Hospital policy of tranexamic acid to reduce transfusion in major non-cardiac surgery (TRACTION): protocol for a phase IV randomised controlled trial.

INTRODUCTION: Tranexamic acid (TXA) is an inexpensive and widely available medication that reduces blood loss and red blood cell (RBC) transfusion in cardiac and orthopaedic surgeries. While the use of TXA in these surgeries is routine, its efficacy and safety in other surgeries, including oncologic surgeries, with comparable rates of transfusion are uncertain. Our primary objective is to evaluate whether a hospital-level policy implementation of routine TXA use in patients undergoing major non-cardiac surgery reduces RBC transfusion without increasing thrombotic risk. METHODS AND ANALYSIS: A pragmatic, registry-based, blinded, cluster-crossover randomised controlled trial at 10 Canadian sites, enrolling patients undergoing non-cardiac surgeries at high risk for RBC transfusion. Sites are randomised in 4-week intervals to a hospital policy of intraoperative TXA or matching placebo. TXA is administered as 1 g at skin incision, followed by an additional 1 g prior to skin closure. Coprimary outcomes are (1) effectiveness, evaluated as the proportion of patients transfused RBCs during hospital admission and (2) safety, evaluated as the proportion of patients diagnosed with venous thromboembolism within 90 days. Secondary outcomes include: (1) transfusion: number of RBC units transfused (both at a hospital and patient level); (2) safety: in-hospital diagnoses of myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism; (3) clinical: hospital length of stay, intensive care unit admission, hospital survival, 90-day survival and the number of days alive and out of hospital to day 30; and (4) compliance: the proportion of enrolled patients who receive a minimum of one dose of the study intervention. ETHICS AND DISSEMINATION: Institutional research ethics board approval has been obtained at all sites. At the completion of the trial, a plain language summary of the results will be posted on the trial website and distributed in the lay press. Our trial results will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT04803747.

Prognostic Factors Associated with Venous Thromboembolism Following Traumatic Injury: A Systematic Review and Meta-Analysis.

INTRODUCTION: Trauma patients are at increased risk of venous thromboembolism (VTE), including deep venous thrombosis (DVT) and/or pulmonary embolism (PE). We conducted a systematic review and meta-analysis summarizing the association between prognostic factors and the occurrence of VTE following traumatic injury. METHODS: We searched the EMBASE and MEDLINE databases from inception to August 2023. We identified studies reporting confounding adjusted associations between patient, injury or post-injury care factors and risk of VTE. We performed meta-analyses of odds ratios (ORs) using the random effects method and assessed individual study risk of bias using the QUIPS tool. RESULTS: We included 31 studies involving 1,981,946 patients. Studies were predominantly observational cohorts from North America. Factors with moderate or higher certainty of association with increased risk of VTE include older age, obesity, male sex, higher injury severity score, pelvic injury, lower extremity injury, spinal injury, delayed VTE prophylaxis, need for surgery and tranexamic acid use. After accounting for other important contributing prognostic variables, a delay in the delivery of appropriate pharmacologic prophylaxis for as little as 24 to 48 hours independently confers a clinically meaningful two-fold increase in incidence of VTE. CONCLUSION: These findings highlight the contribution of patient predisposition, the importance of injury pattern, and the impact of potentially modifiable post-injury care on risk of VTE after traumatic injury. These factors should be incorporated into a risk stratification framework to individualize VTE risk assessment and support clinical and academic efforts reduce thromboembolic events among trauma patients.Study TypeSystematic Review & Meta-Analysis. LEVEL OF EVIDENCE: Level II.

Cost-effectiveness of remdesivir plus usual care versus usual care alone for hospitalized patients with COVID-19: an economic evaluation as part of the Canadian Treatments for COVID-19 (CATCO) randomized clinical trial.

