurance program: a cost-effectiveness study.

BACKGROUND: Audit and Feedback (A&F) interventions based on quality indicators have been shown to lead to significant improvements in compliance with evidence-based care including de-adoption of low-value practices (LVPs). Our primary aim was to evaluate the cost-effectiveness of adding a hypothetical A&F module targeting LVPs for trauma admissions to an existing quality assurance intervention targeting high-value care and risk-adjusted outcomes. A secondary aim was to assess how certain A&F characteristics might influence its cost-effectiveness. METHODS: We conducted a cost-effectiveness analysis using a probabilistic static decision analytic model in the Québec trauma care continuum. We considered the Québec Ministry of Health perspective. Our economic evaluation compared a hypothetical scenario in which the A&F module targeting LVPs is implemented in a Canadian provincial trauma quality assurance program to a status quo scenario in which the A&F module is not implemented. In scenarios analyses we assessed the impact of A&F characteristics on its cost-effectiveness. Results are presented in terms of incremental costs per LVP avoided. RESULTS: Results suggest that the implementation of A&F module (Cost = $1,480,850; Number of LVPs = 6,005) is associated with higher costs and higher effectiveness compared to status quo (Cost = $1,124,661; Number of LVPs = 8,228). The A&F module would cost $160 per LVP avoided compared to status quo. The A&F module becomes more cost-effective with the addition of facilitation visits; more frequent evaluation; and when only high-volume trauma centers are considered. CONCLUSION: A&F module targeting LVPs is associated with higher costs and higher effectiveness than status quo and has the potential to be cost-effective if the decision-makers' willingness-to-pay is at least $160 per LVP avoided. This likely represents an underestimate of true ICER due to underestimated costs or missed opportunity costs. Results suggest that virtual facilitation visits, frequent evaluation, and implementing the module in high-volume centers can improve cost-effectiveness.

Clinical Practice Guideline Recommendations in Pediatric Mild Traumatic Brain Injury: A Systematic Review.

STUDY OBJECTIVE: Our primary objectives were to identify clinical practice guideline recommendations for children with acute mild traumatic brain injury (mTBI) presenting to an emergency department (ED), appraise their overall quality, and synthesize the quality of evidence and the strength of included recommendations. METHODS: We searched MEDLINE, EMBASE, Cochrane Central, Web of Science, and medical association websites from January 2012 to May 2023 for clinical practice guidelines with at least 1 recommendation targeting pediatric mTBI populations presenting to the ED within 48 hours of injury for any diagnostic or therapeutic intervention in the acute phase of care (ED and inhospital). Pairs of reviewers independently assessed overall clinical practice guideline quality using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The quality of evidence on recommendations was synthesized using a matrix based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Evidence-to-Decision framework. RESULTS: We included 11 clinical practice guidelines, of which 6 (55%) were rated high quality. These included 101 recommendations, of which 34 (34%) were based on moderate- to high-quality evidence, covering initial assessment, initial diagnostic imaging, monitoring/observation, therapeutic interventions, discharge advice, follow-up, and patient and family support. We did not identify any evidence-based recommendations in high-quality clinical practice guidelines for repeat imaging, neurosurgical consultation, or hospital admission. Lack of strategies and tools to aid implementation and editorial independence were the most common methodological weaknesses. CONCLUSIONS: We identified 34 recommendations based on moderate- to high-quality evidence that may be considered for implementation in clinical settings. Our review highlights important areas for future research. This review also underlines the importance of providing strategies to facilitate the implementation of clinical practice guideline recommendations for pediatric mTBI.

REVISE: re-evaluating the inhibition of stress erosions in the ICU-statistical analysis plan for a randomized trial.

BACKGROUND: The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in invasively ventilated critically ill patients. OBJECTIVE: To outline the statistical analysis plan for the REVISE trial. METHODS: REVISE is a randomized clinical trial ongoing in intensive care units (ICUs) internationally. Patients ≥ 18 years old, receiving invasive mechanical ventilation, and expected to remain ventilated beyond the calendar day after randomization are allocated to either 40 mg pantoprazole intravenously or placebo while mechanically ventilated. RESULTS: The primary efficacy outcome is clinically important upper GI bleeding; the primary safety outcome is 90-day mortality. Secondary outcomes are ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine concentration, and duration of mechanical ventilation, ICU, and hospital length of stay. Following an interim analysis of results from 2400 patients (50% of 4800 target sample size), the data monitoring committee recommended continuing enrolment. CONCLUSIONS: This statistical analysis plan outlines the statistical analyses of all outcomes, sensitivity analyses, and subgroup analyses. REVISE will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT03374800. November 21, 2017.

REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol.

INTRODUCTION: The Re-Evaluating the Inhibition of Stress Erosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE. METHODS AND ANALYSIS: REVISE is an international, randomised, concealed, stratified, blinded parallel-group individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial. ETHICS AND DISSEMINATION: All participating centres receive research ethics approval before initiation by hospital, region or country, including, but not limited to - Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissão Nacional de Ética em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. The results of this trial will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION NUMBER: NCT03374800.

