Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

BACKGROUND: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear. METHODS: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months. RESULTS: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively. CONCLUSIONS: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.).

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Restrictive Versus Liberal Transfusion in Patients with Type 1 or Type 2 Myocardial Infarction: A Prespecified Analysis of the Myocardial Ischemia and Transfusion (MINT) Trial.

BACKGROUND: The MINT trial raised concern for harm from a restrictive versus liberal transfusion strategy in patients with acute myocardial infarction (MI) and anemia. Type 1 and type 2 MI are distinct pathophysiological entities that may respond differently to blood transfusion. This analysis sought to determine if the effects of transfusion varied among patients with a type 1 or a type 2 MI and anemia. We hypothesized that the liberal transfusion strategy would be of greater benefit in type 2 than in type 1 MI. METHODS: We compared rates of death or MI at 30 days in patients with type 1 (n=1460) and type 2 (n=1955) MI and anemia who were randomly allocated to a restrictive (threshold of 7 to 8 g/dL) or a liberal (threshold of 10 g/dL) transfusion strategy. RESULTS: The primary outcome of death or MI was observed in 16% of type 1 MI and 15.4% of type 2 MI patients. The rate of death or MI was higher in patients with type 1 MI randomized to a restrictive (18.2%) versus liberal (13.2%) transfusion strategy (RR 1.32, 95% CI 1.04 - 1.67) with no difference observed between the restrictive (15.8% ) and liberal (15.1% ) transfusion strategies in patients with type 2 MI (RR 1.05 95% CI 0.85-1.29). The test for a differential effect of transfusion strategy by MI type was not statistically significant (P-interaction = 0.16). CONCLUSIONS: The concern for harm with a restrictive transfusion strategy in patients with acute MI and anemia raised in the MINT primary outcome manuscript may be more apparent in patients with type 1 than type 2 MI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02981407.

Effect of Four Hemoglobin Transfusion Threshold Strategies in Patients With Acute Myocardial Infarction and Anemia : A Target Trial Emulation Using MINT Trial Data.

BACKGROUND: The optimal hemoglobin threshold to guide red blood cell (RBC) transfusion for patients with acute myocardial infarction (MI) and anemia is uncertain. OBJECTIVE: To estimate the efficacy of 4 individual hemoglobin thresholds (<10 g/dL [<100 g/L], <9 g/dL [<90 g/L], <8 g/dL [<80 g/L], and <7 g/dL [<70 g/L]) to guide transfusion in patients with acute MI and anemia. DESIGN: Prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial using target trial emulation methods. (ClinicalTrials.gov: NCT02981407). SETTING: 144 clinical sites in 6 countries. PARTICIPANTS: 3492 MINT trial participants with acute MI and a hemoglobin level below 10 g/dL. INTERVENTION: Four transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Protocol exceptions were permitted for specified adverse clinical events. MEASUREMENTS: Data from the MINT trial were leveraged to emulate 4 transfusion strategies and estimate per protocol effects on the composite outcome of 30-day death or recurrent MI (death/MI) and 30-day death using inverse probability weighting. RESULTS: The 30-day risk for death/MI was 14.8% (95% CI, 11.8% to 18.4%) for a <10-g/dL strategy, 15.1% (CI, 11.7% to 18.2%) for a <9-g/dL strategy, 15.9% (CI, 12.4% to 19.0%) for a <8-g/dL strategy, and 18.3% (CI, 14.6% to 22.0%) for a <7-g/dL strategy. Absolute risk differences and risk ratios relative to the <10-g/dL strategy for 30-day death/MI increased as thresholds decreased, although 95% CIs were wide. Findings were similar and imprecise for 30-day death. LIMITATION: Unmeasured confounding may have persisted despite adjustment. CONCLUSION: The 30-day risks for death/MI and death among patients with acute MI and anemia seem to increase progressively with lower hemoglobin concentration thresholds for transfusion. However, the imprecision around estimates from this target trial analysis precludes definitive conclusions about individual hemoglobin thresholds. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

A Qualitative Study of National Perspectives on Advancing Social Prescribing Using Co-Design in Canada.

