Search

Abstract Background During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. Objective To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. Methods REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. Results The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p

Abstract 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.

Introduction Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk.Methods and analysis We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation.Ethics and dissemination We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309).Trial registration number NCT05148715.

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)

Abstract Background The COVID-19 pandemic has required evidence to be made available more rapidly than usual, in order to meet the needs of decision makers in a timely manner. These exceptional circumstances have caused significant challenges for organizations and teams responsible for evidence synthesis. They had to adapt to provide rapid responses to support decision-making. This study aimed to document (1) the challenges and adaptations made to produce rapid responses during the pandemic, (2) their perceived usefulness, reported use and factors influencing their use and (3) the methodological adaptations made to produce rapid responses. Methods A qualitative study was conducted in 2021 with eight organizations in the health and social services system in Quebec (Canada), including three institutes with a provincial mandate. Data collection included focus groups (n = 9 groups in 8 organizations with 64 participants), interviews with decision makers (n = 12), and a document analysis of COVID-19 rapid responses (n = 128). A thematic analysis of qualitative data (objectives 1 and 2) and a descriptive analysis of documents (objective 3) were conducted. Results The results highlight the teams and organizations’ agility to deal with the many challenges encountered during the pandemic (e.g., increased their workloads, adoption of new technological tools or work processes, improved collaboration, development of scientific monitoring, adaptation of evidence synthesis methodologies and products). The challenge of balancing rigor and speed was reported by teams and organizations. When available at the right time, rapid responses have been reported as a useful tool for informing or justifying decisions in a context of uncertainty. Several factors that may influence their use were identified (e.g., clearly identify needs, interactions with producers, perceived rigor and credibility, precise and feasible recommendations). Certain trends in the methodological approaches used to speed up the evidence synthesis process were identified. Conclusions This study documented rapid responses producers’ experiences during the COVID-19 pandemic in Quebec, and decision makers who requested, consulted, or used these products. Potential areas of improvements are identified such as reinforce coordination, improve communication loops, clarify guidelines or methodological benchmarks, and enhance utility of rapid response products for decision makers.

Abstract 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.

Abstract 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].

Abstract 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 ).

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.

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.

Introduction Traumatic brain injury (TBI) is the leading cause of mortality and long-term disability in young adults. Despite the high prevalence of anaemia and red blood cell transfusion in patients with TBI, the optimal haemoglobin (Hb) transfusion threshold is unknown. We undertook a randomised trial to evaluate whether a liberal transfusion strategy improves clinical outcomes compared with a restrictive strategy.Methods and analysis HEMOglobin Transfusion Threshold in Traumatic Brain Injury OptimizatiON is an international pragmatic randomised open label blinded-endpoint clinical trial. We will include 742 adult patients admitted to an intensive care unit (ICU) with an acute moderate or severe blunt TBI (Glasgow Coma Scale ≤12) and a Hb level ≤100 g/L. Patients are randomly allocated using a 1:1 ratio, stratified by site, to a liberal (triggered by Hb ≤100 g/L) or a restrictive (triggered by Hb ≤70 g/L) transfusion strategy applied from the time of randomisation to the decision to withdraw life-sustaining therapies, ICU discharge or death. Primary and secondary outcomes are assessed centrally by trained research personnel blinded to the intervention. The primary outcome is the Glasgow Outcome Scale extended at 6 months. Secondary outcomes include overall functional independence measure, overall quality of life (EuroQoL 5-Dimension 5-Level; EQ-5D-5L), TBI-specific quality of life (Quality of Life after Brain Injury; QOLIBRI), depression (Patient Health Questionnaire; PHQ-9) and mortality.Ethics and dissemination This trial is approved by the CHU de Québec—Université Laval research ethics board (MP-20-2018-3706) and ethic boards at all participating sites. Our results will be published and shared with relevant organisations and healthcare professionals.Trial registration number NCT03260478.

