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In a trial involving more than 2400 critically ill patients, 90-day mortality was similar among patients receiving blood donated on average 6 days earlier and those receiving blood donated 22 days earlier. The age of the transfused blood did not influence outcomes. Blood transfusions are administered frequently and may have unintended consequences in critically ill patients. 1 – 4 Current regulations permit the storage of red cells for up to 42 days, but prolonged storage has been associated with changes that may render red cells ineffective as oxygen carriers and that lead to the accumulation of substances that have untoward biologic effects. 5 – 8 A systematic review of 18 observational studies involving a total of 409,840 patients and three randomized, controlled trials involving a total of 126 patients suggested that the transfusion of older red cells, as compared with newer red cells, was associated with . . .

PurposeIntravascular fluids are a necessary and universal component of cardiac surgical patient care. Both crystalloids and colloids are used to maintain or restore circulating plasma volume and ensure adequate organ perfusion. In Canada, human albumin solution (5% or 25% concentration) is a colloid commonly used for this purpose. In this narrative review, we discuss albumin supply in Canada, explore the perceived advantages of albumin, and describe the clinical literature supporting and refuting albumin use over other fluids in the adult cardiac surgical population.SourceWe conducted a targeted search of PubMed, Embase, Medline, Web of Science, ProQuest Dissertations and Theses Global, the Cochrane Central Register of Controlled trials, and the Cochrane Database of Systematic Reviews. Search terms included albumin, colloid, cardiac surgery, bleeding, hemorrhage, transfusion, and cardiopulmonary bypass.Principal findingsAlbumin is produced from fractionated human plasma and imported into Canada from international suppliers at a cost of approximately $21 million CAD per annum. While it is widely used in cardiac surgical patients across the country, it is approximately 30-times more expensive than equivalent doses of balanced crystalloid solutions, with wide inter-institutional variability in use and no clear association with improved outcomes. There is a general lack of high-quality evidence for the superiority of albumin over crystalloids in this patient population, and conflicting evidence regarding safety.ConclusionsIn cardiac surgical patients, albumin is widely utilized despite a lack of high- quality evidence supporting its efficacy or safety. A well-designed randomized controlled trial is needed to clarify the role of albumin in cardiac surgical patients.

In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients. Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43–15·45]; p<0·0001). The most frequent haematological adverse events of any grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3–4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3–4 anaemia and three patients (4%) reported grade 3–4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3–4 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group. RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population. Novartis.

PurposeThe mainstay of therapy for coagulation factor deficiency in cardiac surgical patients is frozen plasma (FP); however, prothrombin complex concentrates (PCCs) may offer logistical and safety advantages. As there is limited comparative evidence, we conducted this study to explore the association of comparable PCC or FP doses with transfusion and outcomes.MethodsThis was a post hoc analysis of a multicentre randomized trial comparing fibrinogen concentrate with cryoprecipitate (FIBRES trial) in bleeding cardiac surgical patients. This analysis included 415 patients who received only PCC (n = 72; 17%) or only FP (n = 343; 83%) for factor replacement. The main outcomes of interest were red blood cell (RBC) and platelet transfusion within 24 hr of cardiopulmonary bypass. Secondary outcomes included postoperative adverse events. Associations were examined by hierarchical generalized estimating equation models adjusted for demographic and surgical characteristics.ResultsThe median [interquartile range (IQR)] PCC dose was 1,000 [1,000–2,000] units, while the median [IQR] FP dose was 4 [2–6] units. Each unit of FP was independently associated with increased adjusted odds of RBC (1.60; 95% confidence interval [CI], 1.36 to 1.87; P < 0.01) and platelet transfusion (1.40; 95% CI, 1.15 to 1.69; P < 0.01) while each 500 units of PCC was independently associated with reduced adjusted odds of RBC (0.67; 95% CI, 0.50 to 0.90; P < 0.01) and platelet transfusion (0.80; 95% CI, 0.70 to 0.92; P < 0.01). Adverse event rates were comparable.ConclusionsIn cardiac surgical patients with post-cardiopulmonary bypass bleeding, PCC use was associated with lower RBC and platelet transfusion than FP use was. Prospective, randomized clinical trials comparing FP with PCC in this setting are warranted.

