Comparison of the effects of aprotinin and tranexamic acid on blood loss and red blood cell transfusion requirements during the late stages of liver transplantation. The effect of two different doses of aprotinin on hemostasis in cardiopulmonary bypass surgery: similar transfusion requirements and blood loss. The efficacy of antifibrinolytics in the reduction of blood loss during complex adult reconstructive spine surgery. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass. Aprotinin decreases blood loss and homologous transfusions in patients undergoing major orthopedic surgery. Effects of minimal dose aprotinin on blood loss and fibrinolytic system-complement activation in coronary artery bypass grafting surgery. Aprotinin and dipyridamole for the safe reduction of postoperative blood loss. [Aprotinin (Antilysin Spofa)--its effect on decreasing hemorrhage in the postoperative period in hip arthroplasty]. Intraoperative antifibrinolysis and blood-saving techniques in cardiac surgery. Prospective trial of 3 antifibrinolytic drugs. Prospective randomized placebo-controlled trial of aprotinin for elective aortic reconstruction. Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Aprotinin does not diminish blood loss in elective operations for infrarenal abdominal aneurysms: a randomized double-blind controlled trial. Randomized study of aprotinin and DDAVP to reduce postoperative bleeding after cardiopulmonary bypass surgery. Aprotinin in coronary operation with cardiopulmonary bypass: does "low-dose" aprotinin inhibit the inflammatory response? Tranexamic acid and aprotinin in primary cardiac operations: an analysis of 220 cardiac surgical patients treated with tranexamic acid or aprotinin. Tranexamic acid and aprotinin in low- and intermediate-risk cardiac surgery: a non-sponsored, double-blind, randomised, placebo-controlled trial. Aprotinin reduces blood loss in patients undergoing elective liver resection. Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin versus autologous fresh whole blood transfusion. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. Aprotinin reduces blood loss in off-pump coronary artery bypass (OPCAB) surgery. Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Continuous small-dose aprotinin controls fibrinolysis during orthotopic liver transplantation. Effects of minimal-dose aprotinin on coronary artery bypass grafting. Comparative effects of small and large aprotinin doses on bleeding during orthotopic liver transplantation. Mini-dose pump-prime aprotinin inhibited enhanced fibrinolytic activity and reduced blood loss and transfusion requirements after coronary artery bypass surgery. The influence of aprotinin and tranexamic acid on platelet function and postoperative blood loss in cardiac surgery. Single dose aprotinin in routine cardiac surgery. Fibrinolysis-adjusted perioperative low-dose aprotinin reduces blood loss in bypass operations. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Changes in coagulation patterns, blood loss and blood use after cardiopulmonary bypass: aprotinin vs tranexamic acid vs epsilon aminocaproic acid. Randomized, placebo-controlled, double-blind study of an ultra-low-dose aprotinin regimen in reoperative and/or complex cardiac operations. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting. "Low-dose" aprotinin modifies hemostasis but not proinflammatory cytokine release. A randomized clinical trial investigating the relationship between aprotinin and hypercoagulability in off-pump coronary surgery. Aprotinin decreases exposure to allogeneic blood during primary unilateral total hip replacement. Reduced blood loss by aprotinin in thoracic surgical operations associated with high risk of bleeding. A placebo-controlled, randomized phase IV study. Efficacy of aprotinin in reducing blood loss in spinal fusion for idiopathic scoliosis. Aprotinin and epsilon aminocaproic acid are effective in reducing blood loss after primary total hip arthroplasty--a prospective randomized double-blind placebo-controlled study. Amelioration of the bleeding tendency of preoperative aspirin after aortocoronary bypass grafting. Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of epsilon-aminocaproic acid and aprotinin. Postoperative bleeding after coronary revascularization. Comparison between tranexamic acid and epsilon-aminocaproic acid. [Comparison of the effects of epsilon-aminocaproic acid and aprotinin on intra- and postoperative bleeding in heart surgery]. Low doses of aprotinin in aortocoronary bypass surgery--advantages and disadvantages. Combination of acute preoperative plateletpheresis, cell salvage, and aprotinin minimizes blood loss and requirement during cardiac surgery. The efficacy and safety of aprotinin for hemostasis during intracranial surgery. Comparison of the effects of a cell saver and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing valve surgery. [Reduction of per- and postoperative blood loss with aprotinin (Trasylol) during extracorporeal circulation]. High-dose epsilon-aminocaproic acid versus aprotinin: antifibrinolytic efficacy in first-time coronary operations. The effect of epsilon-aminocaproic acid and aprotinin on fibrinolysis and blood loss in patients undergoing primary, isolated coronary artery bypass surgery: a randomized, double-blind, placebo-controlled, noninferiority trial. Comparison of epsilon aminocaproic acid and low-dose aprotinin in cardiopulmonary bypass: efficiency, safety and cost. Aprotinin reduces blood loss during spinal surgery in children. Prophylactic tranexamic acid decreases bleeding after cardiac operations. A comparison of the effects of tranexamic acid and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing cardiac surgery. Comparison of blood-conservation strategies in cardiac surgery patients at high risk for bleeding. Antifibrinolytic therapy and perioperative blood loss in cancer patients undergoing major orthopedic surgery. Effect of tranexamic acid on blood loss reduction after cardiopulmonary bypass. Aprotinin and tranexamic acid for high transfusion risk cardiac surgery. Decreasing use of donated blood and reduction of bleeding after orthotopic heart transplantation by use of aprotinin. Continuous small-dose tranexamic acid reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation. [Reducing bleeding during extracorporeal circulation interventions by high doses of aprotinin]. Reduction of blood transfusion requirement in open heart surgery by administration of high doses of aprotinin--preliminary results. Reduction of blood loss and transfusion requirement by aprotinin in posterior lumbar spine fusion. A randomized trial of aprotinin (Trasylol) on blood loss, blood product requirement, and myocardial injury in total arterial grafting. Randomized study of aprotinin effect on transfusions and blood loss in primary THA. Aprotinin reduces cardiac troponin I release and inhibits apoptosis of polymorphonuclear cells during off-pump coronary artery bypass surgery. A possible association between aprotinin and improved survival after radical surgery for mesothelioma. Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. The effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic response after cardiac surgery. Hemostatic efficacy of dipyridamole, tranexamic acid, and aprotinin in coronary bypass grafting. [Comparison of effects of aprotinin and tranexamic acid on blood loss in heart surgery]. Tranexamic acid reduces bleeding and the need for blood transfusion in primary myocardial revascularization. A pump-prime aprotinin dose in cardiac surgery: appraisal of its effects on the hemostatic system. Randomized placebo-controlled double-blind study of three aprotinin regimens in primary cardiac surgery. Recombinant aprotinin in coronary artery bypass graft operations. Aprotinin versus desmopressin for patients undergoing operations with cardiopulmonary bypass. A double-blind placebo-controlled study. Tranexamic acid compared with high-dose aprotinin in primary elective heart operations: effects on perioperative bleeding and allogeneic transfusions. Tranexamic acid reduces bleeding after cardiopulmonary bypass when compared to epsilon aminocaproic acid and placebo. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Tranexamic acid in off-pump coronary surgery: a preliminary, randomized, double-blind, placebo-controlled study. Fibrinolytic inhibition with tranexamic acid reduces blood loss and blood transfusion after knee arthroplasty: a prospective, randomised, double-blind study of 86 patients. Comparison between antifibrinolytic and antiprostaglandin treatment in the reduction of increased menstrual blood loss in women with intrauterine contraceptive devices. Aprotinin prevents cardiopulmonary bypass-induced platelet dysfunction. A scanning electron microscope study. Fibrinolytic activity and bleeding after cardiac surgery with cardiopulmonary bypass and low-dose aprotinin therapy. Effect of reduced aprotinin dosage on blood loss and use of blood products in patients undergoing cardiopulmonary bypass. Low-dose aprotinin infusion is not clinically useful to reduce bleeding and transfusion of homologous blood products in high-risk cardiac surgical patients. Mechanical methods of reducing blood transfusion in cardiac surgery: randomised controlled trial. The effect of prophylactic epsilon-aminocaproic acid on bleeding, transfusions, platelet function, and fibrinolysis during coronary artery bypass grafting. Comparison of two doses of aprotinin in patients receiving aspirin before coronary bypass surgery. Aprotinin in elective primary bypass surgery. Graft patency and clinical efficacy. Fibrinolytic inhibitors in off-pump coronary surgery: a prospective, randomized, double-blind TAP study (tranexamic acid, aprotinin, placebo). Aprotinin reduces blood loss and the need for transfusion in orthognathic surgery. High-dose aprotinin reduces blood loss in patients undergoing total hip replacement surgery. Hemostatic effects of aprotinin, tranexamic acid and epsilon-aminocaproic acid in primary cardiac surgery. The use of fibrin tissue adhesive to reduce blood loss and the need for blood transfusion after total knee arthroplasty. A prospective, randomized, multicenter study. Tranexamic acid and aprotinin reduce postoperative bleeding and transfusions during primary coronary revascularization. Aprotinin but not epsilon-aminocaproic acid decreases interleukin-10 after cardiac surgery with extracorporeal circulation: randomized, double-blind, placebo-controlled study in patients receiving aprotinin and epsilon-aminocaproic acid. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency.
During liver transplantation (LT), profound activation of the fibrinolytic system can contribute significantly to perioperative bleeding. Prophylactic administration of antifibrinolytic agents has been shown to reduce blood loss and the need for allogeneic transfusion in these conditions.
                This prospective randomized trial included 51 cirrhotic patients undergoing LT. Patients were randomly assigned to receive either 280 mg of aprotinin (AP) followed by 70 mg per hour or 40 mg per kg tranexamic acid (TA) followed by 40 mg per kg per hour, administered from the end of the anhepatic phase until 2 hours after reperfusion of the graft, and the effects on blood loss and red blood cell (RBC) transfusion requirements were compared. Transfusion policy was standardized in all patients. In addition, the biological effects of the two drugs, as assessed by coagulation and fibrinolytic markers obtained during surgery, were evaluated in a subgroup of patients from each treatment group and compared with an historical control group that did not receive antifibrinolytic drugs.
                There was no significant difference between the two groups in perioperative blood losses (AP, 6200 [4620-8735] mL; TA, 5945 [4495-8527] mL; median [range]) or in RBC transfusions requirements (AP, 9 [6.75-15.25] units; TA, 10 [6.5-13.5] units). Inhibition of fibrinolysis was observed with both drugs compared with the control group. Coagulation appeared to be activated more with AP, however, whereas fibrinolysis was inhibited more by TA.
                Blood losses and RBC transfusion requirements were comparable regardless of the drug administered. TA may be as valuable as AP for controlling fibrinolysis in LT. Various dosages of aprotinin have proven to be effective in reducing blood loss and allogeneic transfusion requirements in cardiopulmonary bypass surgery, despite the controversy surrounding the precise hemostatic mechanisms of this drug. The aim of our prospective, randomized, double-blind study was to assess differences in blood loss and transfusion requirements and the effect of two dosages of aprotinin on hemostatic activation.
                Patients undergoing coronary artery bypass grafting received high-dose aprotinin (n=28), pump-prime-only (PPO) aprotinin (n=28), or placebo (n=28).
                The high-dose and the PPO groups had a significantly lower blood loss (985 mL [95%CI 845-1,102] and 1,255 mL, [95% CI 1,025-1,406], respectively) than the placebo group (1,416 mL, 95%CI 1,248-1,612]. Transfusion requirements were lower in the aprotinin-treated groups than in the patients receiving placebo (21 units and 15 units in the high and low-dose groups vs 59 units in placebo group). As far as concerns parameters of thrombin generation, the aprotinin groups showed a significant reduction of F1+2 prothrombin fragment but not of thrombin-antithrombin complexes. There were higher levels of natural anticoagulants, i.e. antithrombin, protein C and protein S, in the high-dose aprotinin group. As regards fibrinolysis parameters, D-dimer was lower in the aprotinin groups, and the levels of alpha2-antiplasmin and plasmin-alpha2-antiplasmin complexes were raised. In summary, both dosages of aprotinin were equally effective in reducing blood loss and transfusion requirements. There was a lower activation of coagulation and fibrinolysis in cardiopulmonary bypass patients treated with aprotinin: the levels of natural anticoagulants were less decreased in the high-dose group. No differences in thrombotic complications were observed between aprotinin groups.
                Our study shows that both dosages of aprotinin are safe and effective in reducing transfusion requirements. Considering the difference in cost of using a low-dose or high-dose schedule, the former should be recommended for patients undergoing cardiopulmonary bypass surgery. Controlled study to assess the efficacy of aprotinin and Amicar in reducing blood loss during complex spinal fusions.
                To compare blood loss and the clotting profile with a thromboelastogram in patients with spinal deformities undergoing sequential anterior and posterior spinal fusions treated intraoperatively with either aprotinin or Amicar.
                Spinal fusion for correction of adult spinal deformities is associated with large blood losses despite the implementation of multiple factors to reduce this blood loss. The antifibrinolytics aprotinin and Amicar have both been shown to reduce blood loss in other surgical procedures with the potential for large blood loss. Hence, we compared their efficacy for reducing blood loss in complex spinal fusions.