OBJECTIVES:. Venous thromboembolic events (VTE) are frequent complications in hospitalized patients and a leading cause of preventable death in hospital. Pharmacologic prophylaxis is a standard of care to prevent VTE in patients at risk, the additional value of intermittent pneumatic compression (IPC) is uncertain. We aimed to evaluate the efficacy of adding IPC to pharmacologic prophylaxis to prevent VTE in hospitalized adults. DATA SOURCES:. We searched the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and the International Clinical Trials Registry Platform from inception to July 2022. STUDY SELECTION:. We included randomized controlled trials comparing the use of IPC in addition to pharmacological thromboprophylaxis to pharmacological thromboprophylaxis alone in hospitalized adults. DATA EXTRACTION:. Meta-analyses were performed to calculate risk ratio (RR) of VTE, deep venous thrombosis (DVT), and pulmonary embolism (PE). We assessed the risk of bias using the Cochrane Risk of Bias Tool for Randomized Trials, Version 2 and the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS:. We included 17 trials enrolling 8,796 participants. The IPC was mostly applied up to the thigh and pharmacological thromboprophylaxis was primarily low-molecular-weight heparin. Adjunctive IPC was associated with a decreased risk of VTE (15 trials, RR = 0.53; 95% CI [0.35–0.81]) and DVT (14 trials, RR = 0.52; 95% CI [0.33–0.81]) but not PE (seven trials, RR = 0.73; 95% CI [0.32–1.68]). The quality of evidence was graded low, downgraded by risk of bias and inconsistency. Moderate and very low-quality evidence, respectively, suggests that adjunctive IPC is unlikely to change the risk of all-cause mortality or adverse events. Subgroup analyses indicate a more evident apparent benefit in industry-funded trials. CONCLUSIONS:. Results indicate low-quality evidence underpinning the additional use of IPC to pharmacological thromboprophylaxis for prevention of VTE and DVT. Further large high-quality randomized trials are warranted to support its use and to identify patient subgroups for whom it could be beneficial.

Abstract Background Anemia is common in neurocritically ill patients. Considering the limited clinical evidence in this population, preclinical data may provide some understanding of the potential impact of anemia and of red blood cell transfusion in these patients. We aim to estimate the association between different transfusion strategies and neurobehavioral outcome in animal models. Methods We will conduct a systematic review of comparative studies of red blood cell transfusion strategies using animal models of traumatic brain injury, ischemic stroke or cerebral hemorrhage. We will search MEDLINE, EMBASE, and Web of Science databases for eligible studies from inception onwards. Two independent reviewers will perform study selection and data extraction. We will report our results in a descriptive synthesis focusing on characteristics of included studies, reported outcomes, risk of bias, and construct validity. Our primary outcome is the neurological function (neurobehavioral performance) and our secondary outcomes include mortality, infarct size, intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and brain tissue oxygen tension. If appropriate, we will also perform a quantitative synthesis and pool results using random-effect models. Heterogeneity will be expressed with I 2 statistics. Subgroup analyses are planned according to animal model characteristics, co-interventions, and risks of bias. Discussion Our study is aligned with the efforts to better understand the level of evidence on the impact of red blood cell transfusion strategies from preclinical studies in animal models of acute brain injury and the potential translation of information from the preclinical to the clinical research field. Systematic review registration PROSPERO CRD42018086662 .

BackgroundThe LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. ObjectiveWe aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. MethodsThe SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. ResultsThe SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. ConclusionsWe have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. International Registered Report Identifier (IRRID)DERR1-10.2196/36261

