Society of Cardiovascular Anesthesiologists Clinical Practice Improvement Advisory for Management of Perioperative Bleeding and Hemostasis in Cardiac Surgery Patients

      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 coagulation monitors and the use of novel therapeutic strategies for perioperative hemostasis, such as the use of coagulation factor concentrates, has 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 declined only modestly over the last decade, remaining at 50% or greater in high-risk patients.
      Given these limitations and in response to new regulatory and legislature requirements, the Society of Cardiovascular Anesthesiologists has formed the Blood Conservation in Cardiac Surgery Working Group in order 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.

      Key Words

      COAGULOPATHY ASSOCIATED WITH cardiac surgery is a multifactorial serious complication that may result in massive bleeding requiring transfusion of red blood cells and procoagulant products to obtain adequate hemostasis.
      • Gorlinger K.
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      The importance of blood conservation strategies in cardiac surgery is emphasized by the fact that cardiovascular surgical procedures have among the highest overall rate of red blood cell (RBC) transfusion when compared with all other surgeries, accounting for 10% to 15% of all RBC transfusions in the United States and the United Kingdom.
      • Murphy G.J.
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      • Rogers C.A.
      • et al.
      Liberal or restrictive transfusion after cardiac surgery.
      • Robich M.P.
      • Koch C.G.
      • Johnston D.R.
      • et al.
      Trends in blood utilization in United States cardiac surgical patients.
      Furthermore, approximately 10% of all cardiac surgery patients suffer from severe or massive blood loss, and up to 5% of all patients having cardiac surgery require emergent re-exploration in an attempt to correct ongoing bleeding and establish adequate hemostasis.
      • Dyke C.
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      Universal definition of perioperative bleeding in adult cardiac surgery.
      • Ranucci M.
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      • Castelvecchio S.
      • et al.
      Major bleeding, transfusions, and anemia: The deadly triad of cardiac surgery.
      A significant body of evidence associates allogeneic blood transfusions during cardiac surgery with increased risk of serious postoperative morbidities including infections, atrial fibrillation, respiratory complications, acute kidney injury, and short- and long-term mortality,
      • Christensen M.C.
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      Costs of excessive postoperative hemorrhage in cardiac surgery.
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      Blood transfusion and adverse surgical outcomes: The good and the bad.
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      The independent association of massive blood loss with mortality in cardiac surgery.
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      Impact of institutional culture on rates of transfusions during cardiovascular procedures: The Michigan experience.
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      Effect of blood transfusion on long-term survival after cardiac operation.
      • Koch C.G.
      • Li L.
      • Duncan A.I.
      • et al.
      Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting.
      • Koch C.G.
      • Li L.
      • Duncan A.I.
      • et al.
      Transfusion in coronary artery bypass grafting is associated with reduced long-term survival.
      • Koch C.G.
      • Li L.
      • Van Wagoner D.R.
      • et al.
      Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation.
      • Murphy G.J.
      • Reeves B.C.
      • Rogers C.A.
      • et al.
      Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery.
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      • Dulhunty J.
      • Mullany D.V.
      • et al.
      Impact of blood product transfusion on short and long-term survival after cardiac surgery: More evidence.
      showing a dose-response relationship where morbidity and mortality are directly proportional to the number of units of RBC transfused.
      • Karkouti K.
      • Wijeysundera D.N.
      • Yau T.M.
      • et al.
      The independent association of massive blood loss with mortality in cardiac surgery.
      • Murphy G.J.
      • Reeves B.C.
      • Rogers C.A.
      • et al.
      Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery.
      Moreover, reduction of perioperative transfusion by initiation of blood management practices has been associated with a decrease in major postoperative morbidity and mortality.
      • Freedman J.
      • Luke K.
      • Escobar M.
      • et al.
      Experience of a network of transfusion coordinators for blood conservation (Ontario Transfusion Coordinators [ONTraC]).
      • LaPar D.J.
      • Crosby I.K.
      • Ailawadi G.
      • et al.
      Blood product conservation is associated with improved outcomes and reduced costs after cardiac surgery.
      • Moskowitz D.M.
      • McCullough J.N.
      • Shander A.
      • et al.
      The impact of blood conservation on outcomes in cardiac surgery: Is it safe and effective?.
      Despite this evidence base, and the publication of numerous practice guidelines,
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      American Society of Anesthesiologists Task Force on Perioperative Blood Management
      Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management.
      • Kaufman R.M.
      • Djulbegovic B.
      • Gernsheimer T.
      • et al.
      Platelet transfusion: A clinical practice guideline from the AABB.
      • Carson J.L.
      • Guyatt G.
      • Heddle N.M.
      • et al.
      Clinical practice guidelines from the AABB: Red blood cell transfusion thresholds and storage.
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      • Ferraris V.A.
      • Ferraris S.P.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline.
      much confusion remains about the optimal management of perioperative bleeding in cardiac surgery patients.
      • Ranucci M.
      • Baryshnikova E.
      • Castelvecchio S.
      • et al.
      Major bleeding, transfusions, and anemia: The deadly triad of cardiac surgery.
      ,
      • Bennett-Guerrero E.
      • Zhao Y.
      • O'Brien S.M.
      • et al.
      Variation in use of blood transfusion in coronary artery bypass graft surgery.
      • Karkouti K.
      • Wijeysundera D.N.
      • Beattie W.S.
      • et al.
      Risk associated with preoperative anemia in cardiac surgery: A multicenter cohort study.
      • Miceli A.
      • Romeo F.
      • Glauber M.
      • et al.
      Preoperative anemia increases mortality and postoperative morbidity after cardiac surgery.
      • Ranucci M.
      • Aronson S.
      • Dietrich W.
      • et al.
      Patient blood management during cardiac surgery: Do we have enough evidence for clinical practice?.
      Data show that only a small fraction of published guidelines is successfully integrated into daily clinical practice.
      • Stover E.P.
      • Siegel L.C.
      • Parks R.
      • et al.
      Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: A 24-institution study. Institutions of the Multicenter Study of Perioperative Ischemia Research Group.
      • Cabana M.D.
      • Rand C.S.
      • Powe N.R.
      • et al.
      Why don't physicians follow clinical practice guidelines? A framework for improvement.
      As a specific example: publication of the 2011 update to the Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists (SCA) Blood Conservation Guideline
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      did not result in a decrease in blood product utilization in cardiac surgery patients, probably because of a low rate of guideline adoption by practitioners.
      • Robich M.P.
      • Koch C.G.
      • Johnston D.R.
      • et al.
      Trends in blood utilization in United States cardiac surgical patients.
      • Likosky D.S.
      • FitzGerald D.C.
      • Groom R.C.
      • et al.
      Effect of the perioperative blood transfusion and blood conservation in cardiac surgery clinical practice guidelines of the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists upon clinical practices.
      Furthermore, although recent Society of Thoracic Surgeons reports
      • D'Agostino R.S.
      • Jacobs J.P.
      • Badhwar V.
      • et al.
      The Society of Thoracic Surgeons adult cardiac surgery database: 2018 Update on outcomes and quality.
      • D'Agostino R.S.
      • Jacobs J.P.
      • Badhwar V.
      • et al.
      The Society of Thoracic Surgeons adult cardiac surgery database: 2017 Update on outcomes and quality.
      demonstrate a modest decline in blood product utilization in cardiac surgical procedures over the last decade, allogeneic blood transfusions still occur in over 50% of high-risk cardiac surgery patients.
      • Murphy G.J.
      • Pike K.
      • Rogers C.A.
      • et al.
      Liberal or restrictive transfusion after cardiac surgery.
      • Robich M.P.
      • Koch C.G.
      • Johnston D.R.
      • et al.
      Trends in blood utilization in United States cardiac surgical patients.
      • Bennett-Guerrero E.
      • Zhao Y.
      • O'Brien S.M.
      • et al.
      Variation in use of blood transfusion in coronary artery bypass graft surgery.
      • Mazer C.D.
      • Whitlock R.P.
      • Fergusson D.A.
      • et al.
      Restrictive or liberal red-cell transfusion for cardiac surgery.
      In the recently published Transfusion Requirements in Cardiac Surgery III trial, for example, RBC transfusions occurred in 52.3% of the patients in the restrictive transfusion group and in 72.6% of the patients in the liberal transfusion group.
      • Mazer C.D.
      • Whitlock R.P.
      • Fergusson D.A.
      • et al.
      Restrictive or liberal red-cell transfusion for cardiac surgery.
      It is believed, however, that with the successful adoption and implementation of best practice point of care (POC)–based transfusion algorithms, at least some of these transfusions potentially could be avoided.
      • Ranucci M.
      • Baryshnikova E.
      • Pistuddi V.
      • et al.
      The effectiveness of 10 years of interventions to control postoperative bleeding in adult cardiac surgery.
      • Weber C.F.
      • Gorlinger K.
      • Meininger D.
      • et al.
      Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients.
      • Gorlinger K.
      • Fries D.
      • Dirkmann D.
      • et al.
      Reduction of fresh frozen plasma requirements by perioperative point-of-care coagulation management with early calculated goal-directed therapy.
      • Karkouti K.
      • Callum J.
      • Wijeysundera D.N.
      • et al.
      Point-of-care hemostatic testing in cardiac surgery: A stepped-wedge clustered randomized controlled trial.
      • Girdauskas E.
      • Kempfert J.
      • Kuntze T.
      • et al.
      Thromboelastometrically guided transfusion protocol during aortic surgery with circulatory arrest: A prospective, randomized trial.
      In response to recent changes in statutory regulations, and to facilitate improvement in blood conservation and transfusion management in cardiac surgery, SCA formed a Continuous Practice Improvement (CPI) subcommittee. This subcommittee appointed a Blood Conservation In Cardiac Surgery Working Group—a panel of experts that was directed to organize and summarize the existing guidelines and consensus statements related to blood conservation in cardiac surgery. Additional information about the SCA's Continuous Practice Improvement initiative and the various focus working groups can be found in a recent manuscript and accompanying editorial by Muehlschlegel et al. and Schwann et al., respectively.
      • Muehlschlegel J.D.
      • Burrage P.S.
      • Ngai J.Y.
      • et al.
      Society of Cardiovascular Anesthesiologists/European Association of Cardiothoracic Anaesthetists practice advisory for the management of perioperative atrial fibrillation in patients undergoing cardiac surgery.
      • Schwann N.M.
      • Engstrom R.H.
      • Shernan S.K.
      • et al.
      Clinical practice improvement: Mind the gap or fall into the chasm.
      The current report is the summary of recommendations for blood management in cardiac surgery, made by the SCA Continuous Practice Improvement Blood Conservation Working Group. This summary focuses on the perioperative management of adults undergoing cardiovascular surgery in which significant blood loss occurs or is expected. Excluded from this document are neonates, infants, children younger than 18 years old, and adults weighing less than 40 kg.
      The current summary of recommendations is not a set of new guidelines. They may be adopted, modified, or rejected according to clinical and institutional needs and constraints. Furthermore, practitioners will need to consider the clinical situation and exercise judgment in applying the more generalized recommendations contained herein. In addition, the recommendations included here are not intended as standards or absolute requirements, and their use cannot guarantee any specific outcome.

