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Reversing anticoagulation and achieving hemostasis after cardiopulmonary bypass

Reversing anticoagulation and achieving hemostasis after cardiopulmonary bypass
Authors:
Kamrouz Ghadimi, MD, MHSc, FAHA
Ian J Welsby, BSc, MBBS, FRCA
Section Editor:
Jonathan B Mark, MD
Deputy Editor:
Nancy A Nussmeier, MD, FAHA
Literature review current through: Nov 2022. | This topic last updated: Dec 06, 2022.

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

This topic discusses reversal of anticoagulation and management of bleeding after weaning from cardiopulmonary bypass (CPB) during cardiac surgery. Strategies to avoid or minimize blood loss and transfusion of blood products before and during CPB are discussed separately. (See "Blood management and anticoagulation for cardiopulmonary bypass".)

General principles for perioperative blood management and indications for intraoperative transfusion are discussed in separate topics. (See "Perioperative blood management: Strategies to minimize transfusions" and "Intraoperative transfusion of blood products in adults".)

REVERSAL OF ANTICOAGULATION — Systemic heparin anticoagulation is reversed with administration of protamine after weaning from cardiopulmonary bypass (CPB) [3].

Reversal of heparin anticoagulation — Once heparin has been administered, the only available agent to reverse the anticoagulant effect of heparin is protamine [4]. In the absence of reversal, heparin has a half-life of approximately 60 to 90 minutes; thus, its anticoagulant effect may persist for four to six hours. However, blood loss replacement with blood products and/or volume expanders can dilute heparin concentration and correct ongoing coagulopathy until the anticoagulant effects of heparin are no longer clinically evident.

Administration and dosing of protamine

Timing of initial administration – Neutralization of systemic heparin with protamine is typically initiated after weaning from CPB but before aortic decannulation. This timing allows rapid reinstitution of CPB in the event of a catastrophic protamine reaction [5].

Suctioning of blood from the surgical field into the pump reservoir (ie, "cardiotomy suction" or "pump suckers") is discontinued either at the onset of protamine administration or when a small portion (typically less than one-third) of the total initial dose has been administered. It is hypothesized that neutralization of heparin in the blood remaining in the CPB reservoir may cause clot formation, which would prohibit emergency reinstitution of CPB.

Initial dosing – An initial "test dose" of protamine 10 mg is administered to allow early detection of serious hemodynamic changes that may indicate a protamine reaction, without causing significant reversal of heparin effect in case CPB must be urgently re-established. However, later onset of anaphylaxis has been reported in patients who had a nonreactive test dose, typically after administration of the full protamine dose [6]. If there is no adverse reaction, the remainder of the protamine dose is administered slowly, typically over a 10 to 15 minute period via a syringe or by infusion [7,8]. This slower infusion rate may avoid potential vasodilation. (See 'Management of protamine reactions' below.)

Methods typically used to determine the protamine dose to be administered to reverse residual heparin after weaning form CPB include:

Use of a point-of-care (POC) titration assay to existing heparin in the blood, which is ideal if available [4,9].

Calculation of the dose using a fixed ratio of 0.7 mg of protamine per 100 units of the initial pre-bypass heparin dose administered to establish anticoagulation [4]. (See "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Heparin administration and monitoring'.)

However, there are numerous institutional variations for protamine dosing practices. Traditional methods relied on fixed protamine dosing based on body weight and/or the total amount of heparin administered during CPB. A 2013 meta-analysis that compared these traditional standard (fixed) dosing methods with use of a heparin-protamine titration assay noted significantly less mean postoperative blood loss with the assay method [10].

Further intraoperative dosing – After administration of the initial calculated protamine dose, further evaluation for residual heparin effect is accomplished by measuring the activated clotting time (ACT) and activated partial thromboplastin time (aPTT, PTT), as well as rechecking the heparin-protamine titration assay, if available [11-14]. (See "Intraoperative transfusion of blood products in adults".)

Plasma concentrations of residual heparin can insidiously increase after administration of the initial protamine dose as heparinized blood from the CPB pump is reinfused. Also, as patient reperfusion occurs, peripheral tissues may gradually release heparin previously bound in the endothelium into the circulation. For these reasons, it may be necessary to administer an additional protamine dose shortly after CPB, which is calculated using a POC heparin-protamine titration assay, or an additional 25 to 100 mg based on evidence of residual heparin effect noted on ACT or aPTT test results obtained shortly after CBP [11].

