Publications by authors named "Alan Tinmouth"

137 Publications

Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial.

Nat Med 2021 Sep 9. Epub 2021 Sep 9.

Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.
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http://dx.doi.org/10.1038/s41591-021-01488-2DOI Listing
September 2021

New onset of acute heavy menstrual bleeding in a 34-year-old woman.

CMAJ 2021 Aug;193(30):E1173-E1176

Department of Medicine, University of Ottawa at The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Ont.

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http://dx.doi.org/10.1503/cmaj.210169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354654PMC
August 2021

A Systematic Review and Meta-analysis of Randomized Controlled Trials Comparing Intraoperative Red Blood Cell Transfusion Strategies.

Ann Surg 2021 May 12. Epub 2021 May 12.

Department of Surgery, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.

Objective: The objective of this work was to carry out a meta-analysis of RCTs comparing intraoperative RBC transfusion strategies to determine their impact on postoperative morbidity, mortality, and blood product use.

Summary Of Background Data: RBC transfusions are common in surgery and associated with widespread variability despite adjustment for casemix. Evidence-based recommendations guiding RBC transfusion in the operative setting are limited.

Methods: The search strategy was adapted from a previous Cochrane Review. Electronic databases were searched from January 2016 to February 2021. Included studies from the previous Cochrane Review were considered for eligibility from before 2016. RCTs comparing intraoperative transfusion strategies were considered for inclusion. Co-primary outcomes were 30-day mortality and morbidity. Secondary outcomes included intraoperative and perioperative RBC transfusion. Meta-analysis was carried out using random-effects models.

Results: Fourteen trials (8641 patients) were included. One cardiac surgery trial accounted for 56% of patients. There was no difference in 30-day mortality [relative risk (RR) 0.96, 95% confidence interval (CI) 0.71-1.29] and pooled postoperative morbidity among the studied outcomes when comparing restrictive and liberal protocols. Two trials reported worse composite outcomes with restrictive triggers. Intraoperative (RR 0.53, 95% CI 0.43-0.64) and perioperative (RR 0.70, 95% CI 0.62-0.79) blood transfusions were significantly lower in the restrictive group compared to the liberal group.

Conclusions: Intraoperative restrictive transfusion strategies decreased perioperative transfusions without added postoperative morbidity and mortality in 12/14 trials. Two trials reported worse outcomes. Given trial design and generalizability limitations, uncertainty remains regarding the safety of broad application of restrictive transfusion triggers in the operating room. Trials specifically designed to address intraoperative transfusions are urgently needed.
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http://dx.doi.org/10.1097/SLA.0000000000004931DOI Listing
May 2021

Red blood cell transfusion and associated outcomes in patients referred for palliative care: A retrospective cohort study.

Transfusion 2021 08 19;61(8):2317-2326. Epub 2021 Jun 19.

The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: We aim to describe the occurrence of red blood cell transfusion and associated predictive factors and outcomes among patients referred for palliative care.

Study Design And Methods: This retrospective cohort study used linked health administrative data of adults referred for palliative care at an academic hospital from 2014 to 2018. Multivariable regression models were employed to evaluate patient characteristics associated with transfusion and the relationship between transfusion status and location of death. Survival analyses were performed using log-rank tests and Cox proportional hazards modeling.

Results: Of 6980 evaluated patients, 885 (12.7%) were transfused following palliative care consultation. Covariate factors associated with transfusion included younger age, higher performance status, lower baseline hemoglobin, and a diagnosis of hematologic malignancy (OR = 2.97, 95% CI 2.20-4.01) or solid organ tumor (OR = 1.37, 95% CI 1.10-1.71) vs. noncancer diagnosis. Median survival from palliative care consultation was 19 (IQR 5-75) days; 83 (32-305) days in those transfused and 15 (4-57) days in the nontransfused group (p < .0001). Median survival following transfusion was 56 (19-200) days. Solid organ tumor diagnosis was independently associated with poor survival (HR = 1.7, 95% CI 1.39-2.09 vs. non-cancer diagnosis). Among individuals who survived ≥30 days, transfusion was associated with a higher likelihood of death in hospital (OR = 2.15, 95% CI 1.71-2.70 vs. home/subacute setting).

Discussion: Transfusions commonly occurred in patients receiving palliative care, associated with cancer diagnoses and favorable baseline prognostic factors. Poor survival following transfusion, particularly in solid organ tumor patients, and the twofold likelihood of death in hospital associated with this intervention have important implications in prescribing transfusion for this population.
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http://dx.doi.org/10.1111/trf.16560DOI Listing
August 2021

Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial.

Trials 2021 May 4;22(1):323. Epub 2021 May 4.

McMaster Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada.

Background: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection.

Methods: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600).

Discussion: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification.

Trial Registration: Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.
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http://dx.doi.org/10.1186/s13063-021-05235-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094980PMC
May 2021

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

Transfus Med 2021 Aug 2;31(4):236-242. Epub 2021 May 2.

Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada.

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.
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http://dx.doi.org/10.1111/tme.12780DOI Listing
August 2021

Blood Transfusion and Adverse Graft-related Events in Kidney Transplant Patients.

