Blood management and anticoagulation for cardiopulmonary bypass

INTRODUCTION — Blood and coagulation management are key components of anesthetic management for cardiac surgical procedures that require cardiopulmonary bypass (CPB) because of the need for full systemic anticoagulation during CPB with reversal after weaning from CPB, hemodilution due to fluid priming of the extracorporeal circuit, as well as fibrinolysis, platelet dysfunction, coagulation factor consumption, and systemic hypothermia that occur during CPB, and the likelihood of blood loss during surgery involving the heart and great vessels [1,2].

This topic discusses systemic anticoagulation in preparation for initiation of CPB, and strategies to avoid or minimize blood loss and transfusion of blood products before and during CPB. After weaning from CPB, protamine administration to reverse systemic heparin anticoagulation and management of postbypass bleeding are discussed in separate topics. (See "Protamine: Administration and management of adverse reactions during cardiovascular procedures", section on 'Protamine administration after cardiopulmonary bypass' and "Achieving hemostasis after cardiac surgery with cardiopulmonary bypass".)

General principles for perioperative blood management are discussed in separate topics. (See "Perioperative blood management: Strategies to minimize transfusions" and "Intraoperative transfusion and administration of clotting factors".)

EFFECTS OF CARDIOPULMONARY BYPASS ON HEMOSTASIS — Cardiopulmonary bypass (CPB) is a complex pathophysiologic state that induces several hemostatic changes (figure 1). Contact of blood with nonendothelial surfaces of the CPB circuit induces an intense inflammatory response due to the exposure to procoagulant substances, which results in coagulopathy due to platelet activation and dysfunction, initiation of the coagulation cascade, and decreased levels of circulating coagulation factors [3-5]. Thrombin generation and activation of fibrinolytic pathways result in consumption of platelets and pro- and anticoagulant proteins (especially fibrinogen and antithrombin) [6-9].

Furthermore, the priming solution for the CPB circuit (typically 1 to 1.5 L of a balanced crystalloid solution) results in hemodilution that exacerbates anemia and may also worsen coagulopathy and bleeding (see 'Strategies to minimize further hemodilution' below). Typical laboratory findings immediately after CPB include decreased platelet count, low fibrinogen, and increased prothrombin time (PT), activated partial thromboplastin time (aPTT), and D-dimer levels. Postbypass hypothermia may worsen coagulopathy. (See "Achieving hemostasis after cardiac surgery with cardiopulmonary bypass", section on 'Maintenance of normothermia'.)

Due to these effects on hemostasis, successful perioperative blood management strategies can reduce transfusions during cardiac surgery with CPB, although some patients may benefit more than others from this approach [10-13].

MANAGEMENT BEFORE CARDIOPULMONARY BYPASS

Blood conservation strategies

Intraoperative blood salvage — Intraoperative blood salvage is used before and after CPB for most cardiac surgical procedures due to the high likelihood of significant blood loss (>1000 mL), based on evidence that allogeneic blood transfusion and its associated complications can be avoided with a very low incidence of adverse events. Intraoperative blood salvage may also be acceptable to some Jehovah's Witnesses who will not accept allogeneic blood [14]. Details regarding this technique and the evidence supporting its administration are available in a separate topic. (See "Surgical blood conservation: Intraoperative blood salvage".)

Acute normovolemic hemodilution — Acute normovolemic hemodilution (ANH) is used before CPB in selected patients [15]. This technique involves removal of blood from a patient shortly after induction of anesthesia, with maintenance of normovolemia using crystalloid and/or colloid replacement. Factors influencing the decision to use ANH include a preoperative hemoglobin (Hb) >13 g/dL, patient size, hemodynamic stability during the prebypass period, and absence of coagulopathy or significant prebypass bleeding (eg, due to redo sternotomy). It is a good option for Jehovah's Witnesses since many will consent to ANH if their blood is maintained in a closed circuit continuous flow system [16]. (See "Approach to the patient who declines blood transfusion".)