INTRODUCTION: Social prescribing offers a formal pathway of connecting patients in the health system with sources of support within the community to help improve their health and well-being. Since its launch in March 2022, the Canadian Institute for Social Prescribing has acted as a collective impact network to identify, connect and build upon established social prescribing initiatives using a co-design methodology. The institute received input from a participant advisory council, co-design partners and several communities of interest groups. This study aimed to describe the perceptions of the Canadian Institute for Social Prescribing's role in advancing social prescribing using a co-design approach and the barriers and facilitators to implementing social prescribing in Canada. METHODS: We used a qualitative descriptive study design, document analysis, participant observation and semi-structured individual interviews (n = 7) with members of the Canadian Institute for Social Prescribing co-design group and the institute's leadership. We also analysed documents, field notes and transcripts using codebook thematic analysis. RESULTS: Four themes were developed representing the facilitators of implementing the Canadian Institute for Social Prescribing to support social prescribing: Creating relational mechanisms (i.e., partnerships and connections), Bringing awareness to social prescribing and contributing to the evidence (i.e., values and beliefs), Addressing systemic conditions (i.e., having a common language for social prescribing and organizing the community health sector) and Enabling funding and policy to drive social prescribing initiatives (i.e., shifting evidence into policy and securing sustainable funding). CONCLUSION: Participants' reflections on the co-design process demonstrated that the Canadian Institute for Social Prescribing development provided networking opportunities and shared resources relevant to social prescribing. Co-design efforts also fostered relational and informational support, which laid the necessary groundwork in Canada to overcome the complex interplay between the macro- and micro-level settings in which social prescribing is practiced. PATIENT OR PUBLIC CONTRIBUTION: The interviews and observations involved participants with lived experience of delivering, receiving or advocating for social prescribing.

Rationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial.

BACKGROUND: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy. METHODS: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points. CONCLUSIONS: The MINT trial will inform RBC transfusion practice in patients with acute MI.

Outcomes of advance care directives after admission to a long-term care home: DNR the DNH?

BACKGROUND: Residents of long-term care homes (LTCH) often experience unnecessary and non-beneficial hospitalizations and interventions near the end-of-life. Advance care directives aim to ensure that end-of-life care respects resident needs and wishes. METHODS: In this retrospective cohort study, we used multistate models to examine the health trajectories associated with Do-Not-Resuscitate (DNR) and Do-Not-Hospitalize (DNH) directives of residents admitted to LTCH in Ontario, Alberta, and British Columbia, Canada. We adjusted for baseline frailty-related health instability. We considered three possible end states: change in health, hospitalization, or death. For measurements, we used standardized RAI-MDS 2.0 LTCH assessments linked to hospital records from 2010 to 2015. RESULTS: We report on 123,003 LTCH residents. The prevalence of DNR and DNH directives was 71 and 26% respectively. Both directives were associated with increased odds of transitioning to a state of greater health instability and death, and decreased odds of hospitalization. The odds of hospitalization in the presence of a DNH directive were lowered, but not eliminated, with odds of 0.67 (95% confidence interval 0.65-0.69), 0.63 (0.61-0.65), and 0.47 (0.43-0.52) for residents with low, moderate and high health instability, respectively. CONCLUSION: Even though both DNR and DNH orders are associated with serious health outcomes, DNH directives were not frequently used and often overturned. We suggest that policies recommending DNH directives be re-evaluated, with greater emphasis on advance care planning that better reflects resident values and wishes.

Is equity considered in systematic reviews of interventions for mitigating social isolation and loneliness in older adults?

