|FIBrinogen REplenishment in Surgery (FIBRES)||Dr. Keyvan Karkouti & Dr. Jeannie Callum||This is a pragmatic, prospective, multi-center, randomized, active-control, single-blinded, non-inferiority phase 3 trial in adult cardiac surgical patients. Up to 12 Canadian hospitals will participate, and the trial will require up to 2 years for patient recruitment.|
Twelve-hundred bleeding adult cardiac surgical patients who require fibrinogen supplementation due to acquired hypofibrinogenemia after CPB will be included. Patients will be randomized to receive equivalent doses of either fibrinogen concentrate (Octafibrin) or cryoprecipitate when the blood bank receives the first order for fibrinogen supplementation and deems it to be in accordance with accepted clinical standards. Thereafter, patients will be treated according to their assigned group each time fibrinogen supplementation is ordered during the treatment period (24 hours after termination of CPB). No other aspects of care will be modified.
The primary efficacy outcome will be the number of Allogeneic blood products (ABP) (red blood cells [RBCs], pooled or apheresis platelets, and plasma) administered during the first 24 hours after termination of CPB. Safety outcomes will be measured for the first 28 days after surgery, which is the duration of participation of each patient in the trial. Comparisons will be by intention-to-treat (ITT) (primary) and per-protocol (PP) analysis. One interim analysis will be conducted after 600 patients have been treated to determine whether the study should be terminated for safety reasons, demonstrated non-inferiority or futility reasons.
|Completed with manuscript in progress|
|Isoagglutinins in the Development of IVIG-associated Hemolysis||Dr. Don Branch & Dr. Jacob Pendergrast||Patients at high risk of IVIG-associated hemolysis (defined as receipt of a 28-day cumulative dose of ≥ 2 g/kg, adjusted for ideal body weight, and non-O blood group) will be prospectively monitored using a standardized protocol for signs of hemolysis, and will be undergo additional testing for variables that have been hypothesized to increase the risk of hemolysis. The goal of the study is to define the incidence and dynamics of IVIG-mediated hemolysis and identify patient and product-related factors that may predict which patients are especially at risk.||Completed, ABO-zygosity published in Blood, and the eluate IgG subclass testing published in Transfusion|
|A Multifaceted Intervention to Optimize Red Blood Cell Transfusion Practice in Two Provinces (START)||Dr. Kathryn Webert & Dr. Jeannie Callum||People receive red blood cell (RBC) transfusions for many reasons including surgery, injury, cancer, bleeding and being treated for diseases of the blood. A RBC transfusion is the most common procedure performed in the hospitalized patient, with ten percent of hospitalized patients being transfused. The decision to transfuse RBCs is based on a number of factors such as the amount of hemoglobin in your blood, amount of blood loss, your clinical condition and whether you have heart disease. Often however, physicians transfuse patients based solely on the laboratory test results, without taking into account individual patient factors. There is a growing awareness that RBC transfusion is an overused treatment, with as many as 1 in 5 Ontario transfusions being unnecessary. Unnecessary transfusions result in poor patient outcomes and increased hospital costs. The goal of this quality improvement project is to achieve 90% appropriateness of RBC transfusion in 18 hospitals across Ontario and Alberta over a period of two years. In order to achieve this, we will carry out an intervention which includes implementing RBC transfusion hospital guidelines, focused education of nurses and doctors, medical laboratory technologist screening of transfusion orders, and monthly feedback to ordering physicians regarding unnecessary transfusions.||Ongoing|
|Transfusion-Associated Circulatory Overload Best Eliminated With Lasix (TACO-BEL-1)||Dr. Jacob Pendergrast||Transfusion-associated circulatory overload (TACO) is a leading cause of transfusion-attributable morbidity and mortality. While diuretics are standard of care for treatment of heart failure, it is unclear whether they are safe and effective in preventing TACO. This is a pilot double-blinded placebo-controlled randomized controlled trial (RCT) to evaluate the feasibility of conducting a multicenter, randomized, placebo-controlled trial to assess the efficacy of pre-transfusion furosemide in preventing transfusion-associated circulatory overload (TACO) in hemodynamically stable inpatients aged 65 years or older receiving a single unit red blood cell transfusion. Nine months of enrollment were required for 80 patients to complete the study. Factors impacting accrual rate included fewer transfusions than expected meeting eligibility criteria and lower than anticipated consent rates. Protocol compliance was also below target due to missing nursing chart documentation of patient weight and/or fluid balance, and transfusion infusion time. Blinding was maintained throughout the study and treatment arms were well-balanced. A single case of TACO occurred in each arm, for an overall incidence of 2.5%. No differences observed in peritransfusion vital signs or B-natriuretic peptide. No furosemide toxicity observed. |
Conclusion: The study protocol successfully randomized 80 patients to pre-transfusion furosemide while maintaining blinded treatment allocation and outcome assessment. Modifications to trial design to improve feasibility have been identified and will inform the design of future studies.
