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NewsletterAprotinin Should Not Be Routinely Used During Deep Hypothermic Circulatory Arrest CON Christopher J. O'Connor, M.D. Because surgery requiring deep hypothermic circulatory arrest (DHCA) is often associated with significant hemorrhage, many clinicians advocate the use of aprotinin to reduce blood loss and transfusion requirements. However, acceptance of this approach was questioned when Sundt and associates reported a dramatically increased incidence of renal failure, death, and widespread microvascular thrombi when aprotinin was used during DHCA. Subsequent investigations revealed the effect of aprotinin on celite-derived ACT, suggesting inadequate heparinization as the probable mechanism of these excessive thromboemboli. Unfortunately, controversy regarding aprotinin use during DHCA persists, largely because no well-designed, randomized, prospective studies have been performed to clarify either the safety or possible benefits of aprotinin in this setting. Clinical data suggesting a detrimental effect of aprotinin or postoperative outcome after DHCA are, at best, circumstantial. Studies have reported an increase in postoperative complications among aprotinin-treated patients, yet small sample size, vague clinical definitions, limited statistical analysis, and lack of randomization have hindered data interpretation. Ehrlich and associates demonstrated no adverse outcomes in the only prospective, randomized evaluation of aprotinin use during DHCA. Unfortunately, the unusually small dose used, one million KIU, prevents legitimate conclusions regarding the safety of standard-dose aprotinin. In addition, they failed to provide information on intraoperative transfusion requirements, reporting a reduction solely in postoperative homologous transfusions, a limitation also encountered with retrospective investigations. Indeed, evidence for a substantial impact of aprotinin on bleeding and transfusion requirements during DHCA is unimpressive, and retrospective data suggest equivalent blood-sparing effects of epsilon aminocaproic acid compared to aprotinin. Considering recent data, which suggests that 40% of patients undergoing ascending aortic surgery require no blood products at all, the utility of aprotinin in this setting must be further questioned. Despite the impression that DHCA is associated with an increased risk of hemorrhage, surprisingly little is known about the hemostatic disturbance induced by circulatory arrest. While it is assumed that profound hypothermia worsens the unfavorable effects of cold temperature on coagulation factors and platelet function, the influence of stasis and hypothermia-induced hyperviscosity on intravascular thrombus formation is less clear. Okita and associates showed that despite kaolin-ACT values > 500 seconds, aprotinin use during DHCA resulted in laboratory evidence of ongoing coagulation and in two cases contributed to the formation of multiple thromboemboli. Also noteworthy is that ACT values were > 750 seconds at all times during cardiopulmonary bypass in three of the five patients sustaining fatal thrombotic complications reported by Sundt and associates, further suggesting that more aggressive heparinization may be required during DHCA when aprotinin is employed. In summary, given the cost of aprotinin in comparison to other antifibrinolytic agents, the absence of significant reductions in transfusion requirements, and the potential for activation of coagulation during DHCA, it may be prudent to withhold aprotinin until further substantive data are available regarding its beneficial and potentially detrimental effects. Restricting its use to procedures associated with substantial hemorrhage, such as acute aortic dissection repair and reoperations, along with an aggressive approach to intraoperative coagulation monitoring using ACT-independent measurements of heparin activity, is probably currently the most rationale application of aprotinin during DHCA. References:
Pro: Bonnie L. Milas, M.D.; University of Pennsylvania
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