Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pharmacologic manipulation of hemostasis is a prerequisite for cardiac surgery with cardiopulmonary bypass (CPB) to prevent clot formation in the extracorporeal circuit. Children who require surgical correction of congenital heart defects are at increased risk for prolonged and excessive bleeding after separation from CPB. Heparin remains the anticoagulant of choice for surgery requiring CPB. Traditional regimens of empiric heparin dosing and a fixed-dose ratio of protamine to heparin for reversal of anticoagulation do not account for individual differences in the half-life of heparin, clearance of heparin, and duration of CPB, particularly in children. In addition, the use of prolongation of the activated clotting time (ACT) as a measure of adequate anticoagulation does not account for alterations in ACT by factors unrelated to heparin activity, including hemodilution and hypothermia, that are frequently present during CPB. This manuscript reviews the pitfalls in the management of anticoagulation for children undergoing surgery that requires CPB. Pertinent literature related to the use of aprotinin, a serine protease inhibitor that has been shown to improve hemostasis during and after CPB, is discussed. It is hoped that this article will provide a practical guideline for the rational management of anticoagulation in children with congenital heart disease undergoing CPB surgery.
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PMID:Monitoring and management of anticoagulation in children requiring extracorporeal circulation. 946 31

Bleeding remains a complication of certain complex surgical procedures, particularly those cardiac operations associated with long bypass times and profound hypothermia. Clinical and novel experimental strategies to reduce bleeding and the need for blood and blood-product transfusions are the focus of this review. Preoperative assessment of the patient will identify drug-induced, acquired, or inherited coagulation defects that may contribute to this problem. The main attention is directed to the perioperative period, and broad areas discussed include the preoperative use of erythropoietin to increase red blood cell mass, autologous donation either preoperatively or before bypass, autotransfusion/hemofiltration, and acceptance of relative anemia both during the operation and into the postoperative period. A further, often overlooked, management strategy in treating major coagulopathies is the consideration of the cost and half-lives of the coagulation factors in individual blood components. Prevention of bleeding has become possible both by manipulation of the control of coagulation and inflammatory processes and by the introduction of pharmacologic agents such as aprotinin. Aprotinin is widely used and has proven efficacy in the management of excess bleeding. It is a serine protease inhibitor and has several possible mechanisms of action, including inhibition of the plasma enzyme systems activated by contact with the foreign surface of the bypass circuit and preservation of platelet function. Safety issues include the possibility of hypersensitivity and anaphylactic reaction on a second exposure. Concerns that aprotinin may induce a prothrombotic or coagulant state have no basis in theory or any good evidence in the current literature. A recent study specifically sought to identify the presence of disseminated microvascular platelet-fibrin thrombi present at autopsy in patients who had received aprotinin therapy. The study concluded that diffuse platelet-fibrin thrombi were not a direct complication of aprotinin therapy. Finally, modern molecular biology has led to the recent development of an inhibitor for factor IXa that competitively replaced IXa in the intrinsic complex and blocked the conversion of factor X to factor Xa. This compound is under investigation in animal studies. These have so far shown efficacy in reducing blood loss after bypass in comparison with standard heparin anticoagulation.
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PMID:Management of bleeding complications in redo cardiac operations. 956 96

Accelerated thrombin generation is central to the development of hemostatic abnormalities during cardiopulmonary bypass (CPB) that are associated with both thromboembolic complications and serious, abnormal bleeding. Thrombin not only converts fibrinogen to fibrin, but also activates platelets and coagulation factors V, VIII, and XI and causes release of von Willebrand factor from vascular endothelium. Thrombin can also downregulate the hemostatic system by inducing formation of platelet inhibitory agents, such as nitric oxide and prostacyclin, and release of tissue plasminogen activator, facilitating activation of protein C, and releasing tissue factor pathway inhibitor. Excessive thrombin activity may also result in substantial consumption of platelets, fibrinogen, and labile coagulation factors and abnormal bleeding. Elevated tissue plasminogen activator levels secondary to activation of the contact system and surgery catalyze the formation of plasmin, which also consumes or internalizes platelet glycoprotein receptors and coagulation factors V, VIII, and fibrinogen. Heparin can reduce the generation of and mediate neutralization of excessive and CPB-associated thrombin activity. Heparin anticoagulation is commonly monitored with the activated clotting time (ACT). However, the ACT may be prolonged by factors other than heparin during CPB, such as hemodilution and hypothermia, and therefore may not accurately reflect the extent of anticoagulation by heparin. Aprotinin, a nonspecific serine protease inhibitor used with CPB, can also prolong celite-based ACT values, rendering it less reliable for monitoring heparin anticoagulation. Therefore, several alternative anticoagulation strategies have been recommended when aprotinin is used, such as a higher celite ACT trigger (>750 seconds), monitoring of whole blood heparin concentrations (eg, >2.7 U/mL), or administration of heparin based on a CPB duration-dependent, fixed-dose regimen. Administration of heparin doses higher than those generally recommended, as guided by predetermined, patient-specific whole blood heparin concentration measurements during bypass, can reduce excessive thrombin-mediated consumption of platelets and coagulation factors as well as post-CPB blood loss and blood component transfusions. New modalities of improving suppression of excess thrombin generation during CPB include use of heparin-bonded CPB circuits, heparin cofactor II or related analogs, supplemental antithrombin III, direct thrombin inhibitors (eg, hirudin, argatroban), and inhibitors of the contact and tissue factor pathways. The safety and efficacy of these approaches remains to be established by additional, appropriately powered, prospective studies.
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PMID:Anticoagulation and anticoagulation reversal with cardiac surgery involving cardiopulmonary bypass: an update. 1046 45

Deep hypothermic cardiopulmonary bypass with or without circulatory arrest has been used to facilitate the surgical repair of complex cerebrovascular lesions. The advantages of deep hypothermia have been tempered by the occurrence of coagulopathy that is associated with substantial morbidity and mortality. This study analyzed retrospectively the records of 13 patients who underwent cerebrovascular neurosurgery using deep hypothermic cardiopulmonary bypass with or without circulatory arrest during the period 1993 through 1999. All patients received the serine protease inhibitor aprotinin in an effort to avoid the development of a coagulopathy, defined as hemorrhage requiring reoperation. No patients developed postoperative intracranial hemorrhage. There was also no evidence of renal dysfunction, deep venous thrombosis, myocardial infarction, or pulmonary embolism. In conclusion, this study suggests that aprotinin may be beneficial to avoid the coagulopathy that is more likely to occur if deep hypothermic cardiopulmonary bypass with or without circulatory arrest is used for craniotomy without adverse effects on renal function or apparent thrombotic complications.
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PMID:Aprotinin and deep hypothermic cardiopulmonary bypass with or without circulatory arrest for craniotomy. 1190 94