Kidney Int Rep 2021 Apr 2;6(4):1041-1049. Epub 2021 Feb 2.

Division of Nephrology, Kidney Research Center, Department of Medicine, University of Ottawa, Ontario, Canada.

Background: The impact of posttransplant red blood cell transfusion (RBCT) and their potential immunomodulatory effects on kidney transplant recipients are unclear. We examined the risks for adverse graft outcomes associated with post-kidney transplant RBCT.

Methods: We conducted a retrospective cohort study of all adult kidney transplant recipients at The Ottawa Hospital from 2002 to 2018. The exposure of interest was receipt of an RBCT after transplant categorized as 1, 2, 3 to 5, and >5 RBC. Outcomes of interest were rejection and death-censored graft loss (DCGL). Cox proportional hazards models were used to calculate hazard ratios (HR) with RBCT as a time-varying, cumulative exposure.

Results: Among 1258 kidney transplant recipients, 468 (37.2%) received 2373 total RBCTs, 197 (15.7%) had rejection and 114 (9.1%) DCGL. For the receipt of 1, 2, 3 to 5, and >5 RBCT, compared with individuals never transfused, the adjusted HRs (95% confidence interval [CI]) for rejection were 2.47 (1.62-3.77), 1.27 (0.77-2.11), 1.74 (1.00-3.05), and 2.23 (1.13-4.40), respectively; DCGL 2.32 (1.02-5.27), 3.03 (1.62-5.64), 7.50 (4.19-13.43), and 14.63 (8.32-25.72), respectively. Considering a time-lag for an RBCT to be considered an exposure before an outcome to limit reverse causation, RBCT was not associated with rejection; the HRs for DCGL attenuated but remained similar. RBCT was also associated with a negative control outcome, demonstrating possible unmeasured confounding.

Conclusion: RBCT after kidney transplant is not associated with rejection, but may carry an increased risk for DCGL.
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http://dx.doi.org/10.1016/j.ekir.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071620PMC
April 2021

Intraoperative Red Blood Cell Transfusion Decision-making: A Systematic Review of Guidelines.

Ann Surg 2021 07;274(1):86-96

Department of Surgery, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.

Objectives: The objective of this work was to carry out a systematic review of clinical practice guidelines (CPGs) pertaining to intraoperative red blood cell (RBC) transfusions, in terms of indications, decision-making, and supporting evidence base.

Summary Of Background Data: RBC transfusions are common during surgery and there is evidence of wide variability in practice.

Methods: Major electronic databases (MEDLINE, EMBASE, and CINAHL), guideline clearinghouses and Google Scholar were systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative RBC transfusion. Eligible guidelines were retrieved and their quality assessed using AGREE II. Relevant recommendations were abstracted and synthesized to allow for a comparison between guidelines.

Results: Ten guidelines published between 1992 and 2018 provided indications for intraoperative transfusions. No guideline addressed intraoperative transfusion decision-making as its primary focus. Six guidelines provided criteria for transfusion based on hemoglobin (range 6.0-10.0 g/dL) or hematocrit (<30%) triggers. In the absence of objective transfusion rules, CPGs recommended considering other parameters such as blood loss (n = 7), signs of end organ ischemia (n = 5), and hemodynamics (n = 4). Evidence supporting intraoperative recommendations was extrapolated primarily from the nonoperative setting. There was wide variability in the quality of included guidelines based on AGREE II scores.

Conclusion: This review has identified several clinical practice guidelines providing recommendations for intraoperative transfusion. The existing guidelines were noted to be highly variable in their recommendations and to lack a sufficient evidence base from the intraoperative setting. This represents a major knowledge gap in the literature.
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http://dx.doi.org/10.1097/SLA.0000000000004710DOI Listing
July 2021

Pragmatic, double-blind, randomised trial evaluating the impact of red blood cell donor sex on recipient mortality in an academic hospital population: the innovative Trial Assessing Donor Sex (iTADS) protocol.

BMJ Open 2021 02 23;11(2):e049598. Epub 2021 Feb 23.

Eastern Ontario Regional Laboratory Association, Ottawa Hospital, Ottawa, Ontario, Canada.

Introduction: With over 1 million units of blood transfused each year in Canada, their use has a significant clinical and economic impact on our health system. Adequate screening of blood donors is important to ensure the safety and clinical benefit of blood products. Some adverse transfusion reactions have been shown to be related to donor factors (eg, lung injury), whereas other adverse outcomes have been theoretically related to donor factors (mortality and infection). Our clinical trial will test whether male donor blood leads to a greater benefit for transfusion recipients compared with female donor blood.

Methods And Analysis: We have designed a pragmatic, double-blind, randomised trial that will allocate transfusion recipients to receive either male-only or female-only donor transfusions. We will enrol 8850 adult patients requiring at least one transfusion at four sites over an approximate 2-year period. Randomisation and allocation will occur in the blood bank prior to release of the units of blood for transfusion. Our primary outcome is mortality. An intent-to-treat analysis will be applied using all randomised and transfused patients. The principal analysis will be a survival analysis comparing the time from randomisation to death between patients allocated to male donor red blood cells (RBCs) and female donor RBCs.