The amount of blood removed during ANH typically varies between 1 and 3 units (450 to 500 mL constitutes 1 unit), and is calculated based on the patient's estimated blood volume, initial Hb level, and desired Hb level after withdrawal of blood with hemodilution (see "Surgical blood conservation: Acute normovolemic hemodilution", section on 'Amount of blood to withdraw'). This technique decreases Hb concentration during the period when most surgical blood loss is occurring, thereby minimizing the effects of red blood cell (RBC) losses, while allowing reinfusion of the patient's own fresh whole blood (which includes RBCs, viable platelets, and high levels of clotting factors) during or shortly after the surgical procedure. Further details regarding the ANH technique are available in a separate topic. (See "Surgical blood conservation: Acute normovolemic hemodilution".)

●A 2017 meta-analysis of 29 randomized trials that included more than 2400 cardiac surgical patients noted a lower incidence of allogeneic transfusion in the ANH group (42 versus 56 percent), with the number of transfused units reduced by approximately 1 unit compared with usual care [17].

●In a national registry that included more than 18,000 adult cardiac surgical patients, use of ANH resulted in a lower intraoperative transfusion rates (10 percent with or 8 percent without an autologous priming [AP] blood conservation technique), compared with patients who had no blood conservation technique (27 percent were transfused) or those who had only an AP technique (20 percent were transfused) [18]. (See 'Autologous priming techniques' below.)

Avoiding excessive fluid administration — In patients who do not undergo ANH, fluid administration prior to CPB is typically restricted to the relatively small volumes necessary to administer intravenous (IV) medications because hemodilution will occur at onset of CPB as the patient's blood volume intermixes with 1.0 to 1.5 L crystalloid CPB prime. (See "Anesthesia for cardiac surgery: General principles", section on 'Prebypass fluid management'.)

Exceptions include patients with signs of hypovolemia and those who are undergoing ANH. (See 'Acute normovolemic hemodilution' above.)

Systemic anticoagulation — Systemic anticoagulation is necessary before initiation of CPB. Typically this is accomplished with a bolus dose of heparin administered before aortic cannulation for initiation of CPB [19]. (See "Initiation of cardiopulmonary bypass", section on 'Aortic cannulation'.)

In rare instances of drug shortages, multiuse vials may be the only source of heparin [20,21]. In these circumstances, hospital pharmacies may use a single medication vial to prepare multiple syringes under sterile conditions for use in multiple patients. (See "Prevention of perioperative medication errors", section on 'Avoid multiuse vials'.)

Heparin administration and monitoring — The IV dose of heparin administered in preparation for CPB is typically 300 to 400 units/kg, with confirmation of adequacy of systemic anticoagulation so that clot formation in the CPB circuit will be prevented [14,22,23]. In obese patients undergoing CPB, basing the initial heparin dose on ideal rather than total body weight is reasonable, as long as adequate anticoagulation is verified [24,25].

Adequacy of anticoagulation after heparin administration is measured using a point-of-care test that measures the activated whole blood clotting time (ACT) to achieve a targeted value. Blood sampling for ACT testing is performed approximately three minutes after heparin administration. A minimum post-heparin ACT value ≥400 to 480 seconds is targeted before initiation of CPB, although evidence defining optimal ACT is lacking [22,26-29]. (See "Clinical use of coagulation tests", section on 'Monitoring heparins'.)

Advantages of heparin anticoagulation include the ability to rapidly titrate its anticoagulant effect and rapidly reverse this effect with protamine sulfate. Other advantages include clinician familiarity due to decades of use and low cost compared with alternatives such as direct thrombin inhibitors.

However, management of systemic anticoagulation in patients with heparin resistance or heparin-induced thrombocytopenia (HIT) can be challenging, as discussed in the sections below. (See 'Heparin resistance' below and 'Heparin-induced thrombocytopenia (HIT)' below.)

