Welsby, Ian J

Background: Transfusion has a persistent low risk of transfusion-transmitted infection and transfusion-associated graft- versus -host disease that may be addressed using pathogen reduction. The Red Cell Pathogen Inactivation (ReCePI) trial tested whether amustaline/glutathione pathogen-reduced red cells are noninferior to conventional transfusions for support of acute surgical blood loss. Methods: A phase 3, double-blinded, noninferiority trial randomized cardiac or thoracic–aorta surgery patients with increased risk of red cell transfusion to receive pathogen-reduced or conventional red cells during and for 7 days postsurgery. The primary endpoint was the proportion of patients with acute kidney injury (AKI), which is defined as an increase from baseline of greater than or equal to 0.3 mg/dl serum creatinine within 48 h of surgery. Noninferiority was claimed if the upper bound 95% CI of the treatment difference was less than half (50%) of the observed conventional arm incidence. Adverse events and treatment-emergent red cell antibodies were assessed for 28 and 75 days, respectively. Results: A total of 581 subjects were randomized, and 321 (55%) were transfused with study red cells. Transfused subjects in both arms had similar baseline demographics, medical histories, hemoglobin levels, and surgical procedures. Hemoglobin day 3 nadir levels (8.6 g/dl [7.8 to 9.2] in the pathogen-reduced arm; 8.4 g/dl [7.8 to 9.3] in the conventional arm; P = 0.52) were comparable. Incidence of AKI by 48 h was 46 of 157 (29.3%) in the pathogen-reduced arm and 45 of 161 (28.0%) in the conventional arm (treatment difference, 0.7%; 95% CI, −8.9 to 10.4%; noninferiority margin, 14.0%; P = 0.001 for noninferiority). AKI within 7 days by Kidney Disease Improving Global Outcomes staging criteria was not different (59 of 159 [37.1%] in the pathogen-reduced arm; 55 of 162 [34.0%] in the conventional arm; P = 0.53), but stage III was more common in the pathogen-reduced arm (pathogen-reduced arm, 15 of 159 [9.4%]; conventional arm, 7 of 162 [4.3%]; P = 0.075). Of 159 pathogen-reduced red cell recipients, 5 (3.1%) developed specific, low-titer antibodies without evidence of hemolysis. Conclusions: The incidence of AKI in recipients of pathogen-reduced red cells was noninferior to conventional red cell transfusion. Treatment-emergent antibodies were uncommon and not clinically significant.

Background: Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are leading causes of transfusion-related morbidity and mortality. Soluble factors in erythrocyte supernatant may increase risk for these complications. The authors hypothesized that point-of-care allogeneic erythrocyte washing may be an effective intervention to mitigate elevations in soluble factors as well as physiologic responses associated with transfusion-associated respiratory complications in the setting of cardiac surgery. Methods: This is a two-center, nonblinded, randomized clinical trial evaluating point-of-care washed versus standard issue allogeneic erythrocyte transfusions administered during or on the day of cardiac surgery. The primary analysis was performed via modified intention to treat. The primary outcomes assessed were changes in intermediate markers of lung injury as well as cardiopulmonary physiologic responses to erythrocyte transfusion. Secondary outcomes included the duration of intensive care unit and hospital stay, durations of mechanical ventilation and oxygen supplementation, presence of TRALI or TACO, and mortality. Results: Among 154 analyzed patients (81 washed, 73 standard issue), the median age was 66 yr, and 77 (50.0%) were women. The median (interquartile range) number of allogeneic erythrocyte units transfused on the day of surgery was 3.0 (2.0 to 5.0) in the washed erythrocyte group and 3.0 (2.0 to 4.0) in the standard issue group (P = 0.13). No between-group differences were identified in any of the assessed recipient lung injury biomarkers (all P values > adjusted alpha). Durations of intensive care unit stay (median [interquartile range], 3.0 [2.0 to 5.0] vs. 3.0 [2.0 to 4.0] days; P = 0.117) and hospital length of stay (12.0 [9.0 to 17.0] vs. 12.0 [9.0 to 17.0] days; P = 0.801) were similar, as were the number of ventilator-free days at day 28 (27.0 [27.0 to 27.0] vs. 27.0 [26.0 to 27.0]; P = 0.699) and oxygen-free days at day 28 (24.0 [19.0 to 26.0] vs. 24.0 [22.0 to 26.0]; P = 0.400). No significant differences were noted in mortality rate or in incidence rates for TRALI, TACO, and acute kidney injury. Conclusions: Among patients undergoing cardiovascular surgery with high risk of erythrocyte transfusion, point-of-care washing of allogeneic erythrocyte transfusions did not mitigate changes in intermediate markers of lung injury or cardiopulmonary physiologic responses to erythrocyte transfusion and was not associated with improved clinical outcomes.