BACKGROUND: Social isolation and loneliness affect one in four older adults in many regions around the world. Social isolation and loneliness are shown to be associated with declines in physical and mental health. Intersecting social determinants of health influence both the risk of being socially isolated and lonely as well as the access and uptake of interventions. Our objective is to evaluate what evidence is available within systematic reviews on how to mitigate inequities in access to and effectiveness of interventions. METHODS: We performed an overview of reviews following methods of the Cochrane Handbook for Overviews of Reviews. We selected systematic reviews of effectiveness of interventions aimed at mitigating social isolation and loneliness in older adults (aged 60 or above) published in the last 10 years. In addition, we assessed all primary studies from the most recent systematic review with a broad intervention focus. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and Scopus in collaboration with a librarian scientist. We used a structured framework called PROGRESS-Plus to assess the reporting and consideration of equity. PROGRESS-Plus stands for place of residence, race/ethnicity/culture/language, occupation, gender or sex, religion, education, socioeconomic status (SES), social capital, while "plus" stands for additional factors associated with discrimination and exclusion such as age, disability, and sexual orientation. We assessed whether PROGRESS-Plus factors were reported in description of the population, examination of differential effects, or discussion of applicability or limitations. RESULTS: We identified and assessed 17 eligible systematic reviews. We assessed all 23 primary studies from the most recent systematic review with a broad intervention focus. All systematic reviews and primary studies described the population by one or more PROGRESS-Plus factor, most commonly across place of residence and age, respectively. None of the reviews and five primary studies examined differential effects across one or more PROGRESS-Plus dimension. Nine reviews and four primary studies discussed applicability or limitations of their findings by at least one PROGRESS-Plus factor. CONCLUSIONS: Although we know that social isolation and loneliness are worse for the poorest and most socially disadvantaged older adults, the existing evidence base lacks details on how to tailor interventions for these socially disadvantaged older people.

Transfusion thresholds for guiding red blood cell transfusion.