      Methods

       Working Group

      The SCA Blood Conservation Working Group includes appointed members from the United States and internationally. Efforts were made to select members who are experts in patient blood management both from private and academic cardiac anesthesia practices and representatives from international cardiac anesthesiology societies. The working group developed the current recommendations after reviewing existing guidelines and consensus statements and original published research studies from peer-reviewed journals. In addition, expert opinion about the recommendations was solicited from the task force members. All available information was used to build consensus within the working group to finalize the recommendations.

       Search Strategy and Identification of Guidelines

      The following databases were searched for relevant clinical studies from inception until October 30, 2018: MEDLINE (Ovid), EMBASE (Embase.com), PUBMED (NCBI), the Cochrane Central Register of controlled Trials (CENTRAL), BIOSIS (Web of Science), and Google Scholar. The search was not limited by date or publication status but was restricted to articles that were only published in English. In addition, the authors also searched the reference lists of relevant reviews, available online conference proceedings, and published practice guidelines and their respective reference lists. Inclusion criteria included randomized controlled trials (RCTs), meta-analyses, large-scale observational studies, and practice guidelines of patients undergoing cardiovascular surgical procedures with or without cardiopulmonary bypass (CPB). Reviewers independently screened citations to select publications that met inclusion criteria. Studies were not blinded to author, journal, or institution. The specific search terms that were used in obtaining relevant publications are detailed in the online supplementary files (Appendix 1).
      Agreement (defined as consensus of at least 75% of the members of the working group on a specific topic) was reached through conference calls and face-to-face meetings. When no agreement could be obtained, or in cases that guidelines papers lack or differ in recommendations, a consensus was reached after a modified Delphi process.
      • Jones J.
      • Hunter D.
      Consensus methods for medical and health services research.
      Members that were unable to attend a face-to-face meeting voted via email. Three Delphi cycles were required to reach a consensus, and a final decision was made through a series of teleconference calls and electronic communications. In the absence of published evidence or cut-off values for transfusion triggers, expert consensus statements, based on the most updated published literature, were made to cover specific issues that are essential to daily practice. The level of evidence and the strength of the recommendations (when available) are reported as well (Supplemental Table 1, online supplementary files).

