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Ann Thorac Surg 2004;78:2167-2169
© 2004 The Society of Thoracic Surgeons
a Department of Pharmacy Services, Medical University of South Carolina, Charleston, South Carolina, USA
b Department of Cardiovascular Perfusion, Medical University of South Carolina, Charleston, South Carolina, USA
c Department of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
Accepted for publication July 29, 2003.
* Address reprint requests to Dr Uber, Department of Pharmacy Services, 307 Rutledge Tower Annex, Medical University of South Carolina, 150 Ashley Ave, Charleston, SC 29425, USA
uberwe{at}musc.edu
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Abstract |
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Introduction |
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In contrast, bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ) possesses a relatively short half-life, an anticoagulation effect that closely correlates with activated clotting time (ACT), and an alternative metabolic pathway for elimination. These properties may make bivalirudin more suitable and therefore an attractive agent for use in CPB in patients with type II heparin-induced thrombocytopenia [3]. Limited published experience exists using bivalirudin in CPB [4, 5]. We report our experience using bivalirudin in 2 patients requiring CPB for coronary artery bypass grafting.
A 74-year-old woman with a history of coronary artery disease, estimated creatinine clearance of 30 to 40 mL/min, and recently diagnosed type II heparin-induced thrombocytopenia was admitted for a three-vessel on-pump coronary artery bypass grafting using left internal mammary artery and saphenous vein as conduit. A bivalirudin dosing strategy, initiated 20 minutes before anticipated ligation of left internal mammary artery, used a 1.25 mg/kg bolus followed by a 2.5 mg · kg–1 · h–1 continuous infusion. In addition, bivalirudin was added to the pump prime. Aprotinin (Trasylol; Bayer, West Haven, CT) administered as a 280-mg bolus to the patient, 280 mg to the pump priming solution, and an infusion of 70 mg/h during CPB was used to reduce intraoperative and postoperative bleeding. Anticoagulation was monitored by ACT measured with the Hemochron Response ACT monitoring machine using Hemochron Kaolin ACT tubes (International Technidyne Corp, Edison, NJ). Activated clotting time was measured at baseline, at 10-minute intervals on CPB, and after bypass for a target ACT of 500 to 600 seconds on CPB, with additional boluses and infusion adjustments to maintain this goal (Fig 1). Bivalirudin was discontinued on separation from CPB. Activated clotting time declined slowly, reaching 240 seconds 5 hours after CPB. At that time no surgical bleeding was observed, and the wound was closed. No evidence of thrombus was seen in the CPB circuit at any time during the procedure.
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Comment |
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Direct thrombin inhibitors have been suggested as heparin alternatives in CPB. Lepirudin, a recombinant form of hirudin, has been used successfully; however, its anticoagulation effect is prolonged in patients with renal insufficiency (up to 50 hours) [2]. This, coupled with the lack of a reversal agent, increases the risk of prolonged hemorrhage [2]. Further, the lepirudin-ACT dose-response curve is nonlinear at the levels needed for CPB, requiring specialized monitoring techniques that are not widely available [2].
Bivalirudin, a semisynthetic derivative of hirudin, has recently been approved for use in patients undergoing percutaneous coronary interventions [3]. Elimination is both by renal route and by intravascular proteolysis [3]. Bivalirudin possesses the shorter half-life of 25 minutes (in contrast to 60 to 90 minutes for lepirudin) with normal renal function, 1 hour with moderate renal impairment (creatinine clearance 10 to 30 mL/min), and 3.5 hours on dialysis [3]. The peak effect of bivalirudin is observed 5 minutes after a bolus injection and demonstrates a linear dose-response with ACT, making it an attractive agent for use in CPB in patients with type II heparin-induced thrombocytopenia [3].
Our dosing strategy was derived from experience with percutaneous coronary interventions and modified on the basis of limited published experiences in CPB [3–5]. In addition, we chose to add bivalirudin to the bypass pump priming solution on the basis of experience with lepirudin [2]. Dose adjustments were empirically based on trends seen in ACT measurements.
Several observations may explain the differences observed in our 2 patients. Initial ACT targets were derived from the few previous reports [4, 5]. We then lowered the target ACT because of concern about excessive anticoagulation as a result of loss of effective dose-response correlation with ACT more than 500 seconds.
Differences in renal function may account for some of the variability observed. Renal dysfunction requires dose reduction to avoid excessive anticoagulation. As with lepirudin, reduction or discontinuation of the maintenance infusion before separation from CPB or use of ultrafiltration may accelerate normalization of ACT and reduce the risk of severe hemorrhage after CPB [2]. Similarly, normal renal function requires more aggressive dosing to achieve and maintain adequate anticoagulation. Maintenance infusions can be continued until separation from CPB to avoid thrombosis of the bypass circuit in these patients.
The potential effect of aprotinin, a protease inhibitor, on bivalirudin elimination is unknown. The potential for aprotinin to slow the degradation of bivalirudin and prolong its anticoagulant effect remains to be identified.
The appearance of thrombus in the bypass circuit is of major concern. Increased temperature during rewarming may cause a decreased level of anticoagulation and require supplemental dosing. A terminal warm dose of cardioplegia was not used because of potential thrombus formation in the cardioplegia circuit. Thrombus formation in the circuit after CPB must be avoided if return to CPB is necessary. Rapid transfer of blood components in the circuit to a cell-saving device or continued anticoagulation of the bypass circuit by recirculation are possible solutions.
Bivalirudin, with its short half-life and ease of monitoring during CPB, is a promising alternative to heparin. Further experience is necessary to standardize this technique.
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This article has been cited by other articles:
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  Q. A Czosnowski, S. W Finks, and K. C Rogers Bivalirudin for Patients with Heparin-Induced Thrombocytopenia Undergoing Cardiovascular Surgery Ann. Pharmacother., September 1, 2008; 42(9): 1304 - 1309. [Abstract] [Full Text] [PDF]
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