However, protamine overdosing should be avoided [3]. We agree with practice guidelines stating that it is reasonable to limit the ratio of protamine to heparin to ≤2.6 mg protamine per 100 units of heparin [4]. In fact, we rarely exceed 1 mg protamine per 100 units of the initially administered heparin dose. Studies have noted that excess protamine is associated with abnormally prolonged clotting tests and excessive bleeding after CPB, particularly if the ratio of protamine to heparin exceeds 2.6 mg protamine per 100 units of heparin [4,11,15-19].

Postoperative protamine administration – After initial protamine dosing, we also administer a protamine infusion of 25 to 50 mg/hour, beginning later in the intraoperative period and extending over two to four postoperative hours. This can reduce blood loss by avoiding "heparin rebound" that occurs due to slow eventual release of endothelium-bound heparin from less well perfused tissues (such as adipose tissue) into the intravascular space [20,21]. Such rebound may occur after the initial protamine dose has been metabolized [4,21,22]. This is more likely if active cooling was employed during CPB because vasoconstriction in peripheral tissues leads to potential depots of heparin that are later released during reperfusion as the patient continues to rewarm. Heparin rebound is also more likely in patients with altered heparin responsiveness (ie, “heparin resistance”) if a large dose of heparin was required to achieve initial anticoagulation for CPB [4,23]. (See "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Heparin resistance'.)  

Residual heparin effect can be documented using a POC heparin-protamine titration assay in the last stages of the intraoperative period or early in the postoperative period. These are often in the range of 0.1 to 0.3 international units/mL. At this low end of the therapeutic range, ACT and even aPTT measurements are insensitive for detecting residual heparin; concentrations measured with a POC heparin-protamine assay are typically more accurate [24,25].

Management of protamine reactions — Protamine reactions of varying severity may occur rapidly, but it may not be possible to determine the mechanism in an individual patient at the onset. Initial management is similar for each type, but may need to be more aggressive for severe reactions, as described below:

Vasodilation – Vasodilation is the most common reaction, often associated with a faster rate of protamine infusion. This reaction is transient and not typically severe. The mechanism is direct and indirect effects of protamine and potential complement activation by heparin-protamine complexes [4,5,26-28].

Treatment is administration of vasopressors as needed to avoid hypotension (table 1).

Anaphylaxis – A more severe anaphylactic reaction with vasoplegia is less common, but may occur in individuals who have antibodies to protamine due to previous exposure (eg, protamine-containing insulin) or due to allergy [4-6,26,27,29-31]. It is unrelated to the rate of protamine administration. An anaphylactic reaction may be severe, causing cardiovascular collapse.

Treatment includes stopping protamine administration, and administration of epinephrine and other therapies as described in the table (table 2). (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Initial management'.)

In some cases, it may be necessary to readminister systemic heparin to allow reinstitution of CPB for circulatory support [4,32].

Notably, in any patient with a suspected allergic reaction, a blood sample should be collected during or as soon as possible after the event, which may reveal elevations in tryptase when processed later. After postoperative recovery and hospital discharge, patients who had a severe reaction should be referred to an allergy specialist, as discussed in a separate topic. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Laboratory tests at the time of the reaction' and "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Referral for allergy evaluation'.)

Acute pulmonary vasoconstriction – Acute pulmonary vasoconstriction leading to right ventricular failure is a rare and severe reaction to protamine that may be difficult to distinguish from anaphylactic reactions, unless pulmonary artery pressures are being monitored [6]. Bronchospasm and/or noncardiogenic pulmonary edema due to thromboxane release from platelets may occur [4,5,26-28,30,32-34]. These severe reactions are likely caused by either IgG antibodies or heparin-protamine complexes that trigger thromboxane release.

Treatment includes stopping protamine administration and implementing resuscitative measures, similar to management of an anaphylactic reaction (table 2). In addition to these standard measures, inhaled pulmonary vasodilators are administered in some instances. As in patients with a severe anaphylactic reaction to protamine, it may be necessary to readminister heparin and reinstitute CPB [4,32].

Management if heparin is readministered – For any severe protamine reaction requiring heparin readministration to re-establish CPB for temporary cardiopulmonary support, we administer anti-inflammatory and vasoactive agents. Specifically, we treat for presumed anaphylaxis by administering a systemic steroid dose (eg, methylprednisolone 125 mg), together with the H1 antihistamine diphenhydramine 50 mg and a H2 receptor antagonist (eg, famotidine, cimetidine) as noted in the table (table 2). An infusion of epinephrine should be administered, and norepinephrine or vasopressin should be initiated if necessary to treat refractory hypotension (table 1). In patients with persistent refractory vasodilatory shock, it is reasonable to administer a dose of methylene blue 1 to 2 mg/kg before attempting to wean from CPB (table 3) [35-37]. (See "Intraoperative problems after cardiopulmonary bypass", section on 'Vasoplegia'.)