Introduction Viscoelastic assays have been promoted as an improvement over traditional coagulation tests in the management of trauma patients. Rotational thromboelastometry (ROTEM®) has been used to diagnose coagulopathy and guide hemostatic therapy in trauma. This systematic review of clinical studies in trauma investigates the ROTEM® parameters thresholds used for the diagnosing coagulopathy, predicting and guiding transfusion and predicting mortality. Methods Systematic literature search was performed using MEDLINE, EMBASE and Cochrane databases. We included studies without restricting year of publication, language or geographic location. Original studies reporting the thresholds of ROTEM® parameters in the diagnosis or management of coagulopathy in trauma patients were included. Data on patient demographics, measures of coagulopathy, transfusion and mortality were extracted. We reported our findings according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Quality assessment and risk of bias were performed using Newcastle Ottawa Scale (NOS) and the quality assessment of diagnostic accuracy studies (QUADAS-2) tools, respectively. Results A total of 13 observational studies involving 2835 adult trauma patients met the inclusion criteria. Nine studies were prospective and four were retrospective. There were no randomized controlled trials. The quality of the included studies was moderate (mean NOS 5.92, standard deviation 0.26). Using QUADAS-2, only 1 study (7.6 %) had low risk of bias in all domains, and 9 studies (69.2 %) had low risk of applicability concerns. Outcomes from 13 studies were grouped into three categories: diagnosis of coagulopathy ( n  = 10), prediction of massive transfusion or transfusion guidance ( n  = 6) and prediction of mortality ( n  = 6). Overall, specific ROTEM® parameters measured (clot amplitude and lysis) in the extrinsically activated test (EXTEM) and the fibrin-based extrinsically activated test (FIBTEM) were consistently associated with the diagnosis of coagulopathy, increased risk of bleeding and massive transfusion, and prediction of mortality. Presence of hyperfibrinolysis by ROTEM® was associated with increased mortality. Conclusions Most of the evidence indicates that abnormal EXTEM and FIBTEM clot amplitude (CA5, CA10) or maximal clot firmness (MCF) diagnose coagulopathy, and predict blood transfusion and mortality. The presence of fibrinolysis (abnormal lysis index [LI30] or maximum lysis [ML]) was also associated with mortality. ROTEM® thus, may be of value in the early management of trauma patients.

IntroductionMajor haemorrhage is the leading cause of preventable death in trauma, and prehospital blood transfusion may improve survival and outcomes for patients with prolonged out-of-hospital times. Globally, there is increasing interest in the use of whole blood in the prehospital environment, with randomised controlled trials ongoing. However, the results of these studies may not be generalisable to the longer out-of-hospital times seen in the Canadian trauma environment. The aim of this trial is to determine the feasibility of performing a randomised clinical trial evaluating the use of leukocyte-reduced whole blood transfusion compared with component blood transfusion in the Canadian prehospital environment. The secondary objective is to explore whether whole blood transfusion is better in reducing the proportion of patients who die or require massive transfusion within 24 hours.Methods and analysisThis is a multi-centre, open-label, randomised controlled feasibility trial. Patients aged 16 years or older will be eligible if they have suffered a major traumatic haemorrhage, are attended by the provincial air ambulance service and require a prehospital blood transfusion. The primary outcome is feasibility as measured by the following metrics: proportion of patients enrolled with full data collection, proportion of patients who received at least one prehospital transfusion prior to arriving at the receiving trauma centre, proportion of patients who completed transfusion of all assigned blood units, number of patients unable to be enrolled due to lack of whole blood availability and number of whole blood units produced for the study that were wasted or expired. The secondary outcome is a composite outcome of death (all-cause mortality) or receipt of massive transfusion (receipt of 10 units of blood or more) within the first 24 hours from randomisation. We plan to recruit 60 patients, with an anticipated post-randomisation exclusion of ~10 patients for traumatic cardiac arrest or who do not meet eligibility criteria.Ethics and disseminationProvincial ethics approval was obtained (Clinical Trials Ontario REB ID: CTO-4921). An opt-out consent model will be employed for participants. The SWiFT Canada trial will recruit 60 patients through the provincial air ambulance organisation in Ontario who are transported to one of the six participating lead trauma centres. It will investigate the feasibility of a pre-hospital transfusion clinical trial in Canada to compare the effectiveness of whole blood compared with component blood therapy in a future definitive trial.Trial registration numberClinicalTrials.gov: NCT06495294 (https://clinicaltrials.gov/study/NCT06495294), Clinical Trials Ontario: CTO-4921.

Major hemorrhage is life-threatening and can occur in a variety of clinical settings. For the purpose of this review, we defined major hemorrhage as life-threatening bleeding that is likely to result in the need for massive transfusion (i.e., ≥ 10 units of red blood cells in 24 h).1,2 We did not use the commonly used definition of major bleeding from the International Society on Thrombosis and Haemostasis because some bleeding events in the score do not need transfusion (e.g., intraocular or intra-articular bleeding, a 20 g/L decrease in hemoglobin levels).3 Management of major hemorrhage is most challenging in rural settings where the availability of blood products and specialized laboratory tests are limited. The response to major hemorrhage is labour-intensive and requires the support of a multidisciplinary team. Best practice for patients with major hemorrhage is now informed by numerous randomized controlled trials (RCT), as shown in Table 1, which allowed the development of standardized massive hemorrhage protocols (MHPs). However, implementation of and adherence to MHPs has been a challenge. We review the evidence for management of major hemorrhage and MHPs to support the implementation of such protocols at all hospital types to optimize the care of patients with major hemorrhage (Box 1).17,18