                Sixty patients for elective sequential anteroposterior thoracolumbosacral fusions were randomly assigned to three groups: control, aprotinin, and Amicar. Patients were assessed for blood loss, transfusion requirements, postoperative complications, and coagulation profile using a thromboelastogram.
                The study demonstrated a significant reduction in total blood loss (aprotinin 3628 mL, Amicar 4056 mL, control 5181 mL) and transfusion requirements using the half-dose aprotinin regimen compared with Amicar or control. Aprotinin also preserved the thromboelastogram mean clot formation time, clot strength, and clotting index compared with Amicar or control.
                For complex spinal operations with large blood losses, the half-dose aprotinin regimen will reduce blood loss and the need for blood components and may have a role in reducing postoperative lung injury. Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences.
                In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days.
                The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22).
                Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).
                Copyright 2008 Massachusetts Medical Society. Aprotinin reduces blood loss after cardiopulmonary bypass, but may sensitize recipients and is expensive. Tranexamic acid, a synthetic antifibrinolytic, has less disadvantages, but opinions differ regarding its efficacy. We studied three groups of patients undergoing cardiopulmonary bypass for coronary disease: recipients of aprotinin (total dose 4.2 x 10(6) kallikrein inhibiting units, n = 14), recipients of tranexamic acid (total dose 20 mg/kg body weight, n = 15), and nonmedicated controls (n = 14) during 24 hours after cardiopulmonary bypass. Compared with controls, aprotinin reduced blood loss, the number of patients requiring transfusions, and the mean number of transfused red cell units (all with p < 0.05), whereas the recipients of tranexamic acid did not differ either from aprotinin recipients or from controls. Aprotinin and tranexamic acid both mitigated the early postoperative reduction of adenosine diphosphate-induced platelet aggregation seen in the controls (p < 0.05). Postoperative increases of plasma concentrations of the prothrombin activation fragment F1 + 2 and the thrombin-antithrombin III complex showed an activation of intravascular coagulation, without any intergroup differences. The balance between concentrations of tissue plasminogen activator and the type 1 plasminogen activator inhibitor disclosed an activation of fibrinolysis, without differences between the groups. The concentrations of D-dimer, a breakdown product of cross-linked fibrin, remained at baseline in the recipients of aprotinin and tranexamic acid but tripled in the controls (p < 0.05). By contrast, the plasma antiplasmin activity was equally depressed in the tranexamic acid and the control groups but decreased less in the recipients of aprotinin (p < 0.05). This discrepancy may reflect the different modes of action of the two agents, which may make aprotinin more efficacious than tranexamic acid in the "nonfibrinolytic" act of protecting platelet function against attack by plasmin during cardiopulmonary bypass. Major orthopedic surgery can be associated with dramatic blood loss, thereby requiring high-volume homologous transfusions in patients unable to benefit from blood salvage techniques. The effect of aprotinin on blood loss and transfusion requirements during orthopedic surgery for either the resection of malignancies of the removal of infected hardware was prospectively studied.
                Twenty-three patients scheduled for orthopedic surgery of the hip, femur, or pelvis for sepsis or malignant tumors, all under general anesthesia, were randomly allocated to receive during operation, in a blinded manner, either aprotinin administered as a bolus of 1.106 kallikrein inactivation units (KIU) followed by an infusion of 5 x 10(5) KIU/h, or the equivalent volume of saline. The anesthesia and perioperative management, as well as the designated transfusion criteria, were standardized. The total blood loss of each patient was evaluated using intraoperative suction losses, sponge weights, and postoperative volumetric drainage. Homologous transfusion requirements were noted. Hemoglobin and hematocrit measures, as well as coagulation and fibrinolytic pathway explorations, were performed before and after surgery. Deep venous thrombosis prophylaxis was applied, and the incidence of this complication was assessed.
                Twelve patients received aprotinin. Aprotinin reduced the total blood loss from a median of 5,305 ml (range, 3,000-9,770 ml) to a median of 1,783 ml (range, 1,140-4,955 ml; P < 0.05). A blood loss reduction of 56% during surgery and 68% on discharge from the postanesthesia care unit was observed. Seven units (range, 4-16) of packed erythrocytes were transfused per patient in the placebo group, and 3 (range, 2-5) were transfused in the aprotinin group (P < 0.05). In the aprotinin group, platelet counts were higher, and postoperative prothrombin times and D. Dimer values were lower. The activated partial thromboplastin time values showed no significant difference between the two groups. No side effects were observed in the aprotinin group. A deep venous thrombosis developed in one patient in the placebo group.
                Aprotinin treatment during major orthopedic surgery significantly reduces both blood loss and consequent homologous blood transfusion requirements. To determine whether 500,000 KIU aprotinin is effective to reduce blood loss in coronary artery bypass grafting (CABG) and to evaluate the effects of this regimen on hematologic parameters.
                Forty-four patients scheduled for primary CABG were randomly assigned to the aprotinin (n = 24) or control group (n = 20). In aprotinin group, aprotinin was administered in two equal doses (before skin incision and added to the pump prime). Ventilation time, intensive care unit stay, mediastinal tube drainage, hospitalization, transfusion requirements, and postoperative morbidities and mortality were noted. Hematologic markers of fibrinolytic activity and complement activation were also measured pre- and postoperatively.
                Although less mediastinal drainage occurred in aprotinin group, the difference was not statistically significant. Other postoperative variables like transfusion requirements, morbidities, and mortality were also found to be similar between groups. Among hematologic parameters, only postoperative levels of alpha2-antiplasmin and plasminogen activator inhibitor-1 were significantly higher in aprotinin group.
                Although plasmin inhibitors begin to rise at this very low aprotinin dosage, it is not advisable to use this aprotinin regimen in CABG patients. Aprotinin (APR) reduces postoperative blood loss but may induce thrombosis. Dipyridamole (DIP) limits platelet aggregation and may reduce the thrombotic complications associated with APR.
                To evaluate the safety and effectiveness of combined APR and DIP, we undertook a prospective randomized trial in patients undergoing cardiac operations. Patients were stratified according to risk for bleeding (low or high), and received either DIP with placebo (DIP group; n = 59) or DIP with APR (DIP + APR group; n = 56). Blood samples were obtained for the measurement of hematologic and biochemical parameters. Blood loss and transfusion requirements were documented postoperatively.
                Postoperative blood loss and transfusion requirements were significantly lower in the DIP + APR group at 6, 12, and 24 hours after bypass (p < 0.01). No significant differences were found between groups in the incidence of perioperative mortality (DIP, 0%; DIP + APR, 3%), myocardial infarction (DIP, 0%; DIP + APR, 3%), stroke (DIP, 1%; DIP + APR, 1%), or potential thrombotic events (death, myocardial infarction, and stroke: DIP, 2%; DIP + APR, 5%). In addition, these rates did not differ from those of nonparticipating matched control patients.
                Administration of both drugs simultaneously was more effective than DIP alone in reducing postoperative blood loss. A platelet inhibitor may be required to reduce the thrombotic complications associated with APR. Further studies evaluating graft patency and perioperative ischemia are necessary to confirm the potential benefits of the combination of a platelet inhibitor and APR. Aprotinin is a non-specific inhibitor of serine proteases with hemostyptic and hemostatic properties. The effect covers suppression of fibrinolysis and support of the role of thrombocytes in coagulation. In a prospective randomized study we verified whether the application of aprotinin (Antilysin Spofa, Czech Republic) in the dosage effective in cardiosurgical patients reduces blood loss and the need for blood transfusion for orthopaedic patients.
                42 patients indicated to the primary THA were randomly selected into the study and control groups. Excluded were allergic patients and those who used aprotinin before.
                Administration of 2.10(6) KIU of aprotinin was started preoperatively and is continued in the course of the first hour of surgery. In the operated on patients we recorded prior to operation and in the first post-operative morning the level of hemoglobin in blood and hematocrit, the number of infusions and blood transfusion units administered in the course of the surgery and in the post-operative period until the first post-operative morning. We recorded blood loss in the period between the surgery and the first post-operative morning. Data acquired in the patients of the studied and control groups were compared by means of ANOVA test for repeated measuring and with the use of Mann-Whitney and chi 2-test, the level of significance p < or = 0.05. During the hospitalization we the patients were checked for symptoms of deep venous trombosis and tromboembolic or other adverse events.
                Hemoglobinemia and hematocrit in both groups significantly decreased after the operation (p < 0.0005), the differences between the studied and control groups were not significant. The number of administered blood units did not differ in the examined and control groups. The frequency of blood transfusions was postoperatively higher in the control group (59.1% as compared to 30%), however, the difference was not statistically significant (p = 0.059). Blood loss in the post-operative period was higher in the control group (p = 0.048). Patients from the control group got in total blood transfusion more frequently (p = 0.032). Differences in the total frequency of blood transfusion and in the amount of post-operative blood loss were statistically significant. In the course of hospitalisation no signs of deep phlebothrombosis or thromboembolic condition were encountered in either group of patients. Complications were not recorded.
                Our results correspond with most of the published data. Blood loss of the operated on patients who were administered prior to and at the beginning of the operation in total 2.10(6) KIU of aprotinin (Antilysin Spofa) in infusion was on average by 33% less in the post-operative period and in the whole peropetive period they required less frequently blood transfusion (40% vs 73%).
                Infusion of aprotinin (Antilysin Spofa) in the dosage of the order of 106 KIU significantly reduces post-operative blood loss and frequency of transfusion in the peroperative period in patients undergoing THA. Sixty consecutive patients undergoing elective open-heart surgery were prospectively enrolled in a study to compare the efficacy of 3 different antifibrinolytic drugs to reduce postoperative bleeding and to reduce homologous blood requirements in combination with blood-saving techniques and restrictive indications for blood transfusion. The patients were randomized to 1 of 4 intraoperative treatment regimens: 1) control (no antifibrinolytic therapy); 2) epsilon-aminocaproic acid (10 g IV at induction of anesthesia, followed by infusion of 2 g/h for 5 hours); 3) tranexamic acid (10 mg/kg IV within 30 minutes after induction of anesthesia, followed by infusion of 1 mg/kg per hour for 10 hours); or 4) high-dose aprotinin (2 million KIU IV at induction of anesthesia and 2 million KIU added to the extracorporeal circuit, followed by infusion of 500 thousand KIU/h during surgery). Hemoconcentration and reinfusion of blood drained from the operative field and the extracorporeal circuit after operation were used in all patients. Indications for blood transfusion were hypotension, tachycardia, or both, with hemoglobin values < 8.5 g/dL; or severe anemia with hemoglobin values < 7 g/dL. Compared with the blood loss in the control group, patients receiving aprotinin and epsilon-aminocaproic acid showed significantly less postoperative blood loss at 1 hour (control, 128 +/- 94 mL; aprotinin, 54 +/- 47 mL, p = 0.01; and epsilon-aminocaproic acid, 69 +/- 35 mL, p = 0.03); this trend continued at 24 hours after operation (control, 724 +/- 280 mL; aprotinin, 344 +/- 106 mL, p < 0.0001; and epsilon-aminocaproic acid, 509 +/- 148 mL, p = 0.01). Aprotinin was significantly more efficient than epsilon-aminocaproic acid (p=0.002). Tranexamic acid did not have a statistically significant effect on blood loss. Homologous blood requirements were not significantly different among the groups; postoperative hematologic values and coagulation times were also comparable. Despite the efficacy of aprotinin and epsilon-aminocaproic acid shown in the present study, the blood requirements were not significantly different from those that are found when transfusions are restricted, autotransfusions are used, and blood from the operative field and extracorporeal circuit is concentrated and reinfused. Therefore, intraoperative antifibrinolysis may not be indicated in routine cardiac surgery when other blood-saving techniques are adopted. The serine protease antagonist, aprotinin, reduces perioperative blood loss in cardiac surgery and orthotopic liver transplantation. A pilot study suggested that the drug may also reduce bleeding during infrarenal aortic replacement; the aim was to confirm or refute this observation with a prospective, randomized, double-blind, placebo-controlled trial.
                Some 136 patients were randomized to receive either aprotinin, given as a loading dose of 2 x 10(6) kallikrein inactivator (KI) units followed by 0.5 x 10(6) KI units/h or equal volumes of 0.9 per cent saline. After 80 patients had been randomized the infusion dose was doubled to ensure that plasma levels were similar to those seen in successful cardiac studies. Blood loss, coagulation and haematological parameters were recorded throughout surgery and for 7 days afterwards. Blood was transfused to maintain the haemoglobin level at 100 g/l.
                Four patients were withdrawn after randomization when found at laparotomy to be unsuitable for the planned reconstruction. The 30-day mortality rate was 4.5 per cent, with no excess complications in either group. Blood loss collected on swabs was reduced from 480 ml in placebo-treated patients to 379 ml with aprotinin (P = 0.014). Blood loss into suction drains in the first 24 h after operation was reduced from 295 to 205 ml in aprotinin-treated patients (P = 0.002). However, no significant reduction was found in intraoperative or total blood loss, or transfusion requirement.
