Low-dose Aprotinin Administration Research Articles

Continuous Localized Monitoring of Plasmin Activity Identifies Differential and Regional Effects of the Serine Protease Inhibitor Aprotinin: Relevance to Antifibrinolytic Therapy

Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis after cardiac surgery. However, aprotinin was empirically dosed, and although the pharmacological target was the inhibition of plasmin activity (PLact), this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical empirical aprotinin dosing would impart differential and regional effects on PLact. Pigs (30 kg) were instrumented with microdialysis probes to continuously measure PLact in myocardial, kidney, and skeletal muscle compartments (deltoid) and then randomized to high-dose aprotinin administration (2 mKIU load/0.5 mKIU/hr infusion; n = 7), low-dose aprotinin administration (1 mKIU load/0.250 mKIU/hr infusion; n = 6). PLact was compared with time-matched vehicle (n = 4), and PLact was also measured in plasma by an in vitro fluorogenic method. Aprotinin suppressed PLact in the myocardium and kidney at both high and low doses, indicative that both doses exceeded a minimal concentration necessary for PLact inhibition. However, differential effects of aprotinin on PLact were observed in the skeletal muscle, indicative of different compartmentalization of aprotinin. Using a large animal model and a continuous method to monitor regional PLact, these unique results demonstrated that an empirical aprotinin dosing protocol causes maximal and rapid suppression in the myocardium and kidney and in turn would likely increase the probability of off-target effects and adverse events. Furthermore, this proof of principle study demonstrated that continuous monitoring of determinants of fibrinolysis might provide a novel approach for managing fibrinolytic therapy.

Low dose aprotinin and low dose tranexamic acid in elective cardiac surgery with cardiopulmonary bypass

The antifibrinolytic agents aprotinin and tranexamic acid have both been proven to be efficient in reducing postoperative blood loss and transfusion requirements in patients in cardiac surgery. In light of recent safety issues regarding aprotinin, this single-centre study compared efficacy and safety of low dose aprotinin (2 million KIU, pump-prime volume only) and low dose tranexamic acid (1 g, pump-prime volume) in 708 consecutive patients from two prospective registers undergoing elective cardiac procedures with cardiopulmonary bypass (CPB). Incidences of postoperative complications showed no significant differences between groups. Postoperative blood loss and transfusion requirements were significantly lower in aprotinin compared to tranexamic acid patients. Overall, both antifibrinolytic low dose regimens are safe components of perioperative patient management in elective cardiac surgery with CPB. Cardiac procedures requiring longer CPB times might benefit from the administration of low dose aprotinin.

Aprotinin for Patients Exposed to Clopidogrel before Off-Pump Coronary Bypass

To verify whether low-dose aprotinin reduces blood loss and blood product usage in patients with clopidogrel exposure within 5 days before off-pump coronary artery bypass, 51 patients with clopidogrel exposure were randomized in a double-blind fashion to receive low-dose aprotinin (25 patients), or placebo (26 patients). The baseline characteristics and number of distal anastomoses in the patients in each group were comparable. Time between the last dose of clopidogrel and start of the operation was similar in both groups, as was mean left ventricular ejection fraction. Chest tube drainage, blood product usage, and reoperation rate were significantly higher in the placebo group. In patients with unstable angina and recent clopidogrel exposure who are undergoing off-pump coronary artery bypass, intraoperative administration of low-dose aprotinin is recommended to reduce blood loss and transfusion requirements.

The Effect of Low Dose Aprotinin on Postreperfusion Fibrinolysis in Liver Transplantation

