Secondary Logo

Journal Logo

Hemostasis and Thrombosis

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

Raphael, Jacob MD*; Mazer, C. David MD; Subramani, Sudhakar MD; Schroeder, Andrew MD§; Abdalla, Mohamed MD; Ferreira, Renata MD; Roman, Philip E. MD#; Patel, Nichlesh MD**; Welsby, Ian MBBS††; Greilich, Philip E. MD‡‡; Harvey, Reed MD§§; Ranucci, Marco MD‖‖; Heller, Lori B. MD¶¶; Boer, Christa MD##; Wilkey, Andrew MD***; Hill, Steven E. MD‡‡; Nuttall, Gregory A. MD†††; Palvadi, Raja R. MD‡‡‡; Patel, Prakash A. MD§§§; Wilkey, Barbara MD‖‖‖; Gaitan, Brantley MD¶¶¶; Hill, Shanna S. MD###; Kwak, Jenny MD****; Klick, John MD††††; Bollen, Bruce A. MD‡‡‡‡; Shore-Lesserson, Linda MD§§§§; Abernathy, James MD‖‖‖‖; Schwann, Nanette MD¶¶¶¶,####; Lau, W. Travis MD*****

Author Information
doi: 10.1213/ANE.0000000000004355
  • Free

Abstract

GLOSSARY

A10 = amplitude at 10 minutes; ACT = activated clotting time; ANH = acute normovolemic hemodilution; AT = antithrombin; ATACAS = Aspirin and Tranexamic Acid for Coronary Artery Surgery; CPB = cardiopulmonary bypass; CPI = Continuous Practice Improvement; CT = clotting time; DAPT = dual antiplatelet therapy; DDAVP = 1-deamino-8-d-arginine vasopressin; EACA = ε-aminocaproic acid; ECMO = extra corporeal membrane oxygenation; EPO = erythropoietin; EXTEM = extrinsic pathway thromboelastometry; FF = functional fibrinogen; FFP = fresh-frozen plasma; FIBTEM = fibrinogen-based thromboelastometry; Hb = hemoglobin; HEPTEM = heparinase thromboelastometry; HIT = heparin-induced thrombocytopenia; hTEG = heparinase thromboelastography; iCA++ = ionized calcium; INR = international normalized ratio; INTEM = intrinsic pathway thromboelastometry; LY30 = clot lysis at 30 minutes; MA = maximum amplitude; ML = maximum lysis; P2Y12 = platelet receptor P2Y12; PCC = prothrombin complex concentrate; PF24 = plasma frozen within 24 hours after phlebotomy; PLT = platelet; POC = point of care; R = reaction time; RBC = red blood cell; RCT = randomized controlled trial; REPLACE = Randomized Evaluation of Fibrinogen versus Placebo in Complex Cardiovascular Surgery; rFVIIa = recombinant activated factor VII; ROTEM = rotational thromboelastometry; RV = right ventricle; SCA = Society of Cardiovascular Anesthesiologists; STS = Society of Thoracic Surgeons; T = temperature; TEG = thromboelastography; TRICS = Transfusion Requirements in Cardiac Surgery; TXA = tranexamic acid

Coagulopathy associated with cardiac surgery is a multifactorial serious complication that may result in massive bleeding requiring transfusion of red blood cells (RBCs) and procoagulant products to obtain adequate hemostasis.1,2

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 RBC transfusion when compared to all other surgeries, accounting for 10%–15% of all RBC transfusions in the United States and the United Kingdom.3,4 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 reexploration in an attempt to correct ongoing bleeding and establish adequate hemostasis.2,5

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-term and long-term mortality,6–15 showing a dose–response relationship where morbidity and mortality are directly proportional to the number of units of RBC transfused.8,14 Moreover, reduction of perioperative transfusion by initiation of blood management practices has been associated with decrease in major postoperative morbidity and mortality.16–18

Despite this evidence base, and the publication of numerous practice guidelines,19–26 much confusion remains about the optimal management of perioperative bleeding in cardiac surgery patients.5,27–30

Data show that only a small fraction of published guidelines is successfully integrated into daily clinical practice.31,32 As a specific example, publication of the 2011 update to the Society of Thoracic Surgeons (STS)/Society of Cardiovascular Anesthesiologists (SCA) Blood Conservation Guideline19 did not result in a decrease in blood product utilization in cardiac surgery patients, most probably, due to a low rate of guidelines adoption by practitioners.4,33 Furthermore, while recent STS reports34,35 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.3,4,27,36 In the recently published Transfusion Requirements in Cardiac Surgery (TRICS) 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.36 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 could be potentially avoided.37–41

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 CPI initiative and the various focus working groups can be found in a recent article and accompanying editorial by Muehlschlegel et al42 and Schwann et al,43 respectively.

The current report is the summary of recommendations for blood management in cardiac surgery, made by the SCA CPI 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 <18 years old, and adults weighing <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 as well as representatives from international cardiac anesthesiology societies. The working group developed the current recommendations after reviewing existing guidelines and consensus statements as well as 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, we 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 Supplemental Digital Content 1, Appendix 1, https://links.lww.com/AA/C902.

Agreement (defined as consensus of ≥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 lacked or differed in recommendations, a consensus was reached following a modified Delphi process.44 Members who 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 cutoff 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 Digital Content 2, Table 1, https://links.lww.com/AA/C903).