Small-Volume Blood Collection Tubes to Reduce Transfusions in Intensive Care: The STRATUS Randomized Clinical Trial.

Importance: Blood collection for laboratory testing in intensive care unit (ICU) patients is a modifiable contributor to anemia and red blood cell (RBC) transfusion. Most blood withdrawn is not required for analysis and is discarded. Objective: To determine whether transitioning from standard-volume to small-volume vacuum tubes for blood collection in ICUs reduces RBC transfusion without compromising laboratory testing procedures. Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 25 adult medical-surgical ICUs in Canada (February 5, 2019 to January 21, 2021). Interventions: ICUs were randomized to transition from standard-volume (n = 10 940) to small-volume tubes (n = 10 261) for laboratory testing. Main Outcomes and Measures: The primary outcome was RBC transfusion (units per patient per ICU stay). Secondary outcomes were patients receiving at least 1 RBC transfusion, hemoglobin decrease during ICU stay (adjusted for RBC transfusion), specimens with insufficient volume for testing, length of stay in the ICU and hospital, and mortality in the ICU and hospital. The primary analysis included patients admitted for 48 hours or more, excluding those admitted during a 5.5-month COVID-19-related trial hiatus. Results: In the primary analysis of 21 201 patients (mean age, 63.5 years; 39.9% female), which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference in RBC units per patient per ICU stay (relative risk [RR], 0.91 [95% CI, 0.79 to 1.05]; P = .19; absolute reduction of 7.24 RBC units/100 patients per ICU stay [95% CI, -3.28 to 19.44]). In a prespecified secondary analysis (n = 27 411 patients), RBC units per patient per ICU stay decreased after transition from standard-volume to small-volume tubes (RR, 0.88 [95% CI, 0.77 to 1.00]; P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay [95% CI, 0.24 to 20.76]). Median decrease in transfusion-adjusted hemoglobin was not statistically different in the primary population (mean difference, 0.10 g/dL [95% CI, -0.04 to 0.23]) and lower in the secondary population (mean difference, 0.17 g/dL [95% CI, 0.05 to 0.29]). Specimens with insufficient quantity for analysis were rare (≤0.03%) before and after transition. Conclusions and Relevance: Use of small-volume blood collection tubes in the ICU may decrease RBC transfusions without affecting laboratory analysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03578419.

Pediatric vs Adult or Mixed Trauma Centers in Children Admitted to Hospitals Following Trauma: A Systematic Review and Meta-Analysis.

Importance: Adult trauma centers (ATCs) have been shown to decrease injury mortality and morbidity in major trauma, but a synthesis of evidence for pediatric trauma centers (PTCs) is lacking. Objective: To assess the effectiveness of PTCs compared with ATCs, combined trauma centers (CTCs), or nondesignated hospitals in reducing mortality and morbidity among children admitted to hospitals following trauma. Data Sources: MEDLINE, Embase, and Web of Science through March 2023. Study Selection: Studies comparing PTCs with ATCs, CTCs, or nondesignated hospitals for pediatric trauma populations (aged ≤19 years). Data Extraction and Synthesis: This systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Review and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology guidelines. Pairs of reviewers independently extracted data and evaluated risk of bias using the Risk of Bias in Nonrandomized Studies of Interventions tool. A meta-analysis was conducted if more than 2 studies evaluated the same intervention-comparator-outcome and controlled minimally for age and injury severity. Subgroup analyses were planned for age, injury type and severity, trauma center designation level and verification body, country, and year of conduct. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess certainty of evidence. Main Outcome(s) and Measure(s): Primary outcomes were mortality, complications, functional status, discharge destination, and quality of life. Secondary outcomes were resource use and processes of care, including computed tomography (CT) and operative management of blunt solid organ injury (SOI). Results: A total of 56 studies with 286 051 participants were included overall, and 34 were included in the meta-analysis. When compared with ATCs, PTCs were associated with a 41% lower risk of mortality (OR, 0.59; 95% CI, 0.46-0.76), a 52% lower risk of CT use (OR, 0.48; 95% CI, 0.26-0.89) and a 64% lower risk of operative management for blunt SOI (OR, 0.36; 95% CI, 0.23-0.57). The OR for complications was 0.80 (95% CI, 0.41-1.56). There was no association for mortality for older children (OR, 0.71; 95% CI, 0.47-1.06), and the association was closer to the null when PTCs were compared with CTCs (OR, 0.73; 95% CI, 0.53-0.99). Results remained similar for other subgroup analyses. GRADE certainty of evidence was very low for all outcomes. Conclusions and Relevance: In this systematic review and meta-analysis, results suggested that PTCs were associated with lower odds of mortality, CT use, and operative management for SOI than ATCs for children admitted to hospitals following trauma, but certainty of evidence was very low. Future studies should strive to address selection and confounding biases.

Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial.

