The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology

Clinical Practice Guidelines—Anticoagulation During Cardiopulmonary Bypass

Linda Shore-Lesserson, MD; Robert A. Baker, PhD, CCP; Victor A. Ferraris, MD, PhD; Philip E. Greilich, MD; David Fitzgerald, MPH, CCP; Philip Roman, MD, MPH; John W. Hammon, MD


Anesth Analg. 2018;126(2):413-424. 

In This Article

Reversal of Anticoagulation During Cardiac Operations

Class IIa Recommendation

  • Protamine dosing for heparin reversal: It can be beneficial to calculate the protamine reversal dose based on a titration to existing heparin in the blood as this technique has been associated with reduced bleeding and blood transfusion. (Level of Evidence B)

Heparin is by far the most commonly used anticoagulant during the conduct of cardiac operations, whether done with or without CPB. The preeminent benefit of heparin as compared with other anticoagulants is the ability to reverse its effect with protamine in a safe and expeditious manner.

The goals of successful anticoagulation during CPB include limiting clotting and safely reversing the anticoagulation effect during and at the conclusion of operation, respectively. For the vast majority of operations performed using CPB, heparin is the anticoagulant used and protamine is the reversal agent. An important part of the operation is to adequately remove all of the heparin effect at the end of operation. There are at least three methods commonly used to detect residual heparin effect after protamine reversal: (1) ACT measurement; (2) point-of-care testing using protamine titration of heparinized blood samples; and (3) thromboelastography with or without heparinase. Comparisons of these three methods suggest that ACT-based measurements of residual heparin effect are the least accurate means of detecting residual heparin effect.[84,85]

Methods of heparin reversal are several and controversy exists regarding the optimal strategy. Traditional methods administer heparin based on body weight and protamine based on the amount of heparin administered. Certain methods of protamine administration depend on titration of protamine to neutralize heparin in blood samples at the end of CPB. The literature comparisons of these methods are mixed, with most reports[86–88] but not all[89,90] favoring titration methods. A meta-analysis of standard weight-based versus titrated protamine dosing favors titrated dose protamine for heparin reversal because of less postoperative blood loss and decreased packed red blood cell transfusion.[91]

Two studies suggest that viscoelastic measurements are useful indicators of adequate titrated heparin reversal.[92,93] These studies found that individualized heparin-protamine titration decreased the protamine-to-heparin ratio, improved post-CPB thromboelastometric hemostatic factors, and reduced the incidence of severe blood loss compared with an ACT-based strategy. In addition, evidence supports the use of sequential heparin and protamine titrations after CPB to further limit blood loss and to provide adequate protamine reversal.[86]

Class IIa Recommendation

  • Protamine overdose: It is reasonable to limit the ratio of protamine/heparin to less than 2.6 mg protamine per 100 units heparin because total doses above this ratio inhibit platelet function, prolong ACT, and increase the risk of bleeding. (Level of Evidence C)

It is possible to overdose patients with protamine. Excess protamine inhibits platelet function and prolongs the ACT after CPB. Two studies provide convincing evidence that when the ratio of protamine to heparin (protamine mg per 100 units heparin) is above 5:1, platelet aggregation and function are impaired.[94,95] In addition, Mochizuki and associates[94] demonstrated that at ratios above 2.6:1, the ACT significantly increases. The European Association of Cardiothoracic Surgery identified a ratio of 2.6:1 of protamine to heparin as risking excessive bleeding. Their guidelines recommend limiting protamine, preferably using a titration method, after the completion of CPB.[96]

Class IIb Recommendation

  • Heparin rebound: Because of the risk of heparin rebound in patients requiring high doses of heparin and with prolonged CPB times, low-dose protamine infusion (25 mg/h) for as long as 6 hours after the end of CPB may be considered as part of a multimodality blood conservation program. (Level of Evidence C)

Heparin rebound occurs when detectable heparin blood levels are present at some remote time after apparently adequate heparin reversal with protamine. That likely occurs because of the ability of large molecules of heparin to sequester in fat stores and plasma proteins, with eventual reappearance in the blood at some time after protamine neutralization. Heparin dosing in excess of 400 IU/kg can result in heparin rebound. High heparin dosing during CPB results in higher doses of protamine required for reversal.