      Results

      The literature search yielded a total of 892 titles that were identified and their abstracts reviewed, from which 213 relevant publications were fully reviewed by the working group. Out of the 213 reviewed publications, 9 practice guidelines were included for summary in the current publication: (1) “Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline”
      • Ferraris V.A.
      • Ferraris S.P.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline.
      ; (2) “2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines”
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      ; (3) “2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines”
      • Hillis L.D.
      • Smith P.K.
      • Anderson J.L.
      • et al.
      2011 ACCF/AHA guideline for coronary artery bypass graft surgery: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ; (4) “Management of Severe Perioperative Bleeding: Guideline from the European Society of Anaesthesiology”
      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
      ; (5) the “Management of Severe Perioperative Bleeding: Guideline from the European Society of Anaesthesiology, first update 2016”
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      ; (6) “Practice Guidelines for Perioperative Blood Management: An Updated Report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management”
      American Society of Anesthesiologists Task Force on Perioperative Blood Management
      Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management.
      ; (7) “Platelet Transfusion: A Clinical Practice Guideline from the AABB”
      • Kaufman R.M.
      • Djulbegovic B.
      • Gernsheimer T.
      • et al.
      Platelet transfusion: A clinical practice guideline from the AABB.
      ; (8) “Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage”
      • Carson J.L.
      • Guyatt G.
      • Heddle N.M.
      • et al.
      Clinical practice guidelines from the AABB: Red blood cell transfusion thresholds and storage.
      ; and (9) “2017 EACTS/EACTA Guidelines on Patient Blood Management for Adult Cardiac Surgery.”
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      A summary of recommendations for common daily practices, including preoperative management of anemia and platelet function assessment when indicated, in addition to intraoperative monitoring of hemostasis, transfusion of blood products, and administration of pharmacological adjuvants in cardiac surgical patients is presented in Supplemental Table 1 (online supplementary files). This summary is based on the most recent published blood management guidelines. In addition, a graphical best practice advisory for the practicing clinician that can be used at the POC also is included. This graphical advisory includes a summary statement (Fig 1) and the following 2 separate practical algorithms: (1) an algorithm based on viscoelastic POC coagulation testing (Fig 2), and (2) an algorithm based on “conventional” laboratory coagulation tests when viscoelastic tests are unavailable (Fig 3).
      Fig 1
      Fig 1SCA summary statement on blood conservation and transfusion in cardiac surgery. CPB, cardiopulmonary bypass; DDAVP, 1-deamino-8-D-arginine vasopressin; EPO, erythropoietin; FFP, fresh frozen plasma; Hb, hemoglobin; HIT, heparin induced thrombocytopenia; PCC, prothrombin complex concentrate; PRBC, packed red blood cells; ROTEM, rotational thromboelastometry; TEG, thromboelastography.
      Fig 2
      Fig 2SCA ROTEM/TEG–based cardiac surgery intraoperative transfusion algorithm. ANH, acute normovolemic hemodilution; A10, amplitude at 10 minutes; CT, clotting time; DDAVP, 1-deamino-8-D-arginine vasopressin; EXTEM, extrinsic pathway thromboelastometry; FIBTEM, fibrinogen based thromboelastometry; FF, functional fibrinogen; FFP, fresh frozen plasma; Hb, hemoglobin; HEPTEM, heparinase thromboelastometry; hTEG, heparinase thromboelastography; iCA++, ionized calcium; INTEM, intrinsic pathway thromboelastometry; LY30, clot lysis at 30 minutes; .MA, maximum amplitude; ML, maximum lysis; PCC, prothrombin complex concentrate; R, reaction time; ROTEM, rotational thromboelastometry; TEG, thromboelastography.
      Fig 3
      Fig 3SCA non-ROTEM/TEG–based cardiac surgery intraoperative transfusion algorithm. ACT, activated clotting time; ANH, acute normovolemic hemodilution; CPB, cardiopulmonary bypass; DDAVP, 1-deamino-8-D-arginine vasopressin; FFP, fresh frozen plasma; Hb, hemoglobin; iCA++, ionized calcium; INR, international normalized ratio; PCC, prothrombin complex concentrate; PLT, platelets; RBC, red blood cells; rFVIIa, recombinant activated factor VII; T, temperature.

      Discussion

      In an attempt to minimize the existing gap between published guidelines and clinical practice patterns in blood conservation in cardiovascular surgery patients, the current publication is a summary of recommendations that creates a “best practice” advisory that can be easily adopted by clinicians. This advisory contains a summary statement and 2 transfusion algorithms.
      The algorithms are based on a stepwise escalating approach where complete heparin reversal using protamine is the first step. If excessive microvascular bleeding is present after heparin reversal, an assessment of platelets (PLT) and fibrinogen is required in addition to evaluation for coagulation factors deficiency. It is also important to remember that CPB is associated with significant fibrinolysis,
      • Gielen C.L.
      • Grimbergen J.
      • Klautz R.J.
      • et al.
      Fibrinogen reduction and coagulation in cardiac surgery: An investigational study.
      • Gielen C.L.I.
      • Brand A.
      • van Heerde W.L.
      • et al.
      Hemostatic alterations during coronary artery bypass grafting.
      and therefore the use of antifibrinolytic agents
      • Fergusson D.A.
      • Hebert P.C.
      • Mazer C.D.
      • et al.
      A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.
      • Faraoni D.
      • Cacheux C.
      • Van Aelbrouck C.
      • et al.
      Effect of two doses of tranexamic acid on fibrinolysis evaluated by thromboelastography during cardiac surgery: A randomised, controlled study.
      • Myles P.S.
      • Smith J.A.
      • Forbes A.
      • et al.
      Tranexamic acid in patients undergoing coronary-artery surgery.
      should be continued beyond the operating room, or restarted if already discontinued, in cases with excessive postoperative bleeding.
      • Levy J.H.
      • Sniecinski R.M.
      Prohemostatic treatment in cardiac surgery.
      • Sniecinski R.M.
      • Levy J.H.
      Bleeding and management of coagulopathy.
      Patients may require transfusion of a single component but frequently more than one component is required to achieve adequate hemostasis. After each round of treatment, clinical assessment of bleeding and evaluation of hemoglobin and of the coagulation system are needed to avoid unnecessary over transfusion. Regardless of the algorithm used the practitioner also must correct general abnormal physiologic conditions that may contribute to coagulopathy such as hypothermia and acidosis.
      The development and implementation of a successful blood management program in cardiovascular surgical patients is a joint effort that requires involvement of multiple stakeholders and should include cardiovascular surgeons, anesthesiologists, perfusionists, intensivists, blood bank transfusion experts, nursing staff, and hospital administrative and support staff. The recommendations presented here apply to patients undergoing cardiovascular surgical procedures with or without the use of CPB, where blood transfusions or other adjuvant hemostatic therapies are indicated. They are directly applicable to anesthesiologists, surgeons, intensivists, and other care providers who are involved in the perioperative care of these patients.
      The rationale for recommendations for essential common daily practices for blood conservation in cardiac surgical patients is presented in the following sections.