                The small reduction in blood loss in patients treated with aprotinin demonstrated in this study does not support its use in routine elective aortic surgery. The transfusion of allogeneic red blood cells and allogeneic coagulation products is associated with risk to the patient and the depletion of an increasingly scarce resource. This prospective, randomized, double-blind, placebo-controlled trial investigated practices to avoid transfusion in patients undergoing first-time cardiac surgery.
                Patients were randomized to one of three treatment groups: an aprotinin group, a tranexamic acid group, and a control group receiving normal saline. Intra-operative cell salvage was used for all patients. The primary outcomes were the number of patients exposed to allogeneic red blood cells, allogeneic coagulation products or any allogeneic transfusion (allogeneic red blood cells and/or allogeneic coagulation products).
                Patients were 2.5 times more likely to receive any allogeneic transfusion in the tranexamic group than in the aprotinin group (21 patients out of 60 compared with nine out of 60, respectively). The relative risk of any allogeneic transfusion comparing aprotinin with tranexamic acid was 0.43 (95% confidence interval 0.21-0.86; P=0.019). Patients in the control group were four times more likely to receive any allogeneic transfusion when compared with the aprotinin group (37 patients out of 60 compared with nine out of 60, respectively). The relative risk of any allogeneic transfusion comparing aprotinin with control was 0.24 (95% confidence interval 0.13-0.46; P<0.001).
                When used in addition to intra-operative cell salvage, aprotinin is the most efficacious pharmacological therapy for reducing patient exposure to any allogeneic transfusion during first-time cardiac surgery. Fibrinolysis has been recognized as an important cause of intraoperative bleeding during orthotopic liver transplantation (OLT). Several investigators have used prophylactic administration of aprotinin in patients to inhibit fibrinolysis and to decrease transfusion requirements, morbidity, and mortality. Nevertheless, the role of aprotinin in this situation is not yet clear. The goal of this study was to determine the effects of prophylactic administration of aprotinin on intraoperative bleeding and blood requirements, and on hemostatic changes during OLT. Eighty consecutive patients were included in a double-blind, prospective study and were randomized in two groups. In group A (n = 39), an initial dose of 2 x 10(6) kallikrein inactivator units (KIU) of aprotinin was administered in the induction of anesthesia followed by infusion of 5 x 10(5) KIU/h until the end of the procedure. The control group (n = 41) received an identical volume of saline solution. The majority of the operations were performed with vena cava preservation (piggy-back technique) without venovenous bypass. During the anhepatic phase, a significant increase in levels of tissue plasminogen activator, thrombin-antithrombin complexes (TAT) and D-dimers (DD) was noted in both groups. A significant increment of TAT was observed in group A during reperfusion. The remaining hemostatic parameters were similar in both groups. Intraoperative requirements of packed red cells, fresh-frozen plasma (FFP), platelets, and cryoprecipitate were similar in the two groups. Our results suggest that prophylactic administration of aprotinin is not useful in reducing bleeding and blood product requirements during OLT. Surgery for abdominal aneurysm is associated with substantial blood loss. In cardiac surgery, aprotinin, a fibrinolysis inhibitor, has shown to reduce blood loss significantly. Our aim was to assess the effect of aprotinin, when administered during elective surgery of infrarenal abdominal aneurysm, on coagulation, blood loss, and morbidity. A double-blind randomized trial was performed on 35 consecutive patients. They were randomized to either an aprotinin or a placebo group. The aprotinin group received 2,000,000 kallikrein inhibiting units (KIU) of aprotinin (500,000 KIU in 50 mL NaCl 0.9%) as a starting dose, followed by 500,000 KIU per hour during the operation. The placebo group received equal amounts of only NaCl 0.9%. During the operation and 24 hr thereafter, blood samples were taken to assess coagulation factors. Blood loss was measured in suction devices and swabs. All patients were followed until their discharge from the hospital. Statistical analysis was performed by independent t-test or Mann-Whitney U-test and chi-squared test. There was no significant difference in the amount of blood loss or the amount of blood products administered between the two groups. Morbidity and mortality were also comparable. In both groups, consumption of clotting factors could be detected, indicating activation of the coagulation cascade. However, in the aprotinin group, the alpha2-antiplasmin level was raised during surgery, indicating inhibition of fibrinolysis. Administration of aprotinin during elective operations for infrarenal aortic aneurysm induces inhibition of fibrinolysis. However, it does not significantly reduce blood loss or the need for blood products. Patients on cardiopulmonary bypass (CPB) have an increased susceptibility to postoperative bleeding. Previous reports using desmopressin acetate (DDAVP) for the prevention of postoperative bleeding have given contradictory results, whereas the protease inhibitor aprotinin has been shown to reduce blood loss after this type of surgery. This randomized study was performed to assess the efficacy of DDAVP versus aprotinin in the prevention of bleeding after CPB.
                One hundred nine of 122 eligible patients were randomized to four different groups: Group A (n = 28) received aprotinin starting with a bolus of 2 x 10(6) KIU followed by a continuous infusion of 0.5 x 10(6) KIU/h until the end of surgery; group B (n = 25) received of DDAVP 0.3 micrograms/kg i.v. on completion of CPB; group C (n = 28) received two doses of DDAVP, the first as in group B and an additional dose 6 hours after surgery; group D (n = 28) received no treatment. There was a marked reduction of postoperative blood loss either at 12 hours (P < .01) or 72 hours (P < .02) in the aprotinin group compared with all other groups, whereas no significant effect was observed in either of the two DDAVP regimens. A significant reduction in the amount of blood used was observed only in the aprotinin group (P < .01). Of the plasma fibrinolytic components assayed, there was a significant reduction of the fibrin degradation product generation in the aprotinin group (P < .001), whereas a significant systemic hyperfibrinolysis was observed in both DDAVP-treated groups and the control group. No side effects related to the study drugs were observed in any patient.
                Aprotinin inhibited fibrinolysis; this correlated with a significant reduction of postoperative blood loss and need for blood replacement after CPB. Neither one nor two doses of DDAVP had a beneficial effect. Aprotinin offers a better alternative than DDAVP in the prevention of bleeding after CPB. Cardiopulmonary bypass induces a systemic inflammatory response. Aprotinin, a nonspecific proteinase inhibitor is known to improve postoperative hemostasis and may modify the inflammatory reaction. This study evaluates the effects of low-dose aprotinin on inflammatory markers in patients scheduled for elective coronary artery bypass grafting.
                Patients were prospectively randomized into two groups: the control group (C) (n = 14) and the low-dose aprotinin group (A) (n = 15) with (2 x 10(6) KIU = 280 mg) aprotinin added to the pump prime. Cytokine response (interleukin-6, soluble TNF II receptor), terminal complement production (SC5b-9), and neutrophil activation (lactoferrin) were assessed up to 6 hours postoperatively. Clinical data and hemostatic factors including fibrinopeptide A, thrombin-antithrombin complex, D-dimer, and plasmin/alpha2-antiplasmin were investigated.
                In both study groups, a significant increase of all inflammatory markers was seen (IL-6, sTNF-IIR, SC5b-9, lactoferrin), p less than 0.001. Peak levels of complement production occurred after protamine administration, whereas cytokine increases were more pronounced postoperatively with marked elevation up to 6 hours. The markers did not differ significantly between groups throughout the study period (p > 0.05 at each time of determination). However, after protamine administration reduced fibrinolysis (D-dimer, plasmin/alpha2-antiplasmin) was detected in group A. Measurements for coagulation (fibrinopeptide A, thrombin-antithrombin complex) were not significantly influenced by aprotinin. The total amount of blood loss during the first 24 hours was significantly reduced in group A (p < 0.02).
                Low-dose aprotinin added to the pump prime does not inhibit the inflammatory response caused by cardiopulmonary bypass, but improves postoperative hemostasis. A potential effect of high-dose aprotinin on inflammatory markers remains to be elucidated. Antifibrinolytics are widely used in cardiac surgery to reduce bleeding. Allogeneic blood transfusion, even in primary cardiac operations with low blood loss, is still high. In the present study we evaluated the impact of tranexamic acid compared to aprotinin on the transfusion incidence in cardiac surgical patients with low risk of bleeding.
                This prospective, randomized, double-blind study included 220 patients undergoing primary coronary artery revascularization (coronary artery bypass grafting [CABG]) or aortic valve replacement (AVR). Randomized in blocks of 20, patients received either tranexamic acid (approximately 6 g) or full-dose aprotinin (approximately 5-6 x 10(6) Kallikrein Inhibiting Units). Transfusion was guided by a strict transfusion algorithm. Molecular markers of hemostasis were determined to assess differences in the mode of action of the two drugs. Primary end-points were the incidence of allogeneic red cell transfusion and 24-h postoperative blood loss. Data were analyzed according to the intention-to-treat principle and compared using the chi(2) and Mann-Whitney U-test.
                Two-hundred-twenty patients were enrolled (CABG: 134, AVR: 86). In the aprotinin Group 47% of patients received allogeneic blood during the hospital stay as compared to 61% in the tranexamic acid group (P = 0.036). Aprotinin conferred a 23% reduction in allogeneic transfusion risk (RR 0.77, 95% CI 0.53-0.88). Overall, no significant difference in postoperative bleeding was observed, although 24-h blood loss was reduced in aprotinin-treated CABG patients (500, 350-750 mL vs 650, 475-875 mL (median, 25th-75th percentile); P = 0.039). Despite the lower transfusion rate, the hemoglobin concentration on the first postoperative day was higher in the aprotinin group (11.3, 9.9-12.1 vs 10.6, 9.9-11.6 mg/dL; P = 0.023). The fibrinolytic activity at the end of operation determined by D-Dimer was comparable in both groups. (0.15, 0.11-0.17 mg/L [aprotinin] versus 0.18, 0.12-0.24 mg/L [tranexamic acid]). The activated partial thromboplastin time was prolonged up to 4 h postoperatively in the aprotinin group, while the heparin requirement was reduced: 19% of the patients in the aprotinin group and 45% in the tranexamic acid group received at least one additional bolus heparin during cardiopulmonary bypass (P < 0.001). Troponin T levels postoperatively and on postoperative day 1 were significantly higher in the tranexamic acid group (P = 0.017). No differences in renal, cardiac, or mortality outcomes were observed.
                Considering the rate of transfusion of red blood cells, tranexamic acid was slightly inferior in patients undergoing CABG, but there was no difference in patients receiving AVR. Tranexamic acid seems to be less effective in operations with increased bleeding such as CABG. Clinical benefit depends on specific patient and institution characteristics (ClinicalTrials.gov NCT00396760). Tranexamic acid has been suggested to be as effective as aprotinin in reducing blood loss and transfusion requirements after cardiac surgery. Previous studies directly comparing both antifibrinolytics focus on high-risk cardiac surgery patients only or suffer from methodological problems. We wanted to compare the effectiveness of tranexamic acid versus aprotinin in reducing postoperative blood loss and transfusion requirements in the patient group representing the majority of cardiac surgery patients: low- and intermediate-risk patients.
                We conducted a non-sponsored, double-blind, randomised, placebo-controlled trial in which 298 patients scheduled for low- or intermediate-risk (mean logistic EuroSCORE 4.1) first-time heart surgery with use of cardiopulmonary bypass were randomised to receive either tranexamic acid, high-dose aprotinin, or placebo. All patients had preoperative normal renal function. End points of the study were monitored from the time of surgery until patient discharge. This trial was executed between June 2004 and October 2006.
                Both antifibrinolytics significantly reduced blood loss and transfusion requirements when compared with placebo. Aprotinin was about twice as effective as tranexamic acid in reducing total postoperative blood loss (estimated median difference 155 ml, 95% confidence interval (CI) 60-260; p < 0.001). Accordingly, aprotinin reduced packed red blood cell transfusions more than tranexamic acid, although the difference did not reach statistical significance. Only aprotinin significantly reduced the proportion of transfused patients when compared with placebo (mean difference -20.9%, 95% CI 7.3-33.5; p = 0.013), and only aprotinin completely abolished bleeding-related re-explorations (mean difference 6.8%, 95% CI 1.6-13.4%; p = 0.004). Neither antifibrinolytic agent increased the incidence of mortality (mean difference tranexamic acid -0.4%, 95% CI -4.6 to 4.4; p = 0.79, mean difference aprotinin -1.3%, 95% CI -6.2 to 3.5; p = 0.62) or other serious adverse events when compared with placebo.