Introduction: Red blood cell (RBC) transfusion is a lifesaving intervention with a low but persistent risk of transfusion-transmitted infection. Amustaline/glutathione RBC pathogen-reduction (PR) technology is designed to proactively inactivate a broad spectrum of viruses, bacteria, protozoa and leukocytes by chemically crosslinking nucleic acids and preventing replication and transcription. The Red Cell Pathogen Inactivation (ReCePI) trial was a Phase III, double-blinded, randomized non-inferiority study comparing PR and conventional RBCs for the support of acute anemia. Methods/Study Design: Complex cardiac or thoracic-aorta surgery patients received conventional (Control) or PR RBCs (Test) during and for 7 days after surgery. The protocol was conducted with ethics committee approval at all participating centers and written informed consent from all participants. Hemoglobin levels, blood utilization and serum creatinine were assessed as indicators of efficacy and oxygenation of tissues (Karkouti et al. Br J Anaesth. 2012; 109 Suppl 1: i29-i38). The primary endpoint was the incidence of acute kidney injury (AKI) measured as change in serum creatinine from baseline within 48 hours of surgery, a predictor of adverse postoperative outcomes including mortality by Day 30 post-surgery (Lassnig et al. Am Soc Nephrol 2004; 1597-1605). Secondary endpoints included AKI occurring up to 7 days post-surgery (KDIGO Clinical Practice Guideline for AKI, Kidney Inter, Suppl. 2012;2:1-138); death or the need for renal replacement therapy by 30 days post-surgery; PR RBC-specific antibodies; and death by day 75 post-surgery. With >292 subjects enrolled, the study had 80% power to demonstrate non-inferiority, assuming an AKI incidence of 30% with conventional RBCs and a non-inferiority margin of half the conventional RBC rate. Under these circumstances, an absolute treatment increase of 5% in the AKI rate in the PR RBC arm would fail the non-inferiority test. This work was supported by a contract with the US Biomedical Advanced Research and Development Authority (HHS010020160009c) with Cerus Corporation. Results: Five-hundred and eighty-one subjects were randomized and 321 (55%) transfused in 18 US hospitals. In the modified intent-to-treat analysis subjects receiving Test and Control RBCs had similar median [IQR] total blood loss (1500 [940-2475] mL Test, 1733 [1060-2880] mL Control, p=0.310) and comparable median hemoglobin levels at baseline and immediately post-surgery (9.8 [8.9-10.9] g/dL Test, 9.6 [8.6-10.6] g/dL Control, p=0.157) and for 7 days after surgery, The PR RBC arm was transfused with fewer RBCs, measured as total RBC Hb transfused over 7-days (169.0 [102.0-240.0] g Hb PR arm, 188.0 [126.0-295.0] g Hb, conventional RBC arm, p=0.008). The incidence of AKI was 29.3% (46/157) for Test and 28.0% (45/161) for Control. The treatment difference was 0.74% (95% CI -8.9, 10.4%, non-inferiority margin 14.0%, p=0.001 for non-inferiority). Non-inferiority was also achieved by the per protocol analysis. Average mean change in serum creatinine within 48 hours of surgery was comparable (Test 0.020, Control 0.23 mg/dL, P=0.515). Adverse events, serious adverse events and deaths on study were not different. Five of 159 (3.1%) PR RBC recipients developed low titer PR RBC-specific antibodies without clinical signs of hemolysis. Flow cytometry analysis revealed persistent circulating PR RBCs with uniform antigen loss (modulation). Low level human IgG antibody binding was demonstrated in 3 of 5 subjects. Conclusions: PR RBCs showed equivalent hemoglobin support for acute bleeding patients undergoing cardiac or thoracic-aorta surgery while using less transfused total RBC Hb over 7 days. The incidence of AKI in patients transfused with PR RBCs was non-inferior to that observed with conventional RBCs, indicative of effective tissue oxygenation. Treatment-related antibodies to PR-RBC were observed only in Test subjects, the antibodies were low titer, transient, without clinical hemolysis, and persistent circulating PR RBCs were detected with modulated low level acridine antigen expression (www.clinicaltrials.gov #NCT03459287).