Ethics And Dissemination: Approval has been obtained from research ethics boards of all involved institutions, as well as from privacy offices of Canadian Blood Services, Institute for Clinical Evaluative Science and The Ottawa Hospital Data Warehouse. Our findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings.

Trial Registration Number: NCT03344887; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2021-049598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907852PMC
February 2021

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

Can J Anaesth 2021 07 16;68(7):962-971. Epub 2021 Feb 16.

Department of Medical Oncology and Haematology, CancerCare Manitoba and Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.

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.
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http://dx.doi.org/10.1007/s12630-021-01939-xDOI Listing
July 2021

To Treat or Not? Remission Induction of Acquired von Willebrand Syndrome Secondary to Chronic Lymphocytic Leukemia: A Case Report.

Clin Lymphoma Myeloma Leuk 2021 06 13;21(6):e493-e496. Epub 2021 Jan 13.

Department of Medicine (Hematology) and The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.

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http://dx.doi.org/10.1016/j.clml.2021.01.007DOI Listing
June 2021

Exploring Peaks in Hospital Blood Component Utilization: A 10-Year Retrospective Study at a Large Multisite Academic Centre.

Transfus Med Rev 2021 01 12;35(1):37-45. Epub 2020 Nov 12.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Canadian Blood Services, Ottawa, Ontario, Canada; Department of Medicine, Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address:

Peak demand analysis is common in industries such as the energy sector, but can also be applied to the field of transfusion to characterize the nature and timing of peak days in hospital blood utilization. This information can be used to forecast future peak days or to inform hospital emergency preparedness plans. The aims of this study are to characterize peak days in red blood cell (RBC) utilization over the past 10 years at our hospital, and to compare RBC peaks with peaks in platelet, plasma, and cryoprecipitate utilization. This was a retrospective cohort study of RBC, platelet, plasma, and cryoprecipitate transfusions in the inpatient and emergency department setting between May 2009 and April 2019 at a large academic hospital, containing regional trauma and cardiovascular surgery centers. For each blood product, a peak in utilization was defined as a day with a ≥50% increase in the number of units transfused compared to the previous 90-day average. Descriptive and inferential analyses were performed to characterize peak days. There were on average 20,501 RBCs transfused per year and 56 RBCs transfused per day over the 10-year period. A total of 134 peaks in RBC utilization occurred over the study period, with an average of 14 peaks per year. RBC peak days required on average 69% more RBC units compared to nonpeak days (P< .0001). 77% of RBC peaks were caused either solely or in part by surgical bleeding, 34% were caused entirely or in part by trauma, and other causes were infrequent. RBC peaks occurred most often on Fridays and least often on weekends (P< .0001). While there were 134 RBC peaks over the study period, there was a larger number of platelet (n = 292), plasma (n = 467), and cryoprecipitate peaks (n = 579). RBC peak days often coincided with plasma peak days, but less frequently with platelet and cryoprecipitate peaks. More studies are needed to determine whether analysis of peak usage will be of value to hospital blood banks for emergency planning and blood inventory management.
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http://dx.doi.org/10.1016/j.tmrv.2020.10.002DOI Listing
January 2021

The Top 20 Surgical Procedures Associated with the Highest Risk for Blood Transfusion.

Br J Surg 2020 12 3;107(13):e642-e643. Epub 2020 Oct 3.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario.

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http://dx.doi.org/10.1002/bjs.12005DOI Listing
December 2020

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

Transfus Med Rev 2021 01 28;35(1):16-21. Epub 2020 Aug 28.

Department of Medical Oncology and Haematology, CancerCare Manitoba and Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada.

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.
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http://dx.doi.org/10.1016/j.tmrv.2020.08.001DOI Listing
January 2021

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

JAMA 2020 10;324(13):1317-1329

School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.

Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).

Main Outcomes And Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).

Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.

Conclusions And Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
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http://dx.doi.org/10.1001/jama.2020.17022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489418PMC
October 2020

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

Transfusion 2020 09 28;60(9):1929-1939. Epub 2020 Aug 28.

Division of Pediatric Critical Care Medicine, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.

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.
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http://dx.doi.org/10.1111/trf.15933DOI Listing
September 2020

Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial.

Lancet Haematol 2020 Sep;7(9):e640-e648

Michael G DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada; McMaster Centre for Transfusion Research, Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.

Background: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin.

Methods: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 10 cells per L before major surgery or less than 50 × 10 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 10 cells per L before major surgery or 45 × 10 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov, NCT01621204.

Findings: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49-55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; p=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI -2·1%; p=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred.

Interpretation: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles.

Funding: GlaxoSmithKline and Novartis.
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http://dx.doi.org/10.1016/S2352-3026(20)30227-1DOI Listing
September 2020

A Scoping Review of Registered Clinical Trials of Convalescent Plasma for COVID-19 and a Framework for Accelerated Synthesis of Trial Evidence (FAST Evidence).