                Aprotinin has clinically significant advantages over tranexamic acid in patients with normal renal function scheduled for low- or intermediate-risk cardiac surgery. Ninety-seven patients undergoing elective liver resection through a subcostal incision were assigned to large-dose aprotinin treatment or placebo in a double-blind, prospective, randomized fashion. Randomization was stratified by diagnosis: (a) cancer in cirrhosis, (b) cancer in healthy liver, and (c) benign tumor in healthy liver. Intraoperative blood loss, percentage of transfused patients, and total transfusion requirement per group were significantly lower in the aprotinin group than in the placebo group (1217 +/- 966 mL vs 1653 +/- 1221 mL, P = 0.048; 17% vs 39%, P = 0.02; 30 vs 77 red blood cell packs, P = 0.015, respectively). Assessment of hematological markers (a) prior to surgery, (b) at the end of surgery, and (c) 24 h after surgery showed an identical intraoperative increase in thrombin-antithrombin III complexes in patients of both groups (P = 0.86), which indicates a similar activation of coagulation. Intraoperative hyperfibrinolysis was significantly less pronounced in the aprotinin group than in the placebo group (P = 0.0002 and P = 0.004 for D-dimers and fibrinogen, respectively). No adverse drug effects were detected (circulatory disturbances, deep venous thrombosis, increase in serum creatinine). These results suggest that aprotinin significantly reduces blood loss and transfusion requirement in patients undergoing elective liver resection through a subcostal incision. Ninety patients undergoing cardiac surgery were randomly divided into three groups of 30 patients to compare the effects on bleeding and transfusion requirements of either intraoperative infusion of high-dose aprotinin (GpI) or reinfusion of autologous fresh whole blood (GpII) versus a control group (GpIII). Standardized anesthetic, perfusion, and surgical techniques were used. Platelet counts, hemoglobin concentration, hematocrit, fibrinogen, and Ivy-Nelson bleeding times determined at fixed times perioperatively did not differ among the three groups. The total loss from the chest drains was significantly reduced in GpI (328 +/- 28 mL; mean +/- SEM) as compared with the loss in GpII and GpIII (775 +/- 75 mL and 834 +/- 68 mL, respectively). There was a threefold difference in the total hemoglobin loss (GpI, 14.2 +/- 1.7 g; GpII, 50.1 +/- 5.0 g; GpIII, 45.0 +/- 5.2 g). GpI patients also received less banked blood: 250 +/- 53 mL versus 507 +/- 95 mL in GpII and 557 +/- 75 mL in GpIII. No GpI patient required transfusion of platelets or fresh frozen plasma. Fresh whole autologous blood transfusions had no significant hemostatic effect and failed to reduce the homologous blood requirement. Conversely, high-dose aprotinin reduced blood loss and transfusion requirements. Of 22 patients undergoing repeat open-heart surgery through a previous median sternotomy wound 11 were randomised to receive the serine proteinase inhibitor aprotinin in high dosage (about 700 mg intravenously from the start of anaesthesia to the end of operation, depending on the length of the surgical procedure). Their mean blood loss was 286 ml compared with 1509 ml in the 11 control patients (p less than 0.001), and mean haemoglobin losses were 8.3 g and 78 g, respectively (p less than 0.001). Blood transfusion requirements were eightfold higher in the control group than in the aprotinin group, 7 of whom received only the single unit of their own blood taken before cardiopulmonary bypass. Patients with heart disease are frequently maintained on a regimen of aspirin because of its ability to decrease thrombotic complications and reduce the prevalence of unstable angina and myocardial infarction. Aspirin-induced platelet acetylation also increases bleeding caused by impairment of platelet function during cardiac surgery.
                Between October 1990 and November 1991 this double-blind, randomized, placebo-controlled, parallel group interventional study examined the efficacy of high-dose aprotinin administration (up to 7 million KIU) to decrease blood loss and transfusion requirements in patients receiving aspirin within 48 hours of undergoing coronary bypass or valvular heart operations. Primary outcome measures in this study were total volume of blood loss (intraoperative blood loss plus postoperative chest tube drainage) and volume of transfusion during hospitalization.
                Patients treated with aprotinin (n = 29) had significantly lower total blood loss (1409 +/- 232 ml versus 2765 +/- 248 ml; p = 0.0002), intraoperative blood loss (503 +/- 53 ml versus 1055 +/- 199 ml; p = 0.0001), postoperative blood loss (906 +/- 204 ml versus 1710 +/- 202 ml; p = 0.0074), and prevalence of transfusion (59% versus 88% of patients; p = 0.016) than the placebo group (n = 25). The prevalence of complications including myocardial infarction was similar in the two groups.
                High-dose aprotinin significantly reduces blood loss and red blood cell transfusions in patients receiving aspirin who undergo cardiac operations. Effects of aprotinin in off-pump coronary artery bypass (OPCAB) surgery have not yet been described. This study analyses hemostasiologic changes and potential benefit in OPCAB patients treated with aprotinin.
                In a prospective, double-blind, randomized study 47 patients undergoing OPCAB surgery were investigated. Patients received either aprotinin (2 x 10(6) KIU loading dose and 0.5 x 10(6) KIU/h during surgery, n=22) or saline solution (control, n=25). Activated clotting time was adjusted to a target of 250 s intraoperatively. Blood samples were taken up to 18h postoperatively: complete hematologic and hemostasiologic parameters including fibrinopeptide A (FPA) and D-dimer in a subgroup of 31 patients were analyzed. Blood loss, blood transfusion and other clinical data were collected.
                Both groups showed comparable demographic and intraoperative variables. Forty-one (87%) patients of the whole study group received aspirin within 7 days prior to surgery. Number of grafts per patient were comparable (2.9+/-1.0 [mean+/-SD] in the aprotinin group and 2.8+/-1.2 in control, P=0.83). Blood loss during the first 18 h in intensive care unit was significantly reduced in patients treated with aprotinin (median [25th-75th percentiles]: 500 [395-755] ml vs. 930 [800-1170] ml, P<0.001). Postoperatively only two patients (10%) in the aprotinin group received packed red blood cells, whereas eight (35%) in the control group (P=0.07). Perioperatively FPA levels reflecting thrombin generation were elevated in both groups. The increase in D-dimer levels after surgery was significantly inhibited in the aprotinin group (P<0.001). Early clinical outcome was similar in both groups.
                Aprotinin significantly reduces blood loss in patients undergoing OPCAB surgery. Inhibition of enhanced fibrinolysis can be observed. FPA generation during and after OPCAB surgery seems not to be influenced by aprotinin. To determine whether aprotinin can provide a significant improvement of hemostasis in cardiopulmonary bypass using a membrane oxygenator, we tested this drug in a prospective, randomized, double-blind, placebo-controlled clinical trial. The subjects were 80 male patients undergoing cardiopulmonary bypass for coronary artery bypass grafting. Forty patients received aprotinin and 40 patients served as placebo controls. Aprotinin (4 x 10(6) KIU) was given as a continuous infusion, starting before operation and continuing until after cardiopulmonary bypass; additionally, 2 x 10(6) KIU aprotinin was added to the pump prime. Intraoperative and postoperative bleeding, respectively two thirds and one third of the total perioperative blood loss, were both significantly reduced in the aprotinin-treated group (p less than 0.01). The total average perioperative blood loss, corrected to a hemoglobin concentration of 7 mmol/L, was 550 mL in the aprotinin-treated patients versus 900 mL in the control patients. This reduction in blood loss, furthermore, significantly decreased the amount of postoperative blood transfusions (p less than 0.05) and increased the percentage of patients who did not receive postoperative donor blood from 42% to 68%. Aprotinin increased the activated clotting time significantly during cardiopulmonary bypass, which led to a reduction in heparin usage. The improved hemostasis during operation, despite the prolonged activated clotting time, might even abolish the need for heparin conversion with protamine at the end of cardiopulmonary bypass, thus allowing retransfusion through cardiotomy suction to be continued, which saves the blood that is currently lost with vacuum suction. Large doses of aprotinin (1,000,000-2,000,000 kallikrein inhibitor units [KIU] initial dose and a 500,000 KIU/h infusion) have been used during orthotopic liver transplantation (OLT) to reduce the incidence and severity of fibrinolysis. This double-blinded study was designed to investigate whether a small-dose infusion of aprotinin (200,000 KIU/h) would control fibrinolysis. A controlled study was undertaken to compare small-dose aprotinin with a placebo in patients undergoing OLT with veno-venous bypass. Forty-four patients were randomized either to the aprotinin group (n = 21), which received an intravenous infusion of 200,000 KIU/h without an initial dose, or to a control group (n = 23), which received normal saline. Coagulation variables, thrombelastograms, and postoperative blood drainage were measured. Blood levels of fibrin degradation products (FDP) were significantly higher in the control group (95% > 20 micrograms/mL) at the end of surgery compared to the aprotinin group (53% > 20 micrograms/mL, P < 0.01). The transfusion of cryoprecipitate units was more in the control group versus the aprotinin (12.6 +/- 12.8 vs 5.7 +/- 7.5; P < 0.04), as was the number of fresh frozen plasma units (6.6 +/- 3.5 vs 3.6 +/- 6.1; P < 0.05). We conclude that an infusion of a small dose of aprotinin can safely control fibrinolysis during liver transplantation with a concomitant reduction in transfusion of blood products. To evaluate the effects of minimal-dose aprotinin in patients undergoing coronary artery bypass grafting, we conducted a prospective randomized study.
                A total of 167 patients were randomized to receive no aprotinin treatment (control, n = 57), minimal-dose aprotinin (1.0 x 10(6) KIU; n = 55), or low-dose aprotinin (2.7 +/- 0.5 x 10(6) KIU; n = 55). Blood loss and transfusion requirements, parameters of clotting and fibrinolysis, renal function, and early graft patency rates were assessed.
                Postoperative blood loss and transfusion requirements were significantly (p = 0.01) lower in both the minimal-dose and low-dose groups than in the control group. The increase in D-dimer level after cardiopulmonary bypass was significantly (p < 0.05) less marked in the low-dose group than in the control group. The alpha 2-plasmin inhibitor and plasminogen activator inhibitor-1 levels were significantly (p < 0.05) greater in the minimal-dose and low-dose groups than in the control group after bypass, suggesting the prevention of fibrinolysis by both aprotinin doses. No statistically significant differences in postoperative renal function and early vein graft patency rates were noted (control group, 93.8%; minimal-dose group, 95.5%; low-dose group, 92.3%; p = 0.25).
                Aprotinin was not associated with a significant increase in the prevalence of renal dysfunction or early vein graft occlusion. Minimal-dose aprotinin inhibited enhanced fibrinolytic activity and reduced blood loss and transfusion requirements after bypass equivalently to low-dose aprotinin. The dose of 1 x 10(6) KIU added to the pump prime may be acceptably effective in reducing blood loss in patients undergoing primary coronary operations. Large prophylactic doses of aprotinin efficiently reduce blood loss during orthotopic liver transplantation (OLT). Small doses of aprotinin are usually used to treat fibrinolysis. However, no studies have investigated the benefit of prophylactic administration of a smaller dose of aprotinin during liver transplantation. We compared two methods of aprotinin therapy on transfusion outcome in liver transplant patients in a prospective study of 199 patients undergoing OLT who were randomized to large or small prophylactic doses of aprotinin during the transplant procedure. In the large-dose group (n = 94) an initial dose of 2,000,000 kallikrein inactivation units (KIU) was followed by infusion of 500,000 KIU/h until the patient's return to the intensive care unit. In the small-dose group (n = 95), an initial dose of 500,000 KIU was followed by an infusion of 150,000 KIU/h. Outcome measurements included intraoperative transfusion requirements (packed red blood cells, fresh frozen plasma, platelets, intraoperative salvage) and postoperative hematologic values. There were no differences in transfusion requirements in the two groups of patients. Patients treated with low-dose aprotinin had slightly higher postoperative fibrinogen concentrations. Large-dose aprotinin therapy does not appear to offer additional benefit compared to low-dose aprotinin administration. Low-dose aprotinin in the pump during cardiopulmonary bypass (CPB) has been shown to improve postoperative hemostasis and platelet preservation. This investigation was undertaken to evaluate the effects of mini-dose pump prime only aprotinin (70 mg) on the hemostatic parameters and blood transfusion requirements in patients undergoing on-pump coronary artery bypass surgery (CABG).
                We studied 86 patients who underwent CABG. Forty patients received mini-dose aprotinin (500.000 KIU [70 mg] in the pump), and a control group of 46 did not. D-dimer level, full blood count, postoperative blood loss, and transfusion requirements were analyzed before, after one hour operation and first day after operation.
                Twenty-four-hour postoperative blood loss was significantly reduced in the aprotinin group (188+/- 51.5 ml vs. 818+/- 243.5 ml, [mean +/- standard deviation] p < 0.01). Patients in the aprotinin group also received significantly less banked blood posoperatively than the control group (1.20 +/- 0.52 vs. 3.33 +/- 1.13 Units/per patient (p < 0.04). One hour after operation, and 24 hours after operation D-dimer level was significantly reduced in the aprotinin group (p < 0.008 and p < 0.017, respectively).
                Mini dose pump-prime aprotinin reduces postoperative blood loss, transfusion requirements and yet confers hemostatic improvement through reduced fibrinolysis in patients undergoing routine coronary artery bypass grafting. Antifibrinolytic drugs including aprotinin and tranexamic acid are currently used in cardiac surgery to reduce postoperative bleeding and transfusion requirements, and may have different effects on platelets. We therefore evaluated platelet function after cardiopulmonary bypass (CPB) and cardiac surgery to determine the effect of either aprotinin or tranexamic acid.
                In a prospective, randomized study, 50 patients scheduled for elective cardiac surgery with CPB were evaluated. Patients received high-dose aprotinin (n = 25) or tranexamic acid (n = 25) as antifibrinolytic drugs. Coagulation and platelet function were assessed preoperatively, after CPB, 3 and 24 h after surgery using modified thrombelastography and whole blood aggregometry.