Delayed cerebral ischemia (DCI) disproportionately affects poor grade aneurysmal subarachnoid hemorrhage (aSAH) patients. An unreliable neurological exam and the lack of appropriate monitoring leads to unrecognized DCI, which in turn is associated with severe long-term deficits and higher mortality. Near Infrared Spectroscopy (NIRS) offers simple, continuous, real time, non-invasive cerebral monitoring. It provides regional cerebral oxygen saturation (c-rSO2), which reflects the balance between cerebral oxygen consumption and supply. Reports have demonstrated a good correlation with other cerebral oxygen and blood flow monitoring, and credible cerebrovascular reactivity indices were also derived from NIRS signals. Multiple critical c-rSO2 values have been reported in aSAH patients, based on various thresholds, duration, variation from baseline or cerebrovascular reactivity indices. Some were associated with vasospasm, some with DCI and others with clinical outcomes. However, the poor grade aSAH population has not been specifically studied and no randomized clinical trial has been published. The available literature does not support a specific NIRS-based intervention threshold to guide diagnostic or treatment in aSAH patients. We review herein the fundamental basic concepts behind NIRS technology, relationship of c-rSO2 to other brain monitoring values and their potential clinical interpretation. We follow with a critical evaluation of the use of NIRS in the aSAH population, more specifically its ability to diagnose vasospasm, to predict DCI and its association to outcome. In summary, NIRS might offer significant potential for poor grade aSAH in the future. However, current evidence does not support its use in clinical decision-making, and proper technology evaluation is required.

Introduction Evidence suggests the presence of deficiencies in the quality of care provided to up to half of all paediatric trauma patients in Canada, the USA and Australia. Lack of adherence to evidence-based recommendations may be driven by lack of knowledge of clinical practice guidelines (CPGs), heterogeneity in recommendations or concerns about their quality. We aim to systematically review CPG recommendations for paediatric injury care and appraise their quality.Methods and analysis We will identify CPG recommendations through a comprehensive search strategy including Medical Literature Analysis and Retrieval System Online, Excerpta Medica dataBASE, Cochrane library, Web of Science, ClinicalTrials and websites of organisations publishing recommendations on paediatric injury care. We will consider CPGs including at least one recommendation targeting paediatric injury populations on any diagnostic or therapeutic intervention from the acute phase of care with any comparator developed in high-income countries in the last 15 years (January 2007 to a maximum of 6 months prior to submission). Pairs of reviewers will independently screen titles, abstracts and full text of eligible articles, extract data and evaluate the quality of CPGs and their recommendations using Appraisal of Guidelines Research and Evaluation (AGREE) II and AGREE Recommendations Excellence instruments, respectively. We will synthesise evidence on recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision framework and present results within a recommendations matrix.Ethics and dissemination Ethics approval is not a requirement as this study is based on available published data. The results of this systematic review will be published in a peer-reviewed journal, presented at international scientific meetings and distributed to healthcare providers.PROSPERO registration number International Prospective Register of Systematic Reviews (CRD42021226934).

Abstract Background Opioids are commonly used for the management of postoperative pain, but their use is limited by important adverse events, such as respiratory depression and the potential for addiction. Multimodal opioid-sparing analgesia regimens can be effectively employed to manage postoperative pain and reduce exposure to opioids. Gabapentinoids (pregabalin and gabapentin) represent an attractive class of drugs for use in multimodal regimens. The American Pain Society recommends the use of gabapentinoids during the perioperative period; however, evidence to inform such a recommendation is unclear. Methods We will conduct a systematic review and meta-analysis of randomized clinical trials evaluating the use of systemic gabapentinoids, in comparison to other analgesic regimens or placebo in adult patients undergoing surgery. We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the Web of Science, and ClinicalTrials.gov databases for relevant citations. Our primary outcome will be intensity of postoperative acute pain (12 h). Our secondary outcomes will be postoperative pain intensity at 6, 24, 48 h, and 72 h, cumulative dose of opioids administered within 24, 48, and 72 h following surgery, the length of stay, chronic pain, and adverse events. Two investigators will independently select trials and extract data. We will evaluate the risk of bias of included trials using the Cochrane risk of bias tools. We will represent pooled continuous data as weighted mean differences and pooled dichotomous data as risk ratios with a 95% confidence interval. We will use random effect models and assess statistical heterogeneity with the I 2 index. Discussion Our study will provide the best level of evidence to inform the effect of gabapentinoids in the management of postoperative acute pain. Systematic review registration PROSPERO CRD42017067029