Transfus Med Rev 2020 07 15;34(3):158-164. Epub 2020 Jul 15.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Clinical Epidemiology and Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address:

Many parallel studies of convalescent plasma with modest enrolment projections have been launched for the treatment of COVID-19. By pooling data from multiple parallel studies that are similar, we can increase the effective sample size and achieve enough statistical power to determine effectiveness more quickly through meta-analysis. A scoping review of registered clinical trials of convalescent plasma for COVID-19 was conducted to assess the feasibility of performing a rapid and timely meta-analysis that will support accelerated review for approval and implementation. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized convalescent plasma to treat or prevent COVID-19. Forty-eight registered trials (projected to enroll more than 5000 subjects) of convalescent plasma were identified and included for analysis. The majority of studies (33 studies with 4440 projected enrolment) will address the treatment of severe and/or critical cases of COVID-19. Twenty-nine studies are controlled and 17 of these are reported as actively recruiting. The combined enrolment of patients from similar studies should be sufficient to determine meaningful improvements in mortality, rates of admission to intensive care and need for mechanical ventilation by the end of 2020-sooner than any individual study could determine effectiveness. Accessing supplemental outcome data from investigators may be needed; however, to align reporting of some outcomes from these studies. Heterogeneity in product potency due to different antibody titers is anticipated and studies using conventional treatment as controls instead of placebo may complicate our understanding of efficacy. Convalescent plasma is being tested in ongoing controlled studies, largely to treat severe and/or critical cases of COVID-19. Sufficient combined power to detect clinically important reductions in multiple outcomes, including mortality, is expected by September 2020. Regulatory approval, funding and implementation by blood operators could be accelerated by planned meta-analysis as study results become available.
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http://dx.doi.org/10.1016/j.tmrv.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362798PMC
July 2020

Patient-Centred Outcomes in Anaemia and Renal Disease: A Systematic Review.

Kidney Dis (Basel) 2020 Mar 19;6(2):74-84. Epub 2019 Nov 19.

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: Anaemia is a nearly universal complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) have been demonstrated to improve clinical outcomes and quality of life (QOL) in renal patients with anaemia. Patient-reported outcome measures (PROMs) are increasingly being used to evaluate the patient-centred impact of medical therapy. Here, we describe a systematic review of studies that evaluated patient-centred outcomes (PCOs) in renal patients undergoing anaemia treatment.

Methods: We conducted a search of Medline (Ovid), EMBASE (Ovid), PsychINFO, and CINAHL databases for studies published until March 2018 that investigated an intervention to treat anaemia in renal patients and used at least one PROM. We also performed a quality assessment for all included studies. Statistical analyses characterized each study, PROMs used, the quality of PCO reporting, and the association between haematological outcomes and PCOs.

Results: Of the 3,533 studies identified in the database search, 21 met all eligibility criteria. Fourteen (67%) of the studies were randomized-controlled trials. Most studies (81%) investigated CKD patients, 14% investigated post-renal transplant patients and 5% assessed patients with heart disease on haemodialysis. The most common anaemia intervention, used in 95% of studies, was ESAs. Forty-three percent of studies utilized one PROM, most commonly the SF-36, a measure of QOL not specifically created for use in nephrology patients. About a third of studies selectively reported PROM subscales, rather than reporting all subscales. Notable biases among included studies included lack of blinding, selective outcome reporting, and lack of power estimates for PCOs. We did not find a statistically significant association between improvements in haemoglobin and QOL.

Conclusions: Future studies employing anaemia and nephrology-specific PROMs and conducted with greater rigour, standardization in the research methods, and reporting of PCOs in renal populations will improve understanding of PCOs in this patient group and hopefully improve patient outcomes and experiences.
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http://dx.doi.org/10.1159/000502208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154285PMC
March 2020

Liberal Versus Restrictive Red Blood Cell Transfusion Thresholds in Hematopoietic Cell Transplantation: A Randomized, Open Label, Phase III, Noninferiority Trial.

J Clin Oncol 2020 05 21;38(13):1463-1473. Epub 2020 Feb 21.

Ottawa Hospital Centre for Transfusion Research, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Purpose: Evidence regarding red blood cell (RBC) transfusion practices and their impact on hematopoietic cell transplantation (HCT) outcomes are poorly understood.

Patients And Methods: We performed a noninferiority randomized controlled trial in four different centers that evaluated patients with hematologic malignancies requiring HCT who were randomly assigned to either a restrictive (hemoglobin [Hb] threshold < 70 g/L) or liberal (Hb threshold < 90 g/L) RBC transfusion strategy between day 0 and day 100. The noninferiority margin corresponds to a 12% absolute difference between groups in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) score relative to baseline. The primary outcome was health-related quality of life (HRQOL) measured by FACT-BMT score at day 100. Additional end points were collected: HRQOL by FACT-BMT score at baseline and at days 7, 14, 28, 60, and 100; transplantation-related mortality; length of hospital stay; intensive care unit admissions; acute graft-versus-host disease; Bearman toxicity score; sinusoidal obstruction syndrome; serious infections; WHO Bleeding Scale; transfusion requirements; and reactions to therapy.