After an immediate severe protamine reaction requiring reinstitution of CPB to stabilize the patient, we consider next steps in consultation with members of the anesthesiology, surgical, and perfusion teams. There are no clear guidelines regarding the safety of readministering protamine to neutralize the additional systemic dose of heparin necessary to reestablish CPB after a catastrophic protamine reaction [4,28,31]. Options include:

In some reports, clinicians have safely readministered protamine without incident [31]. In theory, the initial anaphylactic reaction leads to a post-anaphylaxis refractory period due to temporary depletion of inflammatory mediators [6,31]. An alternative theory is that the initial reaction may not have been anaphylaxis.

Others avoid readministration of protamine, electing instead to reverse anticoagulation with use of blood products. With this option, excessive bleeding may require transfusion of large volumes of fresh frozen plasma (FFP), platelets, and fibrinogen, as well as red blood cells (RBCs), with the associated adverse effects of massive transfusion [31,38]. (See "Massive blood transfusion".)

In rare patients with severe noncardiogenic pulmonary edema or respiratory distress syndrome, temporary extracorporeal membrane oxygenation (ECMO) may be necessary after weaning from CPB. (See "Intraoperative problems after cardiopulmonary bypass", section on 'Extracorporeal membrane oxygenation'.)

Reversal of bivalirudin anticoagulation — In rare cases, anticoagulation with bivalirudin is used as an alternative to anticoagulation with heparin (eg, in patients with known severe protamine allergy or heparin-induced thrombocytopenia [HIT] when HIT antibodies are present). (See "Management of heparin-induced thrombocytopenia (HIT) during cardiac or vascular surgery".)

Bivalirudin has a half-life of approximately 45 minutes in normothermic patients with normal renal function; thus, all anticoagulant effects typically resolve within approximately two hours of administration of the last dose. If postbypass bleeding persists, termination of the anticoagulant effects of bivalirudin may be achieved by either waiting for usual metabolism or dilution and elimination with combinations of therapies such as blood product replacement, hemodialysis, or plasmapheresis with plasma exchange if bleeding is excessive [4].

ACHIEVING HEMOSTASIS AND MANAGEMENT OF BLEEDING — After weaning from cardiopulmonary bypass (CPB) and reversing anticoagulation, achieving hemostasis depends primarily on surgical control of bleeding sites, but also on maintenance of normothermia and selective administration of blood products as necessary. Bleeding necessitating transfusion occurs commonly after cardiac surgery with CPB, although transfusion rates vary widely among institutions (10 to 90 percent) [39-41]. Patients who are transfused have worse outcomes than those without transfusions, but this may be a marker for other risk factors rather than cause-and-effect [42,43].

Preoperative risk factors for perioperative bleeding and blood transfusion after CPB include advanced age, decreased preoperative red blood cell (RBC) volume (eg, small body size, preoperative anemia), existing coagulopathy, and complex or redo operations [41,44-47]. (See "Perioperative blood management: Strategies to minimize transfusions", section on 'Preoperative strategies'.)

Intraoperative causes of excessive bleeding after CPB include inadequate surgical hemostasis, loss of platelets and coagulation factors due to high volume cell saver use, presence of residual heparin, and effects of CPB such as hemodilution, hypothermic coagulopathy, coagulopathy due to platelet activation (and consumption), and hyperfibrinolysis induced by the extracorporeal circuit. (See "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Effects of cardiopulmonary bypass on hemostasis' and 'Reversal of heparin anticoagulation' above.)

Fastidious surgical hemostasis — The primary means to achieve hemostasis after CPB is meticulous surgical technique including systematic intraoperative checking of potential surgical sites of bleeding. In a meta-analysis of patients requiring mediastinal re-exploration for bleeding or cardiac tamponade after cardiac surgery, a surgical site of bleeding was identified in two-thirds of cases [48].

Maintenance of normothermia — Mild (32 to 35°C) or moderate (28 to 32°C) hypothermia is induced to provide neurologic and cardiac protection for many patients undergoing CPB, while deep hypothermia to temperatures as low as 16 to 18°C is employed for selected patients undergoing elective circulatory arrest. (See "Management of cardiopulmonary bypass", section on 'Management during cooling and hypothermia' and "Anesthesia for aortic surgery requiring deep hypothermia", section on 'Effects of deep hypothermia'.)

Rewarming during CPB and subsequent maintenance of normothermia in the postbypass period are necessary because hypothermia is associated with coagulopathy due to impairment of platelet aggregation and reduced activity of clotting enzymes [49-51]. This combination of platelet and enzyme impairment reduces clot formation and increases perioperative blood loss and the need for blood transfusion [52-54].