Heparin resistance — The term "heparin resistance" is used when the desired preset anticoagulation goal (typically an ACT target value ≥400 to 480 seconds) is not achieved after administration of a standard initial heparin dose (algorithm 1) [28,30].

Approximately 5 percent of cardiac surgical patients are resistant to heparin by one of several mechanisms (eg, preoperative infusions of heparin, liver insufficiency, elevated fibrinogen levels) [31]. Since heparin acts by binding to its cofactor antithrombin (AT; previously called antithrombin III [ATIII]), deficiency of this cofactor is often the cause of inadequate heparin anticoagulation [15,28,32]. AT levels <50 percent are often observed in cardiac surgical patients [33,34]. However, unless AT concentration was measured in the preoperative period, the diagnosis of AT deficiency as the cause of unanticipated heparin resistance cannot be certain. In this situation, it is reasonable to administer additional heparin doses, although an upper limit of heparin dose has not been determined (algorithm 1) [28,35]. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Heparin resistance/antithrombin deficiency'.)

If additional heparin dosing up to a total of 600 units/kg does not achieve the ACT target, and other potential causes have been considered, we administer AT concentrate 500 to 1000 units (if available) [15,32,36-41], or Fresh Frozen Plasma (FFP) 2 to 4 units [22,23,28], in patients who have known or suspected AT deficiency (algorithm 1). Administration of AT concentrate rather than FFP is preferred for patients with heparin resistance since AT concentrate does not result in volume overload and there is less risk of infection transmission and other complications of blood transfusion [15,36,37,42]. ACT measurements are then repeated. Plasma heparin concentrations determined by point-of-care assays such as heparin-protamine titration, if available, provide supplemental information [22]. For example, if a total dose of 600 units/kg of heparin has been administered and plasma heparin concentration is ≥4 units/mL, initiation of CPB is a reasonable strategy since this appears to be the critical concentration of heparin required to prevent thrombosis during CPB (algorithm 1) [28,32,43,44]. (See "Antithrombin deficiency", section on 'Available AT products and dosing'.)

The effect of AT supplementation on clinically meaningful outcomes in adults is under investigation. In pediatric cardiac surgery, normalization of AT level results in reduced coagulopathy and bleeding, while the effect on postoperative thrombotic complications is unclear [45].

Causes of heparin resistance other than AT deficiency (eg, thrombocytosis, elevated factor VIII concentration, elevated fibrinogen concentration) are often mitigated by the hemodilution that occurs after onset of CPB (see 'Strategies to minimize further hemodilution' below). Rarely, a lower ACT value of approximately 350 seconds may be accepted for initiation of CPB in a patient with heparin resistance [26], with administration of additional heparin by a fixed dosing regimen (eg, heparin 100 to 150 units/kg per hour, or 50 units/kg every 30 minutes if the duration of CPB will be brief) (algorithm 1). However, since failure to maintain therapeutic heparin levels has been associated with coagulopathic bleeding due to consumption of clotting factors by a process analogous to low grade disseminated intravascular coagulation, consultation with the surgeon and perfusionist regarding this management strategy is necessary [28].

Although there is no upper limit for heparin dosing, large doses will accumulate in body tissues. Subsequently, gradual release of heparin into the intravascular space may occur, typically after CPB has been terminated and protamine has been administered to neutralize heparin effect. This possibility of significant residual anticoagulation due to "heparin rebound" is preemptively treated by administering a protamine infusion at 25 mg/hour, beginning after initial reversal of heparin anticoagulation, and extending into the postoperative period over approximately four hours. (See "Protamine: Administration and management of adverse reactions during cardiovascular procedures", section on 'Avoiding heparin rebound'.)