Results: A total of 300 patients were randomly assigned to either restrictive-strategy or liberal-strategy treatment groups between 2011 and 2016 at four Canadian adult HCT centers. After HCT, mean pre-transfusion Hb levels were 70.9 g/L in the restrictive-strategy group and 84.6 g/L in the liberal-strategy group ( < .0001). The number of RBC units transfused was lower in the restrictive-strategy group than in the liberal-strategy group (mean, 2.73 units [standard deviation, 4.81 units] 5.02 units [standard deviation, 6.13 units]; = .0004). After adjusting for transfusion type and baseline FACT-BMT score, the restrictive-strategy group had a higher FACT-BMT score at day 100 (difference of 1.6 points; 95% CI, -2.5 to 5.6 points), which was noninferior compared with that of the liberal-strategy group. There were no significant differences in clinical outcomes between the transfusion strategies.

Conclusion: In patients undergoing HCT, the use of a restrictive RBC transfusion strategy threshold of 70 g/L was as effective as a threshold of 90 g/L and resulted in similar HRQOL and HCT outcomes with fewer transfusions.
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http://dx.doi.org/10.1200/JCO.19.01836DOI Listing
May 2020

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

Transfus Med Rev 2020 01 23;34(1):51-62. Epub 2019 Oct 23.

Rady Faculty of Health Sciences, Max Rady College of Medicine, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba; Department of Medical Oncology and Haematology, CancerCare Manitoba, Winnipeg, Manitoba; Rady Faculty of Health Sciences, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba.

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.
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http://dx.doi.org/10.1016/j.tmrv.2019.10.001DOI Listing
January 2020

Evaluating the Clinical Effect of Female Blood Donors of Child-Bearing Age on Maternal and Neonatal Outcomes: A Cohort Study.

Transfus Med Rev 2020 04 2;34(2):117-123. Epub 2019 Dec 2.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Electronic address:

Iron deficiency is a global problem in women of child-bearing age and is associated with adverse maternal and newborn outcomes. Repeated blood donations deplete iron stores and decrease hemoglobin levels. However, the clinical impact of iatrogenic iron deficiency on mothers and neonates due to blood donation is uncertain. The objective of this study was to assess the association between repeated blood donations in female donors of child-bearing age and the associated risk of adverse maternal and neonatal outcomes. We undertook an observational cohort study of all women who delivered a live or stillborn infant in Ontario, Canada, between 1 January 2010 and 31 March 2012 using birth record data from the Better Outcomes Registry & Network, Canadian Blood Services, and the Institute of Clinical Evaluative Sciences. Only a woman's first pregnancy within the study time frame was included for analysis. We excluded women <18 years or >50 years of age at the time of delivery and multiple birth pregnancies. Data on all female donors who made whole blood donations between 1 January 2007 and 31 March 2012 were obtained from Canadian Blood Services. The primary newborn outcome was diagnosis of a small-for-gestational-age neonate (less than 10th centile). Secondary outcomes were preterm birth, stillbirth, APGAR <4 at 5 minutes, cord pH <7, neonatal death, maternal transfusion, infection, preeclampsia, gestational hypertension, gestational diabetes, placental abruption, and maternal death. Regression models evaluated the effect of repeated donation and the time interval between donations and conception on neonatal and maternal outcomes while adjusting for important clinical and demographic risk factors. A total of 260 037 women delivered live or stillborn singleton infants between 1 January 2010 and 31 March 2012. A total of 7919 (3.0%) women were blood donors, with a mean of 2.43 ± 2.10 lifetime donations. Mean maternal age at the time of delivery for nondonors and donors was 30.30 ± 5.38 and 29.74 ± 4.94 years, respectively. Small for gestational age occurred in 23 706 (9.4%) of neonates born to nondonors and 526 (6.6%) of neonates born to donors. There was a reduction in the risk of small for gestational age with increasing number of lifetime donations (adjusted odds ratio 0.89 [0.86-0.92] per additional donation). For the prespecified secondary outcomes, we observed a reduction in the risk of low birth weight (adjusted odds ratio 0.95 [0.91-0.98] per additional donation). There was no association with other secondary neonatal or maternal outcomes except for maternal hypertension. Proximity of donation to conception had no effect on risk of a small-for-gestational age neonate. Our data suggest that there is no increased risk of deleterious neonatal and maternal outcomes associated with repeated blood donations prior to pregnancy. Although possibly a result of a healthy donor effect, our findings are reassuring to female donors and their children as well as to clinicians and blood system stakeholders seeking to inform policy decisions.
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April 2020

A regional massive hemorrhage protocol developed through a modified Delphi technique.

CMAJ Open 2019 Jul-Sep;7(3):E546-E561. Epub 2019 Sep 3.