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, a final list of 9 practice guidelines was 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”26; (2) “2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines”19; (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”45; (4) “Management of Severe Perioperative Bleeding: Guideline from the European Society of Anaesthesiology”20; (5) The “Management of Severe Perioperative Bleeding: Guideline from the European Society of Anaesthesiology, first update 2016”21; (6) “Practice Guidelines for Perioperative Blood Management: an Updated Report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management”22; (7) “Platelet Transfusion: a Clinical Practice Guideline from the AABB”23; (8) “Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage”24; and (9) “2017 EACTS/EACTA Guidelines on Patient Blood Management for Adult Cardiac Surgery.”25

F1
Figure 1.:
SCA Summary Statement on Blood Conservation and Transfusion in Cardiac Surgery. EPO indicates erythropoietin; FFP, fresh-frozen plasma; PCC, prothrombin complex concentrate; ROTEM, rotational thromboelastometry; SCA, Society of Cardiovascular Anesthesiologists; TEG, thromboelastography.
F2
Figure 2.:
SCA ROTEM/TEG-based cardiac surgery intraoperative transfusion algorithm. ANH indicates acute normovolemic hemodilution; A10, amplitude at 10 minutes; CT, clotting time; DDAVP, 1-deamino-8-d-arginine vasopressin; ECMO, extra corporeal membrane oxygenation; EXTEM, extrinsic pathway thromboelastometry; FIBTEM, fibrinogen-based thromboelastometry; FF, functional fibrinogen; FFP, fresh-frozen plasma; Hb, hemoglobin; HEPTEM, heparinase thromboelastometry; HIT, heparin-induced thrombocytopenia; hTEG, heparinase thromboelastography; iCA++, ionized calcium; INTEM, intrinsic pathway thromboelastometry; LY30, clot lysis at 30 min; MA, maximum amplitude; ML, maximum lysis; PCC, prothrombin complex concentrate; R, reaction time; ROTEM, rotational thromboelastometry; TEG, thromboelastography.
F3
Figure 3.:
SCA non-ROTEM/TEG-based cardiac surgery intraoperative transfusion algorithm. ACT indicates 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 cell; rFVIIa, recombinant activated factor VII; RV, right ventricle; T, temperature.

Summary of recommendations for common daily practices, including preoperative management of anemia and platelet (PLT) function assessment when indicated, as well as intraoperative monitoring of hemostasis, transfusion of blood products, and administration of pharmacological adjuvants in cardiac surgical patients is presented in Supplemental Digital Content 2, Table 1, https://links.lww.com/AA/C903. 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 is also included. This graphical advisory includes a summary statement (Figure 1) and 2 separate practical algorithms: (1) an algorithm based on viscoelastic POC coagulation testing (Figure 2) and (2) an algorithm based on “conventional” laboratory coagulation tests when viscoelastic tests are unavailable (Figure 3).

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 PLTs and fibrinogen is required as well as evaluation for coagulation factors deficiency. It is also important to remember that CPB is associated with significant fibrinolysis,46,47 and therefore, the use of antifibrinolytic agents48–50 should be continued beyond the operating room, or restarted if already discontinued, in cases with excessive postoperative bleeding.51,52

Patients may require transfusion of a single component, but frequently >1 component is required to achieve adequate hemostasis. After each round of treatment, clinical assessment of bleeding as well as evaluation of hemoglobin (Hb) and of the coagulation system is needed to avoid unnecessary over transfusion. Regardless of the algorithm used, the practitioner must also 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 and/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 Hb Optimization

Preoperative anemia (defined by the World Health Organization as an Hb level <12.0 g/dL in women and <13.0 g/dL in men) is present preoperatively in 25%–30% of cardiac surgery patients53 and is a strong predictor for perioperative transfusion of allogeneic blood products.54–56 It is recommended that patients be assessed for preoperative anemia several weeks before elective surgery to provide sufficient time for therapy, if needed.20,21 Though studies are somewhat inconclusive regarding the efficacy of iron supplementation before cardiac surgery,57,58 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 noniron deficiency anemia (renal failure, anemia of chronic disease, etc) or in patients who refuse blood transfusions.19–22,25 Prophylactic RBC transfusion in asymptomatic anemic patients, before surgery, is not recommended.19–22,24,25

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).59 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.60–62 Prophylactic use of AT in an attempt to decrease post-CPB bleeding is not recommended and should be avoided.19,25 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.19,25,26,45

Mini-circuits have a smaller priming volume as well as reduced artificial extracorporeal surface due to 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.63–66 Several meta-analyses have shown that the use of mini-circuits is associated with reduced postoperative bleeding and transfusion requirements as well as improved postoperative outcomes.67,68 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.69–71

Removing excess fluid after CPB by modified ultrafiltration may hemoconcentrate the blood as well as remove inflammatory mediators. In an RCT of 573 patients, modified ultrafiltration was associated with reduced post-CPB transfusion requirements as well as reduced incidence of postoperative pulmonary and neurological complications.72 A more recent meta-analysis that evaluated 10 RCTs with 1004 patients demonstrated that ultrafiltration was associated with significantly decreased post-CPB bleeding and transfusions.73