Introduction Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating disease associated with high mortality and morbidity. The main threat to patients is delayed cerebral ischaemia (DCI). Near-infrared spectroscopy (NIRS) is a recent technology allowing continuous, non-invasive cerebral oximetry that could permit timely detection of impending DCI and appropriate intervention to improve outcomes. However, the ability of regional oxygen saturation to detect DCI, its association to the outcome, or benefits of any interventions based on NIRS data, are lacking. Our aims are to evaluate NIRS technology both as a therapeutic tool to improve outcomes in aSAH patients and as a diagnostic tool for DCI.Methods and analysis MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews will be searched from their inception and without language restriction. Our search strategy will cover the themes of subarachnoid haemorrhage and cerebral oximetry, without limitations regarding studied outcomes. We will identify all observational and interventional human studies of adult patients hospitalised after aSAH that were monitored using NIRS. Functional outcome measures, including the modified Rankin Scale, the Glasgow Outcome Scale and the Barthel Index, will constitute the primary outcome. The Cochrane Risk of Bias tool will be used for randomised controlled trials, the ROBINS-I tool to assess non-randomised studies of interventions and the Newcastle-Ottawa Scale for cohort or case–control studies. The Quality Assessment of Diagnostic Accuracy Studies-2 will be applied to studies evaluating NIRS diagnostic accuracy for DCI. We will evaluate the quality of the evidence of the effect based on the Grading of Recommendations Assessment, Development and Evaluation methodology.Ethics and dissemination Dissemination will proceed through submission for journal publication, trial registry completion and abstract presentation. Ethics approval is not required.PROSPERO registration number CRD42020077522.

Introduction Vasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective of the Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65) trial is to ascertain the effect of permissive hypotension (vasopressor titration to achieve MAP 60–65 mm Hg) versus usual care on biomarkers of organ injury in hypotensive patients aged ≥65 years.Methods and analysis OVATION-65 is an allocation-concealed randomised trial in 7 Canadian hospitals. Eligible patients are ≥65 years of age, in an ICU with vasodilatory hypotension, receiving vasopressors for ≤12 hours to maintain MAP ≥65 mm Hg during or after adequate fluid resuscitation, and expected to receive vasopressors for ≥6 additional hours. Patients are excluded for any of the following: active treatment for spinal cord or acute brain injury; vasopressors given solely for bleeding, ventricular failure or postcardiopulmonary bypass vasoplegia; withdrawal of life-sustaining treatments expected within 48 hours; death perceived as imminent; previous enrolment in OVATION-65; organ transplant within the last year; receiving extracorporeal life support or lack of physician equipoise. Patients are randomised to permissive hypotension versus usual care for up to 28 days. The primary outcome is high-sensitivity troponin T, a biomarker of cardiac injury, on day 3. Secondary outcomes include biomarkers of injury to other organs (brain, liver, intestine, skeletal muscle); lactate (a biomarker of global tissue dysoxia); resource utilisation; adverse events; mortality (90 days and 6 months) and cognitive function (6 months). Assessors of biomarkers, mortality and cognitive function are blinded to allocation.Ethics and dissemination This protocol has been approved at all sites. Consent is obtained from the eligible patient, the substitute decision-maker if the patient is incapable, or in a deferred fashion where permitted. End-of-grant dissemination plans include presentations, publications and social media platforms and discussion forums.Trial registration number NCT03431181.

Introduction Ventilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile–associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU.Methods and analysis The objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer’s perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital ‘hoteling’ costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach.Ethics and dissemination Study approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals.Trial registration number NCT01782755; Pre-results.