Background: The patients with end-staged liver failure are subjected to various and complex coagulopathies during liver transplantation. Particularly, fibrinolysis can occur preoperatively and is more prominent and aggravated right after reperfusion to the donated liver. It becomes the main cause of bleeding intraoperatively and postoperatively. We examined the effect of low dose aprotinin on the fibrinolysis and the transfusion amount of the packed red cell during operation. Methods: We divided the patients into an experimental group, administrating aprotinin (n = 20) and a control group, administrating same volume of normal saline (n = 28). Heparinase-guided thromboelastograph (h-TEG) of preanhepatic 60 minutes was done as basic value. Then we administrated 1 million KIU aprotinin for 20 minutes and infused 0.25 million KIU /hr aprotinin for 3 hours of preanhepatic period in the experimental group. Just after the reperfusion to donated liver, another h-TEG of postanhepatic 10 minutes was done. We obtained CL 60 (clot lysis 60) and MA (maximum amplitude) among the TEG parameters and counted the total number of packed red cell transfused before and after the reperfusion period. Results: The results showed that the experimental group had significantly higher value of CL 60 and MA in the h-TEG of postanhepatic 10 minutes and lower amount of packed red cell transfusion during the period after the reperfusion. Conclusions: The administration of low dose aprotinin during preanhepatic period reduced the activation of fibrinolysis and the total packed red blood cell transfusion after the reperfusion in liver transplantation.

Low-dose postoperative aprotinin reduces mediastinal drainage and blood product use in patients undergoing primary coronary artery bypass grafting who are taking aspirin: A prospective, randomized, double-blind, placebo-controlled trial

Background: Although low-dose aprotinin administered after cardiopulmonary bypass has been reported to reduce mediastinal blood loss and blood product requirements in patients not taking aspirin, it is unknown whether low-dose postoperative aprotinin has any beneficial effects in patients undergoing coronary artery bypass operations who are at high risk of excessive postoperative bleeding and increased transfusion requirements because of aspirin use until just before the operation. Methods: Fifty-five patients undergoing primary coronary artery operations with cardiopulmonary bypass who continued taking aspirin (150 mg/d) until the day before the operation were enrolled in a prospective, randomized, double-blind trial to receive a single dose of either placebo (n = 29) or 2 × 10 6 kallikrein inhibiting units of aprotinin (n = 26) at the time of sternal skin closure. Results: Patients in the aprotinin group had a lower rate (28 ± 18 vs 43 ± 21 mL/h [mean ± standard deviation], P < .005) and total volume of mediastinal drainage (955 ± 615 vs 1570 ± 955 mL, P < .007), as well as a shorter duration of mediastinal drain tube insertion (24.4 ± 13.8 vs 31.3 ± 16.5 hours, P < .05). In addition, a smaller proportion of patients receiving aprotinin required a blood product (31% vs 62%, P = .03), resulting in a reduction in the use of packed cells by 47% ( P = .05), platelets by 77% ( P = .01), fresh frozen plasma by 88% ( P = .03), and total blood products by 68% ( P = .01) in this group. Conclusions: These results suggest that postoperative administration of low-dose aprotinin in patients taking aspirin until just before primary coronary artery operations with cardiopulmonary bypass not only reduces the rate and total amount of postoperative mediastinal blood loss but also lowers postoperative blood product use.

The effects of aprotinin on blood product transfusion associated with thoracic aortic surgery requiring deep hypothermic circulatory arrest

Objective: To compare the effects of aprotinin on blood product use and postoperative complications in patients undergoing thoracic aortic surgery requiring deep hypothermic circulatory arrest. Design: A retrospective study. Setting: A university hospital. Participants: Nineteen patients who underwent elective or urgent thoracic aortic surgery. Interventions: None. Measurements and Main Results: The total number of units of packed red blood cells, fresh frozen plasma, and platelets was significantly less in the group that received aprotinin (p = 0.01, 0.04, and 0.01). The intraoperative transfusion of packed red blood cells and platelets, collection and retransfusion of cell saver, and postoperative transfusion of fresh frozen plasma were also significantly less in the aprotinin group (p = 0.01, 0.02, 0.01, and 0.05). No patient in either group sustained renal dysfunction or a myocardial infarction. Two patients who had not received aprotinin suffered from chronic postoperative seizures, and one patient who had received aprotinin sustained a perioperative stroke. Conclusions: Low-dose aprotinin administration significantly decreases blood product transfusion requirements in the setting of thoracic aortic surgery requiring deep hypothermic circulatory arrest, and it does not appear to be associated with renal or myocardial dysfunction. Copyright © 2000 by W.B. Saunders Company

Low-dose aprotinin is ineffective to treat excessive bleeding after cardiopulmonary bypass