Acute normovolemic hemodilution (ANH) is also 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 et al74 reported that ANH was associated with decreased RBC transfusions and a decreased risk for postoperative pulmonary infections. In a recently published meta-analysis that included 2439 patients in 29 RCTs, ANH was associated with a reduced need for RBC transfusions and reduced postoperative bleeding.75 It seems that to achieve maximal benefit of ANH, ≥800 mL of blood needs to be removed before surgery.76 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.19–22,25

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.37–41,77–81 Published transfusion guidelines19,21,22,25 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, we 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 cutoff values recommended in the viscoelastic algorithm (Figure 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) in comparison with TEG 5000 has recently been reported.82

PLT Function Testing

Dual antiplatelet therapy (DAPT) 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. While aspirin therapy alone is not associated with increased postoperative bleeding,83 patients receiving DAPT are at increased risk for perioperative bleeding after cardiac surgery84–87; hence, many institutions have incorporated POC PLT function testing into the preoperative assessment of these patients, in an attempt to optimize the timing of surgery.88–90 The working group suggests that POC PLT 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 delayed, when possible, until the drug effects have disappeared.25

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 Hb levels in the range 7–8 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.25 However, a large RCT comparing restrictive with liberal RBC transfusion strategies in high-risk cardiac surgery patients, the TRICS III trial, as well as a recent consensus statement by an international panel of experts,36,91,92 supports transfusion at an Hb level ≤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.19–22,25,26 When compared with transfusion of blood from the cardiotomy suction, cell salvage was associated with less bleeding and reduced inflammation.93 Recent studies have confirmed that the use of cell salvage was associated with decreased need for allogeneic transfusions,94,95 as well as lower risk of postoperative pulmonary complications.96

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°–6°C after thawing) are also available in many countries throughout the world. In clinical practice and even in the literature, it is a 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.97–99

In patients requiring urgent operations, reversal of vitamin K antagonists was more effective with prothrombin complex concentrates (PCCs) compared to FFP, mainly due to a more rapid hemostatic effect.100 Several studies101–104 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 1 study.102 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.105,106 Furthermore, due to high risk of increased thrombosis, administration of recombinant factor VIIa 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 10–15 u/kg to treat post-CPB bleeding and higher doses of 20–25 u/kg (and up to 50 u/kg in extreme cases) to reverse the effects of vitamin K antagonists. High-dose PCC may also 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 due 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.

PLT Transfusion and Use of 1-Deamino-8-d-Arginine Vasopressin

Transfusion of PLTs is indicated in bleeding patients with thrombocytopenia or evidence of PLT dysfunction.23,107 Recent guidelines recommend a trigger of ≤50,000/μL for PLT transfusion21,23,25; 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.19,22,26 Therefore, the members of the working group agreed that in post-CPB bleeding, PLT should be transfused when the PLT count is ≤50,000/μL; however, in cases of severe ongoing bleeding and/or if evidence of PLT dysfunction exists, a higher threshold of 100,000/μL may be used. Evidence of PLT dysfunction may be demonstrated by PLT function assays or can be assumed if uremia exists if antiplatelet medications were recently administered.

1-Deamino-8-d-arginine vasopressin (DDAVP) 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.108–111 Furthermore, routine prophylactic use of desmopressin without evidence of PLT dysfunction is not recommended.19

Fibrinogen Supplementation

Low levels of fibrinogen identified in the preoperative or the post-CPB period have been associated with increased bleeding and transfusion requirements.112,113 Fibrinogen supplementation is recommended in post-CPB bleeding when there is evidence of hypofibrinogenemia (levels <150 mg/dL). Fibrinogen supplementation may be provided as cryoprecipitate or as human fibrinogen concentrate. Cryoprecipitate is not available in most European countries (due to 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.114,115 However, 2 other recent RCTs evaluating the use of fibrinogen concentrate in post-CPB bleeding did not confirm these results.116,117 In fact, in the Randomized Evaluation of Fibrinogen versus Placebo in Complex Cardiovascular Surgery (REPLACE) trial, patients treated with fibrinogen concentrate had a significantly higher transfusion rate compared to placebo.117 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 to placebo, but there was no difference in mortality or other postoperative morbidities.118

In summary, prophylactic fibrinogen administration is not recommended for reducing postoperative bleeding and transfusion risks. However, in patients with a low fibrinogen level (<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 ε-aminocaproic acid (EACA). A third product, aprotinin, was withdrawn from the market in 2007 due to safety concerns.48,119 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.120,121 However, many of these trials included low-risk patients with relatively short CPB times. The Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) trial50 compared TXA with placebo in patients undergoing coronary bypass surgery and demonstrated that patients who were randomly assigned to TXA therapy had a significantly reduced risk for reoperations due to postoperative bleeding, as well as 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.19–22,25,26,45

Recombinant Activated Factor VII

Off-label administration of recombinant factor VIIa (rFVIIa) is used for refractory severe post-CPB bleeding when other therapeutic options have failed. In a propensity score–matched analysis, Karkouti et al122 demonstrated that the use of rFVIIa reduced blood loss and transfusion requirements after CPB in patients with severe intractable bleeding. A larger retrospective observational trial involving 18 cardiac surgery centers in Canada reported similar results.123 A 3-arm placebo-controlled randomized trial124 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 patients125; therefore, when possible, clinicians should consider a lower dose of factor rFVIIa (20–40 µg/kg) to minimize the risk for thrombotic complications.