BACKGROUND: The role of remdesivir in the treatment of hospitalized patients with COVID-19 remains ill-defined. We conducted a cost-effectiveness analysis alongside the Canadian Treatments for COVID-19 (CATCO) open-label, randomized clinical trial evaluating remdesivir. METHODS: Patients with COVID-19 in Canadian hospitals from Aug. 14, 2020, to Apr. 1, 2021, were randomly assigned to receive remdesivir plus usual care versus usual care alone. Taking a public health care payer's perspective, we collected in-hospital outcomes and health care resource utilization alongside estimated unit costs in 2020 Canadian dollars over a time horizon from randomization to hospital discharge or death. Data from 1281 adults admitted to 52 hospitals in 6 Canadian provinces were analyzed. RESULTS: The total mean cost per patient was $37 918 (standard deviation [SD] $42 413; 95% confidence interval [CI] $34 617 to $41 220) for patients randomly assigned to the remdesivir group and $38 026 (SD $46 021; 95% CI $34 480 to $41 573) for patients receiving usual care (incremental cost -$108 [95% CI -$4953 to $4737], p > 0.9). The difference in proportions of in-hospital deaths between remdesivir and usual care groups was -3.9% (18.7% v. 22.6%, 95% CI -8.3% to 1.0%, p = 0.09). The difference in proportions of incident invasive mechanical ventilation events between groups was -7.0% (8.0% v. 15.0%, 95% CI -10.6% to -3.4%, p = 0.006), whereas the difference in proportions of total mechanical ventilation events between groups was -5.7% (16.4% v. 22.1%, 95% CI -10.0% to -1.4%, p = 0.01). Remdesivir was the dominant intervention (but only marginally less costly, with mildly lower mortality) with an incalculable incremental cost effectiveness ratio; we report results of incremental costs and incremental effects separately. For willingness-to-pay thresholds of $0, $20 000, $50 000 and $100 000 per death averted, a strategy using remdesivir was cost-effective in 60%, 67%, 74% and 79% of simulations, respectively. The remdesivir costs were the fifth highest cost driver, offset by shorter lengths of stay and less mechanical ventilation. INTERPRETATION: From a health care payer perspective, treating patients hospitalized with COVID-19 with remdesivir and usual care appears to be preferrable to treating with usual care alone, albeit with marginal incremental cost and small clinical effects. The added cost of remdesivir was offset by shorter lengths of stay in the intensive care unit and less need for ventilation. STUDY REGISTRATION: ClinicalTrials. gov, no. NCT04330690.

Economic Evaluation of Cost and Time Required for a Platform Trial vs Conventional Trials.

Importance: Platform trial design allows the introduction of new interventions after the trial is initiated and offers efficiencies to clinical research. However, limited guidance exists on the economic resources required to establish and maintain platform trials. Objective: To compare cost (US dollars) and time requirements of conducting a platform trial vs a series of conventional (nonplatform) trials using a real-life example. Design, Setting, and Participants: For this economic evaluation, an online survey was administered to a group of international experts (146 participants) with publication records of platform trials to elicit their opinions on cost and time to set up and conduct platform, multigroup, and 2-group trials. Using the reported entry dates of 10 interventions into Systemic Therapy in Advancing Metastatic Prostate Cancer: Evaluation of Drug Efficacy, the longest ongoing platform trial, 3 scenarios were designed involving a single platform trial (scenario 1), 1 multigroup followed by 5 2-group trials (scenario 2), and a series of 10 2-group trials (scenario 3). All scenarios started with 5 interventions, then 5 more interventions were either added to the platform or evaluated independently. Simulations with the survey results as inputs were used to compare the platform vs conventional trial designs. Data were analyzed from July to September 2021. Exposure: Platform trial design. Main Outcomes and Measures: Total trial setup and conduct cost and cumulative duration. Results: Although setup time and cost requirements of a single trial were highest for the platform trial, cumulative requirements of setting up a series of multiple trials in scenarios 2 and 3 were larger. Compared with the platform trial, there was a median (IQR) increase of 216.7% (202.2%-242.5%) in cumulative setup costs for scenario 2 and 391.1% (365.3%-437.9%) for scenario 3. In terms of total cost, there was a median (IQR) increase of 17.4% (12.1%-22.5%) for scenario 2 and 57.5% (43.1%-69.9%) for scenario 3. There was a median (IQR) increase in cumulative trial duration of 171.1% (158.3%-184.3%) for scenario 2 and 311.9% (282.0%-349.1%) for scenario 3. Cost and time reductions in the platform trial were observed in both the initial and subsequently evaluated interventions. Conclusions and Relevance: Although setting up platform trials can take longer and be costly, the findings of this study suggest that having a single infrastructure can improve efficiencies with respect to costs and efforts.

Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Prognostic Factors Associated With Development of Venous Thromboembolism in Critically Ill Patients-A Systematic Review and Meta-Analysis.

OBJECTIVE: To identify prognostic factors for the development of venous thromboembolism in the ICU. DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception to March 1, 2021. STUDY SELECTION: We included English-language studies describing prognostic factors associated with the development of venous thromboembolism among critically ill patients. DATA EXTRACTION: Two authors performed data extraction and risk-of-bias assessment. We pooled adjusted odds ratios and adjusted hazard ratios for prognostic factors using random-effects model. We assessed risk of bias using the Quality in Prognosis Studies tool and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. DATA SYNTHESIS: We included 39 observational cohort studies involving 729,477 patients. Patient factors with high or moderate certainty of association with increased odds of venous thromboembolism include older age (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29 per 10 yr), obesity (adjusted odds ratio, 1.25; 95% CI, 1.18-1.32), active malignancy (adjusted odds ratio, 1.70; 95% CI, 1.18-2.44), history of venous thromboembolism (adjusted odds ratio, 4.77; 95% CI, 3.42-6.65), and history of recent surgery (adjusted odds ratio, 1.77; 95% CI, 1.26-2.47). ICU-specific factors with high or moderate certainty of association with increased risk of venous thromboembolism include sepsis (adjusted odds ratio, 1.41; 95% CI, 1.12-1.78), lack of pharmacologic venous thromboembolism prophylaxis (adjusted odds ratio, 1.80; 95% CI, 1.14-2.84), central venous catheter (adjusted odds ratio, 2.93; 95% CI, 1.98-4.34), invasive mechanical ventilation (adjusted odds ratio, 1.74; 95% CI, 1.36-2.24), and use of vasoactive medication (adjusted odds ratio, 1.86; 95% CI, 1.23-2.81). CONCLUSIONS: This meta-analysis provides quantitative summaries of the association between patient-specific and ICU-related prognostic factors and the risk of venous thromboembolism in the ICU. These findings provide the foundation for the development of a venous thromboembolism risk stratification tool for critically ill patients.