BACKGROUND: The optimal haemoglobin threshold for use of red blood cell (RBC) transfusions in anaemic patients remains an active field of research. Blood is a scarce resource, and in some countries, transfusions are less safe than in others because of inadequate testing for viral pathogens. If a liberal transfusion policy does not improve clinical outcomes, or if it is equivalent, then adopting a more restrictive approach could be recognised as the standard of care.  OBJECTIVES: The aim of this review update was to compare 30-day mortality and other clinical outcomes for participants randomised to restrictive versus liberal red blood cell (RBC) transfusion thresholds (triggers) for all clinical conditions. The restrictive transfusion threshold uses a lower haemoglobin concentration as a threshold for transfusion (most commonly, 7.0 g/dL to 8.0 g/dL), and the liberal transfusion threshold uses a higher haemoglobin concentration as a threshold for transfusion (most commonly, 9.0 g/dL to 10.0 g/dL). SEARCH METHODS: We identified trials through updated searches: CENTRAL (2020, Issue 11), MEDLINE (1946 to November 2020), Embase (1974 to November 2020), Transfusion Evidence Library (1950 to November 2020), Web of Science Conference Proceedings Citation Index (1990 to November 2020), and trial registries (November 2020). We  checked the reference lists of other published reviews and relevant papers to identify additional trials. We were aware of one trial identified in earlier searching that was in the process of being published (in February 2021), and we were able to include it before this review was finalised. SELECTION CRITERIA: We included randomised trials of surgical or medical participants that recruited adults or children, or both. We excluded studies that focused on neonates. Eligible trials assigned intervention groups on the basis of different transfusion schedules or thresholds or 'triggers'. These thresholds would be defined by a haemoglobin (Hb) or haematocrit (Hct) concentration below which an RBC transfusion would be administered; the haemoglobin concentration remains the most commonly applied marker of the need for RBC transfusion in clinical practice. We included trials in which investigators had allocated participants to higher thresholds or more liberal transfusion strategies compared to more restrictive ones, which might include no transfusion. As in previous versions of this review, we did not exclude unregistered trials published after 2010 (as per the policy of the Cochrane Injuries Group, 2015), however, we did conduct analyses to consider the differential impact of results of trials for which prospective registration could not be confirmed.   DATA COLLECTION AND ANALYSIS: We identified trials for inclusion and extracted data using Cochrane methods. We pooled risk ratios of clinical outcomes across trials using a random-effects model. Two review authors independently extracted data and assessed risk of bias. We conducted predefined analyses by clinical subgroups. We defined participants randomly allocated to the lower transfusion threshold as being in the 'restrictive transfusion' group and those randomly allocated to the higher transfusion threshold as being in the 'liberal transfusion' group. MAIN RESULTS: A total of 48 trials, involving data from 21,433 participants (at baseline), across a range of clinical contexts (e.g. orthopaedic, cardiac, or vascular surgery; critical care; acute blood loss (including gastrointestinal bleeding); acute coronary syndrome; cancer; leukaemia; haematological malignancies), met the eligibility criteria. The haemoglobin concentration used to define the restrictive transfusion group in most trials (36) was between 7.0 g/dL and 8.0 g/dL.  Most trials included only adults; three trials focused on children. The included studies were generally at low risk of bias for key domains including allocation concealment and incomplete outcome data. Restrictive transfusion strategies reduced the risk of receiving at least one RBC transfusion by 41% across a broad range of clinical contexts (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.53 to 0.66; 42 studies, 20,057 participants; high-quality evidence), with a large amount of heterogeneity between trials (I² = 96%). Overall, restrictive transfusion strategies did not increase or decrease the risk of 30-day mortality compared with liberal transfusion strategies (RR 0.99, 95% CI 0.86 to 1.15; 31 studies, 16,729 participants; I² = 30%; moderate-quality evidence) or any of the other outcomes assessed (i.e. cardiac events (low-quality evidence), myocardial infarction, stroke, thromboembolism (all high-quality evidence)). High-quality evidence shows that the liberal transfusion threshold did not affect the risk of infection (pneumonia, wound infection, or bacteraemia). Transfusion-specific reactions are uncommon and were inconsistently reported within trials. We noted less certainty in the strength of evidence to support the safety of restrictive transfusion thresholds for the following predefined clinical subgroups: myocardial infarction, vascular surgery, haematological malignancies, and chronic bone-marrow disorders. AUTHORS' CONCLUSIONS: Transfusion at a restrictive haemoglobin concentration decreased the proportion of people exposed to RBC transfusion by 41% across a broad range of clinical contexts. Across all trials, no evidence suggests that a restrictive transfusion strategy impacted 30-day mortality, mortality at other time points, or morbidity (i.e. cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, infection) compared with a liberal transfusion strategy. Despite including 17 more randomised trials (and 8846 participants), data remain insufficient to inform the safety of transfusion policies in important and selected clinical contexts, such as myocardial infarction, chronic cardiovascular disease, neurological injury or traumatic brain injury, stroke, thrombocytopenia, and cancer or haematological malignancies, including chronic bone marrow failure.  Further work is needed to improve our understanding of outcomes other than mortality. Most trials compared only two separate thresholds for haemoglobin concentration, which may not identify the actual optimal threshold for transfusion in a particular patient. Haemoglobin concentration may not be the most informative marker of the need for transfusion in individual patients with different degrees of physiological adaptation to anaemia. Notwithstanding these issues, overall findings provide good evidence that transfusions with allogeneic RBCs can be avoided in most patients with haemoglobin thresholds between the range of 7.0 g/dL and 8.0 g/dL. Some patient subgroups might benefit from RBCs to maintain higher haemoglobin concentrations; research efforts should focus on these clinical contexts.

Practices in Triage and Transfer of Critically Ill Patients: A Qualitative Systematic Review of Selection Criteria.