CONCLUSIONS/FINAL STATEMENT

Coagulopathy associated with cardiac surgery and CPB is complex and leads to allogeneic blood transfusions that 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 is recommended because they have been associated with improved patient outcomes when compared to 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 to whom the bell tolls; it tolls for thee.”

DISCLOSURES

Name: Jacob Raphael, MD.

Contribution: This author helped with study design, data collection and analysis, and in writing the manuscript.

Conflicts of Interest: J. Raphael received research grant from OctaPharma.

Name: C. David Mazer, MD.

Contribution: This author helped with study design, data collection and analysis, and in writing the manuscript.

Conflicts of Interest: C. D. Mazer received research grants to institution and/or consulting honoraria from AlloCure Inc, Amgen, Boehringer Ingelheim, CSL Behring, OctaPharma, Quark Pharmaceuticals, Tenax Therapeutics, and Thrasos Innovation.

Name: Sudhakar Subramani, MD.

Contribution: This author helped with study design and data collection.

Conflicts of Interest: None.

Name: Andrew Schroeder, MD.

Contribution: This author helped with study design and data collection.

Conflicts of Interest: None.

Name: Mohamed Abdalla, MD.

Contribution: This author helped with study design and data collection.

Conflicts of Interest: None.

Name: Renata Ferreira, MD.

Contribution: This author helped with study design, data collection and analysis, and in writing the manuscript.

Conflicts of Interest: None.

Name: Philip E. Roman, MD.

Contribution: This author helped with study design and data collection and analysis.

Conflicts of Interest: None.

Name: Nichlesh Patel, MD.

Contribution: This author helped with data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: Ian Welsby, MBBS.

Contribution: This author helped with study design and data collection and analysis.

Conflicts of Interest: I. Welsby received research grant from CSL Behring.

Name: Philip E. Greilich, MD.

Contribution: This author helped with study design and data collection and analysis.

Conflicts of Interest: P. E. Greilich research funding from AMAG Pharmaceuticals (IV iron supplementation).

Name: Reed Harvey, MD.

Contribution: This author helped with data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: Marco Ranucci, MD.

Contribution: This author helped with study design, data collection and analysis, and reviewing the manuscript.

Conflicts of Interest: M. Ranucci received consultancy fees for Haemonetics and Medtronic; speaker’s fees from Werfen, CSL Behring, and Grifols; and research grants from Roche Diagnostics, Hemosonics, and Werfen CSL Behring.

Name: Lori B. Heller, MD.

Contribution: This author helped with study design and data collection and analysis.

Conflicts of Interest: None.

Name: Christa Boer, MD.

Contribution: This author helped with study design, data collection and analysis, and reviewing the manuscript.

Conflicts of Interest: None.

Name: Andrew Wilkey, MD.

Contribution: This author helped with study design, data collection and analysis, and in writing the manuscript.

Conflicts of Interest: None.

Name: Steven E. Hill, MD.

Contribution: This author helped with study design and data collection and analysis.

Conflicts of Interest: None.

Name: Gregory A. Nuttall, MD.

Contribution: This author helped with study design and data collection and analysis.

Conflicts of Interest: None.

Name: Raja R. Palvadi, MD.

Contribution: This author helped with data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: Prakash A. Patel, MD.

Contribution: This author helped with data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: Barbara Wilkey, MD.

Contribution: This author helped with study design data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: Brantley Gaitan, MD.

Contribution: This author helped with study design, data collection and analysis, and reviewing the manuscript.

Conflicts of Interest: None.

Name: Shanna S. Hill, MD.

Contribution: This author helped with data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: Jenny Kwak, MD.

Contribution: This author helped with data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: John Klick, MD.

Contribution: This author helped with data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: Bruce A. Bollen, MD.

Contribution: This author helped with study design, data analysis, and in writing the manuscript.

Conflicts of Interest: None.

Name: Linda Shore-Lesserson, MD.

Contribution: This author helped with study design, data collection and analysis, and in writing the manuscript.

Conflicts of Interest: None.

Name: James Abernathy, MD.

Contribution: This author helped with data collection and analysis and reviewing the manuscript.

Conflicts of Interest: None.

Name: Nanette Schwann, MD.

Contribution: This author helped with study design, data analysis, and in writing the manuscript.

Conflicts of Interest: None.

Name: W. Travis Lau, MD.

Contribution: This author helped with study design, data collection and analysis, and in writing the manuscript.

Conflicts of Interest: None.

This manuscript was handled by: Roman M. Sniecinski, MD.