Transfusion in orthopaedic surgery : a retrospective multicentre cohort study.

AIMS: Orthopaedic surgeries are complex, frequently performed procedures associated with significant haemorrhage and perioperative blood transfusion. Given refinements in surgical techniques and changes to transfusion practices, we aim to describe contemporary transfusion practices in orthopaedic surgery in order to inform perioperative planning and blood banking requirements. METHODS: We performed a retrospective cohort study of adult patients who underwent orthopaedic surgery at four Canadian hospitals between 2014 and 2016. We studied all patients admitted to hospital for nonarthroscopic joint surgeries, amputations, and fracture surgeries. For each surgery and surgical subgroup, we characterized the proportion of patients who received red blood cell (RBC) transfusion, the mean/median number of RBC units transfused, and exposure to platelets and plasma. RESULTS: Of the 14,584 included patients, the most commonly performed surgeries were knee arthroplasty (24.8%), hip arthroplasty (24.6%), and hip fracture surgery (17.4%). A total of 10.3% of patients received RBC transfusion; the proportion of patients receiving RBC transfusions varied widely based on the surgical subgroup (0.0% to 33.1%). Primary knee arthroplasty and hip arthroplasty, the two most common surgeries, were associated with in-hospital transfusion frequencies of 2.8% and 4.5%, respectively. RBC transfusion occurred in 25.0% of hip fracture surgeries, accounting for the greatest total number of RBC units transfused in our cohort (38.0% of all transfused RBC units). Platelet and plasma transfusions were uncommon. CONCLUSION: Orthopaedic surgeries were associated with variable rates of transfusion. The rate of RBC transfusion is highly dependent on the surgery type. Identifying surgeries with the highest transfusion rates, and further evaluation of factors that contribute to transfusion in identified at-risk populations, can serve to inform perioperative planning and blood bank requirements, and facilitate pre-emptive transfusion mitigation strategies. Cite this article: Bone Jt Open 2021;2(10):850-857.

Prophylactic tranexamic acid use in non-cardiac surgeries at high risk for transfusion.

BACKGROUND: Tranexamic acid (TXA) reduces transfusion in a wide range of surgical populations, although its real-world use in non-cardiac surgeries has not been well described. The objective of this study was to describe prophylactic TXA use in non-cardiac surgeries at high risk for transfusion. METHODS: This is a retrospective cohort study of all adult patients undergoing major non-cardiac surgery at ≥5% risk of perioperative transfusion at five Canadian hospitals between January 2014 and December 2016. Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database were linked to transfusion and laboratory databases. TXA use was ascertained electronically from The Ottawa Hospital Data Warehouse and via manual chart review for Winnipeg hospitals. For each surgery, we evaluated the percentage of patients who received TXA as well as the specifics of TXA dosing and administration. RESULTS: TXA use was evaluable in 14 300 patients. Overall, 17% of surgeries received TXA, ranging from 0% to 68% among individual surgeries. TXA use was more common in orthopaedic (n = 2043/4942; 41%) and spine surgeries (n = 239/1322; 18%) compared to other surgical domains (n = 109/8036; 1%). TXA was commonly administered as a bolus (n = 2097/2391; 88%). The median TXA dose was 1000 mg (IQR 1000-1000 mg). CONCLUSION: TXA is predominantly used in orthopaedic and spine surgeries, with little uptake in other non-cardiac surgeries at high risk for red blood cell transfusion. Further studies are needed to evaluate the effectiveness and safety of TXA and to understand the barriers to TXA administration in a broad range of non-cardiac surgeries.

Variation in prophylactic tranexamic acid administration among anesthesiologists and surgeons in orthopedic surgery: a retrospective cohort study.