Randomized comparisons of high-dose and low-dose heparin for CPB suggest that heparin rebound increases with high-dose heparin.[21] One study suggests that 10% to 15% of patients receiving usual heparin doses for CPB will have detectable heparin levels 2 hours after protamine reversal.[97] Another study finds that detectable heparin levels, using both anti-Xa and viscoelastic measurements, are present immediately after, 2 hours after, and 4 hours after protamine administration.[22]

Usual methods of monitoring heparin reversal and measuring postoperative coagulation (eg, ACT and activated partial thromboplastin time) do not detect residual heparin levels.[84,98] A randomized trial involving 300 patients showed that a continuous infusion of protamine after initial protamine reversal (25 mg/h for 6 hours) abolishes heparin rebound and results in modest, but significant, reductions in chest tube blood loss but not transfusion requirements.[99]

Class I Recommendation

  • Complications associated with protamine reversal of heparin after CPB: For patients at high risk for anaphylactic response to protamine who have pulmonary hypertension and circulatory collapse shortly after protamine administration, discontinuation of protamine and implementation of resuscitative measures including reinstitution of CPB with adequate anticoagulation may be lifesaving. (Level of Evidence C)

As one might expect with any drug, there are side effects and complications associated with the use of protamine to reverse the effects of heparin after CPB. A unique feature of these complications associated with CPB is that they occur at a crucial time of the operative procedure. Life-threatening complications associated with protamine include anaphylaxis, pulmonary edema, and pulmonary hypertension.[100] Life-threatening cardiovascular compromise after intravenous protamine can occur even in young infants.[101] These complications are associated with operative mortality and serious organ dysfunction.[102,103] It is likely that protamine complications are underreported.[100,104] A comprehensive review of the literature suggests true anaphylactic reactions to protamine are rare (less than 1% of patients having CPB),[100] and approximately 60% occur before CPB, likely related to other drugs used in preoperative preparation of patients (eg, antibiotics or gelatin solution).[105] The results from this limited database of anaphylactic reactions showed that cardiac surgery proceeded without complications after cardiovascular collapse caused by pre-CPB anaphylactic or anaphylactoid reactions. Rapid institution of cardiopulmonary bypass may be lifesaving in this setting.[106]

Catastrophic cardiovascular reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated. That suggests that methylene blue may be the treatment of choice in this setting but high level evidence to support this intervention is lacking.[106] Evidence to date suggests that the site of protamine administration does not influence the incidence of protamine-induced pulmonary vasoconstriction, and aspirin ingestion within 1 week of surgery may decrease it.[107] Furthermore, acute right ventricular failure and pulmonary hypertension often precede catastrophic reactions to protamine.[103,108,109] Prostacyclin and bradykinin B2 attenuate the acute pulmonary hypertension in this setting but, again, no high level evidence supports the use of these agents to reverse the early stages of a reaction to protamine.[108,110] What is known is that serious protamine reactions predispose to operative mortality, and discontinuation of protamine and reinstitution of CPB, if serious protamine reactions occur, may be lifesaving.[103,105]

Studies show that antibodies to the protamine/heparin complex occur commonly after CPB.[111,112] These antibodies share a number of serologic features with HIT-derived antibodies, including platelet activation. In addition, these protamine/heparin antibodies cross react with protamine-containing insulin preparations.[111] Development of these antibodies predisposes to adverse outcomes after cardiac procedures and may pose risks of anamnestic response on reexposure to protamine.[111,112] For example, a meta-analysis of the surgical literature showed the risk of a protamine reaction in surgical patients to be 10 to 20 times higher for patients taking protamine-containing insulin compared with control patients not taking insulin preparations.[107,113]