Heparin-induced thrombocytopenia (HIT) — Occasionally, a patient presents for cardiac surgery with a current or remote history of heparin-induced thrombocytopenia (HIT) (algorithm 2) [46]. If HIT antibodies are present, surgery is delayed if possible. For urgent or emergency cardiac surgery, protocols for use of bivalirudin with or without CPB have been established (table 1) [22,47-51]. Other strategies have also been used, including plasmapheresis prior to surgery, administration of intravenous immune globulin (IVIG) prior to heparinization, use of an intravenous direct thrombin inhibitor (eg, bivalirudin), or coadministration of epoprostenol with heparin. Management of these patients is discussed in detail in a separate topic. (See "Management of heparin-induced thrombocytopenia (HIT) during cardiac or vascular surgery".)

Antifibrinolytic administration — Since fibrinolysis is a major contributor to coagulopathy and bleeding during cardiac surgery with CPB, we recommend administration of prophylactic antifibrinolytic therapy (either epsilon-aminocaproic acid [EACA] or tranexamic acid [TXA]) (figure 1). Details regarding dosing, timing of administration, and efficacy are presented in a separate topic. (See "Intraoperative use of antifibrinolytic agents", section on 'Use of antifibrinolytic agents in cardiac surgery'.)

MANAGEMENT DURING CARDIOPULMONARY BYPASS

Strategies to minimize further hemodilution — Cardiac surgical patients often arrive to the operating room with anemia (see "Preoperative evaluation for anesthesia for cardiac surgery", section on 'Anemia'). Excessive fluid administration and hemodilution before cardiopulmonary bypass (CPB) exacerbates preexisting anemia. (See 'Avoiding excessive fluid administration' above.)

During onset of CPB, further hemodilution occurs as the patient's own blood volume intermixes with the volume of crystalloid in the CPB prime (as much as 1.5 L) [52]. These factors increase the risk of meeting a threshold for transfusion of red blood cells (RBCs). (See 'Management of anemia' below.)

Strategies to minimize hemodilution during CPB may maintain hemoglobin (Hb) levels above transfusion thresholds and avoid the need for transfusion, as discussed in this section. However, safe use of such blood conservation techniques requires adequate prebypass oxygen carrying capacity and intravascular volume status.

Minimizing circuit prime volume — Typically, initiation of CPB with a crystalloid priming solution reduces Hb concentration by 1 to 2 g/dL due to hemodilution occurring as the patient’s blood volume intermixes with 1.0 to 1.5 L of crystalloid CPB prime. Excessive hemodilution may occur if the CPB circuit volume is large or if patient blood volume is limited by small patient size. Selection of a CPB circuit of appropriate size minimizes circuit prime volume and reduces risk for excessive hemodilution [14,15].

Autologous priming techniques — Techniques such retrograde autologous priming (RAP) and/or venous antegrade priming (VAP) are used in many institutions to prime the CPB circuit, thereby allowing reduction of the crystalloid priming volume and decreasing the degree of hemodilution [15]. Either a RAP or a VAP technique allows expulsion of 400 to 800 mL of crystalloid prime, thereby minimizing hemodilution. In a 2021 meta-analysis in cardiac surgical patients that included 11 randomized trials (1337 participants) and 10 observational studies (2327 patients), RAP was associated with a reduced overall incidence of RBC transfusions (odds ratio [OR] 0.34, 95% CI 0.22-0.550) compared with patients not receiving RAP, while incidences of stroke or acute kidney injury (AKI) were similar [53]. (See "Initiation of cardiopulmonary bypass", section on 'Autologous priming'.)

Success of a RAP and/or VAP approach depends on patient size and prebypass intravascular volume status, as well as the prime circuit volume. Pre-existing patient hypovolemia limits the clinicians' ability to safely perform RAP with or without VAP. Furthermore, hypovolemia can be induced as RAP progresses. To avoid organ hypoperfusion with potential consequences such as stroke or AKI, the anesthesiologist and perfusionist must recognize hypovolemia during initiation of CPB, and treat this by infusing either available blood previously salvaged from the surgical field, blood previously harvested during normovolemic hemodilution, or other fluid for volume replacement. (See "Surgical blood conservation: Intraoperative blood salvage" and 'Acute normovolemic hemodilution' above.)