       Preoperative Hemoglobin Optimization

      Preoperative anemia (defined by the World Health Organization as a hemoglobin level less than 12.0 g/dL in women and less than 13.0 g/dL in men), is present preoperatively in 25% to 30% of cardiac surgery patients
      • Dai L.
      • Mick S.L.
      • McCrae K.R.
      • et al.
      Preoperative anemia in cardiac operation: Does hemoglobin tell the whole story?.
      and is a strong predictor for perioperative transfusion of allogeneic blood products.
      • LaPar D.J.
      • Hawkins R.B.
      • McMurry T.L.
      • et al.
      Preoperative anemia versus blood transfusion: Which is the culprit for worse outcomes in cardiac surgery?.
      • von Heymann C.
      • Kaufner L.
      • Sander M.
      • et al.
      Does the severity of preoperative anemia or blood transfusion have a stronger impact on long-term survival after cardiac surgery?.
      • Kim C.J.
      • Connell H.
      • McGeorge A.D.
      • et al.
      Prevalence of preoperative anaemia in patients having first-time cardiac surgery and its impact on clinical outcome. A retrospective observational study.
      It is recommended that patients be assessed for preoperative anemia several weeks before elective surgery to provide sufficient time for therapy, if needed.
      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      Although studies are somewhat inconclusive regarding the efficacy of iron supplementation before cardiac surgery,
      • Garrido-Martin P.
      • Nassar-Mansur M.I.
      • de la Llana-Ducros R.
      • et al.
      The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: A randomized clinical trial.
      • Johansson P.I.
      • Rasmussen A.S.
      • Thomsen L.L.
      Intravenous iron isomaltoside 1000 (Monofer(R)) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: A randomized double-blind placebo-controlled clinical trial (the PROTECT trial).
      there is a strong agreement that supplemental iron is effective in patients with iron-deficiency anemia. Therefore, existing guidelines do recommend preoperative iron therapy for patients with iron deficiency anemia. Erythropoietin with or without iron is recommended for patients with non-iron-deficiency anemia (renal failure, anemia of chronic disease, etc) or in patients who refuse blood transfusions.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      American Society of Anesthesiologists Task Force on Perioperative Blood Management
      Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management.
      ,
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      Prophylactic RBC transfusion in asymptomatic anemic patients, before surgery, is not recommended.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      American Society of Anesthesiologists Task Force on Perioperative Blood Management
      Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management.
      ,
      • Carson J.L.
      • Guyatt G.
      • Heddle N.M.
      • et al.
      Clinical practice guidelines from the AABB: Red blood cell transfusion thresholds and storage.
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.

       Heparin Resistance and Antithrombin Administration

      Heparin resistance or altered heparin responsiveness is the inability to reach a target activated clotting time despite administration of an adequate heparin dose. Patients resistant to heparin, mainly in the context of preoperative heparin infusion, may have low levels of antithrombin (AT).
      • Despotis G.J.
      • Levine V.
      • Joist J.H.
      • et al.
      Antithrombin III during cardiac surgery: Effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation.
      This may result in inability to achieve adequate anticoagulation or may require higher than predicted doses of heparin to do so. Furthermore, with repeated heparin doses it is not uncommon to require higher than predicted doses of protamine to reverse the effects of heparin after CPB, exposing the patient to potential protamine overdose and the associated possible complications. To avoid this, supplementation of AT before CPB (although considered off-label in the United States) may restore AT levels, improve heparin sensitivity, and assist in establishing adequate anticoagulation.
      • Kanbak M.
      The treatment of heparin resistance with Antithrombin III in cardiac surgery.
      • Avidan M.S.
      • Levy J.H.
      • van Aken H.
      • et al.
      Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass.
      • Avidan M.S.
      • Levy J.H.
      • Scholz J.
      • et al.
      A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass.
      Prophylactic use of AT in an attempt to decrease post-CPB bleeding is not recommended and should be avoided.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      Fresh frozen plasma (FFP) may be an alternative source for AT. Nonetheless, when available, the use of AT is preferred to FFP for treatment of heparin resistance, given the risks associated with FFP transfusion.

       Minimizing Hemodilution

      Hemodilution is a major risk factor for perioperative anemia and perioperative transfusions. All the guidelines strongly recommend implementing strategies to minimize hemodilution during cardiac surgery. These strategies may include the use of miniaturized CPB circuits (mini-circuits) with decreased priming volume, retrograde autologous priming of the CPB circuit, and modified hemofiltration.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      • Ferraris V.A.
      • Ferraris S.P.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline.
      • Hillis L.D.
      • Smith P.K.
      • Anderson J.L.
      • et al.
      2011 ACCF/AHA guideline for coronary artery bypass graft surgery: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      Mini-circuits have a smaller priming volume and reduced artificial extracorporeal surface because of elimination of the venous reservoir. In addition, the systems are completely closed to avoid blood-air contact. The reduced priming volume of mini-circuits offers potential benefits in reducing hemodilution. The smaller blood-air interface contributes to an attenuated inflammatory response to CPB.
      • van Boven W.J.
      • Gerritsen W.B.
      • Waanders F.G.
      • et al.
      Mini extracorporeal circuit for coronary artery bypass grafting: Initial clinical and biochemical results: A comparison with conventional and off-pump coronary artery bypass grafts concerning global oxidative stress and alveolar function.
      • Beghi C.
      • Nicolini F.
      • Agostinelli A.
      • et al.
      Mini-cardiopulmonary bypass system: Results of a prospective randomized study.
      • Ohata T.
      • Mitsuno M.
      • Yamamura M.
      • et al.
      Beneficial effects of mini-cardiopulmonary bypass on hemostasis in coronary artery bypass grafting: Analysis of inflammatory response and hemodilution.
      • Benedetto U.
      • Luciani R.
      • Goracci M.
      • et al.
      Miniaturized cardiopulmonary bypass and acute kidney injury in coronary artery bypass graft surgery.
      Several meta-analyses have shown that the use of mini-circuits is associated with reduced postoperative bleeding and transfusion requirements and improved postoperative outcomes.
      • Anastasiadis K.
      • Antonitsis P.
      • Haidich A.B.
      • et al.
      Use of minimal extracorporeal circulation improves outcome after heart surgery; a systematic review and meta-analysis of randomized controlled trials.
      • Harling L.
      • Warren O.J.
      • Martin A.
      • et al.
      Do miniaturized extracorporeal circuits confer significant clinical benefit without compromising safety? A meta-analysis of randomized controlled trials.
      The clinical significance of the attenuated inflammatory response, however, still remains unclear and requires further investigation.
      Retrograde autologous priming refers to priming of the CPB circuit using the patient's blood. This technique is a safe and inexpensive way to attenuate hemodilution and has been associated with decreased post-CPB allogeneic transfusions.
      • Hou X.
      • Yang F.
      • Liu R.
      • et al.
      Retrograde autologous priming of the cardiopulmonary bypass circuit reduces blood transfusion in small adults: A prospective, randomized trial.
      • Saczkowski R.
      • Bernier P.L.
      • Tchervenkov C.I.
      • et al.
      Retrograde autologous priming and allogeneic blood transfusions: A meta-analysis.
      • Sun P.
      • Ji B.
      • Sun Y.
      • et al.
      Effects of retrograde autologous priming on blood transfusion and clinical outcomes in adults: A meta-analysis.
      Removing excess fluid after CPB by modified ultrafiltration may hemoconcentrate the blood and remove inflammatory mediators. In a randomized controlled trial of 573 patients, modified ultrafiltration was associated with reduced post-CPB transfusion requirements and reduced incidence of postoperative pulmonary and neurological complications.
      • Luciani G.B.
      • Menon T.
      • Vecchi B.
      • et al.
      Modified ultrafiltration reduces morbidity after adult cardiac operations: A prospective, randomized clinical trial.
      A more recent meta-analysis that evaluated 10 randomized controlled trials with 1,004 patients demonstrated that ultrafiltration was associated with significantly decreased post-CPB bleeding and transfusions.
      • Boodhwani M.
      • Williams K.
      • Babaev A.
      • et al.
      Ultrafiltration reduces blood transfusions following cardiac surgery: A meta-analysis.
      Acute normovolemic hemodilution (ANH) also is recommended as a blood conservation measure during CPB. With this technique a volume of blood is removed from the patient and stored in the operating room just before the beginning of surgery (or CPB). The removed volume is replaced by crystalloid or colloid to maintain normovolemia. The blood is then transfused back to the patient after CPB. This practice is effective in reducing postoperative bleeding and RBC transfusions, however it comes at the cost of lower hematocrit values during surgery. In a propensity score-matched retrospective analysis Zhou and colleagues reported that ANH was associated with decreased RBC transfusions and a decreased risk for postoperative pulmonary infections.
      • Zhou Z.F.
      • Jia X.P.
      • Sun K.
      • et al.
      Mild volume acute normovolemic hemodilution is associated with lower intraoperative transfusion and postoperative pulmonary infection in patients undergoing cardiac surgery – a retrospective, propensity matching study.
      In a recently published meta-analysis that included 2,439 patients in 29 randomized controlled trials, ANH was associated with a reduced need for RBC transfusions and reduced postoperative bleeding.
      • Barile L.
      • Fominskiy E.
      • Di Tomasso N.
      • et al.
      Acute normovolemic hemodilution reduces allogeneic red blood cell transfusion in cardiac surgery: A systematic review and meta-analysis of randomized trials.
      It seems that in order to achieve maximal benefit of ANH, 800 mL or more of blood needs to be removed before surgery.
      • Goldberg J.
      • Paugh T.A.
      • Dickinson T.A.
      • et al.
      Greater volume of acute normovolemic hemodilution may aid in reducing blood transfusions after cardiac surgery.
      In summary, preventive measures to minimize hemodilution or reduce the need for allogeneic blood transfusion are recommended in patients undergoing cardiac surgery.