PURPOSE: Tranexamic acid (TXA) reduces red blood cell transfusion in various orthopedic surgeries, yet the degree of practice variation in its use among anesthesiologists and surgeons has not been described. To target future knowledge transfer and implementation strategies, and to better understand determinants of variability in prophylactic TXA use, our primary objective was to evaluate the influence of surgical team members on the variability of prophylactic TXA administration. METHODS: This was a retrospective cohort study of all adult patients undergoing primary total hip arthroplasty (THA), hip fracture surgery, and spine fusion ± vertebrectomy at two Canadian hospitals between January 2014 and December 2016. We used Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database which we linked to the Ottawa Data Warehouse. We described the percentage of patients that received TXA by individual surgery, the specifics of TXA dosing, and estimated the effect of anesthesiologists and surgeons on prophylactic TXA using multivariable mixed-effects logistic regression analyses. RESULTS: In the 3,900 patients studied, TXA was most commonly used in primary THA (85%; n = 1,344/1,582), with lower use in hip fracture (23%; n = 342/1,506) and spine fusion surgery (23%; n = 186/812). The median [interquartile range] total TXA dose was 1,000 [1,000-1,000] mg, given as a bolus in 92% of cases. Anesthesiologists and surgeons added significant variability to the odds of receiving TXA in hip fracture surgery and spine fusion, but not primary THA. Most of the variability in TXA use was attributed to patient and other factors. CONCLUSION: We confirmed the routine use of TXA in primary THA, while observing lower utilization with more variability in hip fracture and spine fusion surgery. Further study is warranted to understand variations in use and the barriers to TXA implementation in a broader population of orthopedic surgical patients at high risk for transfusion.

RéSUMé: OBJECTIF: L'acide tranexamique (ATX) réduit la transfusion d'érythrocytes dans diverses chirurgies orthopédiques. Cependant, les variations de pratique quant à son utilisation parmi les anesthésiologistes et les chirurgiens n'ont pas été décrites. Afin de cibler les stratégies futures de transfert des connaissances et de mise en œuvre, et pour mieux comprendre les déterminants de la variabilité dans l'utilisation prophylactique d'ATX, notre objectif principal était d'évaluer l'influence des membres de l'équipe chirurgicale sur la variabilité de l'administration prophylactique d'ATX. MéTHODE: Il s'agissait d'une étude de cohorte rétrospective de tous les patients adultes subissant une arthroplastie totale primaire de la hanche (ATH), une chirurgie de fracture de la hanche et une fusion intervertébrale ± vertébrectomie dans deux hôpitaux canadiens entre janvier 2014 et décembre 2016. Nous avons utilisé les codes de procédure de la Classification canadienne des interventions en santé dans la Base de données sur les congés des patients, que nous avons liée à la banque de données d'Ottawa. Nous avons décrit le pourcentage de patients qui ont reçu de l'ATX par chirurgie individuelle, les détails du dosage de l'ATX, et avons estimé l'effet des anesthésiologistes et des chirurgiens sur l'ATX prophylactique en réalisant des analyses de régression logistique multivariées à effets mixtes. RéSULTATS: Parmi les 3900 patients étudiés, l'ATX était le plus fréquemment utilisé lors d'une ATH primaire (85 %; n = 1344/1582), avec une utilisation plus faible lors de chirurgie de fracture de la hanche (23 %; n = 342/1506) et de chirurgie de fusion intervertébrale (23 %; n = 186/812). La dose totale médiane [écart interquartile] d'ATX était de 1000 mg [1000 à 1000], administrés dans 92 % des cas sous forme de bolus. Les anesthésiologistes et les chirurgiens ont ajouté une variabilité significative aux probabilités de recevoir de l'ATX lors d'une chirurgie de fracture de la hanche et de fusion, mais pas lors d'ATH primaire. La majeure partie de la variabilité dans l'utilisation d'ATX était attribuable aux facteurs liés au patient et à d'autres facteurs. CONCLUSION: Nous avons confirmé l'utilisation de routine de l'ATX dans l'ATH primaire, tout en observant une utilisation moins répandue et plus variable lors de chirurgie de fracture de la hanche et de fusion intervertébrale. Une étude plus approfondie est nécessaire pour comprendre les variations d'utilisation et les obstacles à la mise en œuvre de l'ATX dans une population plus étendue de patients de chirurgie orthopédique à haut risque de transfusion.

Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

Does a Delay in Anterior Cruciate Ligament Reconstruction Increase the Incidence of Secondary Pathology in the Knee? A Systematic Review and Meta-Analysis.

OBJECTIVE: Previous systematic reviews looking at timing of anterior cruciate ligament reconstruction (ACLR) examined the functional outcomes and range of motion; however, few have quantified the effect of timing of surgery on secondary pathology. The goal of this study was to analyze the effects of early ACLRs versus delayed ACLR on the incidence of meniscal and chondral lesions. DATA SOURCES: We searched MEDLINE, EMBASE, and CINAHL on March 20, 2018, for randomized control trials (RCTs) that compared early and delayed ACLR in a skeletally mature population. Two reviewers independently identified trials, extracted trial-level data, performed risk-of-bias assessments using the Cochrane Risk of Bias tool, and evaluated the study methodology using the Detsky scale. A meta-analysis was performed using a random-effects model with the primary outcome being the total number of meniscal and chondral lesions per group. RESULTS: Of 1887 citations identified from electronic and hand searches, we included 4 unique RCTs (303 patients). We considered early reconstruction as <3 weeks and delayed reconstruction as >4 weeks after injury. There was no evidence of a difference between early and late ACLR regarding the incidence of meniscal [relative risk (RR), 0.98; 95% confidence interval (CI), 0.74-1.29] or chondral lesions (RR, 0.88; 95% CI, 0.59-1.29), postoperative infection, graft rupture, functional outcomes, or range of motion. CONCLUSIONS: We found no evidence of benefit of early ACLR. Further studies may consider delaying surgery even further (eg, >3 months) to determine whether there are any real benefits to earlier reconstruction.