Departments of Laboratory Medicine and Molecular Diagnostics (Callum, Chin, Viveiros), Surgery (Nathens, Nascimento), Emergency Services (McDonald), Critical Care Medicine (Adhikari) and Anesthesia (Margarido), Sunnybrook Health Sciences Centre; Departments of Laboratory Medicine and Pathobiology (Callum, Pendergrast, Skeate, Pavenski), Anesthesia (McVey, Karkouti, Alam, Margarido), Surgery (Nathens, Nascimento, Rizoli) and Paediatrics (Beno), University of Toronto; Division of Emergency Medicine (Yeh, Petrosoniak, McDonald, MacDonald), Department of Medicine, University of Toronto; Departments of Emergency Medicine (Petrosoniak), Surgery (Rizoli) and Laboratory Medicine (Sholzberg, Pavenski), St. Michael's Hospital; Department of Anesthesia and Pain Medicine (McVey, Skelton), The Hospital for Sick Children; Ontario Regional Blood Coordinating Network (Cope, Thompson, Collins, Owens); Department of Anesthesia and Pain Management (Karkouti), Sinai Health System, University Health Network, and Women's College Hospital, Toronto, Ont.; Department of Anesthesiology and Pain Medicine (Murto), Children's Hospital of Eastern Ontario; Department of Anesthesiology and Pain Medicine (Murto), University of Ottawa, Ottawa, Ont.; Paediatric Emergency Medicine (Beno), The Hospital for Sick Children; Department of Clinical Pathology (Pendergrast), University Health Network, Toronto, Ont.; Ornge Transport Medicine (McDonald, MacDonald), Mississauga, Ont.; Interdepartmental Division of Critical Care Medicine (Adhikari), University of Toronto; Department of Anesthesia (Alam, Arnold), North York General Hospital, Toronto, Ont.; McMaster Centre for Transfusion Research (Arnold, Pai, Zeller); Departments of Medicine (Pai, Zeller) and Pathology and Molecular Medicine (Pai), McMaster University, Hamilton, Ont.; Canadian Blood Services (Arnold, Skeate, White); St. Michael's Hospital (Barratt, Chaudhry, Harvey), Toronto, Ont.; Department of Surgery (Beckett), McGill University, Montréal, Que.; Canadian Forces Health Services (Beckett), Ottawa, Ont.; Sunnybrook Health Sciences Centre (Brenneman), Toronto, Ont.; General Surgery, Acute Care and Trauma (Lampron), The Ottawa Hospital; Departments of Surgery (Lampron), Medicine (Tinmouth) and Laboratory Medicine and Pathology (Tinmouth), Faculty of Medicine, University of Ottawa, Ottawa, Ont.; Trauma Program and Quality Assurance (McFarlan), St. Michael's Hospital, Toronto, Ont.; Departments of Pathology (Ruijs) and Surgery (Van Heest), William Osler Health Centre, Brampton, Ont.; Lakeridge Health Corporation (Syer), Oshawa, Ont.; Department of Critical Care (Theriault), Health Sciences North, Sudbury, Ont.; Division of Hematology (Tinmouth), The Ottawa Hospital; University of Ottawa Centre for Transfusion Research (Tinmouth), Ottawa Hospital Research Institute, Ottawa, Ont.; Canadian Blood Services (Zeller), Ancaster, Ont.

Background: A massive hemorrhage protocol (MHP) enables rapid delivery of blood components in a patient who is exsanguinating pending definitive hemorrhage control, but there is variability in MHP implementation rates, content and compliance owing to challenges presented by infrequent activation, variable team performance and patient acuity. The goal of this project was to identify the key evidence-based principles and quality indicators required to develop a standardized regional MHP.

Methods: A modified Delphi consensus technique was performed in the spring and summer of 2018. Panellists used survey links to independently review and rate (on a 7-point Likert scale) 43 statements and 8 quality indicators drafted by a steering committee composed of transfusion medicine specialists and technologists, and trauma physicians. External stakeholder input from all hospitals in Ontario was sought.

Results: Three rounds were held with 36 experts from diverse clinical backgrounds. Consensus was reached for 42 statements and 8 quality indicators. Additional modifications from external stakeholders were incorporated to form the foundation for the proposed MHP.

Interpretation: This MHP template will provide the basis for the design of an MHP toolkit, including specific recommendations for pediatric and obstetrical patients, and for hospitals with limited availability of blood components or means to achieve definitive hemorrhage control. We believe that harmonization of MHPs in our region will simplify training, increase uptake of evidence-based interventions, enhance communication, improve patient comfort and safety, and, ultimately, improve patient outcomes.
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http://dx.doi.org/10.9778/cmajo.20190042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726467PMC
September 2019

Guidelines on the intraoperative transfusion of red blood cells: a protocol for systematic review.

BMJ Open 2019 06 17;9(6):e029684. Epub 2019 Jun 17.

Department of Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada.

Introduction: A significant proportion of red blood cell (RBC) transfusions are administered intraoperatively; yet there is limited evidence to guide transfusion decisions in this setting. The objective of this systematic review is to explore the availability, quality and content of clinical practice guidelines (CPGs) reporting on the indication for allogenic RBC transfusion during surgery.

Methods: Major electronic databases (MEDLINE, EMBASE and CINAHL), guideline clearinghouses and Google Scholar, will be systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative allogenic RBC transfusion. Characteristics of eligible guidelines will be reported in a summary table. The AGREE II instrument will be used to appraise the quality of identified guidelines. Recommendations advising on indications for intraoperative RBC transfusion will be manually extracted and presented to allow for comparison of similarities and/or discrepancies in the literature.

Ethics And Dissemination: The results of this systematic review will be disseminated through relevant conferences and peer-reviewed journals.