OBJECTIVES: To identify and appraise articles describing criteria used to prioritize or withhold a critical care admission. DATA SOURCES: PubMed, Embase, Medline, EBM Reviews, and CINAHL Complete databases. Gray literature searches and a manual review of references were also performed. Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed. STUDY SELECTION: We sought all articles and abstracts of original research as well as local, provincial, or national policies on the topic of ICU resource allocation. We excluded studies whose population of interest was neonatal, pediatric, trauma, or noncritically ill. Screening of 6,633 citations was conducted. DATA EXTRACTION: Triage and/or transport criteria were extracted, based on type of article, methodology, publication year, and country. An appraisal scale was developed to assess the quality of identified articles. We also developed a robustness score to further appraise the robustness of the evidence supporting each criterion. Finally, all criteria were extracted, evaluated, and grouped by theme. DATA SYNTHESIS: One-hundred twenty-nine articles were included. These were mainly original research (34%), guidelines (26%), and reviews (21%). Among them, we identified 200 unique triage and transport criteria. Most articles highlighted an exclusion (71%) rather than a prioritization mechanism (17%). Very few articles pertained to transport of critically ill patients (4%). Criteria were classified in one of four emerging themes: patient, condition, physician, and context. The majority of criteria used were nonspecific. No study prospectively evaluated the implementation of its cited criteria. CONCLUSIONS: This systematic review identified 200 criteria classified within four themes that may be included when devising triage programs including the coronavirus disease 2019 pandemic. We identified significant knowledge gaps where research would assist in improving existing triage criteria and guidelines, aiming to decrease arbitrary decisions and variability.

Volume-dependent effect of stored red blood cells: A secondary analysis of the Age of Blood Evaluation trial.

BACKGROUND: An increased risk of complications, including death, has been associated with stored red blood cell (RBC) units in observational studies but not in randomized trials. We aimed to evaluate for volume-dependent effects attributable to length of RBC storage in a secondary analysis of the Age of Blood Evaluation (ABLE) trial. STUDY DESIGN AND METHODS: In the 2510 critically ill adults from the ABLE trial randomized to receive RBC units stored not more than 7 days or the oldest compatible RBC units, we estimated the hazard ratio (HR) for death by intensive care unit (ICU) and hospital discharge and by days 28, 90, and 180, within subgroups defined by the number of RBC units received. Extended Cox proportional hazards regression was used to model the HR. RESULTS: A volume-dependent effect of storage age on survival was present for death by 90 and 180 days, but not earlier endpoints. The HR for death by 90 days was 0.55 (95% confidence interval [CI], 0.11-0.98, fresh vs standard) after transfusion of 6 RBC units but 1.45 (95% CI, 1.06-1.98) after transfusion of 1 RBC unit. CONCLUSION: In this exploratory analysis, volume-dependent effects related to RBC storage were documented in the ABLE trial. The harms associated with small volumes of fresh RBC units and large volumes of older RBC units should be further explored.

Frequency of Screening for Weaning From Mechanical Ventilation: Two Contemporaneous Proof-of-Principle Randomized Controlled Trials.

OBJECTIVES: It is unknown whether more frequent screening of invasively ventilated patients, identifies patients earlier for a spontaneous breathing trial, and shortens the duration of ventilation. We assessed the feasibility of conducting a large trial to evaluate screening frequency in critically ill adults in the North American context. DESIGN: We conducted two contemporaneous, multicenter, pilot, randomized controlled trials (the LibeRation from MEchanicaL VEntilAtion and ScrEening Frequency [RELEASE] and Screening Elderly PatieNts For InclusiOn in a Weaning [SENIOR] trials) to address concerns regarding the potential for higher enrollment, fewer adverse events, and better outcomes in younger patients. SETTING: Ten and 11 ICUs in Canada, respectively. PATIENTS: Parallel trials of younger (RELEASE < 65 yr) and older (SENIOR ≥ 65 yr) critically ill adults invasively ventilated for at least 24 hours. INTERVENTIONS: Each trial compared once daily screening to "at least twice daily" screening led by respiratory therapists. MEASUREMENTS AND MAIN RESULTS: In both trials, we evaluated recruitment (aim: 1-2 patients/month/ICU) and consent rates, reasons for trial exclusion, protocol adherence (target: ≥ 80%), crossovers (aim: ≤ 10%), and the effect of the alternative screening frequencies on adverse events and clinical outcomes. We included 155 patients (53 patients [23 once daily, 30 at least twice daily] in RELEASE and 102 patients [54 once daily, 48 at least twice daily] in SENIOR). Between trials, we found similar recruitment rates (1.32 and 1.26 patients/month/ICU) and reasons for trial exclusion, high consent and protocol adherence rates (> 92%), infrequent crossovers, and few adverse events. Although underpowered, at least twice daily screening was associated with a nonsignificantly faster time to successful extubation and more successful extubations but significantly increased use of noninvasive ventilation in both trials combined. CONCLUSIONS: Similar recruitment and consent rates, few adverse events, and comparable outcomes in younger and older patients support conduct of a single large trial in North American ICUs assessing the net clinical benefits associated with more frequent screening.

