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* From the Department of Anesthesia and Pain Management,
Division of Cardiac Surgery, and
Cardiovascular Perfusion Services, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
Address correspondence to: Dr. Annette Vegas, Department of Anesthesia, Toronto General Hospital, 200 Elizabeth St., 3 EN-406, Toronto, Ontario M5G 2C4, Canada. Phone: 416-340-4800, ext. 6443; Fax: 416-340-3698; E-mail: annette.vegas{at}uhn.on.ca
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Abstract |
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Clinical features: A 62-yr-old patient who underwent stentless tissue aortic valve replacement with a Toronto-SPV valve in 1998, was admitted to hospital with symptoms of stroke. A heparin infusion was started and further investigation revealed positive blood cultures. The patient developed HIT which was confirmed by laboratory tests. Echocardiographic examination performed one month later showed vegetations on the aortic tissue valve and a small aortic root abscess. The patient still tested positively for the presence of HIT antibodies and was treated conservatively with antibiotics. A repeat echocardiographic examination showed progression of the aortic root abscess and it was decided to proceed with urgent redo aortic valve surgery. Anticoagulation for cardiopulmonary bypass (CPB) was achieved with the use of a direct thrombin inhibitor (DTI), bivalirudin. Following an uneventful wean from CPB, hemostasis was achieved within 40 min. The postoperative course was uncomplicated and the patient was discharged from hospital on the seventh postoperative day.
Conclusion: Bivalirudin is a DTI, which can be used as an alternative anticoagulant for CPB in HIT positive patients. This case report showed a favourable outcome with bivalirudin for urgent complex redo cardiac surgery requiring CPB.
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Introduction |
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TOPAbstractIntroductionCase presentationDiscussionReferences |
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Case presentation |
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TOPAbstractIntroductionCase presentationDiscussionReferences |
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A 62-yr-old male patient who underwent stentless tissue aortic valve replacement surgery (Toronto-SPV valve) in 1998 was admitted to hospital with symptoms of stroke. A magnetic resonance imaging exam showed bilateral pontine infarctions due to basilar artery thrombosis and a heparin infusion was started. The patient also had positive blood cultures (Cardiobacterium homminis) without echocardiographic features of bacterial endocarditis. Therapy with antibiotics was started. After ten days of heparin therapy the patient developed thrombocytopenia. An initial screening test for antibodies against PF4/unfractionated heparin complexes (ELISA) and a subsequent serotonin release assay (SRA) were positive for HIT. Heparin therapy was discontinued and no other anticoagulant was administered.
After one month of antibiotic therapy the patient had follow-up transesophageal echocardiography (TEE) that showed an aortic root abscess, small prosthetic valve vegetations, and mild aortic insufficiency. The SRA test remained positive, and it was decided to continue antibiotic therapy and wait until the HIT-antibody test became negative. A repeat TEE performed two weeks later revealed the aortic root abscess had doubled in size, from 0.7 to 1.4 cm. A decision was made to proceed with urgent redo aortic valve surgery with the use of bivalirudin. Preoperative coronary angiography, without anticoagulants or anti-platelet drugs, showed critical arterial stenosis of the first obtuse marginal branch.
Preoperative laboratory investigation included hemoglobin 149 g·L–1, platelet count 281 x 109·L–1, prothrombin time = 13.8 sec, INR = 1.02 and normal liver and kidney function. The patient received a heparin free perioperative course including no heparin in flush bags and a heparin uncoated Swanganz catheter and CPB circuit. Anesthesia was induced with propofol 100 mg iv, midazolam 2 mg iv, fentanyl 0.5 mg iv and pancuronium bromide 10 mg iv. Anesthesia was maintained with isoflurane (1.2–1.5 MAC), intermittent iv fentanyl (total 0.5 mg), and an iv infusion of propofol (80 µg·kg–1·hr–1) during and after CPB. To minimize post-bypass bleeding, aprotinin (4,000,000 KIU) was administered as a 2,000,000 KIU bolus in the CPB circuit prime followed by an iv infusion 250,000 KIU·hr–1 (2,000,000 KIU) during and after CPB.