Active warming techniques must be employed to achieve normothermia during the rewarming phase of CPB, then to maintain normothermia during the postbypass and postoperative periods. Details regarding warming strategies are available in other topics:

(See "Management of cardiopulmonary bypass", section on 'Management during rewarming and weaning'.)

(See "Anesthesia for aortic surgery requiring deep hypothermia", section on 'Rewarming strategies'.)

(See "Perioperative temperature management", section on 'Active warming devices'.)

Use of transfusion algorithms — We use a goal-directed protocol or algorithm to guide transfusion decisions based on measurement of hemoglobin or hematocrit (HCT), as well as assessment of specific abnormalities of hemostasis using standard laboratory tests (algorithm 1), and/or point-of-care (POC) tests of hemostasis. This practice is consistent with guidelines from several professional societies for both cardiac and noncardiac surgical cases [40,41,44,55-58]. Use of such transfusion protocols and algorithms to guide decision-making can avoid or reduce unnecessary transfusions of blood products including red blood cells (RBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate (table 4) [40,41,56,59-70]. (See "Intraoperative transfusion of blood products in adults".)

Hemoglobin or hematocrit levels – We check hemoglobin or HCT levels following weaning from CPB, then approximately every 30 minutes, or more frequently in a profusely bleeding patient.

Standard laboratory coagulation tests – Standard laboratory tests include prothrombin time (PT) and international normalized ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen level, and platelet count. Clinically significant bleeding at any time during the postbypass period should trigger repeat evaluation of standard laboratory tests (algorithm 1), and/or POC tests as noted below, to aid decision-making regarding which therapies will likely reverse coagulation abnormalities.

Although platelet transfusions are typically guided by platelet count in this setting, tests of platelet function can be performed. Detecting a residual effect of P2Y12 inhibitors may be helpful in patients with mild-to-moderate microvascular bleeding. However, most platelet function tests are inaccurate after CPB due to dilutional changes and platelet activation [71]. In addition, these tests may not be useful in an actively bleeding patient since accuracy depends on a relatively normal platelet count. (See "Clinical use of coagulation tests" and "Platelet function testing".)

Point-of-care tests of hemostatic function – We employ POC viscoelastic coagulation tests in addition to standard laboratory coagulation tests to guide transfusion therapy, similar to the recommendations in professional society guidelines for centers with these POC tests [40,41]. Such viscoelastic coagulation tests (eg, thromboelastography [TEG] or an adaptation of TEG known as rotational thromboelastometry [ROTEM] (table 5)) supplement standard laboratory tests of hemostatic function and may be superior to standard tests and/or clinical judgment because assessments of coagulopathy are more rapid. Therefore, responses to interventions such as transfusion of blood products, or administration of hemostatic agents can be more immediately assessed [72]. Details and evidence supporting regarding use of transfusion algorithms guided by viscoelastic testing are available in a separate topic. (See "Intraoperative transfusion of blood products in adults".)

Transfusion of red blood cells — We transfuse RBCs if hemoglobin is <7 to 8 g/dL (or HCT <21 to 24 percent) [44,45], similar to professional society practice guidelines for blood conservation during cardiac surgery (algorithm 1) [3,40,41,44,45,73,74]. However, we may target a higher hemoglobin in a patient with poorly controlled hemorrhage or signs of worsening myocardial or other organ ischemia. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Cardiac surgery' and "Intraoperative transfusion of blood products in adults", section on 'Red blood cells'.)

Transfusion of RBC units is also included in massive blood transfusion protocols. (See "Massive blood transfusion", section on 'Component ratio (1:1:1)'.)

When transfusion is necessary, available salvaged blood is returned first, followed by reinfusion of blood units harvested via normovolemic hemodilution, then transfusion of allogeneic RBCs [40,41]. (See "Surgical blood conservation: Blood salvage" and "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Acute normovolemic hemodilution'.)

Transfusion of other blood products

Fresh frozen plasma — FFP is transfused when PT/INR or aPTT >1.5 times normal value), but only if the patient has active and ongoing bleeding (algorithm 1) [44,75]. Transfusion of FFP is also included in massive transfusion protocols, usually in a 1:1:1 ratio with transfusion of RBC units and platelets [76]. (See "Intraoperative transfusion of blood products in adults", section on 'Plasma' and "Massive blood transfusion", section on 'Component ratio (1:1:1)'.)

Transfusion of FFP is not appropriate in the absence of significant laboratory evidence of coagulopathy and active bleeding [3,40,75].