REFERENCES

1. Görlinger K, Shore-Lesserson L, Dirkmann D, Hanke AA, Rahe-Meyer N, Tanaka KA. Management of hemorrhage in cardiothoracic surgery. J Cardiothorac Vasc Anesth. 2013;27:S20–S34.
2. Dyke C, Aronson S, Dietrich W, et al. Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1458.e1–1463.e1.
3. Murphy GJ, Pike K, Rogers CA, et al.; TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.
4. Robich MP, Koch CG, Johnston DR, et al. Trends in blood utilization in United States cardiac surgical patients. Transfusion. 2015;55:805–814.
5. Ranucci M, Baryshnikova E, Castelvecchio S, Pelissero G; Surgical and Clinical Outcome Research (SCORE) Group. Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. Ann Thorac Surg. 2013;96:478–485.
6. Christensen MC, Krapf S, Kempel A, von Heymann C. Costs of excessive postoperative hemorrhage in cardiac surgery. J Thorac Cardiovasc Surg. 2009;138:687–693.
7. Ferraris VA, Hochstetler M, Martin JT, Mahan A, Saha SP. Blood transfusion and adverse surgical outcomes: the good and the bad. Surgery. 2015;158:608–617.
8. Karkouti K, Wijeysundera DN, Yau TM, et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004;44:1453–1462.
9. Likosky DS, Zhang M, Paone G, et al.; Blue Cross and Blue Shield of Michigan Percutaneous Coronary Interventions Collaborative; Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative. Impact of institutional culture on rates of transfusions during cardiovascular procedures: the Michigan experience. Am Heart J. 2016;174:1–6.
10. Engoren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002;74:1180–1186.
11. Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med. 2006;34:1608–1616.
12. Koch CG, Li L, Duncan AI, et al. Transfusion in coronary artery bypass grafting is associated with reduced long-term survival. Ann Thorac Surg. 2006;81:1650–1657.
13. Koch CG, Li L, Van Wagoner DR, Duncan AI, Gillinov AM, Blackstone EH. Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg. 2006;82:1747–1756.
14. Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007;116:2544–2552.
15. Bhaskar B, Dulhunty J, Mullany DV, Fraser JF. Impact of blood product transfusion on short and long-term survival after cardiac surgery: more evidence. Ann Thorac Surg. 2012;94:460–467.
16. Freedman J, Luke K, Escobar M, Vernich L, Chiavetta JA. Experience of a network of transfusion coordinators for blood conservation (Ontario Transfusion Coordinators [ONTraC]). Transfusion. 2008;48:237–250.
17. LaPar DJ, Crosby IK, Ailawadi G, et al.; Investigators for the Virginia Cardiac Surgery Quality Initiative. Blood product conservation is associated with improved outcomes and reduced costs after cardiac surgery. J Thorac Cardiovasc Surg. 2013;145:796–803; discussion 803.
18. Moskowitz DM, McCullough JN, Shander A, et al. The impact of blood conservation on outcomes in cardiac surgery: is it safe and effective? Ann Thorac Surg. 2010;90:451–458.
19. Ferraris VA, Brown JR, Despotis GJ, et al. Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; International Consortium for Evidence Based Perfusion. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944–982.
20. Kozek-Langenecker SA, Afshari A, Albaladejo P, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2013;30:270–382.
21. Kozek-Langenecker SA, Ahmed AB, Afshari A, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: first update 2016. Eur J Anaesthesiol. 2017;34:332–395.
22. 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*. Anesthesiology. 2015;122:241–275.
23. Kaufman RM, Djulbegovic B, Gernsheimer T, et al.; AABB. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2015;162:205–213.
24. Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA. 2016;316:2025–2035.
25. Boer C, Meesters MI, Milojevic M, et al.; Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgery, the European Association of Cardiothoracic Anaesthesiology. 2017 EACTS/EACTA guidelines on patient blood management for adult cardiac surgery. J Cardiothorac Vasc Anesth. 2018;32:88–120.
26. Ferraris VA, Ferraris SP, Saha SP, et al. Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;83:S27–S86.
27. Bennett-Guerrero E, Zhao Y, O’Brien SM, et al. Variation in use of blood transfusion in coronary artery bypass graft surgery. JAMA. 2010;304:1568–1575.
28. Karkouti K, Wijeysundera DN, Beattie WS; Reducing Bleeding in Cardiac Surgery (RBC) Investigators. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation. 2008;117:478–484.
29. Miceli A, Romeo F, Glauber M, de Siena PM, Caputo M, Angelini GD. Preoperative anemia increases mortality and postoperative morbidity after cardiac surgery. J Cardiothorac Surg. 2014;9:137.
30. Ranucci M, Aronson S, Dietrich W, et al.; European Association of Cardiothoracic Anaesthesiologists. Patient blood management during cardiac surgery: do we have enough evidence for clinical practice? J Thorac Cardiovasc Surg. 2011;142:249.e132.
31. Stover EP, Siegel LC, 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. Anesthesiology. 1998;88:327–333.
32. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282:1458–1465.
33. Likosky DS, FitzGerald DC, Groom RC, 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. Anesth Analg. 2010;111:316–323.