                Impaired coagulation after CPB occurred in both groups compared with preoperative data (P < 0.01). In contrast to modified thrombelastography, thrombin receptor-mediated aggregometry after CPB was significantly decreased only in those patients receiving tranexamic acid until the end of the study period in comparison to the aprotinin group (P < 0.05). Aprotinin-treated patients showed significantly less chest tube drainage (575 mL +/- 228 vs 1033 mL +/- 647, P < 0.05) and need for postoperative transfusion requirements (P < 0.01) compared with the tranexamic acid group.
                Platelet function measured by whole blood aggregometry is better preserved by aprotinin than tranexamic acid and may be responsible for producing less bleeding within the first 24 h after CPB. Evidence exists that the serine protease inhibitor, aprotinin, when used in high dosage, can reduce the bleeding associated with cardiopulmonary bypass. This high dosage is particularly effective in patients at increased risk for bleeding. Less convincing information is available for regimens that use a lower dose and its place in routine cardiac surgery has not been fully resolved. Some studies have shown significant benefit from a single dose added to the cardio-pulmonary bypass prime and we re-examined this alternative. In a randomized, prospective, double-blinded study, we compared this single dose method with placebo in a low risk adults undergoing a first procedure. Benefit was considered established if a significant reduction in blood loss or the use of transfused blood products was seen. We found a significant reduction in red cell transfusion but no improvement in blood loss or blood component transfusion in the treated group. This included patients maintained on aspirin as well as those not receiving aspirin. Aspirin significantly increased blood loss in both control and treatment groups and the usage of blood products in the treatment group. Aprotinin in this low, single dosage was not confirmed as an effective means of improving hemostasis following CPB in routine cardiac surgery. Postoperative bleeding still remains a serious problem in bypass surgery. This study evaluated fibrinolysis and perioperative low-dose antifibrinolytic regimens adjusted to the time course of fibrinolysis.
                In a prospective, randomized study of 42 patients undergoing bypass grafting, patients received low-dose aprotinin (group A; n = 14) or low-dose tranexamic acid (group TA; n = 14) intraoperatively and postoperatively, respectively, with no antifibrinolytics for comparison (group C; n = 14). Parameters of procoagulation, fibrinolysis, and activated factor VII were measured preoperatively, intraoperatively, and postoperatively. Blood loss was determined up to 24 hours.
                The level of thrombin-antithrombin III complex was significantly decreased postoperatively in the treatment groups (group A and TA versus C: 25 +/- 14 and 19 +/- 10 microg/L, respectively, versus 40 +/- 21 microg/L; p < 0.05). Levels of plasmin-antiplasmin complexes were significantly decreased postoperatively in group A (607 +/- 231 microg/L) versus group C (825 +/- 225 microg/L) (p < 0.05) but were increased in group TA (1,145 +/- 394 microg/L) versus group C (p < 0.05). At all times intraoperatively and postoperatively, levels of D-dimers were significantly decreased in group A and group TA versus control (p < 0.001), indicating that fibrinolysis persists after the operation. Intraoperatively, the factor VIIa level decreased significantly in group A (20 +/- 8 mU/mL) versus group C (31 +/- 15 mU/mL) (p < 0.05), but not in group TA (32 +/- 15 mU/mL). Blood loss was significantly lower in group A (135 +/- 37 mL) and group TA (155 +/- 71 mL) versus group C (354 +/- 170 mL) (p < 0.001).
                This low-dose aprotinin regimen adjusted to perioperative fibrinolysis reduces blood loss significantly in coronary bypass grafting. For further progress in this subject, clinical investigations of individual fibrinolysis-adjusted antifibrinolytic treatment seems warranted. Aprotinin is a serine protease inhibitor that reduces blood loss and transfusion requirements when administered prophylactically to cardiac surgical patients. To examine the safety and dose-related efficacy of aprotinin, a prospective, multicenter, placebo-controlled trial was conducted in patients undergoing repeat coronary artery bypass graft (CABG) surgery.
                Two hundred eighty-seven patients were randomly assigned to receive either high-dose aprotinin, low-dose aprotinin, pump-prime-only aprotinin, or placebo. Drug efficacy was determined by the reduction in donor-blood transfusion up to postoperative day 12 and in postoperative thoracic-drainage volume. The percentage of patients requiring donor-red-blood-cell (RBC) transfusions in the high- and low-dose aprotinin groups was reduced compared with the pump-prime-only and placebo groups (high-dose aprotinin, 54%; low-dose aprotinin, 46%; pump-prime only, 72%; and placebo, 75%; overall P = .001). The number of units of donor RBCs transfused was significantly lower in the aprotinin-treated patients compared with placebo (high-dose aprotinin, 1.6 +/- 0.2 U; low-dose aprotinin, 1.6 +/- 0.3 U; pump-prime-only, 2.5 +/- 0.3 U; and placebo, 3.4 +/- 0.5 U; P = .0001). There was also a significant difference in total blood-product exposures among treatment groups (high-dose aprotinin, 2.2 +/- 0.4 U; low-dose aprotinin, 3.4 +/- 0.9 U; pump-prime-only, 5.1 +/- 0.9 U; placebo, 10.3 +/- 1.4 U). There were no differences among treatment groups for the incidence of perioperative myocardial infarction (MI).
                This study demonstrates that high- and low-dose aprotinin significantly reduces the requirement for donor-blood transfusion in repeat CABG patients without increasing the risk for perioperative MI. Cardiopulmonary bypass (CPB) increases risk of postoperative bleeding and need for transfusion. The aim of this study was to evaluate the effects of aprotinin, epsilon aminocaproic acid and tranexamic acid on coagulation patterns and need for banked blood transfusion. Ninety-six consecutive patients who underwent coronary artery bypass surgery were randomly assigned to 4 groups (24 patients each). The following parameters were monitored before, during and after CPB: activated lotting time, hemoglobin, prothrombin time, activated prothromboplastin time, fibrinogen, antithrombin III, xDP, Factor VIII, Thrombin-Antithrombin Complex and plasminogen. Analysis of postoperative bleeding and need for transfusion showed that the aprotinin group had significantly lower mediastinal bleeding. Transfused patients were 2, 4, 12 and 18 respectively in the aprotinin, epsilon aminocaproic acid, tranexamic acid and placebo treated group. In conclusion the use of protease inhibitors significantly reduces postoperative bleeding and transfusion. The aprotinin-treated group had the lower need for transfusion. High-dose aprotinin is an effective but costly method to reduce transfusions after cardiopulmonary bypass (CPB). Very low doses of aprotinin have been shown to be effective in primary cardiac surgery, but not in patients undergoing procedures associated with the greatest usage of allogeneic blood products after CPB. We evaluated the efficacy of ultra-low-dose aprotinin in this patient population.
                Aprotinin 1 million KIU or placebo was added to the priming solution of the CPB circuit of 52 patients undergoing a reoperation and/or a complex surgical procedure. Dryness of operative field, hemoglobin concentrations, coagulation parameters, chest drainage, and transfusion requirements were compared.
                Total chest drainage was not different between groups, but fewer patients in the aprotinin group required additional protamine postoperatively (35% vs 69% for controls, p = 0.03) and fewer received fresh frozen plasma (FFP; 19% vs 46% for controls, p = 0.04). Red cell transfusion was smaller in the aprotinin group compared to placebo (median 4 and 2 units, respectively, p = 0.04). Transfusion of FFP, platelets, cryoprecipitates was not different between groups. Total number of units transfused tended to be reduced in the aprotinin group compared to control (median 2 and 7 units, respectively, p = 0.06).
                Prophylactic administration of ultra-low-dose aprotinin reduced transfusions in patients undergoing repeat operations or complex procedures. Aprotinin could be used in a more economical manner, even in this patient population at high-risk of receiving allogeneic blood products. Hemostatic drugs are widely thought to be unnecessary and potentially detrimental in off-pump coronary artery bypass graft surgery (OPCABG), despite well-established use in on-pump surgery. In a randomized, prospective OPCABG trial, we assessed efficacy and safety of aprotinin through a comprehensive assessment of graft patency and hematologic function.
                Sixty patients were randomly assigned to full-dose aprotinin or placebo. Heparin was titrated to a kaolin-based activated clotting time of greater than 300 seconds. Exclusionary criteria included creatinine greater than 2 mg/dL, conversion to on-pump CABG, and preoperative GPIIb/IIIa inhibition. Hematologic assessments were obtained preoperatively, at the end of surgery, and on days 1 and 3: mean platelet volume, thrombin generation (prothrombin fragment 1.2 assay), and aspirin resistance using a modified thrombelastography, whole blood aggregometry, 11-dehydro-thromboxane B2 levels, and flow cytometry. Thrombotic events were defined as postoperative myocardial infarction by electrocardiography or elevated troponin I, clinical stroke by examination and head computed tomography, and bypass graft failure by multichannel computed tomography angiography on day 5.
                Aprotinin was associated with a significant reduction in intraoperative and postoperative blood loss compared with placebo but had no effect on transfusion rates. Patients treated with aprotinin had significantly fewer thrombotic events (3% versus 23%, p < 0.05, Fisher's exact test) and less postoperative aspirin resistance (20% versus 46%, respectively, p < 0.05, Fisher's exact test). Postoperative prothrombin fragment 1.2 level was reduced by aprotinin use.
                Aprotinin reduced perioperative bleeding after OPCABG. Preserved aspirin sensitivity in the aprotinin group may explain the observed reduction in thrombotic events and might be related to the suppression of perioperative and transmyocardial thrombin formation. Cytokines are implicated in the pathogenesis of the "whole-body inflammatory response" that may complicate the period after cardiopulmonary bypass (CPB). Low-Dose aprotinin in the pump during CPB has been shown to improve postoperative hemostasis and platelet preservation. We tested the hypothesis that low-dose aprotinin influences the inflammatory reaction (in terms of cytokine release) after CPB.
                In a prospective, randomized study, 36 patients undergoing elective coronary artery bypass grafting were investigated. Nineteen patients received low-dose aprotinin (2 x 10(6) KIU (280 mg] in the pump), and a control group of 19 did not. Complement activation, cytokine production, leukocyte elastase release. D-dimer level, full blood count, postoperative blood loss, and transfusion requirements were analyzed before, during, and after after CPB.
                Interleukin-1 beta was not detected in either group, whereas traces of tumor necrosis factor-alpha were infrequently observed. Plasma elastase, interleukin-6, interleukin-8, and neutrophil count increased (p < 0.001) during and after CPB compared with the baseline levels, reaching a peak at 2 hours after protamine administration in both groups before returning toward baseline at 24 hours. Proinflammatory cytokine markers did not differ significantly (p > 0.1) between the groups throughout the study period. The C5b-9 level increased (p < 0.001) in both groups perioperatively, reaching its peak 15 minutes after protamine. Twenty-four-hour postoperative blood loss was significantly (p < 0.001) reduced in the aprotinin group in association with markedly reduced D-dimer levels (p < 0.001). Patients in the aprotinin group also received significantly less banked blood postoperatively than the control group (p < 0.01).
                Low-dose aprotinin fails to modify proinflammatory cytokine release, yet confers hemostatic improvement through reduced fibrinolysis in patients undergoing routine coronary artery bypass grafting. Off-pump coronary artery bypass (OPCAB) surgery is associated with a hypercoagulable state in which the platelet thrombin receptor, protease-activated receptor-1 (PAR-1), helps propagate a thrombin burst within saphenous vein grafts. Aprotinin, used in cardiothoracic surgery mainly for its antifibrinolytic properties, also spares platelet PAR-1 activation due to thrombin. We hypothesized that this PAR-1 antagonistic property provides an antithrombotic benefit during OPCAB surgery.
                Patients were randomly assigned to receive saline (n = 38) or a modified full-dose regimen of aprotinin (n = 37) IV during OPCAB surgery. Blood sampled perioperatively from the coronary sinus, skin wounds, and systemic circulation was analyzed to test coagulation and platelet function. Major adverse cardiovascular events were monitored by obtaining troponin I at 24 h (myocardial infarction), predischarge computed tomography angiography (vein graft thrombosis), and by clinical examination for stroke.
                Coronary sinus blood obtained immediately after OPCAB surgery showed significantly less activation in the aprotinin group, as judged by reduced formation of platelet-leukocyte conjugates (P < 0.02) and platelet-derived microparticles (P < 0.05). The aprotinin group showed inhibition of platelet aggregation induced by thrombin (P = 0.007) but not adenosine diphosphate. Thrombin generation, defined by F1.2 levels, was significantly reduced by aprotinin in the coronary sinus but not in skin wound incisions. Major adverse cardiovascular events were significantly reduced in aprotinin-treated patients (5.4% vs 29.7%, P < 0.05). Aprotinin also demonstrated antifibrinolytic properties through diminished red blood cell transfusion (P < 0.04) and reduced blood loss postoperatively (603 +/- 330 vs 810 +/- 415 mL, P < 0.004).
