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Abstract Background Multifaceted interventions that address barriers and facilitators have been shown to be most effective for increasing the adoption of high-value care, but there is a knowledge gap on this type of intervention for the de-implementation of low-value care. Trauma is a high-risk setting for low-value care, such as unnecessary diagnostic imaging and the use of specialized resources. The aim of our study was to develop and assess the usability of a multifaceted intervention to reduce low-value injury care. Methods We used the Consolidated Framework for Implementation Research and the Expert Recommendations for Implementing Change tool as theoretical foundations to identify barriers and facilitators, and strategies for the reduction of low-value practices. We designed an initial prototype of the intervention using the items of the Template for Intervention Description and Replication. The prototype’s usability was iteratively tested through four focus groups and four think-aloud sessions with trauma decision-makers (n = 18) from seven Level I to Level III trauma centers. We conducted an inductive analysis of the audio-recorded sessions to identify usability issues and other barriers and facilitators to refine the intervention. Results We identified barriers and facilitators related to individual characteristics, including knowledge and beliefs about low-value practices and the de-implementation process, such as the complexity of changing practices and difficulty accessing performance feedback. Accordingly, the following intervention strategies were selected: involving governing structures and leaders, distributing audit & feedback reports on performance, and providing educational materials, de-implementation support tools and educational/facilitation visits. A total of 61 issues were identified during the usability testing, of which eight were critical, 33 were moderately important, and 18 were minor. These issues led to numerous improvements, including the addition of information on the drivers and benefits of reducing low-value practices, changes in the definition of these practices, the addition of proposed strategies to facilitate de-implementation, and the tailoring of educational/facilitation visits. Conclusions We designed and refined a multifaceted intervention to reduce low-value injury care using a process that increases the likelihood of its acceptability and sustainability. The next step will be to evaluate the effectiveness of implementing this intervention using a pragmatic cluster randomized controlled trial. Trial registration This protocol has been registered on ClinicalTrials.gov (February 24th 2023, #NCT05744154, https://clinicaltrials.gov/ct2/show/NCT05744154 ).

Abstract Background Most Canadians receive their care in community hospitals, yet most clinical research is conducted in academic hospitals. This study aims to compare patients with community acquired pneumonia (CAP) treated in academic and community hospitals with respect to their demographics, clinical characteristics, treatments and outcomes. Methods This nested observational cohort substudy of the Community Acquired Pneumonia: Toward InnoVAtive Treatment (CAPTIVATE) trial included 1,329 hospitalized adults with CAP recruited between March 1st, 2018 and September 31st, 2023 from 15 Canadian hospitals. Unadjusted and adjusted analyses for age, sex and co-morbidities using logistic, Cox and censored quantile regressions were conducted. Results Patients in community hospitals were older (mean [SD] 75.0 [15.7] years vs. 68.3 [16.2] years; 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.

Abstract Background This update summarizes key changes made to the protocol for the Frequency of Screening and Spontaneous Breathing Trial (SBT) Technique Trial—North American Weaning Collaborative (FAST-NAWC) trial since the publication of the original protocol. This multicenter, factorial design randomized controlled trial with concealed allocation, will compare the effect of both screening frequency (once vs. at least twice daily) to identify candidates to undergo a SBT and SBT technique [pressure support + positive end-expiratory pressure vs. T-piece] on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American intensive care units. Methods/design Protocols for the pilot, factorial design trial and the full trial were previously published in J Clin Trials ( https://doi.org/10.4172/2167-0870.1000284 ) and Trials (https://doi: 10.1186/s13063-019–3641-8). As planned, participants enrolled in the FAST pilot trial will be included in the report of the full FAST-NAWC trial. In response to the onset of the coronavirus disease of 2019 (COVID-19) pandemic when approximately two thirds of enrollment was complete, we revised the protocol and consent form to include critically ill invasively ventilated patients with COVID-19. We also refined the statistical analysis plan (SAP) to reflect inclusion and reporting of participants with and without COVID-19. This update summarizes the changes made and their rationale and provides a refined SAP for the FAST-NAWC trial. These changes have been finalized before completion of trial follow-up and the commencement of data analysis. Trial registration Clinical Trials.gov NCT02399267.