Platelets — Transfusion of platelets is reserved for patients with platelet count <100,000/microL (algorithm 1), or platelet dysfunction (eg, due to residual anti-platelet drug effect after administration of antiplatelet medication, particularly P2Y12 receptor inhibitors such as clopidogrel, prasugrel, and ticagrelor), but only if there is clinically significant and ongoing microvascular bleeding [40,41]. Thrombocytopenia is common in the immediate postbypass period due to a combination of hemodilution, platelet loss (eg, due to persistent surgical bleeding, adherence to the CPB circuit surface, or consumption as coagulation occurs), and accelerated clearance caused by thrombin-mediated platelet activation. (See "Intraoperative transfusion of blood products in adults", section on 'Platelets' and "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Antiplatelet agents'.)

Transfusion of platelets is also included in massive transfusion protocols. (See "Massive blood transfusion", section on 'Component ratio (1:1:1)'.)

Rarely, thrombocytopenia occurs as a manifestation of acute disseminated intravascular coagulation (DIC) after CPB (see "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Acute DIC'), or due to heparin-induced thrombocytopenia (HIT). (See "Management of heparin-induced thrombocytopenia (HIT) during cardiac or vascular surgery".)

Cryoprecipitate versus fibrinogen concentrate — While administration of cryoprecipitate or fibrinogen concentrate will not always resolve coagulopathic bleeding after CPB, we aggressively correct acquired hypofibrinogenemia if fibrinogen concentration is <150 mg/dL as a component of a multifactorial transfusion algorithm in patients with clinically significant bleeding [59].

Cryoprecipitate – In the United States and the United Kingdom, cryoprecipitate is often used to treat hypofibrinogenemia in cardiac surgical patients because of its wider availability and lower cost in these regions compared with fibrinogen concentrate [77]. Dosing, efficacy, and safety considerations are discussed in detail in separate topics. (See "Intraoperative transfusion of blood products in adults", section on 'Cryoprecipitate' and "Clinical use of Cryoprecipitate".)

Fibrinogen concentrateIf available, we prefer fibrinogen concentrate, rather than cryoprecipitate or FFP, to treat hypofibrinogenemia after CPB in patients with fibrinogen concentration <150 mg/dL and clinically significant bleeding as it is a pasteurized product that does not require a thawing process [40,41,77-84]. However, fibrinogen concentrate is more expensive than cryoprecipitate and will only raise the fibrinogen level as it does not contain other clotting factors (eg, von Willebrand factor [VWF], factors VIII and XIII, and fibronectin). Thus, it may not be ideal for all cardiac surgical patients with hypofibrinogenemia and coagulopathy, particularly after a prolonged duration of CPB [77,84]. (See "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Effects of cardiopulmonary bypass on hemostasis'.)

Fibrinogen concentrate is typically selected to treat hypofibrinogenemia in continental Europe and Canada, in part because cryoprecipitate is not typically available in these regions [84-86]. However, efficacy of prophylactic administration of fibrinogen concentrate has not been demonstrated and is not recommended in professional society guidelines [84,85,87,88]. Dosing, efficacy, and safety considerations for fibrinogen concentrate are discussed in detail in a separate topic. (See "Intraoperative transfusion of blood products in adults".)

A 2019 trial randomly assigned 735 cardiac surgical patients with clinically significant bleeding and documented hypofibrinogenemia (with measured fibrinogen level <150 to 200 mg/dL) to receive 4 g of fibrinogen concentrate or 10 units of cryoprecipitate after CPB [89]. Both groups received a similar number of units of allogeneic blood component transfusions including RBCs, FFP, and platelets. Other outcomes were also similar between the groups, including mortality (9.4 percent after fibrinogen concentrate versus 7.4 percent after cryoprecipitate; hazard ratio [HR] 1.28; 95% CI 0.77-2.12) and thromboembolic complications (7 percent after fibrinogen concentrate versus 9.6 percent after Cryoprecipitate; OR 0.70; 95% CI 0.42-1.20).

Use of clotting factors and hemostatic agents — Clotting factors may be used to treat excessive bleeding in selected patients during the postbypass period. Fibrinogen concentrate administration for hypofibrinogenemia is discussed above. (See 'Cryoprecipitate versus fibrinogen concentrate' above.)

Prothrombin complex concentrate (PCC) products

PCCs – A 4-factor unactivated prothrombin complex concentrate (PCC) is approved for use in emergency surgery in patients chronically taking warfarin or another vitamin K antagonist. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Urgent surgery/procedure' and "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'PCCs'.)