BACKGROUND: Critically ill patients commonly receive proton pump inhibitors (PPIs) to prevent gastrointestinal (GI) bleeding from stress-induced ulceration. Despite widespread use in the intensive care unit (ICU), observational data suggest that PPIs may be associated with adverse outcomes in patients with COVID-19 infection. This preplanned study is nested within a large randomized trial evaluating pantoprazole versus placebo in invasively ventilated patients. The 3 objectives are as follows: (1) to describe the characteristics of patients with COVID-19 in terms of demographics, biomarkers, venous thromboembolism, tracheostomy incidence and timing, and other clinical outcomes; (2) to evaluate the impact of COVID-19 infection on clinically important GI bleeding, 90-day mortality, and other outcomes compared to a propensity-matched non-infected cohort; and (3) to explore whether pantoprazole has a differential treatment effect on clinically important GI bleeding, 90-day mortality, and other outcomes in patients with and without COVID-19 infection. METHODS: The ongoing trial Re-EValuating the Inhibition of Stress Erosions (REVISE) compares pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important GI bleeding and the primary safety outcome of 90-day mortality. The protocol described in this report is for a substudy focused on patients with COVID-19 infection that was not in the original pre-pandemic trial protocol. We developed a one-page case report form to characterize these patients including data related to biomarkers, venous thromboembolism, COVID-19 therapies, tracheostomy incidence and timing, duration of mechanical ventilation, and ICU and hospital stay. Our analysis will describe the trajectory of patients with COVID-19 infection, a propensity-matched analysis of infected and non-infected patients, and an extended subgroup analysis comparing the effect of PPI among patients with and without COVID-19 infection. DISCUSSION: Prophylactic acid suppression in invasively ventilated critically ill patients with COVID-19 infection has unknown consequences. The results of these investigations will inform practice, guidelines, and future research. TRIAL REGISTRATION: REVISE Trial [NCT03374800 December 15, 2017], COVID-19 Cohort Study [NCT05715567 February 8, 2023].

Calcineurin Inhibition in Deceased Organ Donors: A Systematic Review and Meta-analysis of Preclinical Studies.

Background: Preconditioning deceased organ donors with calcineurin inhibitors (CNIs) may reduce ischemia-reperfusion injury to improve transplant outcomes. Methods: We searched MEDLINE, EMBASE, Cochrane Library, and conference proceedings for animal models of organ donation and transplantation, comparing donor treatment with CNIs with either placebo or no intervention, and evaluating outcomes for organ transplantation. Reviewers independently screened and selected studies, abstracted data, and assessed the risk of bias and clinical relevance of included studies. Where possible, we pooled results using meta-analysis; otherwise, we summarized findings descriptively. Results: Eighteen studies used various animals and a range of CNI agents and doses and evaluated their effects on a variety of transplant outcomes. The risk of bias and clinical applicability were poorly reported. Pooled analyses suggested benefit of CNI treatment on early graft function in renal transplants (3 studies; serum creatinine: ratio of means [RoM] 0.54; 95% confidence interval [CI], 0.34-0.86) but not for liver transplants (2 studies; serum alanine transaminase: RoM 0.61; 95% CI, 0.30-1.26; and serum aspartate aminotransferase: RoM 0.58; 95% CI, 0.26-1.31). We found no reduction in graft loss at 7 d (2 studies; risk ratio 0.54; 95% CI, 0.08-3.42). CNI treatment was associated with reduced transplant recipient levels of interleukin-6 (4 studies; RoM 0.36; 95% CI, 0.19-0.70), tumor necrosis factor-alpha (5 studies; RoM 0.36; 95% CI, 0.12-1.03), and cellular apoptosis (4 studies; RoM 0.30; 95% CI, 0.19-0.47). Conclusions: Although this compendium of animal experiments suggests that donor preconditioning with CNIs may improve early kidney graft function, the limited ability to reproduce a true clinical environment in animal experiments and to assess for risk of bias in these experiments is a serious weakness that precludes current clinical application.

Clinical Practice Guideline Recommendations in Pediatric Orthopaedic Injury: A Systematic Review.

BACKGROUND: Lack of adherence to recommendations on pediatric orthopaedic injury care may be driven by lack of knowledge of clinical practice guidelines (CPGs), heterogeneity in recommendations or concerns about their quality. We aimed to identify CPGs for pediatric orthopaedic injury care, appraise their quality, and synthesize the quality of evidence and the strength of associated recommendations. METHODS: We searched Medline, Embase, Cochrane CENTRAL, Web of Science and websites of clinical organizations. CPGs including at least one recommendation targeting pediatric orthopaedic injury populations on any diagnostic or therapeutic intervention developed in the last 15 years were eligible. Pairs of reviewers independently extracted data and evaluated CPG quality using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. We synthesized recommendations from high-quality CPGs using a recommendations matrix based on the GRADE Evidence-to-Decision framework. RESULTS: We included 13 eligible CPGs, of which 7 were rated high quality. Lack of stakeholder involvement and applicability (i.e., implementation strategies) were identified as weaknesses. We extracted 53 recommendations of which 19 were based on moderate or high-quality evidence. CONCLUSIONS: We provide a synthesis of recommendations from high-quality CPGs that can be used by clinicians to guide treatment decisions. Future CPGs should aim to use a partnership approach with all key stakeholders and provide strategies to facilitate implementation. This study also highlights the need for more rigorous research on pediatric orthopaedic trauma. LEVEL OF EVIDENCE: Level II-therapeutic study.