                This study demonstrates that aprotinin protects patients undergoing OPCAB surgery from a hypercoagulable state by diminishing thrombin-induced platelet activation and thrombin generation within saphenous vein grafts, while maintaining systemic hemostatic and antifibrinolytic benefits. These results support further investigation of aprotinin and other PAR-1 antagonists in OPCAB surgery. Aprotinin, a hemostatic agent, regulates fibrinolysis, modulates the intrinsic coagulation pathway, stabilizes platelet function, and exhibits anti-inflammatory properties through inhibition of serine proteases, such as trypsin, plasmin, and kallikrein. Aprotinin has been used successfully for many years in cardiac operations, and there have been preliminary investigations of its use in hip replacement operations. The objectives of this multicenter, randomized, placebo-controlled, double-blind trial were to evaluate the efficacy and safety of aprotinin as a blood-sparing agent in patients undergoing an elective primary unilateral total hip replacement and to examine its effect on the prevalence of deep-vein thrombosis in this population.
                Seventy-three patients received a placebo; seventy-six patients, a low dose of aprotinin (a load of 500,000 kallikrein inhibitor units [KIU]); seventy-five, a medium dose of aprotinin (a load of 1,000,000 KIU, with infusion of 250,000 KIU per hour); and seventy-seven patients, a high dose of aprotinin (a load of 2,000,000 KIU, with infusion of 500,000 KIU per hour). The end points for the determination of efficacy were transfusion requirements and blood loss. Patients received standard prophylaxis against deep-vein thrombosis and underwent compression ultrasonography with color Doppler imaging of the proximal and distal venous systems of both legs to evaluate for the presence of deep-vein thrombosis.
                Aprotinin reduced the percentages of patients who required any form of blood transfusion (47 percent of the patients managed with a placebo needed a transfusion compared with 28 percent of those managed with low-dose aprotinin [p = 0.02],27 percent of those managed with high-dose aprotinin [p = 0.008], and 40 percent of those managed with medium-dose aprotinin [p = 0.5]). Only 6 percent (twelve) of the 212 patients treated with aprotinin required allogeneic blood compared with 15 percent (ten) of the sixty-eight patients treated with the placebo (p = 0.03). Aprotinin decreased the estimated intraoperative blood loss (p = 0.02 for the low-dose group, p = 0.04 for the medium-dose group, and p = 0.1 for the high-dose group), the measured postoperative drainage volume (p = 0.4 for the low-dose group, p = 0.006 for the medium-dose group, and p = 0.000 for the high-dose group), and the mean reduction in the hemoglobin level on the second postoperative day (thirty-four grams per liter for the placebo group, twenty-eight grams per liter for the low-dose group [p = 0.000], twenty-six grams per liter for the medium-dose group [p = 0.000], and twenty-three grams per liter for the high-dose group [p = 0.0001). The rate of deep-vein thrombosis was similar for all groups.
                We concluded that aprotinin is safe and effective for use as a hemostatic agent in primary unilateral total hip replacements. In patients who are at high risk of receiving allogeneic blood, use of aprotinin may be of particular clinical and economic benefit. Although the blood-saving effect of aprotinin has been well documented in cardiac surgery and lung transplantation, its use in lung surgery has received less attention. We present our experience with the intraoperative application of aprotinin in lung resections with a predicted high risk of bleeding.
                Thirty-eight patients undergoing major thoracic surgical procedures were randomized into treatment and placebo groups. The treatment group (n=18) received a bolus of 2 x 10(6) kallikrein inhibitor units (KIU) of aprotinin followed by 5 x 10(5) KIU/h during surgery. The placebo group (n=20) received an isotonic saline infusion instead.
                There was no significant difference between the groups concerning diagnosis, co-morbidity, age, sex, height, and weight. The mean intraoperative blood loss in the treatment group was significantly reduced (342 vs. 808 ml, P<0024), postoperative blood loss was also reduced (623 vs. 1282 ml, P<0.0007) and the need for blood transfusion was less (14 vs. 60, n.s.). No severe side effects of aprotinin were registered. Re-thoracotomy was necessary in two patients of the placebo group because of postoperative bleeding.
                Aprotinin reduces the perioperative blood loss and the need for blood transfusion in thoracic surgical procedures in patients with an increased risk of bleeding. Aprotinin is a proteinase inhibitor with antifibrinolytic properties that has found widespread application during cardiac surgical procedures due to its ability to decrease blood loss and transfusion requirements. Recently it has been used by orthopedic surgeons in hip replacement and other major surgeries except for scoliosis surgery, which is known to be associated with major blood loss. To evaluate the effect of aprotinin in reducing blood loss during spinal fusion surgery for idiopathic scoliosis, a double-blind randomized prospective clinical study was performed. Forty-three patients with idiopathic scoliosis underwent spinal fusion and instrumentation and were divided randomly into two groups. Fifteen patients received aprotinin, whereas 28 patients received placebo. The aprotinin group had less blood loss than the placebo group. The transfusion requirement was less in the aprotinin group than the placebo group. Although the difference was not significant statistically, the benefit of aprotinin in reducing blood loss in spinal surgery for idiopathic scoliosis was consistent. A prospective randomized double-blind placebo-controlled study was undertaken to determine the efficacy and mechanism of action of two antifibrinolytic drugs aprotinin and epsilon aminocaproic acid (EACA) in reducing blood loss in primary unilateral total hip arthroplasty (THA). Aprotinin was administered as a bolus of 2 x 10(6) kallikrein inhibitor units (KIU) followed by 0.5 x 10(6) KIU h(-1) for 3 h, EACA was given as 10 g over 30 min followed by 5 g over 3 h. The median postoperative blood loss 24 h postoperatively was reduced from 450 mL in the placebo group to 180 mL for aprotinin (60% reduction, P < 0.001) and to 210 mL for EACA (53% reduction, P < 0.01). In this population, there was no reduction in the perioperative transfusion requirements. The mechanism of both drugs was independent of platelets as indicated by flow cytometric measurement of change of their expression of P-selectin, platelet-monocyte aggregates, V/Va and CD40 ligand. There were no thrombotic or infective complications and no adverse events were attributable to use of either drug. Infusion of either aprotinin or EACA at the doses described is a safe and effective means of reducing blood loss after THA. These therapies provide a means of reducing blood loss in THA patients. Aspirin therapy is widely used in the treatment of cardiac disease. It has been recognized as a causative factor for increased bleeding and blood loss after open heart operations.
                To determine whether high-dose aprotinin maintained its efficacy in reducing blood loss in the presence of aspirin pretreatment in patients undergoing aortocoronary bypass, we performed a double blind study on 60 adult patients. Half received high-dose aprotinin (Trasylol) and half placebo.
                Total hemoglobin loss, the primary efficacy variable was reduced from 36.1 +/- 31.4 g (mean +/- SD) to 14.1 +/- 16.0 g (p = 0.002). Blood loss was reduced intraoperatively and total loss was reduced from 837.3 mL +/- 404.9 mL to 368.7 mL +/- 164.3 mL (p < 0.001). The number of patients who did not receive any donor blood products was significantly higher in the aprotinin-treated patients (56.7% versus 23.3%, p = 0.008). Activation of the clotting cascade was significantly less in the treated patients toward the end of cardiopulmonary bypass both by measurement of thrombin-antithrombin III complex (p < 0.0001) and prothrombin fragment 1 + 2 (p < 0.0001). D-Dimer generation was significantly less from the onset of bypass and after reversal of heparin in the aprotinin-treated patients (p < 0.0001).
                High-dose aprotinin was highly effective in reducing bleeding in this high-risk group of patients. Biochemical analyses suggest the mechanism by which aspirin increases blood loss after cardiopulmonary bypass is different from the blood-preserving effects of aprotinin, which is acting as an antifibrinolytic agent. Aprotinin is a broad-spectrum serine protease inhibitor that has been shown to attenuate the systemic inflammatory response in patients undergoing cardiac surgery with cardiopulmonary bypass. Although epsilon-aminocaproic acid is similar to aprotinin in its ability to inhibit excessive fibrinolysis (ie, plasmin activity and D-dimer formation), its ability to influence proinflammatory cytokine production remains unclear. This study was designed to compare the effects of epsilon-aminocaproic acid and aprotinin on plasma levels of interleukin-6 and interleukin-8 during and after cardiopulmonary bypass.
                Sixty patients were randomized in a double-blind fashion to receive epsilon-aminocaproic acid, aprotinin, or saline (placebo) in similar dosing regimens (loading dose, pump prime, and infusion). Arterial blood samples were collected before, during, and after cardiopulmonary bypass, and plasma levels of D-dimer, interleukin-6, and interleukin-8 were measured. Data were analyzed using repeated measures analysis of variance.
                Both epsilon-aminocaproic acid and aprotinin administration resulted in significant (P <.05) reductions in D-dimer and interleukin-8 levels compared with saline. These reductions in D-dimer and interleukin-8 levels did not differ between the 2 drug-treated groups. The effect of these two antifibrinolytic agents on interleukin-6 was qualitatively similar to that noted with interleukin-8 but did not reach statistical significance.
                When dosed in a similar manner, epsilon-aminocaproic acid seems to be as effective as aprotinin at reducing interleukin-6 and interleukin-8 levels in patients undergoing primary coronary artery bypass graft surgery. These data indicate that suppression of excessive plasmin activity or D-dimer formation or both may play an important role in the generation of proinflammatory cytokines during and after cardiopulmonary bypass. Microvascular bleeding after Cardiopulmonary bypass (CPB) is mainly due to consumption of clotting factors, platelets damage, and hyperfibrinolysis. Aprotinin, the only antifibrinolytic drug effective in preserving platelets, is no longer available; an alternative regimen based on pure antifibrinolytic drugs has been proposed, since hyperfibrinolysis is known to contribute both to clot lysis and platelet dysfunction. In this study the efficacy of two antifibrinolytic drugs, Tranexamic acid (TA) and epsilon-aminocaproic acid (EACA), was tested in patients undergoing cardiopulmonary bypass (CPB), for primary myocardial revascularization.
                Forty-eight consecutive patients were randomized to receive prophylactically equipotent doses of EACA (group A) or TA (Group B). Platelet count, prothrombin time, fibrin digestion products, blood loss and transfusion requirements recorded after 6 and 24 hours from the end of surgery were compared.
                The two groups were comparable for length of CPB and numbers of grafts; no significant difference was observed in the coagulation parameters considered. Blood losses were less in group B (TA) than in group A (EACA), both at 6 and 24 hours after surgery; homologous blood transfused was also less in group B, but no difference was statistically significant. No adverse effect was observed.
                In coronary patients, TA and EACA exhibit the same effects on blood loss and requirements after CPB; either drug can be safely used in cardiac surgery. Excessive bleeding during and after cardiac surgery with cardiopulmonary bypass is a real problem in this kind of surgery. The use of prophylactic high doses of aprotinin (APROT) reduces blood loss in this context but this treatment is expensive. Some investigators have advocated that epsilon-aminocaproic acid (EACA), a cheaper antifibrinolytic drug, could reduce blood loss in cardiac surgery. The goal of this prospective study was to determine if EACA is as effective as APROT for this clinical condition. Sixty patients undergoing elective surgery for cardiac disease were randomly allocated to one of the two groups. Drugs were administered after induction of anesthesia at a dose of 2.10(6) UIK in the APROT group or 5 g in the EACA group. The same dose was added to the priming of the cardiopulmonary bypass circuit. Until the skin closure the patients received 5.10(5) UIK/h of APROT or 2 g/h of EACA. Bleeding during and after surgery was not different between the two groups. No complication, directly due to the treatment administered, was observed. EACA seems to be as effective as APROT to reduce intra and post cardiac surgery blood loss. EACA has the advantage of being cheaper (treatment is approximately 200 times cheaper), therefore allowing a wider use. Excessive blood loss, as a result of augmented postoperative drainage, is considered one of the most serious cardiosurgical complications. The compounding constitutive anemia seems particularly harmful for patients with coronary artery disease. Aprotinin (Trasylol), a non-specific serine protease inhibitor, is successfully used to reduce excessive postoperative bleeding in such patients. The aim of our study was to verify the hypothesis whether aprotinin used during cardiopulmonary bypass procedure affects hemostatic parameters, which might be crucial for the elevated risk of thromboembolic complications.
                The group of 54 patients subjected to coronary artery surgical treatment included 30 patients, who were given intraoperatively 3 million KIU aprotinin each, and 24 subjects non-treated with aprotinin. Aliquots of blood were withdrawn at several time intervals, until the 5th day after the operation. Whole blood platelet activation and reactivity (the expressions of P-selectin and glycoprotein Ib) were monitored by means of flow cytometry. In addition, several plasma parameters, like PAI-1, t-PA, D-dimers, prothrombin fragment F1 + 2, fibrinogen, ATIII activity, troponin I and CK-MB, as well as platelet count were determined at each time point.