Off-label intraoperative administration of unactivated 4-factor or 3-factor PCC products has been evaluated for patients with intractable coagulopathy and diffuse bleeding after CPB (table 6), although data regarding intraoperative safety of PCC products in cardiac surgical patients are limited [40,41,78,90-100]. A 2022 randomized trial compared administration of PCC 15 International Units/kg versus FFP 10 to 15 mL/kg in 100 patients with excessive microvascular bleeding after CPB accompanied by a point-of-care PT >16.6 seconds and INR >1.6 [96]. Overall efficacy and safety were comparable for PCC and FFP, with improved correction of PT and INR in patients receiving PCC. The numbers of total intraoperative RBC transfusions and total postoperative RBC transfusions were not statistically different between the groups. Other randomized and observational studies in cardiac surgical patients have also noted reductions in blood transfusions in patients receiving PCC compared with those receiving FFP, as discussed in a separate topic [95,99-101]. (See "Intraoperative transfusion of blood products in adults".)  

Before considering administration of a PCC product in a cardiac surgical patient with intractable microvascular bleeding, other common causes of bleeding after CPB should be sought and treated (eg, surgical sources, thrombocytopenia, low levels of fibrinogen, platelet dysfunction, DIC) [97,102].

Also, use of PCC is avoided in patients with prothrombotic risks due to factors such as DIC or heparin-induced thrombocytopenia (HIT). Risk for thromboembolic events may be more likely with repeat or excessive dosing of both 4-factor and 3-factor PCCs, and may extend well into the postoperative period [99,103]. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'PCC risks'.)

Activated PCCs – In contrast with unactivated PCCs, activated PCC (factor eight inhibitor bypassing activity [FEIBA]) contains activated factor VII (table 6) [97]. FEIBA has a greater prothrombotic risk compared with unactivated PCC products and is only rarely used. (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'PCCs'.)

Recombinant activated factor VII (rFVIIa) — Recombinant activated factor VII (rFVIIa) is licensed for prevention of surgical bleeding in patients with hemophilia. In rare instances of severe intractable life-threatening coagulopathic bleeding after CPB, off-label administration of rFVIIa has been used in attempts to achieve bleeding cessation and reduce transfusion requirements [40,41,104-106]. However, high thromboembolism rates >20 percent (including myocardial infarction) with mortality >30 percent have been described in retrospective evaluations of registries for refractory bleeding cases [107,108]. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Off-label uses' and "Intraoperative transfusion of blood products in adults".)

Similar to off-label use of PCCs (see 'Prothrombin complex concentrate (PCC) products' above), other primary causes of coagulopathy should always be sought and treated before considering administration of rFVIIa. Failure to treat the primary coagulation defect increases the likelihood of an inadequate response to the initial dose of rFVIIa [107-109], and may encourage use of higher doses that are more likely to cause thrombosis [110,111]. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'General approach to administration'.)

Although optimal dosing and timing of rFVIIa doses for this off-label use for intractable bleeding after CPB is unknown, we employ a cautious dosing strategy in the rare instances that rFVIIa is administered (eg, small incremental doses of 10 mcg/kg given approximately every 15 minutes). Note that this dose is far less than the 90 to 120 mcg/kg used in hemophilia. Thromboembolic complications are more likely with dose escalation, or in the presence of stagnant flow or presence of devices such as extracorporeal membrane oxygenation (ECMO) [40]. One study in cardiac surgical patients reported cessation of bleeding after administration of incremental aliquots of rFVIIa, at a median dose of 13.3 mcg/kg [104]. Regarding timing of administration, a randomized study reported smaller total doses were necessary if rFVIIa was administered earlier in the postbypass period when no more than one RBC unit had been transfused (12.2 [9.7-16.4] mcg/kg), while higher doses were necessary if five or more units had been transfused (18.0 [11.8-29.0] mcg/kg) [105].

Antifibrinolytic agents — Timing for discontinuing administration of a prophylactic antifibrinolytic agent (eg, epsilon-aminocaproic acid [EACA] or tranexamic acid [TXA]) that is usually initiated in the prebypass period varies among institutions. If active bleeding necessitating transfusion persists, we typically continue administration of the antifibrinolytic agent throughout the postbypass period and into the postoperative period. [112,113]. (See "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Antifibrinolytic administration'.)

Desmopressin (DDAVP) — Routine use of DDAVP in cardiac surgical patients is not warranted [40,58,78]. In selected patients with acquired platelet defects due to uremia or acquired von Willebrand syndrome (eg, due to chronic aortic stenosis or presence of a left ventricular assist device), we administer intravenous (IV) desmopressin (DDAVP) 0.3 mcg/kg in the postbypass period, but only if persistent microvascular bleeding is evident [40,41,78,114-117]. DDAVP should be infused slowly over 15 to 30 minutes to avoid vasodilation. Tachyphylaxis occurs after the initial dose and during the initial three to five days of administration. (See "Uremic platelet dysfunction", section on 'Details of DDAVP administration' and "Acquired von Willebrand syndrome", section on 'Treatment of acute bleeding'.)