34. D’Agostino RS, Jacobs JP, Badhwar V, et al. The Society of Thoracic Surgeons adult cardiac surgery database: 2018 update on outcomes and quality. Ann Thorac Surg. 2018;105:15–23.
35. D’Agostino RS, Jacobs JP, Badhwar V, et al. The Society of Thoracic Surgeons adult cardiac surgery database: 2017 update on outcomes and quality. Ann Thorac Surg. 2017;103:18–24.
36. Mazer CD, Whitlock RP, Fergusson DA, et al.; TRICS Investigators and Perioperative Anesthesia Clinical Trials Group. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med. 2017;377:2133–2144.
37. Ranucci M, Baryshnikova E, Pistuddi V, Menicanti L, Frigiola A; Surgical and Clinical Outcome REsearch (SCORE) Group. The effectiveness of 10 years of interventions to control postoperative bleeding in adult cardiac surgery. Interact Cardiovasc Thorac Surg. 2017;24:196–202.
38. Weber CF, Görlinger K, Meininger D, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology. 2012;117:531–547.
39. Görlinger K, Fries D, Dirkmann D, Weber CF, Hanke AA, Schöchl H. Reduction of fresh frozen plasma requirements by perioperative point-of-care coagulation management with early calculated goal-directed therapy. Transfus Med Hemother. 2012;39:104–113.
40. Karkouti K, Callum J, Wijeysundera DN, et al.; TACS Investigators. Point-of-care hemostatic testing in cardiac surgery: a stepped-wedge clustered randomized controlled trial. Circulation. 2016;134:1152–1162.
41. Girdauskas E, Kempfert J, Kuntze T, et al. Thromboelastometrically guided transfusion protocol during aortic surgery with circulatory arrest: a prospective, randomized trial. J Thorac Cardiovasc Surg. 2010;140:1117.e2–1124.e2.
42. Muehlschlegel JD, Burrage PS, Ngai JY, 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. Anesth Analg. 2019;128:33–42.
43. Schwann NM, Engstrom RH, Shernan SK, Bollen BA. Clinical practice improvement: mind the gap or fall into the chasm. Anesth Analg. 2019;128:19–20.
44. Jones J, Hunter D. Consensus methods for medical and health services research. BMJ. 1995;311:376–380.
45. Hillis LD, Smith PK, Anderson JL, 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. Circulation. 2011;124:e652–e735.
46. Gielen CL, Grimbergen J, Klautz RJ, Koopman J, Quax PH. Fibrinogen reduction and coagulation in cardiac surgery: an investigational study. Blood Coagul Fibrinolysis. 2015;26:613–620.
47. Gielen CLI, Brand A, van Heerde WL, Stijnen T, Klautz RJM, Eikenboom J. Hemostatic alterations during coronary artery bypass grafting. Thromb Res. 2016;140:140–146.
48. Fergusson DA, Hébert PC, Mazer CD, et al.; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008;358:2319–2331.
49. Faraoni D, Cacheux C, Van Aelbrouck C, Ickx BE, Barvais L, Levy JH. Effect of two doses of tranexamic acid on fibrinolysis evaluated by thromboelastography during cardiac surgery: a randomised, controlled study. Eur J Anaesthesiol. 2014;31:491–498.
50. Myles PS, Smith JA, Forbes A, et al.; ATACAS Investigators of the ANZCA Clinical Trials Network. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med. 2017;376:136–148.
51. Levy JH, Sniecinski RM. Prohemostatic treatment in cardiac surgery. Semin Thromb Hemost. 2012;38:237–243.
52. Sniecinski RM, Levy JH. Bleeding and management of coagulopathy. J Thorac Cardiovasc Surg. 2011;142:662–667.
53. Dai L, Mick SL, McCrae KR, et al. Preoperative anemia in cardiac operation: does hemoglobin tell the whole story? Ann Thorac Surg. 2018;105:100–107.
54. LaPar DJ, Hawkins RB, McMurry TL, et al.; Investigators for the Virginia Cardiac Services Quality Initiative. Preoperative anemia versus blood transfusion: which is the culprit for worse outcomes in cardiac surgery? J Thorac Cardiovasc Surg. 2018;156:66.e2–74.e2.
55. 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? J Thorac Cardiovasc Surg. 2016;152:1412–1420.
56. Kim CJ, Connell H, McGeorge AD, Hu R. Prevalence of preoperative anaemia in patients having first-time cardiac surgery and its impact on clinical outcome. A retrospective observational study. Perfusion. 2015;30:277–283.
57. Garrido-Martín P, Nassar-Mansur MI, de la Llana-Ducrós 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. Interact Cardiovasc Thorac Surg. 2012;15:1013–1018.
58. Johansson PI, Rasmussen AS, Thomsen LL. Intravenous iron isomaltoside 1000 (Monofer®) 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). Vox Sang. 2015;109:257–266.
59. Despotis GJ, Levine V, Joist JH, Joiner-Maier D, Spitznagel E. Antithrombin III during cardiac surgery: effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation. Anesth Analg. 1997;85:498–506.
60. Kanbak M. The treatment of heparin resistance with antithrombin III in cardiac surgery. Can J Anaesth. 1999;46:581–585.
61. Avidan MS, Levy JH, van Aken H, et al. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2005;130:107–113.
62. Avidan MS, Levy JH, 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. Anesthesiology. 2005;102:276–284.
63. van Boven WJ, Gerritsen WB, Waanders FG, Haas FJ, Aarts LP. 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. Perfusion. 2004;19:239–246.
64. Beghi C, Nicolini F, Agostinelli A, et al. Mini-cardiopulmonary bypass system: results of a prospective randomized study. Ann Thorac Surg. 2006;81:1396–1400.