|Completed, published in Transfusion|
|Cardiac Stress Biomarkers after Red Cell Transfusion in Patients at Higher Risk for Transfusion|
Associated Circulatory Overload: A Prospective Observational Study (TACO-BEL-2)
|Dr. Jeannie Callum & Dr. Christine Cserti||Background: Transfusion-associated circulatory overload (TACO) is a leading cause of serious reactions. Little is known regarding the value of cardiac biomarkers as a predictor of TACO, in differentiating TACO from other dyspneic reactions, or the optimal timing/thresholds. Methods: Prospective observational study of inpatients at higher risk for TACO (age>50) receiving 1 red cell unit. Cardiac biomarkers, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and high sensitivity troponin measured at baseline, 6-12 hours (except troponin), and 18-24 hours post-transfusion. Primary outcome: critical rise (-CR) in biomarkers (>1.5-fold rise and exceeding a threshold) at 18-24 hours. Results: 51 patientsanalyzed; 29% had pre-existing cardiovascular disease, 73% had ≥1 cardiac risk factors, and 50% took cardiac/antihypertensive therapies. No reactions observed; 8 (16%) developed rise in systolic pressure >30 mmHg and 4 (8%) reported dyspnea/cough. At baseline, BNP level was >100 ng/L in 59% and NTproBNP was >300pg/mL in 83%. 25% had a BNP-CR, 33% had a NT-proBNP-CR, and 2% had a troponin-CR at 18-24 hours. Overall, 38% had at least one biomarker-CR and NT-proBNP/BNP concordance was 84%. The highest biomarker yield was the NT-proBNP (>1.5 fold rise and >300 pg/mL) at 18-24 hours. Conclusions: In higher risk patients for TACO, baseline elevation in biomarkers is common and critical rises occur in a third. The optimal measurement interval as a surrogate marker for TACO is at 18-24 hours post-transfusion. Larger studies are needed to clarify the risk of TACO for a given pre-transfusion biomarker profile and the correlation between TACO and rise in biomarkers post-transfusion.||Completed, published in Transfusion|
|A feasibility study and a retrospective audit of diuretics for patients receiving blood transfusion at ten Canadian hospitals (TACO-BEL-3)||Dr. Jacob Pendergrast||Feasibility was not demonstrated within the two participating sites in TACO-BEL-1, primarily due to slower-than-expected enrollment. In the current study, we tested the feasibility of enrollment for a multi-site trial. For a baseline TACO risk of 3%, 2 600 participants would be required to detect a 40% relative risk reduction with 80% power and alpha of 0.05. This target could be achieved within 1 year at an average monthly enrollment rate of 217 patients. This study suggests that the 10 participating sites could achieve the enrollment target of 2600 patients in approximately 15 months; enrollment could be achieved within 1 year if the consent rate could be improved to 25%. The baseline incidence of TACO was slightly higher than anticipated, despite the inclusion of younger patients than was allowed in the pilot study.||Completed with publication in progress|
|National evaluation of platelet transport bags to reduce wastage||Dr. Jeannie Callum||Annually in Canada 874 platelets are discarded due to improper storage after issue from the blood transfusion laboratory. The estimated cost of platelet wastage is $240,089, assuming 70% buffy coat pools and 30% apheresis platelets. Platelets are in chronic short supply in Canada due to supply-demand mismatch during surges in use. Data from the multisite Pittsburgh transfusion service found that the use of platelet transport bags significantly reduced wastage. When platelets are transported to locations with refrigeration or blood coolers, it is a common error for nurses and physicians (transport medics, trauma surgeons and anaesthesiologists) to place the products in cooling devices with red cells due to inattention and lack of knowledge. The commonly cited reason is to keep all blood products together for “safety” reasons. Chilled platelets undergo modifications to their cell surface proteins which result in rapid clearance from the circulation post transfusion. The goal of this small project is to determine if the same strategy would be effective in the top 50 hospitals across Canada with the highest numerical loss of platelets. Re-usable platelet bags will be distributed to the hospitals together with a standard operating procedure and a PowerPoint with audio file for training of both the technologists and the clinical team. We hypothesize a 35% decrease in platelet wastage (cost savings $84,000).||Ongoing|