Evaluation of Transfusion Practices in Noncardiac Surgeries at High Risk for Red Blood Cell Transfusion: A Retrospective Cohort Study.

Perioperative bleeding is a major indication for red blood cell (RBC) transfusion, yet transfusion data in many major noncardiac surgeries are lacking and do not reflect recent blood conservation efforts. We aim to describe transfusion practices in noncardiac surgeries at high risk for RBC transfusion. We completed a retrospective cohort study to evaluate adult patients undergoing major noncardiac surgery at 5 Canadian hospitals between January 2014 and December 2016. We used Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database, which we linked to transfusion and laboratory databases. We studied all patients undergoing a major noncardiac surgery at ≥5% risk of perioperative RBC transfusion. For each surgery, we characterized the percentage of patients exposed to an RBC transfusion, the mean/median number of RBC units transfused, and platelet and plasma exposure. We identified 85 noncardiac surgeries with an RBC transfusion rate ≥5%, representing 25,607 patient admissions. The baseline RBC transfusion rate was 16%, ranging from 5% to 49% among individual surgeries. Of those transfused, the median (Q1, Q3) number of RBCs transfused was 2 U (1, 3 U); 39% received 1 U RBC, 36% received 2 U RBC, and 8% were transfused ≥5 U RBC. Platelet and plasma transfusions were overall low. In the era of blood conservation, we described transfusion practices in major noncardiac surgeries at high risk for RBC transfusion, which has implications for patient consent, preoperative surgical planning, and blood bank inventory management.

Association of Mindfulness-Based Interventions With Anxiety Severity in Adults With Cancer: A Systematic Review and Meta-analysis.

Importance: Mindfulness-based interventions (MBIs), grounded in mindfulness, focus on purposely paying attention to experiences occurring at the present moment without judgment. MBIs are increasingly used by patients with cancer for the reduction of anxiety, but it remains unclear if MBIs reduce anxiety in patients with cancer. Objective: To evaluate the association of MBIs with reductions in the severity of anxiety in patients with cancer. Data Sources: Systematic searches of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and SCOPUS were conducted from database inception to May 2019 to identify relevant citations. Study Selection: Randomized clinical trials (RCTs) that compared MBI with usual care, waitlist controls, or no intervention for the management of anxiety in cancer patients were included. Two reviewers conducted a blinded screening. Of 101 initially identified studies, 28 met the inclusion criteria. Data Extraction and Synthesis: Two reviewers independently extracted the data. The Cochrane Collaboration risk-of-bias tool was used to assess the quality of RCTs, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Summary effect measures were reported as standardized mean differences (SMDs) and calculated using a random-effects model. Main Outcomes and Measures: Our primary outcome was the measure of severity of short-term anxiety (up to 1-month postintervention); secondary outcomes were the severity of medium-term (1 to ≤6 months postintervention) and long-term (>6 to 12 months postintervention) anxiety, depression, and health-related quality of life of patients and caregivers. Results: This meta-analysis included 28 RCTs enrolling 3053 adults with cancer. None of the trials were conducted in children. Mindfulness was associated with significant reductions in the severity of short-term anxiety (23 trials; 2339 participants; SMD, -0.51; 95% CI, -0.70 to -0.33; I2 = 76%). The association of mindfulness with short-term anxiety did not vary by evaluated patient, intervention, or study characteristics. Mindfulness was also associated with the reduction of medium-term anxiety (9 trials; 965 participants; SMD, -0.43; 95% CI, -0.68 to -0.18; I2 = 66%). No reduction in long-term anxiety was observed (2 trials; 403 participants; SMD, -0.02; 95% CI, -0.38 to 0.34; I2 = 68%). MBIs were associated with a reduction in the severity of depression in the short term (19 trials; 1874 participants; SMD, -0.73; 95% CI; -1.00 to -0.46; I2 = 86%) and the medium term (8 trials; 891 participants; SMD, -0.85; 95% CI, -1.35 to -0.35; I2 = 91%) and improved health-related quality of life in patients in the short term (9 trials; 1108 participants; SMD, 0.51; 95% CI, 0.20 to 0.82; I2 = 82%) and the medium term (5 trials; 771 participants; SMD, 0.29; 95% CI, 0.06 to 0.52; I2 = 57%). Conclusions and Relevance: In this study, MBIs were associated with reductions in anxiety and depression up to 6 months postintervention in adults with cancer. Future trials should explore the long-term association of mindfulness with anxiety and depression in adults with cancer and determine its efficacy in more diverse cancer populations using active controls.

