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Aprotinin Should Be Routinely Used During Deep Hypothermic Circulatory Arrest

PRO

Bonnie L. Milas, MD
Assistant Professor
University of Pennsylvania
Philadelphia, PA

The use of aprotinin in cardiac surgery has been surrounded by controversy. Perhaps the most controversial use of aprotinin is during application of deep hypothermic circulatory arrest (DHCA). Aprotinin has proven to be efficacious and safe in preventing bleeding following primary and repeat coronary artery bypass graft (CABG) surgery. It is logical to speculate that aprotinin would offer similar benefits in cardiac surgical cases that employ DHCA. Concern has been raised regarding aprotinin's prothrombotic effect under conditions of blood stasis and deep hypothermia (conditions unique to DHCA).

Clinical investigations comparing aprotinin with controls in DHCA have primarily focused on complications such as neurologic deficits, renal dysfunction, and mortality. Aprotinin's role in the genesis of renal dysfunction has received the most attention. There are few controlled clinical studies that address these issues and the number of subjects in the treatment groups has been small^1-4. The most alarming findings were the initial studies of Sundt and Westaby^1,2. Sundt and associates found mortality occurred in 35% (7/20) of the aprotinin treated patients versus 5% (1/20) of controls, renal dysfunction (defined as creatinine > 1.5 times preoperative values) in 65% (13/20) of the aprotinin patients versus 5% (1/20) of controls, and 25% (5/20) of the aprotinin treated patients required dialysis versus none of the controls. Westaby and associates reported a greater incidence of coagulation abnormalities in their aprotinin treated group, with reoperation for bleeding required in 6/53 aprotinin treated patients versus 0/27 control patients. They also claimed a higher incidence of thrombosis related deaths in the aprotinin group yet there were five deaths in both the aprotinin and the control groups (some patient deaths in each group may have been attributable to thrombosis). Both the Sundt and Westaby studies were conducted before 1995, when it was recognized that celite activated clotting times (ACT) were prolonged in the presence of aprotinin. The current recommendation is to maintain the celite ACT > 750 seconds or to use the kaolin ACT (which is not affected by aprotinin). Thus, complications emerging in these initial studies have been attributed to inadequate heparinization. Subsequent studies using currently recommended heparin protocols have failed to show a statistically significant increase in mortality, neurologic deficits, or renal dysfunction/failure in aprotinin treated patients undergoing DHCA ^3,4.

While lacking in proven deleterious effects, aprotinin offers potential beneficial effects. Surprisingly, evidence for aprotinin's efficacy in reduction of blood loss and transfusion requirements in DHCA is underwhelming. This may be attributable to the lack of uniform methods of reporting blood loss and the lack of stringent perfusion protocols. However, in the only adult prospective, randomized, placebo-controlled study, Ehrlich and associates found aprotinin significantly reduced blood loss and transfusion requirements⁴. Some investigators suggest that aprotinin may be neuroprotective via anti-inflammatory effects. Levy and colleagues found no instances of stroke in their high- and low-dose aprotinin groups (all patients were repeat CABG surgery)⁵. Of their 287 total patients, six suffered a stroke: one in the pump-prime-only group and five in the control group. Whether aprotinin is neuroprotective in DHCA cases, as well as CABG surgery, remains to be proven. Taylor and associates at the Hammersmith Hospital are currently developing a rat capillary model demon-strating aprotinin's role in preventing the extravascular transmigration of white blood cells (unpublished data). From the transplantation literature, aprotinin has been found to increase pulmonary compliance, decrease pulmonary capillary permeability, decrease pulmonary artery pressure, and decrease alveolar-arterial oxygen gradient. This evolving information suggests that aprotinin offers a variety of beneficial effects in addition to its antifibrinolytic effects.

There remains the need for further prospective, randomized, placebo-controlled, blinded studies on a much larger scale. Variables between these studies must be carefully evaluated, such as acute versus chronic aortic disease, location of aortic pathology, preoperative exclusion creatinine, heparin protocols, aprotinin dosing, use of retrograde cerebral perfusion, etc. More evidence exists supporting the safety of high-dose aprotinin and some authors support only high-dose aprotinin therapy. There appears to be no convincing evidence to withhold aprotinin for cardiac surgery utilizing DHCA.

References

1. Sundt TM, et al. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993; 55: 1418-24.
2. Westaby S, et al. Aprotinin and bleeding in profoundly hypothermic perfusion. Eur J Cardiothorac Surg 1994; 8: 82-6.
3. Parolari A, et al. Aprotinin and deep hypothermic circulatory arrest: there are no benefits even when appropriate amounts of heparin are given. Eur J Cardiothorac Surg 1997; 11: 149-56.
4. Ehrlich M, et al. Operations on the thoracic aorta and hypothermic circulatory arrest: is aprotinin safe? J Thorac Cardiovasc Surg 1998; 115: 220-5.
5. Levy JH, et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995; 92: 2236-44.

Con: Christopher J O'Connor, M.D.; Rush Medical College





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