Trial Registration Number: CRD42018111487.
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http://dx.doi.org/10.1136/bmjopen-2019-029684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586075PMC
June 2019

Saline versus albumin fluid for extracorporeal removal with slow low-efficiency dialysis (SAFER-SLED): study protocol for a pilot trial.

Pilot Feasibility Stud 2019 30;5:72. Epub 2019 May 30.

1Division of Nephrology, Department of Medicine, The Ottawa Hospital, Riverside Campus, 1967 Riverside Drive, Ottawa, ON K1H 7W9 Canada.

Background: Critically ill patients frequently develop acute kidney injury that necessitates renal replacement therapy (RRT). At some centers, critically ill patients who are hemodynamically unstable and require RRT are treated with slow low-efficiency dialysis (SLED). Unfortunately, hypotension is a frequent complication that occurs during SLED treatments and may limit the recovery of kidney function. Hypotension may also limit the amount of fluid that can be removed by ultrafiltration with SLED. Fluid overload can be exacerbated as a consequence, and fluid overload is associated with increased mortality.Occasionally, intravenous albumin fluid is given to prevent or treat low blood pressure during SLED. The intent of doing so is to increase the colloid oncotic pressure in the circulation to draw in extravascular fluid, increase the blood pressure, and enable more aggressive fluid removal with ultrafiltration. Nonetheless, there is little evidence to support this practice and theoretical reasons why it may not be especially effective at augmenting fluid removal in critically ill patients. At the same time, albumin fluid is expensive.As such, we present a protocol for a study to assess the feasibility of a randomized controlled trial evaluating the use of albumin fluid versus saline in critically ill patients receiving SLED.

Methods: This study is a single-center, double-blind, and randomized controlled pilot trial with two parallel arms. It involves randomly assigning patients receiving SLED treatment in the ICU to receive either albumin (25%) boluses or normal saline fluid boluses (placebo) to prevent and treat low blood pressure.

Discussion: The results of this pilot trial will help with planning a larger trial comparing the efficacy of the interventions in achieving fluid removal in critically ill patients with AKI on SLED. They will establish whether enough participants would participate in a larger study and accept the study procedures.

Trial Registration: This trial is registered on ClinicalTrials.gov Identifier NCT03665311, registered on September 11, 2018.
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http://dx.doi.org/10.1186/s40814-019-0460-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542057PMC
May 2019

Exclusion criteria and adverse events in perioperative trials of tranexamic acid in cardiac surgery: a systematic review and meta-analysis.

Can J Anaesth 2019 Oct 17;66(10):1240-1250. Epub 2019 May 17.

Faculty of Medicine, University of Ottawa, Ottawa, Canada.

Purpose: Tranexamic acid (TXA) reduces perioperative blood loss and transfusion requirement following cardiac surgery. Nevertheless, TXA remains underutilized because of concerns regarding development of adverse events. We conducted a systematic review to determine which patients are commonly excluded from TXA cardiac surgery clinical trials to determine if there are patient groups lacking safety data on TXA.

Methods: The databases Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched until September 2017. Eligible studies were randomized-controlled trials (RCTs) administering systemic TXA perioperatively to patients undergoing any cardiac surgery. Our primary outcome was the exclusion criteria for each RCT, and the secondary endpoint was TXA safety. A descriptive synthesis was performed to analyze the exclusion criteria. TXA safety was assessed with meta-analysis.

Principal Findings: Seventy eligible RCTs were included. The most common reasons for excluding patients from TXA cardiac surgery trials were major hepatic, renal, or cardiac comorbidities (76% of studies). Meta-analysis showed that TXA did not increase the risk of adverse events compared with placebo or no intervention (risk ratio, 0.97; 95% confidence interval, 0.88 to 1.07), including thrombosis and seizure.

Conclusion: We found that systemic TXA is safe to use in cardiac surgery. Certain patient groups are frequently excluded from TXA cardiac surgery trials, and may consequently have limited efficacy and safety data on TXA. Further research in these patient groups may be needed; nevertheless, for many patient populations there are sufficient data to inform evidence-based guidelines for TXA use in cardiac surgery.

Trial Registration: PROSPERO (CRD42017060971); registered 4 April, 2017.
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http://dx.doi.org/10.1007/s12630-019-01393-wDOI Listing
October 2019

Trends in IVIG use at a tertiary care Canadian center and impact of provincial use mitigation strategies: 10-year retrospective study with interrupted time series analysis.

Transfusion 2019 06 27;59(6):1988-1996. Epub 2019 Mar 27.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: Intravenous immunoglobulin (IVIG) is a fractionated plasma product used to treat a range of autoimmune or inflammatory conditions, as well as immunodeficiency. Demand for this high-cost product is increasing worldwide. Understanding historical changes in IVIG use is important for inventory management and demand forecasting as well as for the development of initiatives aimed at optimizing blood product use.

Study Design And Methods: This was a 10-year retrospective cohort study of all patient encounters involving an IVIG transfusion from 2007 to 2016 at a four-site tertiary care hospital in Ontario, Canada. IVIG use was reported, including number of hospital encounters and amounts of IVIG prescribed. An interrupted time series analysis was performed to evaluate temporal changes in product use coinciding with the release of 2009-2010 provincial initiatives to optimize IVIG.