Ipilimumab-Induced Enterocolitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Checkpoint inhibitor drugs including ipilimumab have been reported to induce intestinal injury. OBJECTIVE: We aimed to evaluate the risk of chronic (> 6 weeks) enterocolitis following ipilimumab administration, and the likelihood that an enteritis vs colitis or enterocolitis is seen. PATIENTS AND METHODS: We searched MEDLINE, EMBASE, CENTRAL, the World Health Organization International Clinical Trials Registry, and conference proceedings. We included: (1) randomized controlled trials comparing ipilimumab administration with placebo/standard care/other active chemotherapy regimens and (2) prospective observational studies. Separate meta-analyses were performed for randomized controlled trials and observational studies. RESULTS: Of 4760 records, we included ten unique randomized controlled trials (n = 5814 subjects) and 34 unique prospective observational studies (n = 3699 subjects). In randomized controlled trials, the pooled relative risk of ≥ grade 3 enterocolitis or ≥ grade 3 diarrhea associated with ipilimumab was 13.31 (95% confidence interval 6.01-29.48, I2 = 0%, ten trials) and 6.72 (95% confidence interval 3.30-13.65, I2 = 63%, ten trials), respectively. In observational studies, the 3-monthly risk of developing grade 3 or higher enteritis, colitis, or enterocolitis was 4% (95% confidence interval 3-7, I2 = 77.40%, 25 studies). Randomized controlled trials and observational studies did not distinguish between acute and chronic enterocolitis. Of the included observational studies, the pooled risk of incurring small bowel involvement associated with ipilimumab was 1% (95% CI 0-4, I2 = 0%, four studies) per every 3-month time period. CONCLUSIONS: Insufficient data exist to quantify or distinguish the risk of acute vs chronic enterocolitis following ipilmumab use. Because of the serious impact of chronic enterocolitis on quality of life and further cancer treatment, future trials evaluating the safety of immunotherapy should report gastrointestinal events in greater detail.

Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis.

BACKGROUND: Widely used for acute pain management, the clinical benefit from perioperative use of gabapentinoids is uncertain. The aim of this systematic review was to assess the analgesic effect and adverse events with the perioperative use of gabapentinoids in adult patients. METHODS: Randomized controlled trials studying the use of gabapentinoids in adult patients undergoing surgery were included. The primary outcome was the intensity of postoperative acute pain. Secondary outcomes included the intensity of postoperative subacute pain, incidence of postoperative chronic pain, cumulative opioid use, persistent opioid use, lengths of stay, and adverse events. The clinical significance of the summary estimates was assessed based on established thresholds for minimally important differences. RESULTS: In total, 281 trials (N = 24,682 participants) were included in this meta-analysis. Compared with controls, gabapentinoids were associated with a lower postoperative pain intensity (100-point scale) at 6 h (mean difference, -10; 95% CI, -12 to -9), 12 h (mean difference, -9; 95% CI, -10 to -7), 24 h (mean difference, -7; 95% CI, -8 to -6), and 48 h (mean difference, -3; 95% CI, -5 to -1). This effect was not clinically significant ranging below the minimally important difference (10 points out of 100) for each time point. These results were consistent regardless of the type of drug (gabapentin or pregabalin). No effect was observed on pain intensity at 72 h, subacute and chronic pain. The use of gabapentinoids was associated with a lower risk of postoperative nausea and vomiting but with more dizziness and visual disturbance. CONCLUSIONS: No clinically significant analgesic effect for the perioperative use of gabapentinoids was observed. There was also no effect on the prevention of postoperative chronic pain and a greater risk of adverse events. These results do not support the routine use of pregabalin or gabapentin for the management of postoperative pain in adult patients.

The effect of restrictive versus liberal transfusion strategies on longer-term outcomes after cardiac surgery: a systematic review and meta-analysis with trial sequential analysis.

PURPOSE: Blood transfusions are frequently administered in cardiac surgery. Despite a large number of published studies comparing a "restrictive" strategy with a "liberal" strategy, no clear consensus has emerged to guide blood transfusion practice in cardiac surgery patients. The purpose of this study was to identify, critically appraise, and summarize the evidence on the overall effect of restrictive transfusion strategies compared with liberal transfusion strategies on mortality, other clinical outcomes, and transfusion-related outcomes in adult patients undergoing cardiac surgery. SOURCE: We searched MEDLINE (OvidSP), EMBASE (OvidSP) and Cochrane CENTRAL (Wiley) from inception to 1 December 2017 and queried clinical trial registries and conference proceedings for randomized-controlled trials of liberal vs restrictive transfusion strategies in cardiac surgery. PRINCIPAL FINDINGS: From 7,908 citations, we included ten trials (9,101 patients) and eight companion publications. Overall, we found no significant difference in mortality between restrictive and liberal transfusion strategies (risk ratio [RR], 1.08; 95% confidence interval [CI], 0.76 to 1.54; I2 = 33%; seven trials; 8,661 patients). The use of a restrictive transfusion strategy did not appear to adversely impact any of the secondary clinical outcomes. As expected, the proportion of patients who received red blood cells (RBCs) in the restrictive group was significantly lower than in the liberal group (RR, 0.68; 95% CI, 0.64 to 0.73; I2 = 56%; 5 trials; 8,534 patients). Among transfused patients, a restrictive transfusion strategy was associated with fewer transfused RBC units per patient than a liberal transfusion strategy. CONCLUSIONS: In adult patients undergoing cardiac surgery, a restrictive transfusion strategy reduces RBC transfusion without impacting mortality rate or the incidence of other perioperative complications. Nevertheless, further large trials in subgroups of patients, potentially of differing age, are needed to establish firm evidence to guide transfusion in cardiac surgery. TRIAL REGISTRATION: PROSPERO (CRD42017071440); registered 20 April, 2018.