Following redo sternotomy surgical hemostasis was obtained. Ten minutes prior to routine aortic and right atrial cannulation bivalirudin 110 mg iv (1.5 mg·kg–1) was administered as a bolus followed by an iv infusion of 2.5 mg·kg–1·hr–1 (180 mg·hr–1). A 50-mg bolus of bivalirudin was added to the CPB circuit prime. Anticoagulation was monitored using a Medtronic II activated clotting time (ACT) device (Medtronic, Minneapolis, MN, USA) with kaolin based ACT (kACT) tubes and a Hemochron device for standard ACT and plasma modified ACT measurements. Activated clotting times were obtained at baseline, every ten minutes on CPB and post-CPB to attain a target kACT of > 400 sec. Five minutes after the first bivalirudin bolus the anticoagulated blood was sampled. This initial kACT level was 370 sec and we administered an additional 20 mg iv bolus of bivalirudin (0.25 mg·kg–1) and increased the iv infusion by 0.25 mg·kg–1·hr–1 to 2.75 mg·kg–1·hr–1 (198 mg·hr–1). This resulted in an acceptable pre-CPB kACT level of 440 sec. With adequate anticoagulation established, CPB was initiated in the usual fashion and conducted under mild hypothermia (34.5 °C). To avoid blood stagnation in the bypass pump, the cardioplegia line was continuously flushed and blood suctioned from the surgical field was returned to a cell saver.
After opening the aorta the surgeons identified a large aortic root abscess extending under the left main coronary artery and onto the roof of the left atrium. The Toronto SPV aortic valve had multiple vegetations. A 23-mm aortic root homograft was used to replace the damaged prosthetic valve and aortic root, and both coronary ostia were reimplanted. A saphenous vein graft was used to bypass the first obtuse marginal branch. The total CPB time was 121 min with an aortic cross clamp time of 100 min.
The kACT values remained over 400 sec during CPB without further adjustment of the bivalirudin infusion. There were no clots in the CPB system during the pump run, and pressures in the CPB lines remained normal. The only observation of blood clot was in the pericardial sac where blood stagnated. Ten minutes before discontinuation of CPB the bivalirudin infusion was stopped. The patient was weaned from CPB successfully on the first attempt with iv infusions of phenylephrine (0.03 µg·kg–1·min–1) and dopamine (3 µg·kg–1·min–1). Immediately post-CPB to prevent blood stagnation in the pump, the arterial and venous bypass lines were connected at the table. The perfusionist administered bivalirudin as a 50-mg bolus and infusion of 50 mg·hr–1 into the recirculating pump circuit. Eventually all the pump blood was processed through a cell saver using citrate, and reinfused into the patient. Despite an abnormal kACT, satisfactory hemostasis in the surgical field was obtained 30 to 40 min after terminating bypass and the pericardium and chest were closed without complication. The only blood products transfused intraoperatively were two units of fresh frozen plasma (FFP), 30 min post-CPB, for generalized oozing in the surgical field. The patient was transferred to the intensive care unit (ICU) without complications. Within the initial 24 hr postoperatively the patient lost 600 mL of blood, and received two units of packed red blood cells and two units of FFP. The patient had an ICU admission hemoglobin of 94 g·L–1 and an ICU discharge hemoglobin of 103 g·L–1. The patient was discharged from ICU on postoperative day (POD) one and from hospital on POD seven. A pre-discharge echocardiogram showed normal homograft valve function.
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Discussion |
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The optimal anticoagulation strategy for managing patients with HIT during cardiac surgery remains controversial.1,2,7 Heparin alternatives successfully used for CPB (Tables I
and II) have included non-thrombin inhibitors (danaproid,8 ancrod9) and DTI (hirudin,10 argatroban,11 bivalirudin).6 All three DTI drugs bind selectively to circulating and clot-bound thrombin and do not have an antidote. These drugs do not require anti-thrombin III as a cofactor, are not inactivated by PF4 and do not cross-react with heparin antibodies. The DTI drugs differ pharmacologically (Table I) and have been used successfully in the medical management of HIT-positive patients.1 Each DTI has been used off-label, with and without CPB, during cardiac surgery. To use a DTI successfully for CPB, it must be safe, its effects must be easy to monitor, and the drug must have limited effect in the post-bypass period to avoid excessive bleeding.