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 ).

Abstract Background Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). Methods In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

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 .

Abstract Background Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection. Methods CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600). Discussion This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification. Trial registration Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.

Abstract Background Data on postoperative outcomes of the COVID-19 patient population is limited. We described COVID-19 patients who underwent a surgery and the pandemic impact on surgical activities. Methods We conducted a multicenter cohort study between March 13 and June 192,020. We included all COVID-19 patients who underwent surgery in nine centres of the Province of Québec, the Canadian province most afflicted by the pandemic. We also included concomitant suspected COVID-19 (subsequently confirmed not to have COVID-19) patients and patients who had recovered from it. We collected data on baseline characteristics, postoperative complications and postoperative mortality. Our primary outcome was 30-day mortality. We also collected data on overall surgical activities during this first wave and during the same period in 2019. Results We included 44 COVID-19 patients, 18 suspected patients, and 18 patients who had recovered from COVID-19 at time of surgery. Among the 44 COVID-19 patients, 31 surgeries (71%) were urgent and 16 (36%) were major. In these patients, pulmonary complications were frequent (25%) and 30-day mortality was high (15.9%). This mortality was higher in patients with symptoms (23.1%) compared to those without symptoms (5.6%), although not statistically significant (p = 0.118). Of the total 22,616 cases performed among participating centres during the study period, only 0.19% had COVID-19 at the time of surgery. Fewer procedures were performed during the study period compared to the same period in 2019 (44,486 cases). Conclusion In this Canadian cohort study, postoperative 30-day mortality in COVID-19 patients undergoing surgery was high (15.9%). Although few surgeries were performed on COVID-19 patients, the pandemic impact on surgical activity volume was important. Trial registration ClinicalTrials.gov Identifier: NCT04458337 .

Abstract Background Frail seniors often receive ineffective care, which does not meet their needs. It is still unclear how healthcare systems should be redesigned to be more sensitive to the needs and values of frail seniors and their caregivers. We thus aimed to describe key stakeholders’ perspectives on the current healthcare and services available to frail seniors. Methods In this qualitative descriptive study, we conducted semi-structured interviews with a convenience sample of 42 frail seniors, caregivers, clinicians, or healthcare administrators/decision makers involved in frail senior care from five Canadian provinces. We explored participants’ perspectives on the quality of care and services for frail seniors. We used an inductive/deductive thematic data analysis approach based on the Square-of-Care model, including emerging themes using the constant comparison method. Results We grouped participants’ perspectives into strengths, weaknesses and opportunities for improvement, and then into nine themes: care processes, continuity of care, social frailty, access to healthcare and services, models of healthcare delivery, cost of care, healthcare staff management and professional development of healthcare providers, material resources and environmental design of healthcare facilities, and coordination of care. Our findings suggest redesigning assessment, communication with frail seniors and their caregivers, targeting care and services to the needs, and integrating care better across settings and in time. Conclusions A systematic identification of frail older people is the first step to adapt healthcare systems to this population’s needs. Participation of frail older people and their caregivers to decision making would also allow choosing care plans meeting their care goals. The integration of care and services across settings, over time, and with various providers, is also needed to meet frail senior needs.