|The Monocyte Monolater Assay - Enhancing Care for the 'Untransfusables' (MMA-ECU)||Dr. Christine Cserti||Red Blood Cell unit (RBC) compatibility is founded on indirect anti-globulin testing (IAT), with two key fallibilities: “overcall” in high frequency alloantibodies (HFA), and “undercall” in hyperhemolysis syndrome (HHS). In HFA, undertransfusion and/or rare unit consumption may occur unnecessarily; while in (recurrence-prone) HHS, misleadingly compatible crossmatches cannot identify provocative RBCs. A more discriminating tool exists in the monocyte monolayer assay (MMA), which quantifies phagocytic indices (PI) for crosses between patient plasma, candidate RBCs, and (host vs control) monocytes. This has been locally optimized and validated, and applied in ad hoc cases as well as in a research cohort. Being labour-intensive, its adoption remains limited, and more evidence is required before its Canadian expansion. This study seeks to explore the monocyte monolayer assay for its potential to distinguish between units that are more or less likely to survive in the immune environment of the patient for more advanced precision in transfusion medicine.||Approved|
|Transfusion-Associated Dyspnea: Prospective Observation and Laboratory Assessment (TAD-POL)||Dr. Christine Cserti||TAD-POL (Transfusion-Associated Dyspnea: Prospective Observation and Laboratory Assessment): to better distinguish differing etiologies and associated pathophysiology, patients experiencing dyspneic transfusion reactions will undergo a standardized battery of clinical and laboratory tests via a peer-reviewed investigational protocol including NT-pro-BNP, histamine, cytokine profiling, leukoagglutinin assays and microparticle quantification.||Actively recruiting|
|Daily vs. Every Other Day Oral Iron Supplementation in Patients With Absolute Iron Deficiency Anemia (DEODO): a Multi-centered, Pilot Randomized Controlled Trial|
Daily vs. Every Other Day Oral Iron Supplementation in Patients With Absolute Iron Deficiency Anemia
|Dr. Yulia Lin||Iron deficiency anemia is a global health problem and the most common cause of anemia worldwide. Patients with iron deficiency (ID) and IDA can present with a multitude of symptoms including fatigue, restless legs syndrome and pica. Oral iron supplementation is associated with increasing hemoglobin in multiple studies in women, pregnant women and elderly patients. However, the optimal dose and frequency of oral iron supplementation for treatment remains unclear. The current proposed study attempts to address this gap in the literature.|
This is a pilot, pragmatic, non-inferiority, open label randomized controlled trial (RCT) in outpatients with iron deficiency anemia to evaluate the effectiveness of oral ferrous sulfate 300mg (60mg elemental iron) once daily versus every other day to improve hemoglobin at 12 weeks post-initiation. The rationale for this study includes: (1) IDA is a common and prevalent condition with potential adverse consequences if left untreated; (2) optimizing effectiveness of oral iron supplementation while minimizing side effects will improve treatment for patients. Because IDA is a global health problem, common in clinical practice and treatable, this study will have a significant practical impact on how clinicians treat outpatients with iron deficiency anemia and how patients tolerate therapy. For the patient, the expected benefit from taking part in this study is the potential to improve and treat iron deficiency anemia. These potential changes may lead to improved symptoms associated with iron deficiency anemia, such as cognitive and physical functioning, and fatigue.