Postpartum haemorrhage (PPH) is a leading cause of maternal morbidity and mortality. While tranexamic acid (TXA) reduces bleeding and transfusion requirements in established PPH, we sought to determine the feasibility of conducting a fully powered trial assessing the effect of prophylactic tranexamic acid, prior to PPH onset, in a Canadian Obstetric setting. With institutional and Health Canada approval, consenting, eligible parturients (singleton, > 32 weeks gestation, vaginal or caesarian delivery) were randomly assigned to receive TXA (1 g intravenously) or placebo (0.9% saline) prior to delivery. Participants, investigators, data collectors/adjudicators, and analysis was blinded. The primary outcome was administration of study intervention to > 85% of randomized individuals. Secondary outcomes included recruitment rate (feasibility) and safety outcomes. Over 8 months, 611 were approached, 35 consented, and 27 randomized (14 TXA, 13 placebo). 89% of randomized participants received the assigned intervention. Recruitment fell below feasibility (23% target). No serious adverse outcomes occurred. Our pilot trial in a Canadian Obstetric setting was unable to demonstrate feasibility to conduct a large, multicentre trial to examine prophylactic use of tranexamic for PPH secondary to the complex regulatory requirements associated with a trial for an off-label, but commonly utilized intervention. These challenges should inform stakeholders on the resources and challenges of conducting future trials using off-label interventions. Trial registration: www.clinicaltrials.gov , NCT03069859 (03/03/2017).

RESPONSE-2 is a phase 3 study comparing the efficacy and safety of ruxolitinib with the best available therapy (BAT) in hydroxyurea-resistant/hydroxyurea-intolerant polycythemia vera (PV) patients without palpable splenomegaly. This analysis evaluated the durability of the efficacy and safety of ruxolitinib after patients completed the visit at week 80 or discontinued the study. Endpoints included proportion of patients achieving hematocrit control (< 45%), proportion of patients achieving complete hematologic remission (CHR) at week 28, and the durability of hematocrit control and CHR. At the time of analysis, 93% (69/74) of patients randomized to ruxolitinib were receiving ruxolitinib; while in the BAT arm, 77% (58/75) of patients crossed over to ruxolitinib after week 28. No patient remained on BAT by week 80. Among patients who achieved a hematocrit response at week 28, the probability of maintaining response up to week 80 was 78% in the ruxolitinib arm. At week 80, durable CHR was achieved in 18 patients (24%) in the ruxolitinib arm versus 2 patients (3%) in the BAT arm. The safety profile of ruxolitinib was consistent with previous reports. These data support that ruxolitinib treatment should be considered also as a standard of care for hydroxyurea-resistant/hydroxyurea-intolerant PV patients without palpable splenomegaly.

BackgroundGastrointestinal cancer surgery patients often develop perioperative anemia commonly treated with red blood cell (RBC) transfusions. Given the potential associated risks, evidence published over the past 10 years supports restrictive transfusion practices and blood conservation programs. Whether transfusion practices have changed remains unclear. We describe temporal RBC transfusion trends in a large North American population who underwent gastrointestinal cancer surgery.MethodsWe conducted a population-based retrospective cohort study of patients who underwent gastrointestinal cancer resection between 2007 and 2018 using health administrative datasets. The outcome was RBC transfusion during hospitalization. Temporal transfusion trends were analyzed with Cochran-Armitage tests. Multivariable regression assessed the association between year of diagnosis and likelihood of RBC transfusion while controlling for confounding.ResultsOf 79,764 patients undergoing gastrointestinal cancer resection, the median age was 69 years old (interquartile range (IQR) 60–78 years) and 55.5% were male. The most frequent procedures were colectomy (52.8%) and proctectomy (23.0%). A total of 18,175 patients (23%) received RBC transfusion. The proportion of patients transfused decreased from 26.5% in 2007 to 18.9% in 2018 (p < 0.001). After adjusting for patient, procedure, and hospital factors, the most recent time period (2015–2018) was associated with a reduced likelihood of receiving RBC transfusion [relative risk 0.86 (95% confidence interval: 0.83–0.89)] relative to the intermediate time period (2011–2014).ConclusionOver 11 years, we observed decreased RBC transfusion use and reduced likelihood of transfusion in patients undergoing gastrointestinal cancer resection. This information provides a foundation to further examine transfusion appropriateness or explore if additional transfusion minimization in surgical patients can be achieved.