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Experience with argatroban use for CPB is very limited.11,13,14 Several complications were reported including severe hemorrhage resistant to factor VIIa therapy13 and failure to achieve adequate anticoagulation during off-pump coronary artery bypass surgery (CABG).14
Bivalirudin has stable pharmacokinetics: its peak action occurs within five minutes of bolus injection, and the elimination half-life is 25 min. Metabolism occurs by plasma proteolytic cleavage (80%) and renal excretion (20%), with prolonged action in dialysis dependent patients. Monitoring is done with ecarin clotting time (ECT), or kACT as the PT, PTT and thrombin time are all prolonged. There is no antidote and the drug has minimal side effects.3,6
Current experience with bivalirudin for CPB is based mainly on case-reports of HIT-positive patients who underwent CABG,15 heart transplantation,16 left ventricular assist implantation17 and pediatric heart surgery.18 There are small studies6,19 describing bivalirudin use in HIT-negative cardiac surgery patients who underwent elective on or off pump CABG surgery. Some report massive transfusion of blood products and the use of factor VIIa16 during the early postoperative period.
Appropriate monitoring of DTI effects remains an unresolved issue, especially since standard ACT has no linear correlation with DTI plasma concentration.17 The ECT more accurately detects inadequate DTI anticoagulation for CPB than the ACT.20 The ECT test is based on meizothrombin generation from pro-thrombin by ecarin. A DTI binds immediately to the permanently formed meizothrombin in a concentration-dependent fashion. Ecarin clotting time cannot be used to detect disturbed coagulation, but is highly specific for therapeutic monitoring of antithrombin activity.21
In the absence of ECT monitoring, kACT and plasma modified ACT can be used. Koster et al.22 showed a 60% improved accuracy of monitoring unfractionated heparin levels post bypass with modification of the standard ACT assay. In this modified assay, a sample of platelet poor plasma is added in a one-to-one dilution to whole blood measured with the standard ACT tube. Jabr et al.23 used plasma modified ACT to track bivalirudin effect during CPB and obtained reasonable correlation with standard ACT. Similar to other reports,20,24 our comparison showed differences between standard ACT, kACT and plasma modified ACT. The tendency to increase or decrease was consistent in all three measurements. The values of plasma modified ACT were lower when compared to standard ACT or kACT.
Re-establishing hemostasis after CPB relies upon meticulous surgical technique and a decreasing bivalirudin drug effect, since there is no antidote. Case reports, including ours, suggest despite laboratory abnormalities, adequate clinical hemostasis occurs within 30 to 40 min post bypass. Blood product (FFP, platelets) administration should be guided by clinical circumstances beyond 30-min post bypass. Elimination of bivalirudin can be facilitated with the use of modified, zero-balanced ultra filtration.6 Aprotinin can be used to minimize post bypass bleeding.10
Bivalirudin offers one more theoretical advantage when used for patients receiving coronary artery grafts, as our patient did. Merry et al.19 compared 50 patients who had off-pump CABG with heparin vs 50 patients who had the same procedure, using bivalirudin. Graft patency and flow was better in the bivalirudin group. These results are noteworthy, and raised a question as to whether bivalirudin anticoagulation really improved graft patency. This may be possible, because thrombin has mitogenic properties and bivalirudin as a DTI can slow down or inhibit endothelial proliferation, and protect newly sutured grafts.
Our experience with bivalirudin for anticoagulation during CPB in this patient with HIT and endocarditis was highly favourable. This patient had none of the complications reported with the use of alternative anticoagulants for CPB, which included excessive bleeding during the post-bypass period, or thrombosis within the extracorporeal circulation. We did not have problems achieving adequate anticoagulation before CPB or monitoring with kACT during CPB. This case report suggests that bivalirudin is a viable alternative anticoagulant in a HIT-positive patient during CPB for complex redo cardiac surgery.
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Footnotes |
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2 Gurbuz AT, Elliot WG, Zia AA. Heparin-induced thrombocytopenia in the cardiovascular patient: diagnostic and treatment guidelines. Eur J Cardiothorac Surg 2005; 27: 138–49.
3 Sciulli TM, Mauro VF. Pharmacology and clinical use of bivalirudin. Ann Pharmacother 2002; 36: 1028–41.[Abstract]
4 Davis Z, Anderson R, Short D, Garber D, Valgiusti A. Favorable outcome with bivalirudin anticoagulation during cardiopulmonary bypass. Ann Thorac Surg 2003; 75: 264–5.