Evaluating the effectiveness of a multifaceted intervention to reduce low-value care in adults hospitalized following trauma: a protocol for a pragmatic cluster randomized controlled trial.

BACKGROUND: While simple Audit & Feedback (A&F) has shown modest effectiveness in reducing low-value care, there is a knowledge gap on the effectiveness of multifaceted interventions to support de-implementation efforts. Given the need to make rapid decisions in a context of multiple diagnostic and therapeutic options, trauma is a high-risk setting for low-value care. Furthermore, trauma systems are a favorable setting for de-implementation interventions as they have quality improvement teams with medical leadership, routinely collected clinical data, and performance-linked to accreditation. We aim to evaluate the effectiveness of a multifaceted intervention for reducing low-value clinical practices in acute adult trauma care. METHODS: We will conduct a pragmatic cluster randomized controlled trial (cRCT) embedded in a Canadian provincial quality assurance program. Level I-III trauma centers (n = 30) will be randomized (1:1) to receive simple A&F (control) or a multifaceted intervention (intervention). The intervention, developed using extensive background work and UK Medical Research Council guidelines, includes an A&F report, educational meetings, and facilitation visits. The primary outcome will be the use of low-value initial diagnostic imaging, assessed at the patient level using routinely collected trauma registry data. Secondary outcomes will be low-value specialist consultation, low-value repeat imaging after a patient transfer, unintended consequences, determinants for successful implementation, and incremental cost-effectiveness ratios. DISCUSSION: On completion of the cRCT, if the intervention is effective and cost-effective, the multifaceted intervention will be integrated into trauma systems across Canada. Medium and long-term benefits may include a reduction in adverse events for patients and an increase in resource availability. The proposed intervention targets a problem identified by stakeholders, is based on extensive background work, was developed using a partnership approach, is low-cost, and is linked to accreditation. There will be no attrition, identification, or recruitment bias as the intervention is mandatory in line with trauma center designation requirements, and all outcomes will be assessed with routinely collected data. However, investigators cannot be blinded to group allocation and there is a possibility of contamination bias that will be minimized by conducting intervention refinement only with participants in the intervention arm. TRIAL REGISTRATION: This protocol has been registered on ClinicalTrials.gov (February 24, 2023, # NCT05744154 ).

Tracheostomy versus prolonged intubation in moderate to severe traumatic brain injury: a multicentre retrospective cohort study.

PURPOSE: Tracheostomy is a surgical procedure that is commonly performed in patients admitted to the intensive care unit (ICU). It is frequently required in patients with moderate to severe traumatic brain injury (TBI), a subset of patients with prolonged altered state of consciousness that may require a long period of mechanical respiratory assistance. While many clinicians favour the use of early tracheostomy in TBI patients, the evidence in favour of this practice remains scarce. The aims of our study were to evaluate the potential clinical benefits of tracheostomy versus prolonged endotracheal intubation, as well as whether the timing of the procedure may influence outcome in patients with moderate to severe TBI. METHODS: We conducted a retrospective multicentre cohort study based on data from the provincial integrated trauma system of Quebec (Québec Trauma Registry). The study population was selected from adult trauma patients hospitalized between 2013 and 2019. We included patients 16 yr and older with moderate to severe TBI (Glasgow Coma Scale score < 13) who required mechanical ventilation for 96 hr or longer. Our primary outcome was 30-day mortality. Secondary outcomes included hospital and ICU mortality, six-month mortality, duration of mechanical ventilation, ventilator-associated pneumonia, ICU and hospital length of stay as well as orientation of patients upon discharge from the hospital. We used propensity score covariate adjustment. To overcome the effect of immortal time bias, an extended Cox shared frailty model was used to compare mortality between groups. RESULTS: From 2013 to 2019, 26,923 patients with TBI were registered in the Québec Trauma Registry. A total of 983 patients who required prolonged endotracheal intubation for 96 hr or more were included in the study, 374 of whom underwent a tracheostomy and 609 of whom remained intubated. We observed a reduction in 30-day mortality (adjusted hazard ratio, 0.33; 95% confidence interval, 0.21 to 0.53) associated with tracheostomy compared with prolonged endotracheal intubation. This effect was also seen in the ICU as well as at six months. Tracheostomy, when compared with prolonged endotracheal intubation, was associated with an increase in the duration of mechanical respiratory assistance without any increase in the length of stay. No effect on mortality was observed when comparing early vs late tracheostomy procedures. An early procedure was associated with a reduction in the duration of mechanical respiratory support as well as hospital and ICU length of stay. CONCLUSION: In this multicentre cohort study, tracheostomy was associated with decreased mortality when compared with prolonged endotracheal intubation in patients with moderate to severe TBI. This effect does not appear to be modified by the timing of the procedure. Nevertheless, the generalization and application of these results remains limited by potential residual time-dependent indication bias.