       Coagulation Monitoring and Transfusion Algorithms

      All the guidelines support creation of a multidisciplinary patient blood management team and the design of transfusion algorithms based on predefined transfusion triggers measured by POC or other rapid-turnaround coagulation tests.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      American Society of Anesthesiologists Task Force on Perioperative Blood Management
      Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management.
      ,
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      The use of viscoelastic tests such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) has been the focus of extensive research in the management of bleeding after cardiovascular surgery. Multiple observational studies, randomized trials, and meta-analyses have demonstrated the efficacy of viscoelastic POC testing in reducing transfusion requirements and improving patient outcomes.
      • Ranucci M.
      • Baryshnikova E.
      • Pistuddi V.
      • et al.
      The effectiveness of 10 years of interventions to control postoperative bleeding in adult cardiac surgery.
      • Weber C.F.
      • Gorlinger K.
      • Meininger D.
      • et al.
      Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients.
      • Gorlinger K.
      • Fries D.
      • Dirkmann D.
      • et al.
      Reduction of fresh frozen plasma requirements by perioperative point-of-care coagulation management with early calculated goal-directed therapy.
      • Karkouti K.
      • Callum J.
      • Wijeysundera D.N.
      • et al.
      Point-of-care hemostatic testing in cardiac surgery: A stepped-wedge clustered randomized controlled trial.
      • Girdauskas E.
      • Kempfert J.
      • Kuntze T.
      • et al.
      Thromboelastometrically guided transfusion protocol during aortic surgery with circulatory arrest: A prospective, randomized trial.
      ,
      • Shore-Lesserson L.
      • Manspeizer H.E.
      • DePerio M.
      • et al.
      Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery.
      • Gorlinger K.
      • Dirkmann D.
      • Solomon C.
      • et al.
      Fast interpretation of thromboelastometry in non-cardiac surgery: Reliability in patients with hypo-, normo-, and hypercoagulability.
      • Hanke A.A.
      • Herold U.
      • Dirkmann D.
      • et al.
      Thromboelastometry based early goal-directed coagulation management reduces blood transfusion requirements, adverse events, and costs in acute type A aortic dissection: A pilot study.
      • Bolliger D.
      • Tanaka K.A.
      Point-of-care coagulation testing in cardiac surgery.
      • Bolliger D.
      • Tanaka K.A.
      Roles of thrombelastography and thromboelastometry for patient blood management in cardiac surgery.
      Published transfusion guidelines
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      American Society of Anesthesiologists Task Force on Perioperative Blood Management
      Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management.
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      also support this practice. Thus, it is the working group's opinion that viscoelastic coagulation tests are superior to conventional coagulation laboratory studies in guiding transfusion therapy in patients undergoing cardiovascular surgical procedures. Nonetheless, the authors recognize that these devices are still not widely available in many medical centers. Therefore, the use of conventional coagulation laboratory tests is recommended when viscoelastic tests are unavailable. In addition, it is important to mention that the cut-off values recommended in the viscoelastic algorithm (Fig 2) are for known devices that use the “cup and pin” technology. Newer devices that utilize different measurement platforms may have different threshold values and are yet to be extensively studied. Nevertheless, validation of the accuracy of the TEG 6S system (Haemonetics Corporation, Braintree, MA, USA) in comparison with TEG 5000 recently has been reported.
      • Gurbel P.A.
      • Bliden K.P.
      • Tantry U.S.
      • et al.
      First report of the point-of-care TEG: A technical validation study of the TEG-6S system.

       Platelet Function Testing

      Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor has become the main antithrombotic treatment in patients presenting with cardiovascular pathological conditions such as acute coronary syndrome or myocardial infarction. Although aspirin therapy alone is not associated with increased postoperative bleeding,
      • Myles P.S.
      • Smith J.A.
      • Forbes A.
      • et al.
      Stopping vs. continuing aspirin before coronary artery surgery.
      patients receiving dual antiplatelet therapy are at increased risk for perioperative bleeding after cardiac surgery,
      • Malm C.J.
      • Hansson E.C.
      • Akesson J.
      • et al.
      Preoperative platelet function predicts perioperative bleeding complications in ticagrelor-treated cardiac surgery patients: A prospective observational study.
      • Hansson E.C.
      • Jeppsson A.
      Platelet inhibition and bleeding complications in cardiac surgery: A review.
      • Ranucci M.
      • Colella D.
      • Baryshnikova E.
      • et al.
      Effect of preoperative P2Y12 and thrombin platelet receptor inhibition on bleeding after cardiac surgery.
      • Gherli R.
      • Mariscalco G.
      • Dalen M.
      • et al.
      Safety of preoperative use of ticagrelor with or without aspirin compared with aspirin alone in patients with acute coronary syndromes undergoing coronary artery bypass grafting.
      hence many institutions have incorporated POC platelet function testing into the preoperative assessment of these patients in an attempt to optimize the timing of surgery.
      • Mahla E.
      • Suarez T.A.
      • Bliden K.P.
      • et al.
      Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: The timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study.
      • Bedeir K.
      • Bliden K.
      • Tantry U.
      • et al.
      Timing of coronary bypass surgery in patients receiving clopidogrel: The Role of Verify Now.
      • Mahla E.
      • Prueller F.
      • Farzi S.
      • et al.
      Does platelet reactivity predict bleeding in patients needing urgent coronary artery bypass grafting during dual antiplatelet therapy?.
      The working group suggests that POC platelet function testing be considered before surgery, if available, in patients treated with P2Y12 inhibitors in whom there is a concern about the presence of active drug effect, and that surgery be delayed, when possible, until the drug effects have disappeared.
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.