5 Bott JN, Reddy K, Krick S. Bivalrudin use in off-pump myocardial revascularization in patients with heparin-induced thrombocytopenia. Ann Thorac Surg 2003; 76: 273–5.
6 Koster A, Spiess B, Chew DP, et al. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 2004; 93: 356–9.[Medline]
7 Matthai WH Jr. Thrombocytopenia in cardiovascular patients. Diagnosis and management. Chest 2005; 127: 46S–52S.
8 Magnani HN, Beijering RJ, Ten Cate JW, Chong BH. Orgaran anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. In: Pifarre R (Ed.). New Anticoagulants for the Cardiovascular Patient. Philadelphia: Hanley & Belfus Inc.; 1997: 487–500.
9 Zulys VJ, Teasdale SJ, Michel ER, et al. Ancrod (Arvin®) as an alternative to heparin anticoagulation for cardiopulmonary bypass. Anesthesiology 1989; 71: 870–7.[Medline]
10 Koster A, Hansen R, Kuppe H, Hetzer R, Crystal GJ, Mertzlufft F. Recombinant hirudin as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients. J Cardiothorac Vasc Anesth 2000; 14: 243–8.[Medline]
11 Edwards JT, Hamby JK, Worrall NK. Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg 2003; 75: 1622–4.
12 Nuttall GA, Oliver WC Jr, Santrach PJ, et al. Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmonary bypass: a prospective observational case series. Anesth Analg 2003; 96: 344–50.
13 Malherbe S, Tsui BC, Stobart K, Koller J. Argatroban as anticoagulant in cardiopulmonary bypass in an infant and attempted reversal with recombinant activated factor VII. Anesthesiology 2004; 100: 443–5.[Medline]
14 Cannon MA, Butterworth J, Riley RD, Hyland JM. Failure of argatroban anticoagulation during off-pump coronary artery bypass surgery. Ann Thorac Surg 2004; 77: 711–3.
15 Clayton SB, Acsell JR, Crumbley III AJ, Shackelford AG, Uber WE. Cardiopulmonary bypass with bivalirudin in type II heparin-induced thrombocytopenia. Ann Thorac Surg 2004; 78: 2167–9.
16 Stratmann G, deSilva AM, Tseng EE, et al. Reversal of direct thrombin inhibition after cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. Anesth Analg 2004; 98: 1635–9.
17 Welsby IJ, Stafford-Smith M. Monitoring direct thrombin inhibitors: time for standardization (Letter). Anesthesiology 2004; 101: 1048–9.[Medline]
18 Klenner AF, Lubenow N, Raschke R, Greinacher A. Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature. Thromb Haemost 2004; 91: 719–24.[Medline]
19 Merry AF, Raudkivi PJ, Middleton NG, et al. Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Ann Thorac Surg 2004; 77: 925–31.
20 Koster A, Chew D, Grundel M, Bauer M, Kuppe H, Spiess BD. Bivalirudin monitored with ecarin clotting time for anticoagulation during cardiopulmonary bypass. Anesth Analg 2003; 96: 383–6.
21 Lange U, Nowak G, Bucha E. Ecarin chromogenic assay - a new method for quantitative determination of direct thrombin inhibitors like hirudin. Pathophysiol Haemost Thromb 2003; 33: 184–91.[Medline]
22 Koster A, Despotis G, Gruendel M, et al. The plasma supplemented modified activated clotting time for monitoring of heparinization during cardiopulmonary bypass: a pilot investigation. Anesth Analg 2002; 95: 26–30.
23 Jabr K, Johnson JH, McDonald MH, et al. Plasma modified ACT can be used to monitor bivalirudin (Angiomax®) anticoagulation for on-pump cardiopulmonary bypass surgery in a patient with heparin-induced thrombocytopenia. J Extra Corpor Technol 2004; 36: 174–7.[Medline]
24 Despotis GJ, Hogue CW, Saleem R, et al. The relationship between hirudin and activated clotting time: implications for patients with heparin-induced thrombocytopenia undergoing cardiac surgery. Anesth Analg 2001; 93: 28–32.
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