Abstract Background Whether a restrictive strategy for red blood cell (RBC) transfusion is applied to patients with aneurysmal subarachnoid hemorrhage (aSAH) is unclear. To inform the design and conduct of a future clinical trial, we sought to describe transfusion practices, hemoglobin (Hb) triggers, and predictors of RBC transfusion in patients with aSAH. Methods This is a retrospective cohort study of all consecutively admitted adult patients with aSAH at four tertiary care centers from January 1, 2012, to December 31, 2013. Patients were identified from hospital administrative discharge records and existing local aSAH databases. Data collection by trained abstractors included demographic data, aSAH characteristics, Hb and transfusion data, other major aSAH cointerventions, and outcomes using a pretested case report form with standardized procedures. Descriptive statistics were used to summarize data, and regression models were used to identify associations between anemia, transfusion, and other relevant predictors and outcome. Results A total of 527 patients met inclusion eligibility. Mean (±SD) age was 57 ± 13 years, and 357 patients (67.7%) were female. The median modified Fisher grade was 4 (IQR 3–4). Mean nadir Hb was 98 ± 20 g/L and occurred on median admission day 4 (IQR 2–11). RBC transfusion occurred in 100 patients (19.0%). Transfusion rates varied across centers (12.1–27.4%, p = 0.02). Patients received a median of 1 RBC unit (IQR 1–2) per transfusion episode and a median total of 2 units (IQR 1–4). Median pretransfusion Hb for first transfusion was 79 g/L (IQR 74–93) and did not vary substantially across centers (78–82 g/L, p = 0.37). Of patients with nadir Hb

ObjectivesAs Canada’s second largest province, the geography of Quebec poses unique challenges for trauma management. Our primary objective was to compare mortality rates between trauma patients treated at rural emergency departments (EDs) and urban trauma centres in Quebec. As a secondary objective, we compared the availability of trauma care resources and services between these two settings.DesignRetrospective cohort study.Setting26 rural EDs and 33 level 1 and 2 urban trauma centres in Quebec, Canada.Participants79 957 trauma cases collected from Quebec’s trauma registry.Primary and secondary outcome measuresOur primary outcome measure was mortality (prehospital, ED, in-hospital). Secondary outcome measures were the availability of trauma-related services and staff specialties at rural and urban facilities. Multivariable generalised linear mixed models were used to determine the relationship between the primary facility and mortality.ResultsOverall, 7215 (9.0%) trauma patients were treated in a rural ED and 72 742 (91.0%) received treatment at an urban centre. Mortality rates were higher in rural EDs compared with urban trauma centres (13.3% vs 7.9%, p

OBJECTIVES:Vasopressors are not recommended by current trauma guidelines, but recent reports indicate that they are commonly used. We aimed to describe the early hemodynamic management of trauma patients outside densely populated urban centers. METHODS:We conducted a single-center retrospective cohort study in a Canadian regional trauma center. All adult patients treated for traumatic injury in 2013 who died within 24 hours of admission or were transferred to the intensive care unit were included. A systolic blood pressure

Introduction Trauma remains the primary cause of death in individuals under 40 years of age in Canada. In Quebec, the Trauma Care Continuum (TCC) has been demonstrated to be effective in decreasing the mortality rate among trauma victims. Although rural citizens are at greater risk for trauma and trauma death, no empirical data concerning the effectiveness of the TCC for the rural population in Quebec are available. The emergency departments (EDs) are important safety nets for rural citizens. However, our data indicate that access to diagnostic support services, such as intensive care units and CT is limited in rural areas. The objectives are to (1) draw a portrait of trauma services in rural EDs; (2) explore geographical variations in trauma care in Quebec; (3) identify adaptable factors that could reduce variation; and (4) establish consensus solutions for improving the quality of care.Methods and analysis The study will take place from November 2015 to November 2018. A mixed methodology (qualitative and quantitative) will be used. We will include data (2009–2013) from all trauma victims treated in the 26 rural EDs and tertiary/secondary care centres in Quebec. To meet objectives 1 and 2, data will be gathered from the Ministry's Database of the Quebec Trauma Registry Information System. For objectives 3 and 4, the project will use the Delphi method to develop consensus solutions for improving the quality of trauma care in rural areas. Data will be analysed using a Poisson regression to compare mortality rate during hospital stay or death on ED arrival (objectives 1 and 2). Average scores and 95% CI will be calculated for the Delphi questionnaire (objectives 3 and 4).Ethics and dissemination This protocol has been approved by CSSS Alphonse-Desjardins research ethics committee (Project MP-HDL-2016-003). The results will be published in peer-reviewed journals.