RéSUMé: INTRODUCTION: La trachéotomie est une intervention chirurgicale communément pratiquée chez les personnes admises à l'unité de soins intensifs (USI). Elle est fréquemment requise chez les patient·es victimes d'un traumatisme craniocérébral (TCC) modéré à grave, un sous-groupe présentant une altération prolongée de l'état de conscience qui peut nécessiter une longue période d'assistance respiratoire mécanique. Bien que bon nombre de cliniciens et cliniciennes soient favorables à l'utilisation d'une trachéotomie précoce chez cette patientèle, les données probantes en faveur de cette pratique restent insuffisantes. Les objectifs de notre étude étaient d'évaluer l'effet de la trachéotomie par rapport à l'intubation endotrachéale prolongée, ainsi que si le moment où la procédure est effectuée pouvait influencer cet effet, chez les personnes ayant subi un TCC modéré à grave. MéTHODES: Nous avons effectué une étude de cohorte rétrospective multicentrique basée sur le système provincial intégré de traumatologie du Québec (Registre des traumatismes du Québec). La population de l'étude a été sélectionnée parmi les patient·es adultes victimes de traumatismes hospitalisé·es entre 2013 et 2019. Nous avons inclus les patient·es âgé·es de 16 ans et plus présentant un TCC modéré à grave (score sur l'échelle de coma de Glasgow [GCS] < 13) ayant nécessité une assistance respiratoire mécanique pendant 96 h ou plus. Notre critère d'évaluation principal était la mortalité à 30 jours. Les critères d'évaluation secondaires comprenaient la mortalité hospitalière et à l'USI, la mortalité à 6 mois, la durée d'assistance respiratoire mécanique, les pneumonies acquises en lien avec l'assistance respiratoire mécanique, les durées de séjour à l'USI et à l'hôpital ainsi que l'orientation des patient·es à leur sortie de l'hôpital. Nous avons utilisé un score de propension pour l'ajustement des covariables. Pour corriger l'effet du biais du temps immortel, un modèle de régression de la fragilité partagée de Cox étendu a été utilisé pour estimer la mortalité entre les groupes. RéSULTATS: De 2013 à 2019, 26 923 personnes victimes de TCC ont été inscrites dans le Registre des traumatismes du Québec. Un total de 983 patient·es ayant nécessité une intubation endotrachéale prolongée de 96 h ou plus ont été inclus·es dans l'étude, dont 374 ont subi une trachéotomie et 609 sont resté·es intubé·es. Nous avons observé une réduction de la mortalité à 30 jours (aHR : 0,33 [0,21 − 0,53]) associée à la trachéotomie en comparaison à l'intubation endotrachéale prolongée. Cet effet a également été observé à l'USI ainsi qu'à 6 mois. La trachéotomie, comparée à l'intubation endotrachéale prolongée, était associée à une augmentation de la durée d'assistance respiratoire mécanique sans augmentation de la durée de séjour. Aucun effet sur la mortalité n'a été observé en comparant les procédures de trachéotomie précoces et tardive. Une procédure précoce a été associée à une réduction de la durée d'assistance respiratoire mécanique ainsi que la durée de séjour à l'USI et à l'hôpital. CONCLUSION: Dans cette étude de cohorte multicentrique, nous avons observé que la trachéotomie est associée à une diminution de la mortalité en comparaison à l'intubation endotrachéale prolongée chez la patientèle ayant subi un TCC modéré ou grave. Cet effet ne semble pas modifié par le moment de la procédure durant l'hospitalisation. La généralisation et l'application de ces résultats restent toutefois limitées par un biais d'indication résiduel potentiel.

Association of age with death and withdrawal of life-sustaining therapy after severe traumatic brain injury.

BACKGROUND: Compared to younger age, older age (≥ 65 yr) is associated with worse outcomes after severe traumatic brain injury (TBI). We sought to describe the association of older age with in-hospital death and aggressiveness of intervention. METHODS: We conducted a retrospective cohort study of adult (age ≥ 16 yr) patients with severe TBI admitted to a single academic tertiary care neurotrauma centre between January 2014 and December 2015. We collected data through chart review as well as from our institutional administrative database. We provided descriptive statistics and used multivariable logistic regression to evaluate the independent association of age with the primary outcome, in-hospital death. The secondary outcome was early withdrawal of life-sustaining therapy. RESULTS: There were 126 adult patients (median age 67 yr [Q1-Q3, 33-80 yr]) with severe TBI during the study period who met our eligibility criteria. The most common mechanism was high-velocity blunt injury (55 patients [43.6%]). The median Marshall score was 4 (Q1-Q3, 2-6), and the median Injury Severity Score was 26 (Q1-Q3, 25-35). After controlling for confounders including clinical frailty, pre-existing comorbidity, injury severity, Marshall score and neurologic examination at admission, we observed that older patients were more likely than younger patients to die in hospital (odds ratio 5.10, 95% confidence interval 1.65-15.78). Older patients were also more likely to experience early withdrawal of life-sustaining therapy and less likely to receive invasive interventions. CONCLUSION: After controlling for confounding factors relevant to older patients, we observed that age was an important and independent predictor of in-hospital death and early withdrawal of life-sustaining therapy. The mechanism by which age influences clinical decision-making independent of global and neurologic injury severity, clinical frailty and comorbidities remains unclear.

