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Ann Thorac Surg 2003;75:1622-1624
© 2003 The Society of Thoracic Surgeons
a The Heart Institute of Spokane, Spokane, Washington, USA
Accepted for publication October 27, 2002.
* Address reprint requests to Mr Edwards, The Heart Institute of Spokane, 122 W. 7th Ave, Suite 330, Spokane, WA 99204, USA.
e-mail: jte11{at}mindspring.com
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Abstract |
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Introduction |
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Because of its ease of use, sensitivity, and linearity up to high doses of heparin, the ACT has become very popular to monitor anticoagulation during surgery requiring CPB. However, the thrombin time (TT) is a much more sensitive and specific index of anticoagulation because it is an exclusively thrombin-dependent test. Unlike the traditional TT, the HiTT test (Hemochron; ITC, Edison, NJ) is a convenient point-of-care monitoring test when high levels of anticoagulation are used during CPB, especially when a direct thrombin inhibitor is substituted for heparin. Argatroban is a direct thrombin inhibitor developed in Japan and recently approved for use in the US for patients with HIT with or without thrombosis [6]. Argatroban selectively and reversibly binds the catalytic site on both clot-bound and soluble thrombin, and has the additional advantages of not requiring the cofactor antithrombin III to exert its effect, is excreted by the liver, provides a dose-dependent response, and neither interacts with nor induces heparin-dependent antibodies in patients with HIT [4, 6]. Because there is no antagonist to Argatroban, hepatic excretion is the only means of reversal.
A 68-year-old, 63-kg woman with diabetes and end-stage renal disease presented to the emergency room after experiencing ventricular fibrillatory arrest and resuscitation during hemodialysis. Subsequent evaluation revealed severe three-vessel coronary artery disease, ischemic cardiomyopathy, mild mitral insufficiency, severe tricuspid insufficiency, and an ejection fraction of 20%. Additionally, the patient had a platelet count of less than 40,000/µL and was found to have antibodies positive for type II HIT. Due to the patient’s unstable presentation, she was felt to require urgent myocardial revascularization. Of immediate concern, however, was the need to avoid heparin. Because of the patient’s end-stage renal disease, Argatroban was felt to be the best choice for anticoagulation during CPB.
The extracorporeal circuit consisted of nonheparin-bonded components (Terumo Cardiovascular Systems, Ann Arbor, MI). The priming solution was 1,800 mL lactated Ringer’s solution, 25 mEq NaHO3, and 0.05 mg/kg of Argatroban instead of the usual dose of heparin. A citrate-dextrose solution was used as an anticoagulant in the cell saver (Hemonetics Inc., Braintree, MA).
The patient was brought to the operating room after preoperative placement of an intraaortic balloon pump (IABP). Upon arrival in the operating room, the patient had the following laboratory data: hematocrit (HCT), 31.9%; platelet count (PLT), 154,000/µL; prothrombin time (PT), 12.9 seconds; partial thromboplastin time (PTT), 28.3 seconds; ACT, 136 seconds. A preoperative HiTT test was not performed. Once the adequacy of conduit was confirmed, the initial bolus of Argatroban (0.1 mg/kg) was administered and a continuous infusion (5 to 10 µg/kg/min) established. Twenty minutes after the intitial bolus of Argatroban, the first ACT was found to be 265 seconds. Two additional boluses (2 mg each) were required to raise the ACT to 349 seconds, at which time, aortic and bicaval cannulation were performed to prepare for CPB. A fourth bolus (2 mg) of Argatroban was required to raise the ACT above 400 seconds, at which point, CPB was initiated.
The patient was cooled to a nasopharyngeal temperature of 32°C. The aorta was cross-clamped and the heart arrested with antegrade and retrograde blood cardioplegia. Quadruple coronary artery bypass grafting and tricuspid annuloplasty were performed without incident. During CPB, the ACT and HiTT were maintained above 400 seconds by titrating the infusion of Argatroban. Serial ACT and HiTT tests were performed at approximate 20-minute intervals (Fig 1).