       RBC Transfusion and Use of Cell Salvage

      RBC transfusion may be required to maintain oxygen delivery and hemodynamic stability in the presence of active ongoing bleeding or severe anemia. All guidelines recommend the use of a restrictive blood transfusion strategy, maintaining hemoglobin (Hb) levels in the range 7 to 8 g/dL, because this was found to maintain adequate oxygen delivery while avoiding unnecessary allogeneic RBC transfusions. The most recent guidelines published by the European Association of Cardio-Thoracic Surgery and the European Association of Cardio-Thoracic Anaesthesiology do not define a specific Hb trigger for RBC transfusion, but rather recommend that transfusion decisions be made based on the patient's clinical condition.
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      However, a large randomized controlled trial comparing restrictive versus liberal RBC transfusion strategies in high-risk cardiac surgery patients, the Transfusion Requirements in Cardiac Surgery III trial, and a recent consensus statement by an international panel of experts,
      • Mazer C.D.
      • Whitlock R.P.
      • Fergusson D.A.
      • et al.
      Restrictive or liberal red-cell transfusion for cardiac surgery.
      • Mazer C.D.
      • Whitlock R.P.
      • Fergusson D.A.
      • et al.
      Six-month outcomes after restrictive or liberal transfusion for cardiac surgery.
      • Mueller M.M.
      • Van Remoortel H.
      • Meybohm P.
      • et al.
      Patient blood management: Recommendations From the 2018 Frankfurt Consensus Conference.
      support transfusion at a Hb level equal to or lower than 7.5 g/dL. The members of the working group agree that an RBC transfusion threshold of Hb ≤ 7.5 g/dL is clinically reasonable and practical in most cardiac surgery patients and will be accepted by most practitioners.
      Transfusion of cell-salvaged blood is strongly recommended and is associated with reduced perioperative anemia and decreased need for allogeneic RBC transfusions.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      American Society of Anesthesiologists Task Force on Perioperative Blood Management
      Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management.
      ,
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      • Ferraris V.A.
      • Ferraris S.P.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline.
      When compared with transfusion of blood from the cardiotomy suction, cell salvage was associated with less bleeding and reduced inflammation.
      • Carless P.A.
      • Henry D.A.
      • Moxey A.J.
      • et al.
      Cell salvage for minimising perioperative allogeneic blood transfusion.
      Recent studies have confirmed that the use of cell salvage was associated with decreased need for allogeneic transfusions
      • Vonk A.B.
      • Meesters M.I.
      • Garnier R.P.
      • et al.
      Intraoperative cell salvage is associated with reduced postoperative blood loss and transfusion requirements in cardiac surgery: A cohort study.
      • Weltert L.
      • Nardella S.
      • Rondinelli M.B.
      • et al.
      Reduction of allogeneic red blood cell usage during cardiac surgery by an integrated intra- and postoperative blood salvage strategy: Results of a randomized comparison.
      and lower risk of postoperative pulmonary complications.
      • Engels G.E.
      • van Klarenbosch J.
      • Gu Y.J.
      • et al.
      Intraoperative cell salvage during cardiac surgery is associated with reduced postoperative lung injury.

       Plasma/Prothrombin Complex Concentrate

      FFP refers to plasma frozen within 8 hours after phlebotomy. Other plasma-derived products such as PF24 (plasma frozen within 24 hours after phlebotomy) and thawed plasma (FFP that is stored up to 5 days at a temperature of 1°C–6°C after thawing) are also available in many countries throughout the world. In clinical practice and even in the literature, it is common practice to use these terms interchangeably. Therefore, throughout this document, the term FFP will refer to the use of any of these plasma products.
      FFP may be effective in treating post-CPB coagulopathic bleeding with laboratory evidence of coagulation factor deficiency. Prophylactic administration of FFP during cardiac surgery, without evidence of coagulation factor deficiency, is not effective in reducing post-CPB bleeding and is not recommended.
      • Desborough M.
      • Sandu R.
      • Brunskill S.J.
      • et al.
      Fresh frozen plasma for cardiovascular surgery.
      • Casbard A.C.
      • Williamson L.M.
      • Murphy M.F.
      • et al.
      The role of prophylactic fresh frozen plasma in decreasing blood loss and correcting coagulopathy in cardiac surgery. A systematic review.
      • Yang L.
      • Stanworth S.
      • Hopewell S.
      • et al.
      Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials.
      In patients requiring urgent operations, reversal of vitamin K antagonists was more effective with prothrombin complex concentrates (PCC) compared with FFP, mainly because of a more rapid hemostatic effect.
      • Goldstein J.N.
      • Refaai M.A.
      • Milling Jr, T.J.
      • et al.
      Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: A phase 3b, open-label, non-inferiority, randomised trial.
      Several studies
      • Arnekian V.
      • Camous J.
      • Fattal S.
      • et al.
      Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery.
      • Cappabianca G.
      • Mariscalco G.
      • Biancari F.
      • et al.
      Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery.
      • Ortmann E.
      • Besser M.W.
      • Sharples L.D.
      • et al.
      An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery.
      • Fitzgerald J.
      • Lenihan M.
      • Callum J.
      • et al.
      Use of prothrombin complex concentrate for management of coagulopathy after cardiac surgery: A propensity score matched comparison to plasma.
      have reported that administration of PCC is also more effective than FFP in CPB-related coagulopathic bleeding and leads to decreased postoperative bleeding and transfusion. However, concerns regarding increased risk for postoperative acute kidney injury have been raised in one study.
      • Cappabianca G.
      • Mariscalco G.
      • Biancari F.
      • et al.
      Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery.
      Additional benefits of PCC over FFP include a significantly smaller administered volume and the avoidance of risks associated with plasma transfusion.
      PCC is available in 3-factor and 4-factor preparations (4-factor PCC contains factor VII, whereas 3-factor PCC does not). In addition, some PCC preparations contain various amounts of heparin or other anticoagulants to avoid excessive coagulation.
      • Tanaka K.A.
      • Esper S.
      • Bolliger D.
      Perioperative factor concentrate therapy.
      • Ghadimi K.
      • Levy J.H.
      • Welsby I.J.
      Prothrombin complex concentrates for bleeding in the perioperative setting.
      Furthermore, because of a high risk of increased thrombosis, administration of recombinant factor VIIa (rFVIIa) after the use of 4-factor PCC is not recommended. Recommendations for dosing of PCC are not completely established because the use of PCC to treat post-CPB bleeding is regarded off label. However, most centers use 10 to 15 u/kg to treat post-CPB bleeding and higher doses of 20 to 25 u/kg (and up to 50 u/kg in extreme cases) to reverse the effects of vitamin K antagonists. High-dose PCC also may be effective in reversing the effects of dabigatran and factor Xa inhibitors, however, with the recent development of specific reversal agents (idarucizumab for dabigatran and andexanet alfa for factor Xa inhibitors), the clinical use of PCC for reversal of these agents is anticipated to decrease.
      In summary, both FFP and PCC may be used to reverse the anticoagulation effects of vitamin K antagonists and to treat post-CPB bleeding owing to coagulation factors deficiency. Nevertheless, PCC (when available) offers several benefits over FFP and may be preferred, especially when large volume of FFP is required to achieve hemostasis.