65. 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. ASAIO J. 2008;54:207–209.
66. Benedetto U, Luciani R, Goracci M, et al. Miniaturized cardiopulmonary bypass and acute kidney injury in coronary artery bypass graft surgery. Ann Thorac Surg. 2009;88:529–535.
67. Anastasiadis K, Antonitsis P, Haidich AB, Argiriadou H, Deliopoulos A, Papakonstantinou C. Use of minimal extracorporeal circulation improves outcome after heart surgery; a systematic review and meta-analysis of randomized controlled trials. Int J Cardiol. 2013;164:158–169.
68. Harling L, Warren OJ, Martin A, et al. Do miniaturized extracorporeal circuits confer significant clinical benefit without compromising safety? A meta-analysis of randomized controlled trials. ASAIO J. 2011;57:141–151.
69. 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. Eur J Anaesthesiol. 2009;26:1061–1066.
70. Saczkowski R, Bernier PL, Tchervenkov CI, Arellano R. Retrograde autologous priming and allogeneic blood transfusions: a meta-analysis. Interact Cardiovasc Thorac Surg. 2009;8:373–376.
71. Sun P, Ji B, Sun Y, et al. Effects of retrograde autologous priming on blood transfusion and clinical outcomes in adults: a meta-analysis. Perfusion. 2013;28:238–243.
72. Luciani GB, Menon T, Vecchi B, Auriemma S, Mazzucco A. Modified ultrafiltration reduces morbidity after adult cardiac operations: a prospective, randomized clinical trial. Circulation. 2001;104:I253–I259.
73. Boodhwani M, Williams K, Babaev A, Gill G, Saleem N, Rubens FD. Ultrafiltration reduces blood transfusions following cardiac surgery: a meta-analysis. Eur J Cardiothorac Surg. 2006;30:892–897.
74. Zhou ZF, Jia XP, 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. BMC Anesthesiol. 2017;17:13.
75. 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. Anesth Analg. 2017;124:743–752.
76. Goldberg J, Paugh TA, Dickinson TA, et al. PERForm registry and the michigan society of thoracic and cardiovascular surgeons quality collaborative. Greater volume of acute normovolemic hemodilution may aid in reducing blood transfusions after cardiac surgery. Ann Thorac Surg. 2015;100:1581–1587.
77. Shore-Lesserson L, Manspeizer HE, DePerio M, Francis S, Vela-Cantos F, Ergin MA. Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg. 1999;88:312–319.
78. Görlinger K, Dirkmann D, Solomon C, Hanke AA. Fast interpretation of thromboelastometry in non-cardiac surgery: reliability in patients with hypo-, normo-, and hypercoagulability. Br J Anaesth. 2013;110:222–230.
79. Hanke AA, Herold U, Dirkmann D, Tsagakis K, Jakob H, Görlinger K. Thromboelastometry based early goal-directed coagulation management reduces blood transfusion requirements, adverse events, and costs in acute type a aortic dissection: a pilot study. Transfus Med Hemother. 2012;39:121–128.
80. Bolliger D, Tanaka KA. Point-of-care coagulation testing in cardiac surgery. Semin Thromb Hemost. 2017;43:386–396.
81. Bolliger D, Tanaka KA. Roles of thrombelastography and thromboelastometry for patient blood management in cardiac surgery. Transfus Med Rev. 2013;27:213–220.
82. Gurbel PA, Bliden KP, Tantry US, et al. First report of the point-of-care TEG: a technical validation study of the TEG-6S system. Platelets. 2016;27:642–649.
83. Myles PS, Smith JA, Forbes A, et al.; ATACAS Investigators of the ANZCA Clinical Trials Network. Stopping vs continuing aspirin before coronary artery surgery. N Engl J Med. 2016;374:728–737.
84. Malm CJ, Hansson EC, Åkesson J, et al. Preoperative platelet function predicts perioperative bleeding complications in ticagrelor-treated cardiac surgery patients: a prospective observational study. Br J Anaesth. 2016;117:309–315.
85. Hansson EC, Jeppsson A. Platelet inhibition and bleeding complications in cardiac surgery: a review. Scand Cardiovasc J. 2016;50:349–354.
86. Ranucci M, Colella D, Baryshnikova E, Di Dedda U; Surgical and Clinical Outcome Research (SCORE) Group. Effect of preoperative P2Y12 and thrombin platelet receptor inhibition on bleeding after cardiac surgery. Br J Anaesth. 2014;113:970–976.
87. Gherli R, Mariscalco G, Dalén 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. JAMA Cardiol. 2016;1:921–928.
88. Mahla E, Suarez TA, Bliden KP, 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. Circ Cardiovasc Interv. 2012;5:261–269.
89. Bedeir K, Bliden K, Tantry U, Gurbel PA, Mahla E. Timing of coronary bypass surgery in patients receiving clopidogrel: the role of verifyNow. Can J Cardiol. 2016;32:724–725.
90. 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? Ann Thorac Surg. 2016;102:2010–2017.
91. Mazer CD, Whitlock RP, Fergusson DA, et al.; TRICS Investigators and Perioperative Anesthesia Clinical Trials Group. Six-Month outcomes after restrictive or liberal transfusion for cardiac surgery. N Engl J Med. 2018;379:1224–1233.
92. Mueller MM, Van Remoortel H, Meybohm P, Aranko K, Aubron C, Burger R, et al. Patient blood management: recommendations from the 2018 Frankfurt consensus conference. JAMA. 2019;321:983–997.
93. Carless PA, Henry DA, Moxey AJ, O’Connell D, Brown T, Fergusson DA. Cell salvage for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2010;(4):CD001888.