Results: A total of 1,658,159.50 g of IVIG was administered from 2007 to 2016. Total annual volume administered initially decreased after implementation of new policies (-2032 g/quarter). The number of IVIG patient encounters also decreased (-49.8 encounters/quarter) but was mirrored by an increase in the total volume administered per patient encounter (+0.88 g/quarter). Use increased 820 g/quarter from 2013 to 2016 but was 21% lower than projected before implementation of provincial policies.

Conclusion: Trends in IVIG use show ongoing increases in the number of patients treated with the product. Development and implementation of provincial initiatives to optimize IVIG use coincided with significant short-term changes at a large tertiary care hospital. Novel initiatives aimed at dose minimization and prescription rationalization for this therapy are needed on local as well as larger scales.
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http://dx.doi.org/10.1111/trf.15271DOI Listing
June 2019

Trends and outcomes in multicomponent blood transfusion: an 11-year cohort study of a large multisite academic center.

Transfusion 2019 06 22;59(6):1971-1987. Epub 2019 Mar 22.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Background: Most studies reporting on blood component utilization overlook patients transfused with more than one type of blood product (multicomponent transfusion). These patients are of importance, as they are large consumers of blood products and likely have different characteristics and outcomes than nontransfused patients and patients transfused with only one blood component type. Our study aimed to determine the prevalence of multicomponent transfusion at a large multisite academic center, as well as the patient characteristics and outcomes associated with multicomponent transfusion.

Methods: A retrospective cohort study of transfused adult inpatients at the Ottawa Hospital between 2007 and 2017 was performed. Eligible transfusions were red blood cells (RBCs), platelets, plasma, cryoprecipitate, and/or fibrinogen concentrate. Descriptive analyses were done to determine multicomponent transfusion prevalence. Patient characteristics and outcomes associated with multicomponent transfusion were assessed using multivariable regressions.

Results: Of 55,719 adult transfused inpatient admissions, 25% received a multicomponent transfusion. Multicomponent transfusion prevalence was highest in hematology (51%), cardiac surgery (45%), and critical care (40%) patients. Multivariable regression analysis showed that compared to RBC-only transfusion, multicomponent transfusion was associated with increased odds of in-hospital mortality (odds ratio, 3.48; 95% confidence interval [CI], 3.26-3.73), greater odds of institutional discharge as opposed to discharge home (odds ratio, 1.22; 95% CI, 1.15-1.30), and a 1.58 time increase in duration of hospitalization (95% CI, 1.54-1.62).

Conclusion: Multicomponent transfusion recipients make up a large proportion of transfused patients and have poorer outcomes. It is necessary to continue studying these patients, including outcomes and transfusion appropriateness, to inform best practices.
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http://dx.doi.org/10.1111/trf.15260DOI Listing
June 2019

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.

Can J Anaesth 2019 06 26;66(6):696-705. Epub 2019 Feb 26.

CHU de Québec - Université Laval Research Centre, Population Health and Optimal Health Practices Research Unit, Trauma - Emergency - Critical Care Medicine, Université Laval, Quebec City, QC, Canada.

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.
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http://dx.doi.org/10.1007/s12630-019-01326-7DOI Listing
June 2019

Exclusion criteria and adverse events in perioperative trials of tranexamic acid: a systematic review and meta-analysis.

Transfusion 2019 02 5;59(2):806-824. Epub 2018 Dec 5.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Background: Tranexamic acid (TXA) is an inexpensive therapy effective at minimizing perioperative blood loss and transfusion. However, it remains underutilized due to safety concerns. To date, no evidence-based guidelines exist identifying which patients should not receive TXA therapy. This study determined patient groups for whom safety information regarding TXA is lacking due to common exclusion from perioperative TXA trials.

Study Design And Methods: A systematic review searching the databases Medline, EMBASE, CENTRAL, and Clinicaltrials.gov was performed. Randomized controlled trials (RCTs) administering systemic TXA perioperatively to elective or emergent surgery patients were eligible. Our primary outcome was to describe exclusion criteria of RCTs, and the secondary outcome was TXA safety. A descriptive synthesis of exclusion criteria was performed, and TXA safety was assessed by meta-analysis.

Results: A total of 268 eligible RCTs were included. Meta-analysis showed that systemic TXA did not increase risk of adverse events compared to placebo or no intervention (relative risk, 1.05; 95% confidence interval, 0.99-1.12). Patient groups commonly excluded from perioperative TXA trials, and thus potentially lacking TXA safety data, were those with major comorbidities, a history of thromboembolism, medication use affecting coagulation, TXA allergy, and coagulopathy. Exclusion of patients with major comorbidities may not be necessary; we showed that the risk of adverse events was similar in studies that excluded patients with major comorbidities and those that did not.

Conclusion: Sufficient evidence exists to develop perioperative guidelines for TXA use in many populations. Further studies evaluating perioperative TXA use in patients with a history of thromboembolism are warranted.
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http://dx.doi.org/10.1111/trf.15030DOI Listing
February 2019
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