                In this study we confirmed the essential advantage of the use of aprotinin: both the postoperative blood drainage and the blood units to be transfused postoperatively to cardiosurgical patients were vastly reduced in the aprotinin-treated subjects. The enhanced overall frequency of perioperative myocardial infarction events was not attributed to this group of patients, nor the non Q-wave infarctions were observed more often in patients treated with aprotinin. In these patients, fibrinolysis parameters tended to be depressed (with increased PAI-1 dominating over elevated t-PA) on the first day after the operation, and no significant differences with regard to fibrinogen, prothrombin fragment F1 + 2, troponin I and platelet count. There was a continuous rise in D-dimers in all the postoperative patients, which lasted until the third day and tended to reach plateau at the 5th day after the operation. We failed to reveal the preventive effects of aprotinin on platelet function: both platelet activation and reactivity remained apparently unchanged. Overall, our results rather support the reasoning on the advantageous effects of low doses of aprotinin. The use of this inhibitor reduces the risk of postoperative undesirable bleeding and results in a decreased postoperative drainage and reduced transfused blood units. On the other hand, however, a higher incidence of perioperative Q-wave infarction in the aprotinin-treated patients, although purely apparent and not statistically significant, might question the unlimited safety of the use of aprotinin in cardiovascular operations. Acute preoperative plateletpheresis (APP), cell salvage (CS) technique, and the use of aprotinin have been individually reported to be effective in reducing blood loss and blood component transfusion while improving hematological profiles in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). In this prospective randomized clinical study, the efficacy of these combined approaches on reducing blood loss and transfusion requirements was evaluated. Seventy patients undergoing primary coronary artery bypass grafting (CABG) were randomly divided into four groups: a control group (group I, n = 10) did not receive any of the previously mentioned approaches. An APP and CS group (group II, n = 20) experienced APP in which preoperative platelet-rich plasma was collected and reinfused after reversal of heparin, along with the cell salvage technique throughout surgery. The third group (group III, n = 22) received aprotinin in which 5,000,000 KIU Trasylol was applied during surgery, and a combination group (group IV, n = 18) was treated with all three approaches, i.e., APP, CS, and aprotinin. Compared with group I (896+/-278 mL), the postoperative total blood loss was significantly reduced in groups II, III, and IV (468+/-136, 388+/-122, 202+/-81 mL, respectively, p < 0.05). The requirements of packed red blood cells in the three approached groups (153+/-63, 105+/-178, 0+/-0 mL, respectively) also were reduced when compared with group I (343+/-118 mL, p < 0.05). In group I, six patients (6/10) received fresh-frozen plasma and three patients (3/10) received platelet transfusion, whereas no patients in the other three groups required fresh-frozen plasma and platelet. In conclusion, both plateletpheresis concomitant with cell salvage and aprotinin contribute to the improvement of postoperative hemostasis, and the combination of these two approaches could minimize postoperative blood loss and requirement. The aim of this study was to determine the safety and efficacy of prophylactic high-dose intravenous aprotinin in reducing intraoperative blood loss in the neurosurgical population.
                A randomized, double-blind, placebo-controlled trial was conducted in parallel groups in two regional neurosurgical departments. One hundred patients with a preoperative diagnosis of intracranial meningioma or vestibular schwannoma subsequently confirmed on histological studies were included. All patients were older than 18 years of age, pregnancy had been excluded, there was no history of bleeding diathesis, no previous exposure to aprotinin, and no ingestion of antiplatelet or anticoagulant medications within the 2 weeks preceding surgery. Aprotinin was administered in doses of 30,000 kallikrein-inhibiting units (KIU)/kg body weight on induction of anesthesia and was continued as an infusion of 10,000 KIU/kg/hr until surgery was complete, or for a maximum of 8 hours. Intraoperative blood loss, blood transfusion, the Glasgow Outcome Scale score, and the Index of Independence were measured, and screening for deep vein thrombosis and the Mini-Mental State Examination were performed.
                Intraoperative blood loss was reduced from 1014 ml (geometric mean) to 508 ml (p = 0.028). Although this study was not designed to evaluate the need for blood transfusion, 37 U of blood was used in 11 patients in the aprotinin group and 58 U in 13 patients in the placebo group (not significant). There were no significant differences in postoperative thrombotic risk or other outcome measures between treatment groups. Aprotinin therefore can be safely used to reduce intraoperative blood loss in patients who are not receiving anticoagulation therapy. To compare 2 important techniques of blood conservation, use of a cell saver and low-dose aprotinin, in terms of blood loss and homologous blood usage in patients undergoing cardiac valve surgery.
                Prospective, randomized.
                Tertiary care hospital.
                Sixty adult patients undergoing elective valve surgery.
                The patients were divided into 3 groups of 20 each. In group 1, aprotinin in the dose of 30,000 KIU/kg was added to the pump prime, with a further dose of 15,000 KIU/kg added at the end of each hour of cardiopulmonary bypass. In group 2, a cell-saver system was used to collect all blood at the operation site for processing in preparation for subsequent reinfusion. Group 3 patients acted as a control group and underwent routine management, which included collection of autologous blood during the pre-cardiopulmonary bypass period. A hemoglobin of <8 g/dL was considered as an indication for bank blood transfusion in the postoperative period.
                The chest tube drainage was significantly less in group 1 compared with groups 2 and 3, with total drainage (median [interquartile range]) amounting to 250 mL [105 to 325 mL] vs. 700 mL [525 to 910 mL] in group 2 and 800 mL [650 to 880 mL] in group 3 (p < 0.001). The patients in groups 1 and 2 required significantly less bank blood (median [interquartile range]) as compared with group 3 (350 mL [0 to 525 mL], 350 mL [0 to 350 mL], and 1050 mL [875 to 1050 mL]; p < 0.001), respectively. Cell saver provided 410 +/- 130 mL of hemoconcentrated blood in group 2. The average preoperative hemoglobin concentration was 11.3 g/dL, and it was around 9 g/dL on the 7th postoperative day. The hemoglobin concentration at various stages during hospitalization in all 3 groups was similar.
                Low-dose aprotinin and a cell saver are effective and comparable methods of blood conservation. Aprotinin helps by decreasing the postoperative drainage, and a cell saver helps by making the patient's own blood available for transfusion.
                Copyright 2001 by W.B. Saunders Company. Aprotinin is a pharmacological agent which, when given in high doses during cardiopulmonary bypass (CPB), seems to reduce postoperative blood loss significantly and thereby reduces the need for blood transfusion. This study was undertaken to confirm these claims and to show that there was also decreased peroperative bleeding and a shorter operation time. The immediate postoperative clinical course was also assessed. The study was a prospective, randomised double-blind trial versus placebo in 60 coronary patients undergoing at least 2 aorto-coronary bypass grafts for the first time within a 3 month period. During surgery after stopping the CPB the blood loss recorded by aspiration was 49 +/- 61 ml in the aprotinin group and 90 +/- 84 ml in the placebo group (p less than 0.05). The quality of haemostasis in the operated area evaluated independently by the anaesthetist was judged to be excellent in 30 patients in the aprotinin group compared with only 19 in the placebo group (p less than 0.001). The time between coming off CPB and skin closure was significantly shorter in the aprotinin group (42 +/- 10 min versus 49 +/- 12 min) and the dose of protamine injected at the end of the operation was 19 +/- 38 mg in the aprotinin group compared to 43 +/- 46 mg in the placebo group (p less than 0.05). The blood loss recorded over 48 hours in the intensive care unit was nearly three times less in the aprotinin group (380 +/- 125 ml) than with placebo (852 +/- 523 ml).(ABSTRACT TRUNCATED AT 250 WORDS) The antifibrinolytic efficacy of a high-dose regimen of epsilon-aminocaproic acid (epsilon-ACA) was compared with aprotinin in first-time coronary operations.
                In a prospective, double-blinded, randomized study, 20 patients received high-dose epsilon-ACA (10 g both as a loading and cardiopulmonary bypass priming dose, 2.5 g/h until 4 hours after protamine), and another 20 patients received aprotinin (2 x 10(6) KIU [280 mg] for loading and priming, 0.5 x 10(6) KIU/h [70 mg/h]). Ten untreated patients served as controls.
                Both agents reduced postoperative levels of thrombin/antithrombin III complexes, D-dimers, fibrin degradation products, free plasma hemoglobin (epsilon-ACA versus aprotinin, p = not significant; p < 0.05 versus controls), and amount of retransfused autologous blood (p < 0.001). Epsilon-ACA increased, aprotinin suppressed antiplasmin-plasmin complex generation (epsilon-ACA versus controls, p < 0.02; epsilon-ACA versus AP, p < 0.0001). For 4 hours after discontinuation, more chest drainage occurred with epsilon-ACA than aprotinin (137 +/- 90 mL versus 62 +/- 29 mL; means +/- standard deviation; p < 0.02). Cumulative 12-hour drainage was similar for aprotinin (391 +/- 220 mL) and epsilon-ACA (582 +/- 274 mL), but higher without inhibitor (1,091 +/- 541 mL; p < 0.001 versus drugs). Postoperatively, aprotinin was associated with the lowest autologous retransfusion incidence and highest hematocrits (p < 0.01 versus epsilon-ACA). Homologous transfusion exposures did not differ.
                In first-time coronary operations, higher postoperative hematocrit and less shed blood retransfusion constitute only subtle advantages of aprotinin over high-dose epsilon-ACA. Until recently, aprotinin was the only antifibrinolytic drug with a licensed indication in cardiac surgery in the United States. The most popular alternative, epsilon-aminocaproic acid (EACA), has not been adequately compared with aprotinin. We undertook this study to test the hypothesis that EACA, when dosed appropriately, is not inferior to aprotinin at reducing fibrinolysis and blood loss.
                Seventy-eight patients scheduled for primary, isolated coronary artery bypass graft surgery were randomly assigned to receive "full Hammersmith" dose aprotinin, high dose EACA (100 mg/kg initial loading dose, 5 g in the pump prime solution, 30 mg x kg(-1) x h(-1) maintenance infusion) or equal volumes of a saline-placebo in a double-blind trial. Reductions in peak D-dimer formation (a measure of fibrinolysis) and 24-h chest tube drainage (CTD) were the primary end points by which noninferiority of EACA was tested. The noninferiority limit was set at a 30% increase in peak D-dimer formation (a difference of 250 microg/mL) and 24-h CTD (a difference of 350 mL) relative to aprotinin.
                The between-group differences (EACA versus aprotinin) in peak D-dimer formation (-3.58 microg/L, 95% CI -203 to 195 microg/L) and 24-h CTD (67 mL, 95% CI -90 to 230 mL) were within the predetermined noninferiority margins (250 microg/mL and 350 mL, respectively) and satisfied the criteria for noninferiority. Compared with saline, significant between-group reductions in peak D-dimer formation were observed using EACA (589 microg/L, 95% CI 399-788 microg/L; P < 0.0001) and aprotinin (585 microg/L, 95% CI 393-778 microg/L; P < 0.0001). Similar reductions in 24 h CTD were also seen using EACA (239 mL, 95% CI 50-415 mL; P < 0.05) and aprotinin (323 mL, 95% CI 105-485 mL; P < 0.05) compared with saline. Plasma EACA levels were maintained well above a target of 260 microg/mL.
                When dosed in a pharmacologically guided manner, EACA is not inferior to aprotinin in reducing fibrinolysis and blood loss in patients undergoing primary, isolated coronary artery bypass surgery. In this study we compared the clinical efficiency, safety, and economic benefit of low-dose aprotinin with epsilon aminocaproic acid (EACA) in reducing bleeding after cardiopulmonary bypass operation.
                In a double-blind, randomized study, 100 patients received low-dose aprotinin (2 x 10(6) kallikrein inhibitor units) or EACA (20 g). The surgical procedure was single- or double-valve replacement with or without coronary artery bypass grafts.
                Mediastinal chest drainage and transfusion requirements with both therapies were similar. There were no urgent reoperations to secure hemostasis in either group. Similar levels of D-dimer with both therapies indicate a similar inhibition of fibrinolysis. Release of troponin I was less in the low-dose aprotinin group 1 and 4 hours after bypass, although electrocardiographic measurements did not reflect this difference. Levels of S-100beta and neuron-specific enolase were similar with both therapies, confirming that there was no difference in the occurrence of any adverse neurologic events in either group.
                Low-dose aprotinin and EACA showed similar effects on the reduction of intraoperative and postoperative bleeding. The lower cost of EACA with no change in safety outcome suggests it is the preferred treatment. A prospective blinded, randomized controlled study compared the effect of a perioperative infusion of aprotinin versus placebo during long segment spinal fusions in children.
                To determine whether aprotinin decreases blood loss and transfusion requirements in pediatric patients with spinal deformities undergoing posterior spinal fusions of seven or greater segments.
                Blood loss is a major cause of morbidity during long segment spinal fusion. Several preoperative and intraoperative techniques are currently used to reduce blood loss and transfusion requirements. Aprotinin, an antifibrinolytic and anti-inflammatory agent, has been used to decrease blood loss in cardiac surgical patients. We designed a prospective, randomized, and blinded controlled study to evaluate aprotinin's efficacy in reducing bleeding during pediatric spine surgery.
                After obtaining informed written consent, we studied 44 children and adolescents who were anticipated to be at higher risk for major blood loss during posterior spinal fusion. Children were randomly assigned to receive high dose aprotinin or placebo infusion during the perioperative period. Patients were assessed for blood loss, transfusion requirements, days in the intensive care unit, and days in hospital.
                Demographics in the two groups of patients were similar. The study demonstrated a significant reduction in estimated blood loss (aprotinin 545 cc, placebo 930 cc) and transfusion requirements (aprotinin 1.1 U, placebo 2.2 U). The duration of intensive care unit admission was similar in the two groups, as was the time until discharge.
