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Aprotinin and Deep Hypothermic Circulatory Arrest Reviewer: Mark A. Chaney, MD
One of the most important clinical complications associated with utilization of deep hypothermic circulatory arrest (DHCA) is coagulopathy. Aprotinin, a serine protease inhibitor introduced into clinical practice in the early 1990s, has been shown to reliably attenuate the coagulopathy associated with routine hypothermic cardiopulmonary bypass (CPB) and thus represents a potentially useful drug during utilization of DHCA. However, reports of excessive thromboembolic events and end-organ damage in patients subjected to DHCA while also receiving aprotinin has made use of the drug in this setting controversial. The majority of investigations involving aprotinin use associated with DHCA are retrospective in nature, making interpretation of data difficult. Controversy regarding use of aprotinin in patients subjected to DHCA exists because previous investigations have hinted that use of the drug in this setting may increase morbidity and mortality, the incidence of coagulopathy and thrombosis, or the risk of renal dysfunction (1,2). Because DHCA is typically utilized for complex major aortic surgery in individuals with multiple co-morbidities, it is reasonable to expect high incidences of morbidity and mortality with or without aprotinin. It is now clear that aprotinin has anticoagulant properties and can reduce thrombin and fibrin generation during CPB. On the other hand, aprotinin may initiate or amplify thrombus formation by a tissue factor-dependent process. To complicate matters further, DHCA is unique and different than routine CPB because blood stasis may stimulate intravascular coagulation and thrombosis. Furthermore, it remains unclear how to appropriately anticoagulate and monitor the level of anticoagulation in patients subjected to DHCA,especially when aprotinin is being used. Most of the coagulopathic and thrombotic complica-tions associated with aprotinin were described in the early 1990s, and may have been the consequence of inadequate heparinization when it was not clear how to adjust the dose of heparin. With current recommendations, it is felt by most investigators that risk of coagulopathy or thrombosis in patients receiving aprotinin and subjected to DHCA is minimal. Controversy regarding use of aprotinin in patients subjected to DHCA is fueled by the fact that, at present, the data supporting its ability to reduce blood loss is not compelling, mainly because most investigations in this area have suboptimal study designs. The few well-controlled studies have revealed minimal clinical differences between patients receiving aprotinin or placebo (3, 4). A more recent retrospective investigation has also revealed that, in patients subjected to DHCA, aprotinin did not decrease perioperative blood loss and was not associated with increased risk of renal dysfunction (5). Other frequently-mentioned potential benefits of aprotinin, such as attenuation of the systemic inflammatory response, improved neurologic outcome, and myocardial protection require further proof. In conclusion, many questions remain unanswered regarding the use of aprotinin in patients subjected to DHCA. Its potential to decrease blood loss, attenuate the systemic inflammatory response are supported by limited studies. The potential detrimental effects of aprotinin on morbidity; mortality; coagulopathy; thrombosis; and renal dysfunction also remain controversial. These controversies exist mainly because the vast amount of investigations in this area are not well-controlled. It is also important, when critically assessing these investigations, to consider the anticoagulation protocol used, which is directly related to the time period during which the investigation was performed. Much work still needs to be performed before we can truly assess the risk: benefit ratio of aprotinin when used in patients subjected to DHCA. REFERENCES 1. Royston D. Pro: Aprotinin should be used in patients undergoing
hypothermic circulatory arrest. J Cardiothorac Vasc Anesth 15:121-125,
2001 Table of Contents
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