RéSUMé: OBJECTIF: Les transfusions sanguines sont fréquentes après une chirurgie cardiaque. Malgré le nombre important d'études publiées comparant une stratégie « restrictive ¼ à une stratégie « libérale ¼, aucun consensus clair n'est apparu pour guider la pratique de la transfusion sanguine chez les patients de chirurgie cardiaque. L'objectif de cette étude était d'identifier, d'évaluer de façon critique et de résumer les données probantes sur l'effet global des stratégies de transfusion restrictives comparativement aux stratégies libérales sur la mortalité, les autres devenirs cliniques, et les devenirs liés à la transfusion chez des patients adultes subissant une chirurgie cardiaque. SOURCE: Nous avons réalisé des recherches dans les bases de données MEDLINE (OvidSP), EMBASE (OvidSP) et Cochrane CENTRAL (Wiley) de leur création jusqu'au 1er décembre 2017 et avons exploré les registres d'études cliniques et les actes de conférence pour en tirer les études randomisées contrôlées évaluant des stratégies transfusionnelles restrictives vs libérales en chirurgie cardiaque. CONSTATATIONS PRINCIPALES: Sur 7908 citations, nous avons inclus dix études (9101 patients) et huit publications connexes. Globalement, nous n'avons observé aucune différence significative en matière de mortalité entre les stratégies transfusionnelles restrictives et libérales (risque relatif [RR], 1,08; intervalle de confiance [IC] 95 %, 0,76 à 1,54; I2 = 33 %; sept études; 8661 patients). Le recours à une stratégie de transfusion restrictive n'a semblé avoir aucun impact négatif sur quelque résultat clinique secondaire que ce soit. Comme anticipé, la proportion de patients ayant reçu des érythrocytes dans le groupe restrictif était significativement plus basse que dans le groupe libéral (RR, 0,68; IC 95 %, 0,64 à 0,73; I2 = 56 %; 7 études; 8534 patients). Parmi les patients transfusés, une stratégie de transfusion restrictive a été associée à un nombre moindre d'unités d'érythrocytes transfusées par patient que dans une stratégie transfusionnelle libérale. CONCLUSION: Dans une population de patients adultes subissant une chirurgie cardiaque, une stratégie transfusionnelle restrictive réduit la transfusion d'érythrocytes sans avoir d'impact sur le taux de mortalité ou sur l'incidence d'autres complications périopératoires. D'autres grandes études sur différents sous-groupes de patients, peut-être d'âges différents, sont toutefois nécessaires afin d'établir des données probantes concluantes pour guider les transfusions en chirurgie cardiaque. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42017071440); enregistrée le 20 avril 2018.

Resveratrol for adults with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic disorder that is characterised by insulin resistance and hyperglycaemia, which over time may give rise to vascular complications. Resveratrol is a plant-derived nutritional supplement shown to have anti-diabetic properties in many animal models. Less evidence is available on its safety and efficacy in the management of T2DM in humans. OBJECTIVES: To assess the efficacy and safety of resveratrol formulations for adults with type 2 diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and International Pharmaceutical Abstracts, as well as the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. The date of the last search was December 2018 for all databases. No language restrictions were applied. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing effects of oral resveratrol (any dose or formulation, duration, or frequency of administration) with placebo, no treatment, other anti-diabetic medications, or diet or exercise, in adults with a diagnosis of T2DM. DATA COLLECTION AND ANALYSIS: Two review authors independently identified and included RCTs, assessed risk of bias, and extracted study-level data. Study authors were contacted for any missing information or for clarification of reported data. We assessed studies for certainty of the evidence using the GRADE instrument. MAIN RESULTS: We identified three RCTs with a total of 50 participants. Oral resveratrol not combined with other plant polyphenols was administered at 10 mg, 150 mg, or 1000 mg daily for a period ranging from four weeks to five weeks. The comparator intervention was placebo. Overall, all three included studies had low risk of bias. None of the three included studies reported long-term, patient-relevant outcomes such as all-cause mortality, diabetes-related complications, diabetes-related mortality, health-related quality of life, or socioeconomic effects. All three included studies reported that no adverse events were observed, indicating that no deaths occurred (very low-quality evidence for adverse events, all-cause mortality, and diabetes-related mortality). Resveratrol versus placebo showed neutral effects for glycosylated haemoglobin A1c (HbA1c) levels (mean difference (MD) 0.1%, 95% confidence interval (CI) -0.02 to 0.2; P = 0.09; 2 studies; 31 participants; very low-certainty evidence). Due to the short follow-up period, HbA1c results have to be interpreted cautiously. Similarly, resveratrol versus placebo showed neutral effects for fasting blood glucose levels (MD 2 mg/dL, 95% CI -2 to 7; P = 0.29; 2 studies; 31 participants), and resveratrol versus placebo showed neutral effects for insulin resistance (MD -0.35, 95% CI -0.99 to 0.28; P = 0.27; 2 studies; 36 participants). We found eight ongoing RCTs with approximately 800 participants and two studies awaiting assessment, which, when published, could contribute to the findings of this review. AUTHORS' CONCLUSIONS: Currently, research is insufficient for review authors to evaluate the safety and efficacy of resveratrol supplementation for treatment of adults with T2DM. The limited available research does not provide sufficient evidence to support any effect, beneficial or adverse, of four to five weeks of 10 mg to 1000 mg of resveratrol in adults with T2DM. Adequately powered RCTs reporting patient-relevant outcomes with long-term follow-up periods are needed to further evaluate the efficacy and safety of resveratrol supplementation in the treatment of T2DM.

