Year : 2009 | Volume
: 12 | Issue : 1 | Page : 84--86
Intraoperative coronary vein graft thrombosis: Should we blame the use of aprotinin?
S Sivasubramaniam, B Murali, CJ Smallpiece, BAC Smith, M Kalkat
University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, United Kingdom
1 Rhein Way, Stafford-ST17 4XZ
|How to cite this article:|
Sivasubramaniam S, Murali B, Smallpiece C J, Smith B, Kalkat M. Intraoperative coronary vein graft thrombosis: Should we blame the use of aprotinin?.Ann Card Anaesth 2009;12:84-86
|How to cite this URL:|
Sivasubramaniam S, Murali B, Smallpiece C J, Smith B, Kalkat M. Intraoperative coronary vein graft thrombosis: Should we blame the use of aprotinin?. Ann Card Anaesth [serial online] 2009 [cited 2022 Aug 19 ];12:84-86
Available from: https://www.annals.in/text.asp?2009/12/1/84/45022
We present a case of intraoperative coronary graft thrombosis in a patient presenting for urgent CABG on whom aprotinin was used. Coronary artery bypass grafting (CABG) undertaken in patients who are still administering anti-platelet drugs increases the risk of bleeding peri-operatively. Numerous studies have emphasized that aspirin administered before surgery does not necessarily lead to more mediastinal blood loss, transfusion, and repeated operations.  The use of aprotinin has shown to counterbalance the risk of peri-operative haemorrhage in patients treated with aspirin.  High-dose aprotinin significantly reduces blood loss and red blood cell transfusions in these patients. , Despite this beneficial effect of aprotinin in normalising haemostasis, there is concern that it may cause occlusion of coronary grafts. ,
A 65-year-old female was urgently transferred from a district general hospital to our hospital with symptoms of unstable angina and requiring urgent CABG. She administered aspirin until 48 h prior to the operation. Coronary angiography demonstrated severe 3-vessel disease with a well-preserved LV function. She had no other co-morbidity.
On the morning of the operation, the patient had a premedication of diazepam 0.15 mg kg -1 . General anaesthesia was induced with a combination of midazolam 2 mg, etomidate 4vmg, fentanyl 1mg and pancuronium 10 mg. After tracheal intubation, anaesthesia was maintained with air-oxygen-isoflurane mixture. In order to reduce the risk of intraoperative bleeding as a result of continuing aspirin prior to surgery, Aprotinin was administered according to the Hammersmith regime. 2 million kallikrein inhibitory units (KIU) was given prior to sternotomy, 2 million units was added to the cardiopulmonary bypass (CPB) pump, and an infusion of 500,000 KIU h -1 was administered until the completion of the operation. Prior to cannulating the aorta, heparin at a dose of 3 mg kg -1 was administered, and after attaining a kaolin-activated clotting time (kACT) of greater than 480 s, CPB was initiated . Further doses of heparin were administered on CPB to maintain the same level of anticoagulation.
The venous grafts were anastomosed sequentially to the posterior descending artery and the obtuse marginal artery. The left internal mammary artery (LIMA) was anastomosed sequentially to the mid left anterior descending artery and the diagonal branch. All these vessels were of good size and quality.
Following the completion of the anastomoses, separation from cardiopulmonary bypass was easily achieved without any pharmacological or mechanical support. When two-thirds of the dose of protamine had been administered, the ST segments were noted to be elevated > 2 mm in leads II, III and aVF corresponding to the inferior wall. There was no haemodynamic compromise and nitroglycerine infusion was maintained to promote coronary vasodilation. Protamine administration was discontinued, and heparin 3 mg/kg was administered in preparation to return back onto CPB. After the administration of heparin, it was noted that the ST segment changes in leads II, III and aVF had reverted and appeared isoelectric. The grafts appeared to be functioning satisfactorily on external examination, and they milked and filled easily. After observing for a further 5 min for haemodynamic stability, we decided to reverse anticoagulation with protamine. The ST segment elevation reappeared in leads II, III and aVF, as observed previously. This was accompanied by a decrease in the blood pressure. Adrenaline infusion was commenced for maintenance of blood pressure. Protamine administration was discontinued, and heparin was re-administered to achieve full anticoagulation. At this stage, aprotinin administration was stopped due to suspicion of acute graft occlusion. Cardiopulmonary bypass was reinstituted, aortic cross-clamp was applied and VF was stimulated at 37°C. The right coronary artery vein graft, which supplied the area corresponding to the ST segment changes, was opened, revealing a clot sticking at the toe area of the anastomosis, although the anastamosis seemed to be otherwise mechanically patent. The clot was removed, and the anastomosis of the vein to the coronary artery was refashioned. After the removal of the cross clamp, normal sinus rhythm was restored by internal defibrillation. Separation from CPB was achieved with an atrial pacing at 90 beats per minute, and adrenaline infusion was commenced at 0.1 mcg/kg/min. Reversal of heparin with protamine did not cause any ischaemic changes or haemodynamic instability at this instance. At the end of the operation, the patient was transferred to the Intensive Care Unit (ICU). After a few hours of mechanical ventilation on the ICU, the trachea was extubated. It was possible to gradually reduce the dose of adrenaline overnight. She was sent to the High Dependency Unit the next day, where she made an uneventful recovery. She was discharged home on the 6th post-operative day. At the follow-up clinic after 6 weeks, she was feeling well with no chest pain, mobilising well and continuing with the administration of aspirin.