Ultrafiltration techniques — Zero-balance ultrafiltration (UF) techniques can be used to prevent further hemodilution after the initial decrease in Hb level at onset of CPB, and to subsequently remove additional accumulated volume after administration of cardioplegia solution [14,15]. However, the authors do not recommend the routine use of negative balance UF during CPB to attempt to "reverse" hemodilution in favor of a higher hematocrit (Hct), as there has been an association with AKI [54,55].

Conventional UF employs a hemofiltration filter in parallel to the CPB circuit that can continuously remove plasma-free solute and water from diverted blood, thereby concentrating Hb levels, and possibly removing inflammatory mediators [56], or small molecules such as potassium [57]. In one multicenter trial performed in patients undergoing coronary artery bypass grafting (CABG) surgery, conventional UF used during CPB in 1362 patients increased risk of acute kidney injury (AKI) compared with 5045 patients who did not have UF [58]. The investigators emphasized the importance of avoiding excessive filtration that may result in induced hypovolemia.

Management of anemia — For Hb <7.5 g/dL (or Hct <22 percent), initial treatment during CPB is removal of fluid by ultrafiltration (hemoconcentration), if volume status allows, to account for hemodilution due to the CPB prime [59] (see 'Ultrafiltration techniques' above). One retrospective analysis of more than 1600 adult cardiac surgery patients without baseline kidney disease from a single academic medical center suggested that high-volume conventional ultrafiltration (CUF) >32 mL/kg was associated with AKI [55]. However, a systemic review and meta-analysis of more than 8000 patients did not show any increased risk for kidney injury even with high-volume CUF [60]. Furthermore, subgroup analysis of those with previous renal insufficiency suggested no significance differences in incremental AKI development (RR = 0.84, 95% CI, 0.53-1.33, p = 0.47). Nevertheless, in the absence of evidence from randomized controlled trials, large-volume CUF should be used cautiously, particularly in patients at risk for AKI [54].

If further treatment for severe anemia or hypovolemia is necessary, available salvaged blood is returned first, followed by reinfusion of blood units harvested via normovolemic hemodilution, and then if needed, administration of allogeneic RBCs. (See "Surgical blood conservation: Intraoperative blood salvage" and 'Acute normovolemic hemodilution' above.)

Transfusion of allogeneic RBCs is reasonable if Hb remains <7.5 g/dL when hemoconcentration is not possible or is ineffective, and neither salvaged nor harvested blood is available [61-63]. Leukocyte-reduced blood is preferred [64]. However, the optimal Hb level during cardiac surgery is not known. Thus, transfusion decisions are individualized, taking into account patient-related factors (eg, age, severity of illness, cardiac function, risk for critical end-organ ischemia), the clinical setting (massive or active blood loss, the operation being performed), and clinical or laboratory parameters indicating hypoperfusion (eg, metabolic acidosis, lactic acidosis, SvO₂ <60 percent) [36,65,66].

Guidelines published by professional societies recommend RBC transfusion for Hb <6 g/dL, but also recommend avoiding red cell transfusion for Hb >10 g/dL [14,36]. Both transfusion of RBCs and very low nadir Hb levels <6 to 7 g/dL during CPB are associated with increased morbidity and mortality [59,65,67-71]. In particular, nadir Hct during CPB has been associated with postoperative AKI [70,72-81]. Although decline in postoperative renal function may be attributable to adverse effects of reduced oxygen delivery due to anemia during CPB, no critical Hb threshold predicting AKI has been identified. Notably, RBC transfusion during cardiac surgery is also associated with AKI [72,78,81,82]. Furthermore, unnecessary transfusion of blood products in patients who are normovolemic and hemodynamically stable may also have adverse consequences such as transfusion-associated circulatory overload (TACO) [83]. Details regarding evidence supporting decisions to withhold or transfuse RBCs during cardiac surgery are available in a separate topic. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Cardiac surgery'.)