Abstract Background Liver transplant recipients suffer many complications, but few intraoperative interventions supported by high-quality evidence have been found effective to reduce their incidence or severity. Fluid balance has been proposed as an important aspect of perioperative care in high-risk recipients. We will conduct a systematic review aimed at evaluating the effects of restrictive perioperative fluid management strategies compared to liberal ones on clinically significant postoperative outcomes. Methods We will search through major databases (CINAHL Complete, EMB Reviews, EMBASE, MEDLINE, PubMed, and the gray literature (CADTH, Clinical Trials, National Guideline Clearing House, NICE, MedNar, Google Scholar and Open Grey)), from inception up to a date close to the review submission for publication, for eligible studies. Randomized controlled trials and comparative non-randomized studies (prospective or retrospective) comparing two fluid management strategies (or two outcomes with available data on fluid volume received for observational studies) on adult liver recipients will be included. Eligible studies will have to report at least one postoperative complication or mortality. Our primary outcome will be acute renal failure and our secondary exploratory outcomes will be all other postoperative complications and mortality. Study selection and data abstraction using an electronic standardized form will be performed by three authors. Risk of bias will be evaluated and data will be pooled if limited clinical diversity is observed. Discussion Human organs available for transplantation are scarce resources. Strategies to improve recipients’ survival are needed. We hypothesize that restrictive fluid management strategies will be associated with better postoperative outcomes than liberal fluid management strategies. This systematic review will improve our understanding of the available evidence and help us better inform future clinical trials. Systematic review registration This systematic review protocol is registered in PROSPERO (CRD42017054970).

Abstract Background Current guidelines identify the choice of fluid resuscitation as important in minimizing the incidence of secondary brain injury from cerebral edema. It is widely accepted that isotonic crystalloid resuscitation fluids, specifically normal saline (NS), are optimal for resuscitation and that other relatively hypotonic fluids, such as Ringer’s lactate (RL), should be avoided in this patient population. The aim of this review is to systematically compare the use of relatively hypotonic versus isotonic crystalloid resuscitation fluids in clinical and pre-clinical models of acute brain injury and their effect on outcomes. In recognition of the potential need for a network meta-analysis (NMA), we have also included all other relevant crystalloid resuscitation fluids as interventions of relevance to potentially inform indirect comparisons. Methods Systematic searches of MEDLINE, Embase, and Web of Science BIOSIS Previews® will be used to identify eligible clinical and pre-clinical studies, which included studies examining acute brain injury (human and in vivo animal brain injury models) within the first 7 days of therapy. The intervention of interest is the intravenous use of relatively hypotonic crystalloid resuscitation fluids (e.g., Ringer’s lactate, Hartmann’s or Plasma Lyte® fluids). The main comparator of interest is an isotonic crystalloid resuscitation fluid, specifically normal saline (0.9%). Other crystalloid resuscitation fluids (e.g., hypertonic saline (3–23.4%)) will also be included as an additional intervention of interest. The primary outcome measures of interest are intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Secondary outcomes include the effect of resuscitation on cerebral edema, brain and serum osmolarity, and electrolyte concentrations and clinical outcomes including modified Rankin Scale (mRS), (extended) Glasgow Outcome Scale (GOS/eGOS), and mortality. Separate meta-analyses will be conducted to quantify the effects of the different fluid resuscitation on acute brain injury outcomes in clinical and pre-clinical populations. Network meta-analyses to compare interventions will also be performed to compare the effects of different interventions. Discussion This systematic review will comprehensively summarize the difference in treatment efficacy of various crystalloid resuscitation fluids in acute brain injury. This review is essential to underscore the evidence, or lack thereof, present in the literature to date to support current preference-driven practice and to direct future study. Systematic review registration PROSPERO #CRD42016042960

Abstract Background The “Age of Blood in Children in Pediatric Intensive Care Unit” (ABC PICU) study is a randomized controlled trial (RCT) that aims to determine if red blood cell (RBC) unit storage age affects outcomes in critically ill children. While RBCs can be stored for up to 42 days in additive solutions, their efficacy and safety after long-term storage have been challenged. Preclinical and clinical observational evidence suggests loss of efficacy and lack of safety of older RBC units, especially in more vulnerable populations such as critically ill children. Because there is a belief that shorter storage will improve outcomes, some physicians and institutions systematically transfuse fresh RBCs to children. Conversely, the standard practice of blood banks is to deliver the oldest available RBC unit (first-in, first-out policy) in order to decrease wastage. Methods/design The ABC PICU study, is a double-blind superiority trial comparing the development of “New or Progressive Multiple Organ Dysfunction Syndrome” (NPMODS) in 1538 critically ill children randomized to either transfusion with RBCs stored for ≤ 7 days or to standard-issue RBCs (oldest in inventory). Patients are being recruited from 52 centers in the US, Canada, France, Italy, and Israel. Discussion The ABC PICU study should have significant implications for blood procurement services. A relative risk reduction of 33% is postulated in the short-storage arm. If a difference is found, this will indicate that fresher RBCs do improve outcomes in the pediatric intensive care unit population and would justify that use in critically ill children. If no difference is found, this will reassure clinicians and transfusion medicine specialists regarding the safety of the current system of allocating the oldest RBC unit in inventory and will discourage clinicians from preferentially requesting fresher blood for critically ill children. Trial registration ClinicalTrials.gov, ID: NCT01977547. Registered on 6 November 2013.

