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Ann Thorac Surg 2003;75:483-484
© 2003 The Society of Thoracic Surgeons
Department of Anesthesiology, Emory University Hospital, 1364 Clifton Rd, NE, Atlanta, GA 30322, USA
e-mail: jerrold_levy{at}emoryhealthcare.org
Stroke is one of the most devastating complications following cardiac surgery. In 1995, we reported a prospective study in patients undergoing repeat coronary artery bypass graft surgery and noted that administration of full dose and half dose aprotinin significantly reduces the requirement for donor-blood transfusion. Although the study was not specifically designed to assess aprotinin and stroke risk, the decreased need for transfusion was associated with a decreased incidence of stroke [1]. Interestingly, this finding has been confirmed in both a retrospective analysis of aprotinin use in clinical studies [2] and in the study reported by Furmin and colleagues from Columbia [3]. Furmin and colleagues, using their recent database of 1,524 patients, retrospectively evaluated patients at an increased risk of stroke who had half and full dose regimens of aprotinin. Postoperative stroke was specifically defined as a new cerebral infarct confirmed by computed tomography or magnetic resonance imaging. They noted that intraoperative administration of only full dose aprotinin to cardiac surgical patients at high risk of perioperative stroke was associated with a reduced incidence of stroke. These data further support the concept that aprotinin may have a neuroprotective effect.
The mechanism of action for aprotinin’s neuroprotective effect may be via antiinflammatory effects. Inflammation and thrombosis are closely linked, and inflammation is an important contributing factor in ischemic brain injury [4, 5]. Furthermore, atheromatous debris from the aorta can embolize to the cerbral circulation to produce endothelial dysfunction and prothrombotic effects. Aprotinin inhibits thrombin mediated protease activation receptor (PAR) [5], and experimental evidence suggests that inhibition of thrombin attenuates neurodegeneration after an ischemic insult [6]. Aprotinin also inhibits platelet PAR receptors, suggesting that aprotinin may have significant antithrombtic effects [4, 5]. Thrombin mediated activation of central nervous system protease-activated receptors (PAR) may contribute to brain injury associated with stroke [7]. Therefore, aprotinin may prevent and/or decrease the severity of stroke by an antiinflammatory mechanism and by its inhibition of PARs.
Other factors, including the reduction in the need for platelets, may also be important in reducing the potential for stroke in association with aprotinin administration. Platelet transfusions may potentially increase the risk for stroke and other serious adverse events [8]. Platelet concentrates contain multiple proinflammatory mediators; cytokine levels are increased 100–1000-fold over baseline in platelet products [9–11]. Although many blood banks now use leukoreduction for platelets and other products, this practice may be only partially effective in reducing the immunosuppressive effects of platelets [12].
In summary, drugs like aprotinin, that exhibit a broad spectrum of beneficial effects via multiple mechanisms, tend to have unique efficacy in pharmacology, especially in the complex milieu of cardiac surgery. The current study by Furmin and colleagues further supports the growing concept that aprotinin may exhibit multiple direct and indirect antiinflammatory effects that may be mediated by multiple potential mechanisms inhibiting kallikrein, inhibiting PARs, and decreasing the need for transfused platelets, all of which are potential mechanisms for stroke reduction. The ability to administer prophylactic therapy to patients at increased risk for perioperative events is an important therapeutic approach, as older and more complex patients now undergo cardiac surgery. The more complex, critically ill patients provide an important patient group for new antiinflammatory strategies as we attempt to make cardiac surgery safer.
References
This article has been cited by other articles:
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  A. P. Furnary, Y. Wu, L. F. Hiratzka, G. L. Grunkemeier, and U. S. Page 3rd Aprotinin Does Not Increase the Risk of Renal Failure in Cardiac Surgery Patients Circulation, September 11, 2007; 116(11_suppl): I-127 - I-133. [Abstract] [Full Text] [PDF]
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