Efficacy and Safety of Tranexamic Acid in Major Non-Cardiac Surgeries at High Risk for Transfusion: A Systematic Review and Meta-Analysis.

Tranexamic acid (TXA) reduces transfusion requirements in cardiac surgery and total hip and knee arthroplasty, where it has become standard of care. Our objective is to determine the efficacy and safety of TXA in other surgeries associated with a high risk for red blood cell (RBC) transfusion. We identified randomized controlled trials in Medline, Embase, CENTRAL, and CAB abstracts from inception to June 2019. We included trials evaluating intraoperative IV TXA in adult patients undergoing a non-cardiac and non-hip and knee arthroplasty surgeries at high-risk for RBC transfusion, defined as a baseline transfusion rate ≥5% in comparator arm. We assessed risk of bias using the Cochrane Risk of Bias tool. We used GRADE methodology to assess certainty of evidence. From 8565 citations identified, we included 69 unique trials, enrolling 6157 patients. TXA reduces both the proportion of patients transfused RBCs (relative risk (RR) 0.59; 95% confidence interval (CI) 0.48 to 0.72; low certainty evidence) and the volume of RBC transfused (MD -0.51 RBC units; 95%CI -0.13 to -0.9 units; low certainty evidence) when compared to placebo or usual care. TXA was not associated with differences in deep vein thrombosis, pulmonary embolism, all-cause mortality, hospital length of stay, need for re-operation due to hemorrhage, myocardial infarction, stroke or seizure. In patients undergoing a broad range of non-cardiac and non-hip and knee arthroplasty surgeries at high risk for RBC transfusion, perioperative TXA reduced exposure to RBC transfusion. No differences in thrombotic outcomes were identified; however, summary effect estimates were limited by lack of systemic screening and short duration of follow-up.

Training interventions to improve adenoma detection rates during colonoscopy: a systematic review and meta-analysis.

BACKGROUND: Colonoscopies are effective means of detecting and removing precancerous adenomatous polyps. The adenoma detection rate (ADR) is a marker of colonoscopy quality and an independent predictor of colorectal cancer incidence. Focused training interventions may improve an endoscopist's ADR, but the supporting research is limited. This systematic review and meta-analysis identified, critically appraised, and meta-analyzed data from randomized trials (RCTs) evaluating the effect of training interventions on ADRs. METHODS: Ovid Medline, EMBASE, CENTRAL, Eric, CINAHL, Scopus, Web of Science, and ClinicalTrials.gov were searched for RCTs investigating the effect of an educational intervention on ADRs. Two reviewers independently screened, identified, and extracted trial-level data. Internal validity was assessed in duplicate using the Risk of Bias tool. Our primary outcome was the ADR. Secondary outcomes were advanced ADR, adenocarcinoma detection rate, polyp detection rate, and withdrawal times. Safety outcomes were post-polypectomy bleeding rate and colonoscopy-related perforation rate. RESULTS: From 2837 screened citations, we identified 3 trials (119 endoscopists) meeting our inclusion criteria. Training interventions were associated with a trend toward increased ADRs (odds ratio 1.16, 95% confidence interval (CI) 1.00-1.34; I2 83%; 3 trials; 119 endoscopists). When limited to screening colonoscopies, the odds ratio for ADRs associated with training interventions was 1.17 (95% CI 1.00-1.36; I2 80%; 3 trials; 119 endoscopists). There was a high level of heterogeneity between the trials' training interventions. Training intervention improved the advanced ADR, adenocarcinoma detection rate, polyp detection rate, and withdrawal times. Safety outcomes were not reported. CONCLUSIONS: A focused training intervention was associated with a strong trend toward increased ADRs among certified endoscopists. While the described training interventions definitely show promise, further efforts around continuing professional developments activities are needed to more consistently improve ADRS among certified endoscopists.