Abstract Background Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leucocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. Methods ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, paralleldesign, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to Day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥0.3 mg/dL (or 26.5 µmol/L) from presurgery baseline within 48±4 hours of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen reduced RBCs through 75 days after the last study transfusion. With ≥292 evaluable, transfused patients (>146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. Discussion RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBC.

Abstract Abstract 1159 Background. Heparin induced thrombocytopenia (HIT) is an immune disorder where platelets are activated by antibodies to a complex of platelet factor 4 antigen and heparin (PF4/H), leading to thrombocytopenia (HIT) and, potentially, thrombosis (HITT). Documentation of anti-PF4/H antibodies in addition to the appropriate clinical findings is essential for making a diagnosis of HIT. In the post-cardiac bypass surgery setting, however, the frequency of elevated anti-PF4/H antibodies is high, whereas the frequency of clinical HIT or HITT is relatively uncommon. Several studies have shown that the presence of anti-PF4/H antibodies may be associated with an increased frequency of adverse outcomes, even in the absence of clinical HIT. The primary objective of this study was to determine the relationship between a positive PF4/H antibody in the postoperative setting with adverse thromboembolic events occurring up to 3 months after cardiac surgery. Methods. Patients undergoing cardiac surgery who were not going to be treated with chronic anticoagulation postoperatively were eligible for this multi-center prospective cohort study. Data were collected daily during hospitalization, and then at 30 and 90 days after surgery using a structured interview format with a standardized questionnaire that included all thrombotic as well as hemorrhagic events, platelet counts, and utilization of antithrombotics in the postoperative setting. The primary outcome variable was a composite endpoint comprising arterial and venous thrombotic events and other miscellaneous events compatible with HIT, as well as death attributable to an event compatible with HIT. Citrated plasma was collected at baseline, pre-discharge (∼4–5 days after surgery), and the 30 day follow-up visit, processed, and stored at −80°C for testing. Laboratory analyses included an anti-PF4/H antibody ELISA (GTI, Waukesha, WI) on all samples, a high-heparin confirmatory test on samples with an OD reading >0.40, and a serotonin release assay (SRA) on all postoperative samples with an OD reading >0.40. A sample size of 800 patients was estimated in order to detect a 3% difference in thromboembolic events assuming a 2 to 10-fold increase risk attributable to seropositivity. Chi-squared testing was used to test the relationship between the primary outcome and postoperative anti-PF4/H levels. Results. Informed consent was obtained from 1030 eligible patients between August 2006 and May 2009, and laboratory and follow-up data were analyzable for 1016 patients. Thirty-day antibody data were available for 888 patients, and fully complete laboratory and 90-day follow-up data were available for 815 patients. The average age was 62 ± 12 years, and 73% of participants were male. A total of 769 patients underwent coronary artery bypass grafting and 237 underwent valve repair or replacement. During the entire study period, there were 17 (1.7%) deaths, 46 thromboembolic events in 44 patients (4.3%), and 25 hemorrhagic events in 24 patients (2.4%). Using an OD cutoff of 0.40 for the ELISA, 339 patients (33.4%) were positive for anti-PF4/H antibodies at the time of discharge, and 630 patients (62%) were positive by day 30. There was no correlation between seropositivity for anti-PF4/H antibodies at the day of discharge or at day 30 and the primary outcome (p=0.47 and 0.73, respectively). Incorporating the high-heparin confirmatory step did not improve the relationship between positive antibody results and the primary outcome. Using a higher cut-off value for the anti-PF4/H antibody ELISA of 1.0 decreased the number of patients with positive results (96 patients at the time of discharge [9.4%] and 221 patients at the 30-day follow-up visit [21.8%]), but this did not improve the relationship between antibody positivity at the day of discharge or day 30 and the primary clinical endpoint, since most patients with the primary endpoint had an ELISA OD below 1.0 (75th percentile of 0.90; 90th percentile of 1.22). Similarly, using the SRA did not identify a relationship between assay results and outcome. Conclusions. The presence of anti-PF4/H antibodies in the postoperative setting following cardiac bypass surgery is not associated with an increased risk for thromboembolic complications. Positive anti-PF4/H results in this clinical setting should be interpreted with caution and only in the context of clinical suspicion for HIT. Disclosures: Ortel: Instrumentation Laboratory: Consultancy; Eisai: Research Funding; GSK: Research Funding. Welsby:CSL Behring: Speaker; CSL Behring: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Principal Investigator. Heit:Daiichi Sankyo: Honoraria; Ortho-McNeil Janssen: Honoraria; Covidien: Honoraria.