Effect of age of transfused red blood cells on neurologic outcome following traumatic brain injury (ABLE-tbi Study): a nested study of the Age of Blood Evaluation (ABLE) trial.

BACKGROUND: Anemia is common in critically ill patients with traumatic brain injury, and often requires red blood cell transfusion. Studies suggest that prolonged storage causes lesions of the red blood cells, including a decreased ability to carry oxygen. Considering the susceptibility of the brain to hypoxemia, victims of traumatic brain injury may thus be more vulnerable to exposure to older red blood cells. METHODS: Our study aimed to ascertain whether the administration of fresh red blood cells (seven days or less) results in a better neurologic outcome compared with standard red blood cells in critically ill patients with traumatic brain injury requiring transfusion. The Age of Blood Evaluation in traumatic brain injury (ABLE-tbi) study was a nested study within the ABLE study (ISRCTN44878718). Our primary outcome was the extended Glasgow Outcome Scale (GOSe) at six months. RESULTS: In the ABLE study, 217 subjects suffered a traumatic brain injury: 110 in the fresh group, and 107 in the standard group. In the fresh group, 68 (73.1%) of the patients had an unfavourable neurologic outcome (GOSe ≤ 4) compared with 60 (64.5%) in the standard group (P = 0.21). Using a sliding dichotomy approach, we observed no overall effect of fresh red blood cells on neurologic outcome (odds ratio [OR], 1.34; 95% confidence interval [CI], 0.72 to 2.50; P = 0.35) but observed differences across prognostic bands with a decreased odds of unfavourable outcome in patients with the best prognosis at baseline (OR, 0.33; 95% CI, 0.11 to 0.96; P = 0.04) but an increased odds in those with intermediate and worst baseline prognosis (OR, 5.88; 95% CI,1.66 to 20.81; P = 0.006; and OR, 1.67; 95% CI, 0.53 to 5.30; P = 0.38, respectively). CONCLUSION: Overall, transfusion of fresh red blood cells was not associated with a better neurologic outcome at six months in critically ill patients with traumatic brain injury. Nevertheless, we cannot exclude a differential effect according to the patient baseline prognosis. TRIAL REGISTRATION: ABLE study (ISRCTN44878718); registered 22 August, 2008.

Effect of Fresh vs Standard-issue Red Blood Cell Transfusions on Multiple Organ Dysfunction Syndrome in Critically Ill Pediatric Patients: A Randomized Clinical Trial.