Background. Uncontrolled clinical experience at our institution suggested that low-dose aprotinin could control excessive bleeding after cardiopulmonary bypass (CPB). A randomized clinical trial was conducted to determine the efficacy of low-dose aprotinin in the treatment of hemorrhage after cardiac surgery.Methods. One hundred seventy-one patients undergoing cardiac surgery with CPB were included. Forty-four patients (26%) bled significantly in the intensive care unit (>100 mL/h) and received either aprotinin (200,000 KIU bolus + 100,000 KIU/h for 8 hours) or placebo in addition to our standard management of excessive bleeding.Results. Median bleeding before study drug administration was not different between aprotinin (200 mL) and placebo (212.5 mL) groups. Bleeding decreased significantly with time and similarly in both groups. Ninety-five percent of patients required transfusions in both groups. Median blood products transfused were 13 and 8 units per patient in the aprotinin and placebo groups respectively (p = NS).Conclusions. Routine administration of low-dose aprotinin as part of the treatment protocol to control hemorrhage after CPB does not reduce bleeding or transfusion requirements and, therefore, cannot be recommended.

Aprotinin and recombinant human erythropoietin reduce the need for homologous blood transfusion in cardiac surgery

The effects of low dose aprotinin (Trasylol) and preoperative administration of recombinant human erythropoietin (EPO) were evaluated in 144 patients undergoing cardiopulmonary bypass divided into four groups. Group I (n = 43) received a subcutaneous administration of EPO (18,000 U) one week before operation and intraoperative administration of low-dose aprotinin (mean; 1.38 +/- 0.26 x 10(6) kallikrein inactivator units; KIU) from extracorporeal circulation, group II (n = 39) received only preoperative administration of EPO, group III (n = 28) received only intraoperative administration of low-dose aprotinin (mean; 1.46 +/- 0.25 x 10(6) KIU), and group IV (n = 34) were not administered either drug. Compared with group IV, the intraoperative blood loss was significantly lower in group I (p < 0.01), and in group II or III (p < 0.05). The postoperative drainage in 24 hours was significantly lower in groups I and III receiving aprotinin than in the other groups. The mean volume of total homologous blood transfusion and the percentage of cases not requiring a homologous blood transfusion in each group was, respectively, 74 +/- 235 ml and 88.4% in group I, 282 +/- 1289 ml and 87.2% in group II, 414 +/- 584 ml and 60.7% in group III, and 976 +/- 1931 ml and 44.1% in group IV. Significant differences were recognized between group I and group IV (p < 0.05). These findings indicate that when used in combination, both drugs reduce blood loss and the need for a homologous blood transfusion more effectively than either drug alone.

Effect of low-dose aprotinin on coagulation and fibrinolysis in cardiopulmonary bypass

To study the effect of low-dose aprotinin on hemostasis in patients undergoing cardiopulmonary bypass (CPB) for coronary artery bypass operations and to elucidate the mechanism of aprotinin action, we randomized 14 of 27 patients to receive 30,000 KIU/kg aprotinin in the CPB priming volume and 7,500 KIU/kg aprotinin intravenously each hour during CPB (1 patient was excluded from the aprotinin group because of protamine shock). Intraoperative and postoperative blood loss was significantly reduced in the aprotinin group. Antithrombin III level was significantly decreased, and the levels of thrombin-antithrombin III complexes were significantly increased during CPB in both groups, indicating activation of the clotting system. The marked increase in fibrin(ogen) degradation products during CPB in the control group, indicating enhanced fibrinolytic activity, was significantly reduced in the aprotinin group. α 2-Plasmin inhibitor was significantly reduced during CPB in the control group. The marked increase in α 2-plasmin inhibitor-plasmin complexes in the control group, indicating plasmin activity, was significantly reduced in the aprotinin group. A marked decrease in the platelet count was observed during CPB similarly in both groups. These findings demonstrated that low-dose aprotinin administration was effective in reducing intraoperative and postoperative blood loss and that activation of the clotting system during CPB was not followed by hyperfibrinolysis in aprotinin-treated patients. The improved hemostasis is mainly attributable to the prevention of hyperfibrinolysis during CPB.