Bleeding after cardiac surgery is a common and serious complication leading to transfusion of multiple blood products and resulting in increased morbidity and mortality. Despite the publication of numerous guidelines and consensus statements for patient blood management in cardiac surgery, research has revealed that adherence to these guidelines is poor, and as a result, a significant variability in patient transfusion practices among practitioners still remains. In addition, although utilization of point-of-care (POC) coagulation monitors and the use of novel therapeutic strategies for perioperative hemostasis, such as the use of coagulation factor concentrates, have increased significantly over the last decade, they are still not widely available in every institution. Therefore, despite continuous efforts, blood transfusion in cardiac surgery has only modestly declined over the last decade, remaining at ≥50% in high-risk patients. Given these limitations, and in response to new regulatory and legislature requirements, the Society of Cardiovascular Anesthesiologists (SCA) has formed the Blood Conservation in Cardiac Surgery Working Group to organize, summarize, and disseminate the available best-practice knowledge in patient blood management in cardiac surgery. The current publication includes the summary statements and algorithms designed by the working group, after collection and review of the existing guidelines, consensus statements, and recommendations for patient blood management practices in cardiac surgery patients. The overall goal is creating a dynamic resource of easily accessible educational material that will help to increase and improve compliance with the existing evidence-based best practices of patient blood management by cardiac surgery care teams.

Background and objectivesExtracorporeal membrane oxygenation (ECMO) is a method of life support for either isolated cardiac failure or respiratory failure, with or without cardiac failure. When used for hemodynamic support, the ECMO circuit presents a non‐endothelialized, artificial surface to blood inciting an inflammatory response which activates haemostatic pathways. Anticoagulation may complicate a pre‐existing coagulopathy and/or inadequate surgical hemostasis of varying severity. There is no standardized method to achieve and monitor anticoagulation or guide transfusion therapy during ECMO. We tested the hypothesis that institutions across the world conduct similar management of anticoagulation and transfusion during adult ECMO support.MethodsThis is a descriptive, self‐reporting cross‐sectional survey of anticoagulation and transfusion practice for patients age 18 or older on ECMO. This 38 multiple‐choice question survey was sent to 166 institutions, internationally, utilizing adult ECMO. About 32·4% (54) of institutions responded. Responses were anonymously collected. Descriptive analyses were calculated.ResultsOur findings indicate there appears to be a significant practice variation among institutions regarding anticoagulation and transfusion during adult ECMO support.DiscussionThe lack of standard practices among institutions may reflect a paucity of data regarding optimal anticoagulation and transfusion for patients requiring ECMO. Standardized protocols for anticoagulation and transfusion may help increase quality of care for and reduce morbidity, mortality and cost to patients and healthcare centres. Further study is required for standardized, high quality care.