Importance: The clinical consequences of red blood cell storage age for critically ill pediatric patients have not been examined in a large, randomized clinical trial. Objective: To determine if the transfusion of fresh red blood cells (stored ≤7 days) reduced new or progressive multiple organ dysfunction syndrome compared with the use of standard-issue red blood cells in critically ill children. Design, Setting, and Participants: The Age of Transfused Blood in Critically-Ill Children trial was an international, multicenter, blinded, randomized clinical trial, performed between February 2014 and November 2018 in 50 tertiary care centers. Pediatric patients between the ages of 3 days and 16 years were eligible if the first red blood cell transfusion was administered within 7 days of intensive care unit admission. A total of 15 568 patients were screened, and 13 308 were excluded. Interventions: Patients were randomized to receive either fresh or standard-issue red blood cells. A total of 1538 patients were randomized with 768 patients in the fresh red blood cell group and 770 in the standard-issue group. Main Outcomes and Measures: The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured for 28 days or to discharge or death. Results: Among 1538 patients who were randomized, 1461 patients (95%) were included in the primary analysis (median age, 1.8 years; 47.3% girls), in which there were 728 patients randomized to the fresh red blood cell group and 733 to the standard-issue group. The median storage duration was 5 days (interquartile range [IQR], 4-6 days) in the fresh group vs 18 days (IQR, 12-25 days) in the standard-issue group (P < .001). There were no significant differences in new or progressive multiple organ dysfunction syndrome between fresh (147 of 728 [20.2%]) and standard-issue red blood cell groups (133 of 732 [18.2%]), with an unadjusted absolute risk difference of 2.0% (95% CI, -2.0% to 6.1%; P = .33). The prevalence of sepsis was 25.8% (160 of 619) in the fresh group and 25.3% (154 of 608) in the standard-issue group. The prevalence of acute respiratory distress syndrome was 6.6% (41 of 619) in the fresh group and 4.8% (29 of 608) in the standard-issue group. Intensive care unit mortality was 4.5% (33 of 728) in the fresh group vs 3.5 % (26 of 732) in the standard-issue group (P = .34). Conclusions and Relevance: Among critically ill pediatric patients, the use of fresh red blood cells did not reduce the incidence of new or progressive multiple organ dysfunction syndrome (including mortality) compared with standard-issue red blood cells. Trial Registration: ClinicalTrials.gov Identifier: NCT01977547.

Ottawa Criteria for Appropriate Transfusions in Hepatectomy: Using the RAND/UCLA Appropriateness Method.

OBJECTIVE: Create practice guidelines for the appropriate use of red blood cell transfusions in hepatectomy. BACKGROUND: Hepatectomy is associated with a high prevalence of transfusions. A transfusion can be life-saving, but can be associated with important adverse effects. Given the prevalence, the potential for benefit and harm, and the difficulty in conducting clinical trials, transfusion in hepatectomy is well-suited for a study of appropriateness. METHODS: Using the RAND/UCLA appropriateness method, an international, multidisciplinary expert panel in hepatobiliary surgery, anesthesia, transfusion medicine, and critical care rated a series of 468 perioperative scenarios for transfusion appropriateness. Scenarios were rated individually, and again during an inperson group moderated session. Median scores and level of agreement were calculated to classify each scenario as appropriate, inappropriate, or uncertain. RESULTS: Approximately, 47.4% of scenarios were rated as appropriate for transfusion, 28.2% were inappropriate, and 24.4% were uncertain. The key recommendations for intraoperative transfusion were (i) it is never inappropriate to transfuse for significant bleeding or ST segment changes; (ii) it is never inappropriate to transfuse for an intraoperative hemoglobin ≤75 g/L; and (iii) in the absence of significant bleeding or ST changes, transfusion for hemoglobin of ≥95 g/L is inappropriate, and transfusion for hemoglobin of ≥85 g/L requires strong justification. The key recommendations for postoperative transfusions were: (i) in a stable, asymptomatic patient, an appropriate transfusion trigger is 70 g/L (without coronary artery disease) or 80 g/L (with coronary artery disease) and (ii) it is appropriate to transfuse any patient for a hemoglobin of ≤75 g/L either immediately post-operative, or with a significant decrease from the previous day (>15 g/L). CONCLUSIONS: Based on best available evidence and expert opinion, criteria for appropriate perioperative red blood cell transfusions in hepatectomy were determined.

Age of transfused blood in critically ill adults.