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

Abstract Background Little is known about documentation during transitions of patient care between clinical specialties. Therefore, we examined the focus, structure and purpose of physician progress notes for patients transferred from the intensive care unit (ICU) to hospital ward to identify opportunities to improve communication breaks. Methods This was a prospective cohort study in ten Canadian hospitals. We analyzed physician progress notes for consenting adult patients transferred from a medical-surgical ICU to hospital ward. The number, length, legibility and content of notes was counted and compared across care settings using mixed-effects linear regression models accounting for clustering within hospitals. Qualitative content analyses were conducted on a stratified random sample of 32 patients. Results A total of 447 patient medical records that included 7052 progress notes (mean 2.1 notes/patient/day 95% CI 1.9–2.3) were analyzed. Notes written by the ICU team were significantly longer than notes written by the ward team (mean lines of text 21 vs. 15, p

Abstract Background We performed a systematic review and meta-analysis to evaluate the efficacy and safety of high-flow oxygen via nasal cannulae (HFNC) compared to non-invasive ventilation (NIV) and/or standard oxygen in patients with acute, hypoxemic respiratory failure. Methods We reviewed randomized controlled trials from CENTRAL, EMBASE, MEDLINE, Scopus and the International Clinical Trials Registry Platform (inception to February 2016), conference proceedings, and relevant article reference lists. Two reviewers independently screened and extracted trial-level data from trials investigating HFNC in patients with acute, hypoxemic respiratory failure. Internal validity was assessed in duplicate using the Cochrane Risk of Bias tool. The strength of evidence was assessed in duplicate using the Grading of Recommendations Assessment, Development and Evaluation framework. Our primary outcome was mortality. Secondary outcomes included dyspnea, PaO2:FiO2 ratio, PaCO2, and pH. Safety outcomes included respiratory arrest, intubation, delirium, and skin breakdown. Results From 2023 screened citations, we identified seven trials (1771 patients) meeting inclusion criteria. All trials were at high risk of bias due to lack of blinding. There was no evidence for a mortality difference in patients receiving HFNC vs. NIV and/or standard oxygen (RR 1.01, 95% CI 0.69 to 1.48, I 2 = 63%, five trials, 1629 patients). In subgroup analyses of HFNC compared to NIV or standard oxygen individually, mortality differences were not observed. Measures of patient tolerability were heterogeneous. The PaO2:FiO2 ratio at 6–12 h was significantly lower in patients receiving oxygen via HFNC compared to NIV or standard oxygen for hypoxemic respiratory failure (MD − 53.34, 95% CI − 71.95 to − 34.72, I 2 = 61%, 1143 patients). There were no differences in pH, PaCO2, or rates of intubation or cardio-respiratory arrest. Delirium and skin breakdown were infrequently reported in included trials. Conclusions In patients with acute hypoxemic respiratory failure HFNC was not associated with a difference in mortality compared to NIV or standard oxygen. Secondary outcomes including dyspnea, tolerance, and safety were not systematically reported. Residual heterogeneity and variable reporting of secondary outcomes limit the conclusions that can be made in this review. Prospective trials designed to evaluate the efficacy and safety of HFNC in patients with acute hypoxemic respiratory failure are required.