Hospital mortality rates are elevated in critically ill patients with bloodstream infections. Given that mortality may be even higher if appropriate treatment is delayed, we sought to determine the effect of inadequate initial empiric treatment on mortality in these patients. A retrospective cohort study was conducted across 13 intensive care units in Canada. We defined inadequate initial empiric treatment as not receiving at least one dose of an antimicrobial to which the causative pathogen(s) was susceptible within one day of initial blood culture. We evaluated the association between inadequate initial treatment and hospital mortality using a random effects multivariable logistic regression model. Among 1,190 patients (1,097 had bacteremia and 93 had candidemia), 476 (40%) died and 266 (22%) received inadequate initial treatment. Candidemic patients more often had inadequate initial empiric therapy (64.5% versus 18.8%), as well as longer delays to final culture results (4 vs 3 days) and appropriate therapy (2 vs 0 days). After adjustment, there was no detectable association between inadequate initial treatment and mortality among bacteremic patients (Odds Ratio (OR): 1.02, 95% Confidence Interval (CI) 0.70-1.48); however, candidemic patients receiving inadequate treatment had nearly three times the odds of death (OR: 2.89, 95% CI: 1.05-7.99). Inadequate initial empiric antimicrobial treatment was not associated with increased mortality in bacteremic patients, but was an important risk factor in the subgroup of candidemic patients. Further research is warranted to improve early diagnostic and risk prediction methods in candidemic patients.

Background: The physician workforce in Quebec is regulated by a government-controlled plan. Many specialty trainees expressed concerns about securing a position. Our objective was to analyze physicians’ employment issues in Quebec and their impact on residents’ training in specialty programs. Methods: We distributed a web-based self-administrated survey to all Quebec residents training in specialty programs to capture data about residents’ ability to find employment, career plans and perceptions regarding the workforce policy. Three groups were considered: graduates, non-graduating senior residents, and junior residents. Results: The overall response rate was 41.5% (985/2372). 47.3% of graduates did not have a position two months before finishing their training. Among residents without a position, 27.1% of graduates intend to leave Quebec, and 19.6% to complete a fellowship to postpone their start in practice. Overall, 77.9% of respondents believed there are not enough job opportunities for the number of trainees. Conclusion: Quebec specialty residents experience significant difficulties obtaining a position in the province and perceive that there are not enough job opportunities, which impacts their career plans and could drive them to complete a fellowship or plan to practice outside the province. Trainees' experience in finding employment needs to be considered in planning the physician workforce.

INTRODUCTION: Worldwide, severe traumatic brain injury is a frequent pathology and is associated with high morbidity and mortality. Mannitol and hypertonic saline are therapeutic options for intracranial hypertension occurring in the acute phase of care. However, current practices of emergency physicians are unknown. METHODS: We conducted a self-administered survey of emergency physicians in the province of Québec, Canada, to understand their attitudes surrounding the use of hyperosmolar solutions in patients with severe traumatic brain injury. Using information from a systematic review of hypertonic saline solutions and experts' opinion, we developed a questionnaire following a systematic approach (items generation and reduction). We tested the questionnaire for face and content validity, and test-retest reliability. Physicians were identified through the department head of each eligible level I and II trauma centers. We administered the survey using a web-based interface and planned email reminders. RESULTS: We received 210 questionnaires out of 429 potentials respondents (response rate 49%). Most respondents worked in level II trauma centers (69%). Fifty-three percent (53%) of emergency physicians stated using hypertonic saline to treat severe traumatic brain injury. Most reported using hyperosmolar therapy in the presence of severe traumatic brain injury and unilateral reactive mydriasis, midline shift or cistern compression on brain computed tomography. CONCLUSION: Hyperosmolar therapy is believed being broadly used by emergency physicians in Quebec following severe traumatic brain injury. Despite the absence of clinical practice guidelines promoting the use of hypertonic saline, a majority of them said to use these solutions in specific clinical situations.