|Massive hemorrhage protocol||Dr. Katerina Pavenski||Determine the impact of a standardized provincial massive transfusion protocol on outcomes of patients with acute traumatic injury, with a utilization sub-study to determine effectiveness of protocol on preventing blood wastage.||Completed with publication in progress|
|Impact of Transfusion Camp-1||Dr. Yulia Lin||The optimal method of providing transfusion medicine (TM) education has not been determined. Transfusion Camp was established in 2012 at the University of Toronto as a centrally-delivered TM education program for postgraduate trainees. The impact of Transfusion Camp on knowledge, attitudes and self-reported behavior was evaluated. Didactic lectures (delivered locally, by webinar or recorded) and locally facilitated team-based learning seminars were delivered over 5 days during the academic year to 8 sites: 7 in Canada and 1 in the United Kingdom. Knowledge assessment using a validated 20 question multiple choice exam was conducted pre- and post-Transfusion Camp. Attitudes and self-reported behavior were collected through survey. |
CONCLUSIONS: Transfusion Camp increased TM knowledge, fostered a positive attitude towards TM and enabled a self-reported positive impact on transfusion practice in postgraduate trainees. It is a novel and scalable approach to delivering TM education.
|Completed, published in Transfusion|
|Big Data-1||Dr. Robert Skeate||Demonstrate the impact of implementation of best practices in transfusion in the UofT QUEST hospitals through development of information technology systems linking the blood supplier, transfusion service, laboratory information systems and the discharge abstraction database. A pilot of this process has been conducted at Sunnybrook Health Sciences Centre, with a grant from the Ministry of Health, Ontario for $30,000. Computer provider order entry for transfusion has begun in a pilot phase at the hospital with full implementation planned for 2018-2019. With this infrastructure in place, we will be able to directly measure the impact of transfusion initiatives on individual clinical transfusion practice, including categorizing physicians who have and have not completed transfusion camp.||Ongoing|
|TESS Error System||Dr. Jeannie Callum & Dr. Christine Cserti||Transfusion errors in Canada. The UofT QUEST investigators have received approval from the Public Health Agency of Canada to conduct an analysis to characterize the sample collection and handling errors that have occurred in Canada over the past 10 years (PI: Callum). Sunnybrook Health Sciences Centre is a sentinel site for transfusion error data collection as part of the Transfusion Error Surveillance System (TESS). In 2017, our research team has been requested to analyze the national data and submit to a peer reviewed journal. Our goal is to identify where, when and why these errors are occurring in hospitals and utilize this as a base to influence hospital policy and transfusion standards that relate to sample collection for transfusion compatibility testing. This will allow the UofT QUEST to identify frequent high risk errors and then develop and test innovative strategies to determine how best to prevent these errors. Indeed, Sunnybrook Health Sciences Centre is at the beginning of a phased rollout of bedside computer technology to facilitate error-free sample collection. If we can scientifically prove these innovative technologies improve safety we can lobby to ensure transfusion standards are modified to require accurate labelling strategies.||Ongoing|
|The role of splenic macrophage Fc gamma receptors in two autoimmune conditions; immune thrombocytopenia and autoimmune hemolytic anemia (R2A2)||Dr. Alan Lazarus, Dr. Christine Cserti, Dr. Yulia Lin||In immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) antibody and Fc gamma receptors are involved in cellular destruction. Immunoglobin G antibodies opsonizing either platelets or erythrocytes trigger macrophage phagocytosis primarily through interactions with activating Fcgamma receptors (FcgammaR). Macrophages have several different FcgammaRs available. These include high affinity FcgammaR1, and the low affinity FcgammaRIIa and FcgammaRIIIa. However, the role of specific activating FcgammaRs in ITP patients is not well defined. The proposed study will incubate antibody coated blood cells sampled from ITP or AHA patient sera with macrophages and define the specific FcgammaRs involved in platelet and red cell destruction. Identifying which Fc receptors mediate phagocytosis of platelets and red cells can establish a known signaling pathway for the development of drugs/pharmaceutical agents to block and disrupt the antibody mediated signal for cellular destruction. Fc receptor blockade has long been considered a viable strategy to treat antibody-mediated platelet destruction.||Actively recruiting|
|Yield of serologic investigations from transfusion reactions||Dr. Christine Cserti||Serologic testing (ST) of acute transfusion reactions examines for potentially accountable immune haemolytic incompatibility. At our institutions, ST applies to all|
reported reactions, with the exception of low-risk fevers (subclinical temperature ≤39⁰C) or uncomplicated allergic reactions. Compliance with these guidelines, and reaction-specific yields, are unknown. Such measures may reflect quality of practice and inform investigation algorithms.
Conclusion: Analysis of the performance and contextual yields of ST revealed product-specific hierarchies. A re-evaluation of traditional ST algorithms may reduce costs and allow reinvestment in other more informative reaction-specific assays.
|Completed with publication in progress|