Potential Avoidable Costs of Low-Value Clinical Practices in Acute Injury Care in an Integrated Canadian Provincial Trauma System.

This economic evaluation estimated the direct health care costs associated with 11 low-value clinical practices in acute trauma care in the integrated health care system of Quebec, Canada.

Clinical practice guideline recommendations for pediatric solid organ injury care: A Systematic Review.

BACKGROUND: Observed variations in the management of pediatric solid organ injuries (SOIs) may be due to difficulty in finding and integrating recommendations from multiple clinical practice guidelines (CPGs) with heterogeneous methodological approaches. We aimed to systematically review CPG recommendations for pediatric SOIs. METHODS: We conducted a systematic review of CPGs including at least one recommendation targeting pediatric SOI populations, using Medical Analysis and Retrieval System Online, Excerpta Medica dataBASE, Web of Science, and websites of clinical organizations. Pairs of reviewers independently assessed eligibility, extracted data, and evaluated the quality of CPGs using the Appraisal of Guidelines Research and Evaluation II tool. We synthesized recommendations from moderate to high-quality CPGs using a recommendations matrix based on Grades of Recommendation, Assessment, Development, and Evaluation criteria. RESULTS: We identified eight CPGs, including three rated moderate or high quality. Methodological weaknesses included lack of stakeholder involvement beyond surgeons, consideration of applicability (e.g., implementation tools), and clarity around the definition of pediatric populations. Five of the 15 recommendations from moderate to high-quality CPGs were based on moderate quality evidence or were rated as strong; these reflected nonoperative management and angioembolization for renal injuries and required length of stay for liver and spleen injuries. CONCLUSION: We identified 15 recommendations on pediatric SOI management from 3 moderate or high-quality CPGs, but only one third were based on at least moderate-quality evidence or were rated as strong. Our results prompt the following recommendations for future CPG development or updates: (1) include all types of clinicians involved in the care of pediatric SOIs and patient and family representatives in the process, (2) develop clear definitions of the target population, and (3) provide advice and tools to promote implementation. Results also underline the urgent need for more rigorous research to support strong evidence-based recommendations in this population. LEVEL OF EVIDENCE: Systematic Review/Meta-analysis; Level III.

Pediatric Moderate and Severe Traumatic Brain Injury: A Systematic Review of Clinical Practice Guideline Recommendations.

Traumatic brain injury (TBI) is the leading cause of death and disability in children. Many clinical practice guidelines (CPGs) have addressed pediatric TBI in the last decade but significant variability in the use of these guidelines persists. Here, we systematically review CPGs recommendations for pediatric moderate-to-severe TBI, evaluate the quality of CPGs, synthesize the quality of evidence and strength of included recommendations, and identify knowledge gaps. A systematic search was conducted in MEDLINE®, Embase, Cochrane CENTRAL, Web of Science, and Web sites of organizations publishing recommendations on pediatric injury care. We included CPGs developed in high-income countries from January 2012 to May 2023, with at least one recommendation targeting pediatric (≤ 19 years old) moderate-to-severe TBI populations. The quality of included clinical practice guidelines was assessed using the AGREE II tool. We synthesized evidence on recommendations using a matrix based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. We identified 15 CPGs of which 9 were rated moderate to high quality using AGREE II. We identified 90 recommendations, of which 40 (45%) were evidence based. Eleven of these were based on moderate to high quality evidence and were graded as moderate or strong by at least one guideline. These included transfer, imaging, intracranial pressure control, and discharge advice. We identified gaps in evidence-based recommendations for red blood cell transfusion, plasma and platelet transfusion, thromboprophylaxis, surgical antimicrobial prophylaxis, early diagnosis of hypopituitarism, and mental health mangement. Many up-to-date CPGs are available, but there is a paucity of evidence to support recommendations, highlighting the urgent need for robust clinical research in this vulnerable population. Our results may be used by clinicians to identify recommendations based on the highest level of evidence, by healthcare administrators to inform guideline implementation in clinical settings, by researchers to identify areas where robust evidence is needed, and by guideline writing groups to inform the updating of existing guidelines or the development of new ones.

Sex differences in thromboprophylaxis of the critically ill: a secondary analysis of a randomized trial.