       Platelet Transfusion and Use of Desmopressin

      Transfusion of PLT is indicated in bleeding patients with thrombocytopenia or evidence of PLT dysfunction.
      • Kaufman R.M.
      • Djulbegovic B.
      • Gernsheimer T.
      • et al.
      Platelet transfusion: A clinical practice guideline from the AABB.
      • Kumar A.
      • Mhaskar R.
      • Grossman B.J.
      • et al.
      Platelet transfusion: A systematic review of the clinical evidence.
      Recent guidelines recommend a trigger of 50,000/μL or less for PLT transfusion,
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology: First update 2016.
      • Kaufman R.M.
      • Djulbegovic B.
      • Gernsheimer T.
      • et al.
      Platelet transfusion: A clinical practice guideline from the AABB.
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      however in the context of post-CPB bleeding the PLT may be dysfunctional, and thus transfusion may be necessary even with a higher PLT count.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.
      American Society of Anesthesiologists Task Force on Perioperative Blood Management
      Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management.
      • Ferraris V.A.
      • Ferraris S.P.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline.
      Therefore, the members of the working group agreed that in post-CPB bleeding, PLT should be transfused when the PLT count is less than or equal to 50,000/μL, however, in cases of severe ongoing bleeding or if evidence of PLT dysfunction exists, a higher threshold of 100,000/μL may be used. Evidence of PLT dysfunction can be documented by PLT function assays or can be assumed if uremia exists or if antiplatelet medications were recently administered.
      Desmopressin improves PLT function by promoting the release of von Willebrand factor from endothelial cells. Desmopressin may be considered when PLT dysfunction exists or when acquired von Willebrand factor deficiency is suspected. However, the supporting evidence does not demonstrate a robust effect on bleeding or transfusion requirements.
      • Levi M.
      • Cromheecke M.E.
      • de Jonge E.
      • et al.
      Pharmacological strategies to decrease excessive blood loss in cardiac surgery: A meta-analysis of clinically relevant endpoints.
      • Wademan B.H.
      • Galvin S.D.
      Desmopressin for reducing postoperative blood loss and transfusion requirements following cardiac surgery in adults.
      • Crescenzi G.
      • Landoni G.
      • Biondi-Zoccai G.
      • et al.
      Desmopressin reduces transfusion needs after surgery: A meta-analysis of randomized clinical trials.
      • Desborough M.J.
      • Oakland K.A.
      • Landoni G.
      • et al.
      Desmopressin for treatment of platelet dysfunction and reversal of antiplatelet agents: A systematic review and meta-analysis of randomized controlled trials.
      Furthermore, routine prophylactic use of desmopressin without evidence of PLT dysfunction is not recommended.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      2011 Update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.

       Fibrinogen Supplementation

      Low levels of fibrinogen identified in the preoperative or the post-CPB period have been associated with increased bleeding and transfusion requirements.
      • Karlsson M.
      • Ternstrom L.
      • Hyllner M.
      • et al.
      Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: A prospective observational study.
      • Karkouti K.
      • Callum J.
      • Crowther M.A.
      • et al.
      The relationship between fibrinogen levels after cardiopulmonary bypass and large volume red cell transfusion in cardiac surgery: An observational study.
      Fibrinogen supplementation is recommended in post-CPB bleeding when there is evidence of hypofibrinogenemia (levels below 150 mg/dL). Fibrinogen supplementation may be provided as cryoprecipitate or as human fibrinogen concentrate. Cryoprecipitate is not available in most European countries (because of safety concerns). In contrast, fibrinogen concentrate use in cardiac surgical patients is considered off-label in the United States and therefore not available in many centers. Studies evaluating post-CPB fibrinogen supplementation in cardiac surgery patients have yielded conflicting results. Two RCTs in patients undergoing complex cardiac surgery demonstrated decreased blood loss and transfusion of allogeneic blood products.
      • Rahe-Meyer N.
      • Solomon C.
      • Hanke A.
      • et al.
      Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: A randomized, placebo-controlled trial.
      • Ranucci M.
      • Baryshnikova E.
      • Crapelli G.B.
      • et al.
      Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery.
      However, 2 other recent RCTs evaluating the use of fibrinogen concentrate in post-CPB bleeding did not confirm these results.
      • Bilecen S.
      • de Groot J.A.
      • Kalkman C.J.
      • et al.
      Effect of fibrinogen concentrate on intraoperative blood loss among patients with intraoperative bleeding during high-risk cardiac surgery: A randomized clinical trial.
      • Rahe-Meyer N.
      • Levy J.H.
      • Mazer C.D.
      • et al.
      Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): A double-blind phase III study of haemostatic therapy.
      In fact, in the Randomized Evaluation of Fibrinogen versus Placebo in Complex Cardiovascular Surgery trial, patients treated with fibrinogen concentrate had a significantly higher transfusion rate compared with placebo.
      • Rahe-Meyer N.
      • Levy J.H.
      • Mazer C.D.
      • et al.
      Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): A double-blind phase III study of haemostatic therapy.
      It is important to mention, however, that patients were enrolled into the study even if they did not exhibit post-CPB hypofibrinogenemia. In a recently published meta-analysis of 8 RCTs with 597 patients, administration of fibrinogen concentrate was associated with significantly decreased post-CPB blood loss compared with placebo, but there was no difference in mortality or other postoperative morbidities.
      • Li J.Y.
      • Gong J.
      • Zhu F.
      • et al.
      Fibrinogen concentrate in cardiovascular surgery: A meta-analysis of randomized controlled trials.
      In summary, prophylactic fibrinogen administration is not recommended for reducing postoperative bleeding and transfusion risks. However, in patients with a low fibrinogen level (less than 150 mg/dL) and persistent post-CPB bleeding, fibrinogen supplementation, provided as cryoprecipitate of fibrinogen concentrate, should be considered to reduce bleeding and blood transfusion.