Cardiac anaesthetists and cardiac surgeons have long sought pharmacologic means to reduce bleeding resulting from non-surgical sources. The use of aprotinin for reducing blood loss has been of particular interest. This serine protease inhibitor has a long history of use in clinical medicine, including its use in cardiac surgery as far back as in the 1960s. There was a resurgence of interest in aprotinin in the 1980s following the reports from the United Kingdom by Royston et al,  who demonstrated its blood-sparing effects during cardiac surgery. Favourable results from randomized, double-blind and placebo-controlled trials in the United States led to the approval of aprotinin by the Food and Drug Administration (FDA) (U.S) in 1993 for patients undergoing re-operative CABG surgery or for those at high-risk for excessive bleeding . This approval was later extended to all CABG patients in 1998.
The International Multicenter Aprotinin Graft Patency Experience (IMAGE)  trial was performed to determine whether the frequency of vein graft closure was greater with aprotinin than placebo. The IMAGE trial enrolled 870 patients at 10 U.S. sites and 3 additional sites within Israel and Denmark. In this study, the probability of early vein graft occlusion was increased by aprotinin, but this outcome was promoted by multiple risk factors for graft occlusion. However, aprotinin did not affect the occurrence of myocardial infarction or mortality.
The benefits of aprotinin for reducing bleeding complications from cardiac surgery are not disputed,  albeit its relative efficacy when compared with the lysine analogs, antifibrinolytics tranexamic acid and aminocaproic acid is not completely resolved, particularly for patients at high risk for bleeding. The major question on clinicians' mind is the safety profile of aprotinin. 
Concerns about the potential for aprotinin to lead to intravascular thrombosis are not new and were noted early after its introduction into clinical practice. This was before it was widely known that aprotinin could artifactually prolong the celite-based activated clotting time. Several studies support the conclusion that high-dose aprotinin reduces the incidence of bleeding.
Whilst the IMAGE trial suggests that aprotinin could contribute to coronary graft thrombosis, recent studies suggest the contrary. In an analysis of 8281 cardiac surgical patients treated with aprotinin by Wulf Dietrich et al ,  they tested the hypothesis that aprotinin doses of more than 6 × 10² KIU per patient may be more effective in reducing bleeding compared with a high-dose regimen of 5-6 × 10² KIU aprotinin. The aprotinin doses administered for 8281 adult cardiac surgical patients were correlated to the body weight and time of operation. The proportion of patients requiring allogeneic blood transfusion was reduced from 55% to 47% on comparison between the lowest with the highest dosing group ( p <0.01). Aprotinin dose was also an independent predictor for rethoracotomy for surgical haemostasis. The results support the hypothesis that a more individualized aprotinin regimen with potentially higher doses may optimize the effectiveness of aprotinin therapy in cardiac surgery.
|1||Bybee KA, Powell BD, Valeti U, Rosales AG, Kopecky SL, Mullany C, et al . Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting. Circulation 2005;112:I286-92.|
|2||Royston D, Taylor KM, Bidstrup BP, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-91.|
|3||Dietrich W, Spannagl M, Jochum M, Wendt P, Schramm W, Barankay A, et al . Influence of high-dose aprotinin treatment on blood loss and coagulation pattern in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119-26.|
|4||Dietrich W, Busley R, Kriner M. High-dose aprotinin in cardiac surgery: Is high-dose high enough? An analysis of 8281 cardiac surgical patients treated with aprotinin. Anesth Analg 2006;103:1074-81.|
|5||Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, et al . Analyses of coronary graft patency after aprotinin use: Results from the International Multicenter A protinin Graft Patency Experience (IMAGE) trial. J Thoracic Cardiovasc Surg 1998;116:716-30.|
|6||Alvarez JM, Chandraratna H, Newman MA, Levy JH. Intraoperative coronary thrombosis in association with low dose aprotinin therapy. J Cardiothorac Vasc Anesth 1999;13:623-8.|
|7||Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, et al . Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007 297;5:471-9.|
|8||Grant MC, Kon Z, Joshi A, Christenson E, Kallam S, Burris N, et al. Is aprotinin safe to use in a cohort at increased risk for thrombotic events: Results from a randomized, prospective trial in off-pump coronary artery bypass. Ann Thorac Surg 2008;86:815-22.|