PURPOSE: Venous thromboembolism (VTE) is a common complication of critical illness. Sex- or gender-based analyses are rarely conducted and their effect on outcomes is unknown. We assessed for an effect modification of thromboprophylaxis (dalteparin or unfractionated heparin [UFH]) by sex on thrombotic (deep venous thrombosis [DVT], pulmonary embolism [PE], VTE) and mortality outcomes in a secondary analysis of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT). METHODS: We conducted unadjusted analyses using Cox proportional hazards analysis, stratified by centre and admission diagnostic category, including sex, treatment, and an interaction term. Additionally, we performed adjusted analyses and assessed the credibility of our findings. RESULTS: Critically ill female (n = 1,614) and male (n = 2,113) participants experienced similar rates of DVT, proximal DVT, PE, any VTE, ICU death, and hospital death. In unadjusted analyses, we did not find significant differences in treatment effect favouring males (vs females) treated with dalteparin (vs UFH) for proximal leg DVT, any DVT, or any PE, but found a statistically significant effect (moderate certainty) favouring dalteparin in males for any VTE (males: hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52 to 0.96 vs females: HR, 1.16; 95% CI, 0.81 to 1.68; P = 0.04). This effect remained after adjustment for baseline characteristics (males: HR, 0.70; 95% CI, 0.52 to 0.96 vs females: HR, 1.17; 95% CI, 0.81 to 1.68; P = 0.04) and weight (males: HR, 0.70; 95% CI, 0.52 to 0.96 vs females: HR, 1.20; 95% CI, 0.83 to 1.73; P = 0.03). We did not identify a significant effect modification by sex on mortality. CONCLUSIONS: We found an effect modification by sex of thromboprophylaxis on VTE in critically ill patients that requires confirmation. Our findings highlight the need for sex- and gender-based analyses in acute care research.

RéSUMé: OBJECTIF: La maladie thromboembolique veineuse (MTEV) est une complication fréquente au cours des maladies critiques. Des analyses basées sur le sexe ou le genre sont rarement effectuées et leur effet sur les critères d'évaluation est inconnu. Nous avons évalué une modification de l'effet de la thromboprophylaxie (daltéparine ou héparine non fractionnée [HNF]) selon le sexe sur la maladie thrombotique (thrombose veineuse profonde [TVP], embolie pulmonaire [EP], MTEV) et sur les critères de mortalité au cours d'une analyse secondaire de l'étude PROTECT (essai de prophylaxie de la thromboembolie en soins critiques). MéTHODE: Nous avons réalisé des analyses non ajustées au moyen d'une analyse des risques proportionnels de Cox, stratifiées par site et catégorie diagnostique à l'admission, incluant le sexe, le traitement et un terme d'interaction. Nous avons aussi réalisé des analyses ajustées et avons évalué la crédibilité de nos constatations. RéSULTATS: Les participant·es dans un état critique de sexe féminin (n = 1 614) et masculin (n = 2 113) ont présenté des taux semblables de TVP, EP, et MTEV de tout type, de décès en soins intensifs et de décès en milieu hospitalier. Nous n'avons pas trouvé de différences significatives dans les analyses non ajustées en faveur des hommes (par rapport aux femmes) traités par la daltéparine (par rapport à l'HNF) pour la TVP de la cuisse, la TVP de tout type, ou tout type d'EP; en revanche, nous avons trouvé un effet statistiquement significatif (certitude modérée) en faveur de la daltéparine pour la MTEV de tout type (hommes : rapport de risque [RR], 0,71; intervalle de confiance [IC] à 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,16; IC 95 %, 0,81 à 1,68; P = 0,04). Cet effet a persisté après ajustement pour les caractéristiques à l'inclusion (hommes : RR, 0,70; IC 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,17; IC 95 %, 0,81 à 1,68; P = 0,04) et le poids (hommes : RR, 0,70; IC 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,20; IC 95 %, 0,83 à 1,73; P = 0,03). Nous n'avons pas identifié de modification significative de l'effet en fonction du sexe sur la mortalité. CONCLUSION: Nous avons trouvé une modification de l'effet en fonction du sexe sur la thromboprophylaxie sur la MTEV chez les patient·es en état critique; cette constatation nécessite une confirmation. Nos constatations soulignent le besoin d'analyses en fonction du sexe et du genre dans la recherche sur les soins aigus.

Diagnostic accuracy of ancillary tests for death by neurologic criteria: a systematic review and meta-analysis.

PURPOSE: Ancillary tests are frequently used in death determination by neurologic criteria (DNC), particularly when the clinical neurologic examination is unreliable. Nevertheless, their diagnostic accuracy has not been extensively studied. Our objective was to synthesize the sensitivity and specificity of commonly used ancillary tests for DNC. SOURCE: We performed a systematic review and meta-analysis by searching MEDLINE, EMBASE, Cochrane databases, and CINAHL Ebsco from their inception to 4 February 2022. We selected cohort and case-control studies including patients with 1) clinically diagnosed death by neurologic criteria or 2) clinically suspected death by neurologic criteria who underwent ancillary testing for DNC. We excluded studies without a priori diagnostic criteria and studies conducted solely on pediatric patients. Accepted reference standards were clinical examination, four-vessel conventional angiography, and radionuclide imaging. Data were directly extracted from published reports. We assessed the methodological quality of studies with the QUADAS-2 tool and estimated ancillary test sensitivities and specificities using hierarchical Bayesian models with diffuse priors. PRINCIPAL FINDINGS: Overall, 137 records met the selection criteria. One study (0.7%) had a low risk of bias in all QUADAS-2 domains. Among clinically diagnosed death by neurologic criteria patients (n = 8,891), ancillary tests had similar pooled sensitivities (range, 0.82-0.93). Sensitivity heterogeneity was greater within (σ = 0.10-0.15) than between (σ = 0.04) ancillary test types. Among clinically suspected death by neurologic criteria patients (n = 2,732), pooled ancillary test sensitivities ranged between 0.81 and 1.00 and specificities between 0.87 and 1.00. Most estimates had high statistical uncertainty. CONCLUSION: Studies assessing ancillary test diagnostic accuracy have an unclear or high risk of bias. High-quality studies are required to thoroughly validate ancillary tests for DNC. STUDY REGISTRATION: PROSPERO (CRD42013005907); registered 7 October 2013.