Maintenance of anticoagulation — Maintenance of heparin anticoagulation throughout CPB is discussed in a separate topic. (See "Management of cardiopulmonary bypass", section on 'Maintenance of anticoagulation'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management" and "Society guideline links: Management of cardiopulmonary bypass".)

SUMMARY AND RECOMMENDATIONS

●Effects of cardiopulmonary bypass (CPB) – Contact of blood with nonendothelial surfaces of the CPB circuit induces an intense inflammatory response resulting in coagulopathy due to platelet activation and dysfunction, initiation of the coagulation cascade, and decreased levels of circulating coagulation factors (figure 1). Thrombin generation and activation of fibrinolytic pathways result in consumption of platelets and pro- and anticoagulant proteins (especially fibrinogen and antithrombin). Hemodilution and hypothermia may exacerbate coagulopathy after CPB. (See 'Effects of cardiopulmonary bypass on hemostasis' above.)

●Strategies to conserve blood before CPB – Blood conservation strategies often used in the prebypass period include aggressive reversal of preoperative anemia with iron supplementation, as indicated, blood salvage technology and, in selected patients, acute normovolemic hemodilution (ANH). (See "Surgical blood conservation: Intraoperative blood salvage" and "Surgical blood conservation: Acute normovolemic hemodilution".)

●Strategies to minimize excessive hemodilution before and during CPB

•Prebypass – Restriction to the small volumes necessary to administer intravenous (IV) medications in patients who are euvolemic and not undergoing ANH. (See 'Avoiding excessive fluid administration' above.)

•During CPB – Use of minimal CPB circuit prime volume, autologous blood priming (AP) of circuit tubing, and ultrafiltration (UF) techniques. (See 'Strategies to minimize further hemodilution' above.)

●Management of anemia – During CPB, initial treatment of hemoglobin (Hb) <7.5 g/dL (or hematocrit [Hct] <22 percent) is removal of fluid by UF (hemoconcentration) when possible [59]. Transfusion of packed red blood cells (RBCs) is reasonable if Hb remains <7.5 g/dL during or after CPB when further hemoconcentration is ineffective or not possible. (See 'Management of anemia' above and "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Cardiac surgery'.)

●Management of anticoagulation

•Routine heparin management – An IV dose of heparin is administered before aortic cannulation, typically 300 to 400 units/kg, and adequate systemic anticoagulation is confirmed to prevent clot formation in the CPB circuit. The degree of thrombin inhibition after heparin administration is measured with point-of-care tests such as activated whole blood clotting time (ACT) to achieve and maintain a targeted value, typically 400 to 480 seconds, before initiation of CPB. (See 'Systemic anticoagulation' above and 'Maintenance of anticoagulation' above.)

•Management of heparin resistance – Management of "heparin resistance" is shown in the algorithm (algorithm 1). In patients who have known or suspected antithrombin (AT) deficiency, we suggest administration of AT concentrate 500 to 1000 units (if available), rather than Fresh Frozen Plasma (FFP) two to four units (Grade 2B). AT concentrate is preferred to FFP since it does not result in volume overload and there is a lower risk of infection transmission and other complications of blood transfusion. Rarely, a lower ACT value of approximately 350 seconds may be accepted for initiation of CPB in a patient with heparin resistance, with administration of additional heparin by a fixed dosing regimen. (See 'Heparin resistance' above.)

•Management of heparin-induced thrombocytopenia (HIT) – Occasionally, a patient presents for cardiac surgery with a current or remote history of HIT (algorithm 2). If HIT antibodies are present, surgery is delayed if possible. Details regarding management of these patients are available in a separate topic. (See "Management of heparin-induced thrombocytopenia (HIT) during cardiac or vascular surgery".)

●Use of antifibrinolytic agents – We administer prophylactic antifibrinolytic therapy (aminocaproic acid [EACA] or tranexamic acid [TXA]) before initiation of CPB, as discussed separately. (See "Intraoperative use of antifibrinolytic agents", section on 'Use of antifibrinolytic agents in cardiac surgery'.)