Some clinicians administer IV DDAVP to reduce blood loss in cardiac surgical patients with intractable microvascular bleeding due to platelet dysfunction suspected to be caused by hypothermia, acidosis, aspirin use, and/or the effects of CPB. Although very limited data suggest its benefit in such cases [40,118-121], studies are inconsistent [122,123]. Two 2017 meta-analyses of the efficacy of DDAVP in patients undergoing cardiac or noncardiac surgery noted only small reductions in perioperative blood loss and volume of RBC transfusions compared with placebo, with quality of evidence rated as low [120,121].

Possible adverse side effects of DDAVP include hypertension, hypotension, flushing, fluid overload, hyponatremia (which may cause seizures if close attention to free water restriction is not used), and rare thrombotic events (table 7).

EARLY POSTOPERATIVE MANAGEMENT

Management of bleeding and coagulopathy — Close monitoring for bleeding continues in the postoperative period. Return to the operating room for mediastinal re-exploration and intervention may be necessary based on the rate and presumed location of bleeding, as well as the surgeon’s assessment of potential for a surgical cause [124,125]. Excessive bleeding requiring mediastinal re-exploration has been associated with adverse outcomes that include mortality, need for mechanical circulatory support, stroke, acute renal failure, sternal wound infection, and prolonged mechanical ventilation [126,127].

Measures to prevent postoperative blood transfusions and surgical re-exploration include timely preoperative cessation of anticoagulants and antiplatelet drugs. Fastidious surgical hemostasis is particularly important. (See 'Fastidious surgical hemostasis' above and "Perioperative blood management: Strategies to minimize transfusions", section on 'Management of medications affecting hemostasis'.)

We use a hemoglobin threshold of <7 to 8 mg/dL for decisions to transfuse red blood cells (RBCs) in the postoperative period, similar to the intraoperative period (see 'Transfusion of red blood cells' above). We obtain viscoelastic tests and laboratory data, including coagulation tests and hemoglobin measurements, to guide transfusion decisions [60,70,73,74,99,128]. As an alternative, one randomized trial reported use of central venous oxygen saturation (SvO2) measurements ≤65 percent as the trigger for RBC administration [129]. Transfusion of fewer RBC units was reported with this target, compared with use of a fixed hemoglobin target of <9 mg/dL (odds ratio [OR] 0.03, 95% CI 0-0.15). (See "Perioperative blood management: Strategies to minimize transfusions", section on 'Management of medications affecting hemostasis' and 'Fastidious surgical hemostasis' above and 'Use of transfusion algorithms' above.)

Management of anemia — Postoperative anemia is common due to exacerbation of preexisting anemia, blood loss during surgery, and excessive postoperative phlebotomies [75,130]. Management strategies are noted in the algorithm and discussed separately (algorithm 2). (See "Perioperative blood management: Strategies to minimize transfusions", section on 'Management of postoperative anemia'.)

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

Reversal of heparin anticoagulation with protamine Systemic heparin anticoagulation is reversed with protamine. (See 'Administration and dosing of protamine' above.)

Initial dosing

-Timing – Neutralization of heparin is initiated after weaning from cardiopulmonary bypass (CPB), but before aortic decannulation.

-Dose calculation – Calculation of protamine dosing for heparin reversal is based on a point-of-care (POC) titration to existing heparin in the blood, or by administering 0.7 mg protamine per 100 units of the initial pre-bypass heparin dose if POC titration equipment is not available.

-Administration – An initial "test dose" of protamine 10 mg is administered to allow early detection of serious hemodynamic changes indicative of a protamine reaction. The remainder of the protamine dose is administered slowly, typically over a 10 to 15 minute period.

Further dosing Additional protamine is administered according to assay measurements of residual heparin, or an additional 25 to 100 mg of protamine may be administered if evidence of residual heparin effect is noted on the activated clotting time (ACT) or activated partial thromboplastin time (aPTT) measurements.

We suggest also administering a protamine infusion of 25 to 50 mg/hour over two to four postoperative hours to avoid "heparin rebound" (Grade 2C).

Management of protamine reactions Vasodilation due to direct and indirect effects of protamine commonly occurs, particularly if administration is rapid. Such reactions are treated with administration of vasopressors as needed (table 1). More severe reactions (ie, anaphylaxis and acute pulmonary vasoconstriction) are uncommon; management is described in the table (table 2). Inhaled pulmonary vasodilators may be added to treat pulmonary vasoconstriction. (See 'Management of protamine reactions' above.)