94. Vonk AB, Meesters MI, Garnier RP, et al. Intraoperative cell salvage is associated with reduced postoperative blood loss and transfusion requirements in cardiac surgery: a cohort study. Transfusion. 2013;53:2782–2789.
95. Weltert L, Nardella S, Rondinelli MB, Pierelli L, De Paulis R. Reduction of allogeneic red blood cell usage during cardiac surgery by an integrated intra- and postoperative blood salvage strategy: results of a randomized comparison. Transfusion. 2013;53:790–797.
96. Engels GE, van Klarenbosch J, Gu YJ, van Oeveren W, de Vries AJ. Intraoperative cell salvage during cardiac surgery is associated with reduced postoperative lung injury. Interact Cardiovasc Thorac Surg. 2016;22:298–304.
97. Desborough M, Sandu R, Brunskill SJ, et al. Fresh frozen plasma for cardiovascular surgery. Cochrane Database Syst Rev. 2015;(7):CD007614.
98. Casbard AC, Williamson LM, Murphy MF, Rege K, Johnson T. The role of prophylactic fresh frozen plasma in decreasing blood loss and correcting coagulopathy in cardiac surgery. A systematic review. Anaesthesia. 2004;59:550–558.
99. Yang L, Stanworth S, Hopewell S, Doree C, Murphy M. Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials. Transfusion. 2012;52:1673–1686; quiz 1673.
100. Goldstein JN, Refaai MA, Milling TJ Jr, 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. Lancet. 2015;385:2077–2087.
101. Ortmann E, Besser MW, Sharples LD, et al. An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery. Anesth Analg. 2015;121:26–33.
102. Arnékian V, Camous J, Fattal S, Rézaiguia-Delclaux S, Nottin R, Stéphan F. Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery. Interact Cardiovasc Thorac Surg. 2012;15:382–389.
103. Cappabianca G, Mariscalco G, Biancari F, et al. Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery. Crit Care. 2016;20:5.
104. 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. Br J Anaesth. 2018;120:928–934.
105. Tanaka KA, Esper S, Bolliger D. Perioperative factor concentrate therapy. Br J Anaesth. 2013;111suppl 1i35–i49.
106. Ghadimi K, Levy JH, Welsby IJ. Prothrombin complex concentrates for bleeding in the perioperative setting. Anesth Analg. 2016;122:1287–1300.
107. Kumar A, Mhaskar R, Grossman BJ, et al.; AABB Platelet Transfusion Guidelines Panel. Platelet transfusion: a systematic review of the clinical evidence. Transfusion. 2015;55:1116–1127; quiz 1115.
108. Levi M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet. 1999;354:1940–1947.
109. Wademan BH, Galvin SD. Desmopressin for reducing postoperative blood loss and transfusion requirements following cardiac surgery in adults. Interact Cardiovasc Thorac Surg. 2014;18:360–370.
110. Crescenzi G, Landoni G, Biondi-Zoccai G, et al. Desmopressin reduces transfusion needs after surgery: a meta-analysis of randomized clinical trials. Anesthesiology. 2008;109:1063–1076.
111. Desborough MJ, Oakland KA, 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. J Thromb Haemost. 2017;15:263–272.
112. Karlsson M, Ternström L, Hyllner M, Baghaei F, Nilsson S, Jeppsson A. Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: a prospective observational study. Transfusion. 2008;48:2152–2158.
113. Karkouti K, Callum J, Crowther MA, et al. The relationship between fibrinogen levels after cardiopulmonary bypass and large volume red cell transfusion in cardiac surgery: an observational study. Anesth Analg. 2013;117:14–22.
114. 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. Anesthesiology. 2013;118:40–50.
115. Ranucci M, Baryshnikova E, Crapelli GB, Rahe-Meyer N, Menicanti L, Frigiola A; Surgical Clinical Outcome REsearch (SCORE) Group. Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. J Am Heart Assoc. 2015;4:e002066.
116. Bilecen S, de Groot JA, Kalkman CJ, et al. Effect of fibrinogen concentrate on intraoperative blood loss among patients with intraoperative bleeding during high-risk cardiac surgery: a randomized clinical trial. JAMA. 2017;317:738–747.
117. Rahe-Meyer N, Levy JH, Mazer CD, et al. Randomized evaluation of Fibrinogen versus Placebofibrinogen versus placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy. Br J Anaesth. 2016;117:41–51.
118. Li JY, Gong J, Zhu F, et al. Fibrinogen concentrate in cardiovascular surgery: a meta-analysis of randomized controlled trials. Anesth Analg. 2018;127:612–621.
119. Shaw AD, Stafford-Smith M, White WD, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med. 2008;358:784–793.
120. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012;344:e3054.
121. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011;(3):CD001886.
122. Karkouti K, Beattie WS, Wijeysundera DN, et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion. 2005;45:26–34.
123. Karkouti K, Beattie WS, Arellano R, et al. Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery. Circulation. 2008;118:331–338.
124. 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. Circulation. 2009;120:21–27.
125. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791–1800.

Supplemental Digital Content

Copyright © 2019 International Anesthesia Research Society and Elsevier Inc. All rights reserved.