BACKGROUND: Fresh red cells may improve outcomes in critically ill patients by enhancing oxygen delivery while minimizing the risks of toxic effects from cellular changes and the accumulation of bioactive materials in blood components during prolonged storage. METHODS: In this multicenter, randomized, blinded trial, we assigned critically ill adults to receive either red cells that had been stored for less than 8 days or standard-issue red cells (the oldest compatible units available in the blood bank). The primary outcome measure was 90-day mortality. RESULTS: Between March 2009 and May 2014, at 64 centers in Canada and Europe, 1211 patients were assigned to receive fresh red cells (fresh-blood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group). Red cells were stored a mean (±SD) of 6.1±4.9 days in the fresh-blood group as compared with 22.0±8.4 days in the standard-blood group (P<0.001). At 90 days, 448 patients (37.0%) in the fresh-blood group and 430 patients (35.3%) in the standard-blood group had died (absolute risk difference, 1.7 percentage points; 95% confidence interval [CI], -2.1 to 5.5). In the survival analysis, the hazard ratio for death in the fresh-blood group, as compared with the standard-blood group, was 1.1 (95% CI, 0.9 to 1.2; P=0.38). There were no significant between-group differences in any of the secondary outcomes (major illnesses; duration of respiratory, hemodynamic, or renal support; length of stay in the hospital; and transfusion reactions) or in the subgroup analyses. CONCLUSIONS: Transfusion of fresh red cells, as compared with standard-issue red cells, did not decrease the 90-day mortality among critically ill adults. (Funded by the Canadian Institutes of Health Research and others; Current Controlled Trials number, ISRCTN44878718.).

Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease.

BACKGROUND: Several new trials evaluating transfusion strategies in patients with cardiovascular disease have recently been published, increasing the number of enrolled patients by over 30%. The objective was to evaluate transfusion thresholds in patients with cardiovascular disease. METHODS: We conducted an updated systematic review of randomized trials that compared patients assigned to maintain a lower (restrictive transfusion strategy) or higher (liberal transfusion strategy) hemoglobin concentration. We focused on new trial data in patients with cardiovascular disease. The primary outcome was 30-day mortality. Specific subgroups were patients undergoing cardiac surgery and with acute myocardial infarction. RESULTS: A total of 37 trials that enrolled 19,049 patients were appraised. In cardiac surgery, mortality at 30days was comparable between groups (risk ratio 0.99; 95% confidence interval 0.74-1.33). In 2 small trials (n=154) in patients with myocardial infarction, the point estimate for the mortality risk ratio was 3.88 (95% CI, 0.83-18.13) favoring the liberal strategy. Overall, from 26 trials enrolling 15,681 patients, 30-day mortality was not different between restrictive and liberal transfusion strategies (risk ratio 1.0, 95% CI, 0.86-1.16). Overall and in the cardiovascular disease subgroup, there were no significant differences observed across a range of secondary outcomes. CONCLUSIONS: New trials in patients undergoing cardiac surgery establish that a restrictive transfusion strategy of 7 to 8g/dL is safe and decreased red cell use by 24%. Further research is needed to define the optimal transfusion threshold in patients with acute myocardial infarction.

Age of transfused blood in critically ill adult trauma patients: a prespecified nested analysis of the Age of Blood Evaluation randomized trial.

BACKGROUND: Blood transfusion is common in the resuscitation of patients with traumatic injury. However, the clinical impact of the length of storage of transfused blood is unclear in this population. STUDY DESIGN AND METHODS: We undertook a prespecified nested analysis of 372 trauma victims of the 2510 critically ill patients from 64 centers treated as part of the Age of Blood Evaluation (ABLE) randomized controlled trial. Patients were randomized according to their trauma status to receive either a transfusion of fresh blood stored not more than 7 days or standard-issue blood. Our primary outcome was 90-day all-cause mortality. RESULTS: Overall, 186 trauma patients received fresh blood and 186 received standard-issue blood. Adherence to transfusion protocol was 94% (915/971) for all fresh blood transfused and 100% (753/753) for all standard-issue blood transfused. Mean ± SD blood storage duration was 5.6 ± 3.8 days in the fresh group and 22.7 ± 8.4 days in the standard-issue group (p < 0.001). Ninety-day mortality in the fresh group was 21% (38/185), compared to 16% (29/184) in the standard-issue group, with an unadjusted absolute risk difference of 5% (95% confidence interval [CI], -3.1 to 12.6) and an adjusted absolute risk difference of 2% (95% CI, -3.5 to 6.8). CONCLUSION: In critically ill trauma patients, transfusion of fresh blood did not decrease 90-day mortality or secondary outcomes, a finding similar to the overall population of the ABLE trial.