RéSUMé: OBJECTIF: Les examens auxiliaires sont fréquemment utilisés dans la détermination du décès selon des critères neurologiques (DCN), en particulier lorsque l'examen neurologique clinique n'est pas fiable. Néanmoins, leur précision diagnostique n'a pas été étudiée de manière approfondie. Notre objectif était de synthétiser la sensibilité et la spécificité des examens auxiliaires couramment utilisés pour la DCN. SOURCES: Nous avons réalisé une revue systématique et une méta-analyse en effectuant des recherches dans les bases de données MEDLINE, EMBASE, Cochrane et CINAHL Ebsco de leur création jusqu'au 4 février 2022. Nous avons sélectionné des études de cohorte et cas témoins incluant des patients présentant 1) un décès selon des critères neurologiques diagnostiqué cliniquement ou 2) un décès selon des critères neurologiques soupçonné cliniquement qui ont été soumis à des examens auxiliaires pour un DCN. Nous avons exclu les études sans critères diagnostiques a priori et les études menées uniquement auprès de patients pédiatriques. Les normes de référence acceptées étaient l'examen clinique, l'angiographie conventionnelle à quatre vaisseaux et l'imagerie nucléaire. Les données ont été directement extraites de comptes rendus publiés. Nous avons évalué la qualité méthodologique des études avec l'outil QUADAS-2 et estimé les sensibilités et les spécificités des examens auxiliaires à l'aide de modèles hiérarchiques bayésiens avec des distributions préalables diffuses. CONSTATATIONS PRINCIPALES: Au total, 137 études répondaient aux critères de sélection. Une étude (0,7 %) présentait un faible risque de biais dans tous les domaines de QUADAS-2. Parmi les patients ayant reçu un diagnostic clinique de décès selon des critères neurologiques (n = 8891), les examens auxiliaires présentaient des sensibilités combinées similaires (intervalle de 0,82 à 0,93). L'hétérogénéité de sensibilité était plus grande au sein (σ = 0,10-0,15) plutôt qu'entre (σ = 0,04) les types d'examens auxiliaires. Parmi les patients cliniquement soupçonnés de décès selon des critères neurologiques (n = 2732), les sensibilités combinées des examens auxiliaires variaient entre 0,81 et 1,00 et les spécificités entre 0,87 et 1,00. La plupart des estimations comportaient une grande incertitude statistique. CONCLUSION: Les études évaluant la précision diagnostique des examens auxiliaires présentent un risque de biais incertain ou élevé. Des études de haute qualité sont nécessaires pour valider en profondeur les examens auxiliaires pour la DCN. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42013005907); enregistrée le 7 octobre 2013.

Interdisciplinary strategies to prevent long-term and detrimental opioid use following trauma: a stakeholder consensus study.

OBJECTIVE: Prolonged opioid use is common following traumatic injuries. Although preventive strategies have been recommended, the evidence supporting their use is low. The objectives of this study were to select interdisciplinary strategies to prevent long-term, detrimental opioid use in trauma patients for further evaluation and to identify implementation considerations. DESIGN: A consensus study using the nominal group technique. SETTING: Four trauma systems in Canada. SUBJECTS: Participants included expert clinicians and decision makers, and people with lived experience. METHODS: Participants had to discuss the relevance and implementation of 15 strategies and then rank them using a 7-point Likert scale. Implementation considerations were identified through a synthesis of discussions. RESULTS: A total of 41 expert stakeholders formed the nominal groups. Overall, eight strategies were favored: 1) using multimodal approach for pain management, 2) professional follow-up in physical health, 3) assessment of risk factors for opioid misuse, 4) physical stimulation, 5) downward adjustment of opioids based on patient recovery, 6) educational intervention for patients, 7) training offered to professionals on how to prescribe opioids, and 8) optimizing communication between professionals working in different settings. Discussions with expert stakeholders revealed the rationale for the selected strategies and identified issues to consider when implementing them. CONCLUSION: This stakeholder consensus study identified, for further scientific study, a set of interdisciplinary strategies to promote appropriate opioid use following traumatic injuries. These strategies could ultimately decrease the burden associated with long-term opioid use.