       Antifibrinolytic Agents

      Antifibrinolytic medications are commonly used during cardiovascular surgical procedures with CPB to reduce post-CPB bleeding and allogeneic blood transfusions. The 2 most commonly used antifibrinolytic medications are the lysine analogs tranexamic acid (TXA) and epsilon aminocaproic acid. A third product, aprotinin, was withdrawn from the market in 2007 because of safety concerns.
      • Fergusson D.A.
      • Hebert P.C.
      • Mazer C.D.
      • et al.
      A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.
      • Shaw A.D.
      • Stafford-Smith M.
      • White W.D.
      • et al.
      The effect of aprotinin on outcome after coronary-artery bypass grafting.
      Since then the drug has been reapproved for use in several European countries and in Canada, but still remains unavailable in the United States. Numerous studies have demonstrated the efficacy of antifibrinolytics in reducing bleeding and transfusion requirements after CPB,
      • Ker K.
      • Edwards P.
      • Perel P.
      • et al.
      Effect of tranexamic acid on surgical bleeding: Systematic review and cumulative meta-analysis.
      • Henry D.A.
      • Carless P.A.
      • Moxey A.J.
      • et al.
      Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion.
      although many of these trials included low-risk patients with relatively short CPB times. The Aspirin and Tranexamic Acid for Coronary Artery Surgery trial
      • Myles P.S.
      • Smith J.A.
      • Forbes A.
      • et al.
      Tranexamic acid in patients undergoing coronary-artery surgery.
      compared TXA with placebo in patients undergoing coronary bypass surgery and demonstrated that patients who were randomized to TXA therapy had a significantly reduced risk for reoperations because of postoperative bleeding and a decreased need for transfusion of any blood products. Based on these data all the transfusion guidelines support the use of antifibrinolytic agents in patients undergoing cardiac surgery with CPB.
      • Ferraris V.A.
      • Brown J.R.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
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      • Kozek-Langenecker S.A.
      • Afshari A.
      • Albaladejo P.
      • et al.
      Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology.
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
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      American Society of Anesthesiologists Task Force on Perioperative Blood Management
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      ,
      • Boer C.
      • et al.
      Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgeons, the European Association of Cardiothoracic Anaesthesiologists
      2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.
      • Ferraris V.A.
      • Ferraris S.P.
      • et al.
      Society of Thoracic Surgeons Blood Conservation Guideline Task Force
      Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline.
      • Hillis L.D.
      • Smith P.K.
      • Anderson J.L.
      • et al.
      2011 ACCF/AHA guideline for coronary artery bypass graft surgery: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

       Recombinant Activated Factor VII

      Off-label administration of rFVIIa is used for refractory severe post-CPB bleeding when other therapeutic options have failed. In a propensity score-matched analysis, Karkouti demonstrated that the use of rFVIIa reduced blood loss and transfusion requirements after CPB in patients with severe intractable bleeding.
      • Karkouti K.
      • Beattie W.S.
      • Wijeysundera D.N.
      • et al.
      Recombinant factor VIIa for intractable blood loss after cardiac surgery: A propensity score-matched case-control analysis.
      A larger retrospective observational trial involving 18 cardiac surgery centers in Canada reported similar results.
      • Karkouti K.
      • Beattie W.S.
      • Arellano R.
      • et al.
      Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery.
      A 3-arm placebo controlled randomized trial
      • Gill R.
      • Herbertson M.
      • Vuylsteke A.
      • et al.
      Safety and efficacy of recombinant activated factor VII: A randomized placebo-controlled trial in the setting of bleeding after cardiac surgery.
      showed that there were significantly fewer reoperations for bleeding and fewer blood transfusions in patients receiving rFVIIa. There were also no significant differences in serious adverse events among groups; however, if a difference were to exist, the study was likely underpowered to detect differences in adverse events. Taken together, the off-label use of rFVIIa is effective in decreasing blood loss and allogeneic blood transfusions in patients with severe intractable post-CPB coagulopathic bleeding. The working group cautions that there may be a risk of arterial thrombosis with the use of rFVIIa that can result in myocardial infarction, especially in older patients,
      • Levi M.
      • Levy J.H.
      • Andersen H.F.
      • et al.
      Safety of recombinant activated factor VII in randomized clinical trials.
      therefore, when possible, clinicians should consider a lower dose of factor rFVIIa (20-40 μg/kg) to minimize the risk for thrombotic complications.

      Conclusions

      Coagulopathy associated with cardiac surgery and CPB is complex and leads to allogeneic blood transfusions, which are associated with a high rate of postoperative complications and mortality. Despite the existence of guidelines and consensus statements regarding perioperative blood management in cardiac surgery patients, practitioner adherence to these guidelines is low and significant variability in practices exists. Current guidelines are lengthy documents and may cause confusion if conflicting recommendations exist. The current summary statement of the SCA Blood Conservation Working Group is an attempt to create a clear and succinct document containing recommendations for perioperative blood management for cardiac surgical patients. Individualized therapy using POC-guided algorithms are recommended because they have been associated with improved patient outcomes when compared with standard laboratory-based or empiric transfusion therapy. The publication of these viscoelastic and nonviscoelastic testing algorithms will hopefully consolidate the existing evidence and provide clinicians with a simple tool that will aid them in managing the bleeding cardiovascular surgery patient.

      Acknowledgments

      The Clinical Practice Improvement Subcommittee and the Blood Conservation Working Group dedicate this paper to William Travis Lau, MD. He was a physician dedicated to setting national standards and best practices for patient blood management in cardiac surgery. To all who knew him, he was a passionate physician and an exemplary human being. His life was tragically taken on January 28, 2019. The Society of Cardiovascular Anesthesiologists, his colleagues, and friends mourn a life cut short of its prime and maximum impact.
      “And therefore never send to know for whom the bell tolls; it tolls for thee.”John Donne

      Conflicts of Interest

      Philip Greilich, MD, recieved research funding from AMAG Pharmaceuticals (IV iron supplementation). C. David Mazer, MD, received research grants to institution and consulting honoraria from Allocure Inc, Amgen, Boehringer Ingelheim, CSL Behring, OctaPharma, Quark Pharmaceuticals, Tenax Therapeutics and Thrasos Innovation. Marco Ranucci, MD, received consultancy fees from Haemonetics and Medtronic; speaker's fees from Werfen, CSL Behring, Grifols; and research grants from Roche Diagnostics, Hemosonics, Werfen, and CSL Behring. Jacob Raphael, MD, received a research grant from OctaPharma. Ian Welsby, MBBS, received a research grant from CSL Behring.

      Appendix 1

       Key words and Search Terms

      The following key words and search terms were used for the literature search: cardiac surgery, heart surgery, cardiovascular surgical procedures (including CABG, OPCABG, myocardial revascularization, mitral valve repair/replacement, aortic valve repair/replacement, tricuspid valve repair/replacement, pulmonic valve repair/replacement, aortic dissections, aortic aneurysms, left ventricular aneurysms and all other operations on the heart), extracorporeal circulation (including extracorporeal membrane oxygenation [ECMO], left heart bypass, hemofiltration, hemoperfusion, and cardiopulmonary bypass), anemia, bleeding, transfusion, hemostasis, coagulation, RBC/erythrocyte transfusion, platelets transfusion, cryoprecipitate, FFP (Fresh Frozen Plasma), antifibrinolytics, recombinant factor VII (Novoseven), prothrombin complex concentrate (PCC), fibrinogen concentrate, transfusion guidelines/algorithms, blood conservation, patient blood management, point of care coagulation testing, rotational thromboelastometry (ROTEM), thromboelastography (TEG), viscoelastic coagulation tests.

      Appendix. Supplementary materials

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