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The TT (normal at all points of occurrence [nl] < 17 seconds) and International Normalized Ratio were significantly prolonged at more than 110 and 5.5 seconds, 110 and 2.8 seconds, 77 and 1.8 seconds, and 56 and 1.6 seconds, respectively, at 4, 8, 12, and 18 hours after discontinuing Argatroban. By the morning of postoperative day (POD) 2, the patient’s coagulation profile had returned to baseline. Her platelet counts were as follows: 78,000/µL immediately postoperatively; 98,000/µL on POD 1; 109,000/µL on POD 2; 60,000/µL on POD 4; 112,000/µL on POD 5; and 209,000/µL on POD 8 (nl > 140,000/µL). Chest tube output was 2,600 mL during the first 12 hours postoperatively, 1,200 mL during the subsequent 12 hours (total of 3,800 mL for first 24 hours), 800 mL of serous fluid during the second 24 hours, and trace amounts of serous fluid during the third 24 hours. The patient received a total of 9 U of packed red blood cells, 13 U of random donor platelets, 9 U of fresh-frozen plasma, and 20 U of cryoprecipitate during the first 24 hours and no subsequent transfusions. The IABP was removed on POD 2 and the patient was transferred to the floor on POD 3. The patient recovered without further complications and was discharged home on POD 11. She was seen in follow-up 6 weeks later and was doing well with no apparent sequelae.
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Comment |
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Argatroban appeared to be the most promising solution to the need for a safe, effective, and convenient alternative to heparin anticoagulation in this patient. The convenience of using the ACT and HiTT to monitor the anticoagulation effect of Argatroban was a significant advantage, as was the fact that its clearance is predominantly through the liver. Despite these notable characteristics, there are no reports describing the use of Argatroban during CPB in the US. Monitoring the anticoagulant effect of Argatroban during CPB utilizing only the ACT has, however, been performed in Japan and has recently been reported by Furukawa and associates, although clot formation was observed in the extracorporeal circuit [4]. Our strategy of maintaining the ACT and HiTT greater than 400 seconds provided safe and effective anticoagulation during this case. HiTT results appeared to trend similarly to the ACT and were felt to be a more accurate measure of anticoagulation when using a direct thrombin inhibitor such as Argatroban.
The only clinical disadvantages encountered in this case were the extended times required to reach adequate levels of anticoagulation to facilitate CPB (100 minutes) and that required to achieve hemostasis after CPB despite the fact that Argatroban has a terminal half-life of approximately 1 hour. Unfamiliarity with the onset of Argatroban’s anticoagulant effect was certainly an inconvenience, but reaching adequate levels of anticoagulation for CPB in a more timely manner would likely have been achieved if the bolus and infusion were initiated earlier. The hemostatic challenge after CPB likely reflects the high levels of Argatroban required and hepatic impairment secondary to severe tricuspid insufficiency, thus reducing the anticipated clearance rate and reducing the preoperative coagulation factor levels. Additionally, the Argatroban infusion was discontinued after it was clear that the patient would not require prolonged extracorporeal support due to her severe left ventricular dysfunction. In patients with better left ventricular function, it would be preferable to stop the Argatroban infusion earlier. Studies to determine the correlation between HiTT results and circulating Argatroban concentrations would be of significant importance to formulate a more standardized and controlled dosage protocol.
Argatroban was able to provide effective anticoagulation without cross-reacting with heparin-dependent antibodies, offered a relatively predictable dose-response, proved to be easily monitored, and did not require dose adjustment for renal disease. Argatroban met all the requirements for the ideal anticoagulant in this case and appears to be an important advance in the prevention of a potentially lethal drug reaction for which practical therapeutic options are clearly limited for high-risk cardiac surgical patients with known HIT.
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