Reversal of bivalirudin anticoagulation Bivalirudin is an alternative anticoagulant agent that is infrequently used. Its anticoagulant effects typically resolve within two hours, but more rapid reversal may be achieved with combinations of therapies (eg, blood product replacement, hemodialysis, plasmapheresis with plasma exchange) if bleeding is excessive. (See 'Reversal of bivalirudin anticoagulation' above.)

Management of intraoperative bleeding

Surgical hemostasis The primary means to achieve hemostasis is meticulous surgical technique. (See 'Fastidious surgical hemostasis' above.)

Maintain normothermia Active warming techniques to achieve and maintain normothermia are employed as necessary. (See 'Maintenance of normothermia' above.)

Use a transfusion algorithm We use a goal-directed protocol or algorithm to guide transfusion decisions, based on measurement of hemoglobin or hematocrit (HCT), assessment of specific abnormalities of hemostasis using standard laboratory tests of hemostatic function (algorithm 1), as well as point-of care viscoelastic tests of coagulation if available (eg, thromboelastography [TEG], rotational thromboelastometry [ROTEM] (table 5)). (See 'Use of transfusion algorithms' above.)

Transfusion decisions for individual blood components include (table 4):

-Red blood cells (RBCs) – We typically transfuse RBCs for hemoglobin <7 to 8 g/dL (or HCT < 21 to 24 percent). Available salvaged blood is returned first, followed by reinfusion of blood units harvested via normovolemic hemodilution, then transfusion of allogeneic RBCs. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Cardiac surgery' and "Intraoperative transfusion of blood products in adults", section on 'Red blood cells' and 'Transfusion of red blood cells' above.)

-Fresh frozen plasma (FFP) – FFP is transfused when prothrombin time (PT)/international normalized ratio (INR) or aPTT >1.5 times normal value, but only if the patient has active and ongoing bleeding. (See 'Fresh frozen plasma' above.)

-Platelets – Transfusion of platelets is reserved for patients with platelet count <100,000/microL or platelet dysfunction (eg, due to residual anti-platelet drug effects), but only if there is clinically significant and ongoing bleeding. (See 'Platelets' above.)

-Cryoprecipitate or fibrinogen concentrate – We aggressively correct hypofibrinogenemia <150mg/dL, but only if the patient has active and ongoing bleeding. (See 'Cryoprecipitate versus fibrinogen concentrate' above.)

In the United States and the United Kingdom, cryoprecipitate is often used to treat hypofibrinogenemia because of its wider availability and lower cost in these regions compared with fibrinogen concentrate.

In continental Europe and Canada, fibrinogen concentrate is preferred for treatment of hypofibrinogenemia because it is a pasteurized product that does not require a thawing process and is available in those regions.

Use of other clotting factors and hemostatic agents

-Prothrombin complex concentrate (PCC) – For patients with intractable coagulopathy and diffuse bleeding after CPB, or for those intolerant of high FFP transfusion volume, off-label intraoperative use of unactivated 4-factor or 3-factor PCC products is reasonable (table 6). However, other causes of intractable microvascular bleeding should be treated before considering a PCC product, and it is avoided in patients with prothrombotic risks. (See 'Prothrombin complex concentrate (PCC) products' above.)

-Recombinant activated factor VII (rFVIIa) – In rare instances of severe intractable life-threatening coagulopathic bleeding after CPB, off-label administration of rFVIIa has been used in attempts to achieve bleeding cessation and reduce transfusion requirements. (See 'Recombinant activated factor VII (rFVIIa)' above.)

-Antifibrinolytics If active bleeding necessitating transfusion persists, we typically continue administration of the antifibrinolytic agent throughout the postbypass period and into the postoperative period. (See 'Antifibrinolytic agents' above.)

-Desmopressin (DDAVP) – Intravenous (IV) DDAVP 0.3 mcg/kg is administered in selected patients with acquired platelet defects due to uremia or those with acquired von Willebrand disease (table 7), but only if persistent microvascular bleeding is evident. (See 'Desmopressin (DDAVP)' above.)

Postoperative management

Management of postoperative bleeding – Close monitoring for bleeding continues in the postoperative period. Return to the operating room for surgical re-exploration is occasionally necessary based on the rate and presumed location of bleeding, as well as the surgeon’s assessment of potential for a surgical cause. (See 'Management of bleeding and coagulopathy' above.)

Management of postoperative anemia (algorithm 2) – (See 'Management of anemia' above.)

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Topic 122792 Version 12.0

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