Reports

Speakers here agreed that correcting risk factors for post-operative bleeding prior to surgery, meticulous surgical technique and restricted use of transfusion products all help conserve blood in the cardiac surgery setting. But in cases where massive, uncontrolled post-operative hemorrhage does occur, there is increasing interest in the use of recombinant factor VIIa (rFVIIa) to slow down and stop bleeding when all other strategies have failed.

Considering the Risk Factors

As pointed out by Dr. John Murkin, Professor of Anesthesia and Perioperative Medicine, University of Western Ontario, London, in patients undergoing repeat median sternotomy or those in whom combined coronary bypass and valvular surgery are undertaken, there is an increased risk of significant bleeding requiring blood component therapy.

The same is also true for patients undergoing major vascular surgery, including aorta and aortic arch procedures. Cardiac patients almost always are on antiplatelet or anticoagulant therapy, both of which increase bleeding risk, while patients who are anemic or who have a low red cell mass (RCM) are also at heightened risk of requiring transfusion therapy. Advanced age is also predictive of post-operative bleeding, as is the presence of other comorbidities such as congestive heart failure.

As Dr. Murkin commented, “Transfusion is not innocuous.” According to one review on the performance of a system designed to prevent the possibility of transfusion error, the rate of methodological errors was 1/55 units transfused. In this review, the system detected and avoided four potential fatal errors, estimated to occur at a rate of 1/2748 units. The development of antibodies to antigens in homologous blood products can result in acute hemolytic reactions, Dr. Murkin noted. Transfusion of homologous blood and blood products may also lead to immunosuppression, febrile reactions and bacterial and viral transmission.

Evidence also suggests that patients who receive transfusions in a variety of settings may not fare as well as those who receive fewer or no transfusions. In one Ottawa-based study cited by Dr. Murkin, ICU patients with multi-organ dysfunction were no more likely to deteriorate as a consequence of receiving fewer transfusions than those who were transfused more liberally. Indeed, outcomes were somewhat better in patients who received fewer transfusions. Another study showed that the risk of renal injury was greater in patients who had received intraoperative transfusions compared with those who had not.

The prophylactic use of fresh frozen plasma (FFP) does not affect perioperative blood loss in cardiac surgery, nor does reinfusion of chest tube drainage decrease red blood cell (RBC) use. Cell salvage is only marginally effective in cardiac surgery, Dr. Murkin indicated. In fact, transfusion appears to increase mortality risk in cardiac patients.

In one study of over 1900 high-risk coronary artery bypass patients from July 1994 to December 1997, transfused patients had twice the mortality rate at 15% at five years than did non-transfused patients (Engoren et al. Ann Thorac Surg 2002;74(4):1180-6). Adjusted for comorbidities, “transfusion was still associated with a 70% increase in mortality,” Dr. Murkin emphasized. In order to minimize bleeding risk and transfusion-associated complications, he recommended that hemoglobin (Hb) be optimized and RCM augmented through the use of erythropoietin plus supplemental iron prior to surgery. Up to 4 units of blood may also be stored within one month of surgery without compromising preoperative Hb concentrations, he told the audience.

New STS Guidelines

New guidelines from the Society of Thoracic Surgeons (STS) presented by Dr. Victor Ferraris, Professor and Chief, Cardiovascular and Thoracic Surgery, University of Kentucky Chandler Medical Center, Lexington, recommend a number of strategies to lessen the risk of blood loss during cardiac surgery.

There is solid evidence supporting the use of a blood transfusion algorithm, with point of care testing, as a means of conserving blood. High-dose aprotinin has also been shown to help conserve blood during cardiac surgery. In contrast, the use of low-dose heparin on cardiopulmonary bypass (CPB), heparin-bonded circuits and plasma- or platelet-pheresis do not help conserve blood in surgical settings. The guidelines also recommend that clopidogrel be stopped five days prior to surgery, abciximab 12 to 24 hours before surgery and short-acting glycoprotein IIb/IIIa inhibitors stopped two to six hours prior to surgery, although the latter may be protective in certain circumstances, noted Dr. Ferraris. In recognition of the fact that ASA is essential in the treatment of many cardiac patients, especially those with acute coronary syndromes, the guidelines recommend ASA be stopped prior to surgery but only in selected patients.

The STS guidelines suggest RBC transfusion is indicated in patients whose Hb drops to £6 g/dL (£60 g/L) on CPB. In contrast, the benefits of transfusion are less certain in stable patients with Hb between 8 and 10 g/dL (80 to 100 g/L). Transfusion is not indicated in patients with Hb ³10 g/dL (³100 g/L) after CPB, provided they have no signs of end-organ ischemia.

Management Option for Significant Bleeding

According to Dr. C. David Mazer, Professor of Anesthesia, St. Michael’s Hospital, University of Toronto, Ontario, significant bleeding following cardiac surgery occurs in about one-third of patients, while approximately 20% of patients develop significant microvascular bleeding after cardiac surgery. Massive, uncontrolled post-cardiac surgery bleeding requiring urgent re-operation occurs much less commonly (2 to 6%) and can be very difficult to control using traditional transfusion strategies. Hence, the increasing interest in the use of rFVIIa, a recombinant human protein similar to human coagulation factor VIIa. Its main mechanism of action is to boost thrombin generation from activated platelets which then leads to fibrin formation.

In an initial experience at Toronto General Hospital, researchers observed that prior to receiving rFVIIa, bleeding in a series of cardiac surgery patients was occurring at a rate of 200 to almost 400 mL/hr (Karkouti et al. Transfusion 2005;45(1):26-34). “After rFVIIa, blood loss dramatically and for a prolonged period fell to <100 mL/hr, and the average change in blood loss [pre- and post-rFVIIa] was approximately 250 mL/hr,” Dr. Mazer reported.

To date, only one randomized trial with this agent has been carried out in the cardiac surgery setting. Investigators evaluated transfusion required prior to the ICU, in the ICU and a combination of both (Diprose et al. Br J Anaesth 2005;95(5):596-602). Some 20 cardiac surgery patients were randomized to rFVIIa 90 µg/kg or placebo. Overall, entire allogeneic blood exposure was significantly reduced in the rFVIIa arm, as was the total number of patients transfused and the total number of units transfused compared with placebo controls, Dr. Mazer noted.

As a prothrombotic, there is a potential for thrombotic complications to arise with rFVIIa use and in his own experimental models, Dr. Mazer and colleagues observed occlusive thrombi in both veins and arteries in animals treated with very high doses of rFVIIa. However, safety data from 13 clinical trials did not show an increased risk of thromboembolic events with rFVIIa use in a variety of clinical settings (Levy et al. Transfusion 2006;46(6):919-33).

As Karkouti et al. suggested, rFVIIa might also be considered if there is excessive blood loss >2000 mL; if bleeding required the transfusion of at least 4 units of RBCs and prevented closure in the operating room; or if bleeding was ongoing at >100 mL/hr in the ICU—“provided you have eliminated surgical bleeding and done your best to normalize or optimize coagulation,” Dr. Mazer emphasized. Doses ranging from 2.4 to 4.8 mg may be considered for a maximum of two doses.