                This randomized, blinded study suggests that aprotinin significantly decreased blood loss and transfusion requirements in pediatric and adolescent scoliosis surgical patients at increased risk for intraoperative bleeding. Thirty-eight patients undergoing a cardiac operation randomly received either tranexamic acid, a potent inhibitor of plasminogen, or placebo in an effort to determine whether prophylactic antifibrinolytic therapy reduces chest tube drainage. Twelve-hour blood loss was 750 +/- 314 (standard deviation) ml in the placebo group and 496 +/- 228 ml in the drug group (p = 0.0057). Fibrin split products were present more frequently in patients in the placebo group (17 of 20 compared with four of 18 in the drug group; p = 0.0002). Tranexamic acid markedly decreased plasminogen availability (112 +/- 104 units in the placebo group versus 36 +/- 18 units in the drug group, p = 0.0058). Plasma fibrinogen concentrations were similar in the placebo and drug groups. Patients in the placebo group received more fresh-frozen plasma and more mediastinal shed blood than those in the drug group. No coagulation-related complication occurred in the group receiving tranexamic acid. We conclude that prophylactic tranexamic acid can be administered safely to inhibit fibrinolysis during cardiac operations, decrease postoperative bleeding, and possibly decrease the frequency of blood product transfusion. To assess the relative efficacy of a "low-dose" aprotinin regimen and tranexamic acid on blood loss and homologous blood usage in patients undergoing primary cardiac surgery.
                The trial was prospective, randomized, and controlled.
                A single center study in a regional cardiothoracic unit in the UK.
                75 Patients, age 18 years or over, who were scheduled for routine primary cardiac surgery.
                The patients were randomly allocated to receive neither drug nor placebo, a total of 5 g of tranexamic acid, or a total of 2 x 10(6) kallikrein inhibitory units of aprotinin in the perioperative period.
                The volume of blood loss and blood replacement were measured in the operative and postoperative periods. Hemoglobin concentration, platelet count, and white cell counts were determined preoperatively and at 24 hours postoperatively. Patients receiving tranexamic acid or aprotinin showed a significant reduction in postoperative blood loss (median[interquartile range] 375 mL [252 to 542] and 230 mL [137 to 547]), respectively, compared with the control group (615 mL [430 to 861]). Blood usage was also reduced in patients in both the tranexamic acid group (600 mL [415 to 800]) and the aprotinin-treated group (420 mL [350 to 887]) compared with the control group (1,050 mL [0 to 1,337]). There was no significant difference in blood loss or homologous blood use between patients treated with tranexamic acid or aprotinin.
                Tranexamic acid is as effective as low-dose aprotinin in the reduction of postoperative blood loss and homologous blood transfusion in patients undergoing primary cardiac surgery. Aprotinin and tranexamic acid are routinely used to reduce bleeding in cardiac surgery. There is a large difference in agent price and perhaps in efficacy.
                In a prospective, randomized, partially blinded study, 168 cardiac surgery patients at high risk for bleeding received either a full-dose aprotinin infusion, tranexamic acid (10-mg/kg load, 1-mg x kg(-1) x h(-1) infusion), tranexamic acid with pre-cardiopulmonary bypass autologous whole-blood collection (12.5% blood volume) and reinfusion after cardiopulmonary bypass (combined therapy), or saline infusion (placebo group).
                There were complete data in 160 patients. The aprotinin (n = 40) and combined therapy (n = 32) groups (data are median [range]) had similar reductions in blood loss in the first 4 h in the intensive care unit (225 [40-761] and 163 [25-760] ml, respectively; P = 0.014), erythrocyte transfusion requirements in the first 24 h in the intensive care unit (0 [0-3] and 0 [0-3] U, respectively; P = 0.004), and durations of time from end of cardiopulmonary bypass to discharge from the operating room (92 [57-215] and 94 [37, 186] min, respectively; P = 0.01) compared with the placebo group (n = 43). Ten patients in the combined therapy group (30.3%) required transfusion of the autologous blood during cardiopulmonary bypass for anemia.
                The combination therapy of tranexamic acid and intraoperative autologous blood collection provided similar reduction in blood loss and transfusion requirements as aprotinin. Cost analyses revealed that combined therapy and tranexamic acid therapy were the least costly therapies. Aprotinin has been reported to reduce blood loss and transfusion requirements in patients having major orthopedic operations. Data on whether epsilon amino-caproic acid (EACA) is effective in this population are sparse.
                Sixty-nine adults with malignancy scheduled for either pelvic, extremity or spine surgery during general anesthesia entered this randomized, double-blind, placebo-controlled trial, and received either intravenous aprotinin (n = 23), bolus of 2 x 10(6) kallikrein inactivator units (KIU), followed by an infusion of 5 x 10(5) KIU/h, or EACA (n = 22), bolus of 150 mg/kg, followed by a 15 mg/kg/h infusion or saline placebo (n = 24) during surgery. Our goal was to determine whether prophylactic EACA or aprotinin therapy would reduce perioperative blood loss (intraoperative + first 48h) >30% when compared to placebo.
                The mean age of the study population was 52 +/- 17 yr. The groups did not differ in age, duration of surgery, perioperative blood loss or number of packed erythrocyte units transfused. When compared to the placebo group, the two treated groups had a significantly lower D-Dimer level immediately after surgery, P < 0.01.
                Under the conditions of this study, we were unable to find a clinical benefit to using aprotinin or EACA to reduce perioperative blood loss or transfusion requirements during major orthopedic surgery in cancer patients. We evaluated the effect of tranexamic acid on blood loss in patients undergoing elective cardiopulmonary bypass for coronary artery bypass surgery.
                We randomly assigned 7 of 14 patients to a group receiving 50 mg/kg tranexamic acid before skin incision and after the start of cardiopulmonary bypass and the other 7 as controls.
                Intraoperative and postoperative blood loss was significantly (p = 0.025) reduced in the tranexamic acid group. A similar decrease in platelet count was observed during cardiopulmonary bypass in both groups. Antithrombin III was significantly (p = 0.013) decreased in both groups during cardiopulmonary bypass. Antithrombin III and thrombin-antithrombin III complexes were significantly (p = 0.001) increased after protamine administration. A significant (p = 0.010) decrease in alpha 2-plasmin inhibitor was noted at 5 and 60 minutes after the start of cardiopulmonary bypass in the tranexamic acid group. alpha 2-plasmin inhibitor-plasmin complexes were significantly (p = 0.001) increased after the start of cardiopulmonary bypass in both groups and were significantly (p = 0.012) decreased after protamine administration. alpha 2-plasmin inhibitor-plasmin complexes in the tranexamic acid group were significantly (p = 0.030) lower than in controls 60 minutes after the start of cardiopulmonary bypass, just prior to the end of cardiopulmonary bypass, and after protamine administration.
                These findings showed that tranexamic acid administration effectively prevented perioperative blood loss without thromboembolic complications and that tranexamic acid during cardiopulmonary bypass coordinates the anticoagulative effect of heparin and the antifibrinolytic effect of tranexamic acid. Studies have shown that aprotinin and tranexamic acid can reduce postoperative blood loss after cardiac operation. However, which drug is more efficacious in a higher risk surgical group of patients, has yet to be defined in a randomized study.
                With informed consent, 80 patients undergoing elective high transfusion risk cardiac procedures (repeat sternotomy, multiple valve, combined procedures, or aortic arch operation) were randomized in a double-blind fashion, to receive either high dose aprotinin or tranexamic acid. Patient and operative characteristics, chest tube drainage and transfusion requirements were recorded.
                There was no significant difference between the 2 treatment groups with respect to age, cardiopulmonary bypass time, complications (myocardial infarction, stroke, death), chest tube drainage (6, 12, or 24 hours), blood transfusions up to 24 hours postoperatively, total allogeneic blood transfusions for entire hospital stay, or induction/postoperative hemoglobin levels. However, multiple regression analysis revealed a positive relationship between cardiopulmonary bypass time and 24 hour blood loss in the tranexamic acid group (p = 0.001), unlike the aprotinin group where 24 hour blood loss is independent of cardiopulmonary bypass time (p = 0.423).
                Overall, there was no significant difference in blood loss, or transfusion requirements, when patients received either aprotinin or tranexamic acid for high transfusion risk cardiac operation. Aprotinin, when given as an infusion in a high-dose regimen, was able to negate the usual positive effect of cardiopulmonary bypass time on chest tube blood loss. Twenty patients undergoing orthotopic heart transplantation were randomized preoperatively to receive either the serine proteinase inhibitor aprotinin in a low dose (560 mg; n = 10) or a placebo (control group, n = 10) at the time of transplantation. Blood loss 24 and 48 hours after transplantation was significantly lower in the group treated with aprotinin (i.e., 510 ml vs 820 ml, p less than 0.01, and 690 ml vs 1000 ml, p less than 0.03, respectively. Accordingly, the aprotinin group required significantly less transfused blood in the first 48 postoperative hours 0 to 250 ml versus 0 to 1000 ml (p less than 0.04). Seventy percent of the patients treated with aprotinin underwent transplantation without the need of nonautologous blood, compared with only 30% in the control group. Tranexamic acid (TA) is a synthetic drug that inhibits fibrinolysis. It has been administered to decrease the use of blood products during cardiac surgery and orthotopic liver transplantation when infused in larger doses. A small-dose infusion of aprotinin causes a reduction in fibrinolysis and blood product requirement during orthotopic liver transplantation without apparent risk of intravascular thrombosis. This prospective study was designed to investigate whether a small-dose infusion of TA would be equally effective in reducing fibrinolysis and blood product transfusions during orthotopic liver transplantation. A double-blind, controlled study was undertaken to compare the efficacy of a small-dose TA infusion with that of a placebo. Thirty-two consecutive patients were randomized either to the TA group (n = 16), which received an intravenous infusion of 2 mg x kg(-1) x h(-1), or to the control group (n = 16), which received an identical volume of normal saline. Coagulation values were measured, a field rating was made by the surgeon, and a thromboelastogram was produced at four predetermined intervals throughout the case-before TA infusion was started, after portal vein ligation, 10 min after reperfusion, and at the end of surgery. Intraoperative transfusion requirements were recorded during the procedure and for the first 24 h postoperatively. A record was kept of any intraoperative epsilon-aminocaproic acid administered for uncontrolled fibrinolysis. The thromboelastogram clot lysis index was significant for lysis in the control group during both the anhepatic and the neohepatic phases (P < 0.01 and P < 0.05, respectively) when compared with the TA group. Fibrin degradation products were significantly increased (>20 microg/mL) in the control group at reperfusion (P < 0.03) and at the end of surgery (P < 0.01). D-dimers were also significantly increased (>1 mg/L) in the control group at the end of surgery (P < 0.04). Nine of the 16 control patients versus 3 of the 16 TA patients required epsilon-aminocaproic acid rescue for fibrinolysis. There were no other significant differences between groups. Transfusion requirements during surgery and for the first 24 h postoperatively did not differ significantly between the two groups. We conclude that the use of small-dose TA reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation. The great risk of severe infectious diseases transmission through blood transfusion, has increased during the last years the effort to reduce the bank blood and its derivates use. Many techniques have proposed to achieve this purpose during and post cardiopulmonary bypass: normovolemic hemodilution, perioperative blood autotransfusion, postoperative return of extra corporeal circuit and chest drains blood and the particular use of some drugs. In the last few years several reports have been presented in the literature concerning the reduction of intra and postoperative bleeding in cardiac surgery by high dose Aprotinin administration. A randomized study with the use of this pharmacologic agent is presented: a group of patients was treated with Aprotinin (shared in two subgroups receiving respectively a different dose of the drug) and a control group. The results were highly encouraging both because of the reduction of peri and postoperative bleeding and because of the bank blood use important reduction. Reduction of homologous blood requirement in cardiac surgery is of increasing interest and may be achieved by various technical and pharmacological means. High-dose aprotinin (about 840 mg, equivalent to 6 million Kallikrein inactivator units), a serine proteinase inhibitor, was administered during open heart surgery to 60 patients refusing homologous blood transfusions or suspected to have an increased risk of bleeding. As a significant decrease in donor blood requirement could be observed, a prospective, randomised double blind study in 80 male patients undergoing primary coronary surgery with high-dose aprotinin administration was performed. Mean blood loss was reduced by 45.9% (652 ml in the treated vs 1204 ml in the untreated group, p less than 0.01) and the mean amount transfused was decreased by 74.2% (242 ml vs 937 ml, p less than 0.01). No homologous blood was needed in 57.9% of the aprotinin-treated patients and in 31.6% of patients not treated with aprotinin. Aprotinin reduces blood loss in many orthopedic procedures. In posterior lumbar spine fusion, blood loss results primarily from large vein bleeding and also occurs after the wound is closed. Seventy-two patients undergoing posterior lumbar spine fusion were randomly assigned to large-dose aprotinin therapy or placebo. All patients donated three units of packed red blood cells (RBCs) preoperatively. Postoperative blood loss was harvested from the surgical wound in patients undergoing two- and/or three-level fusion for reinfusion. The target hematocrit for RBC transfusion was 26% if tolerated. Total (intraoperative and 24 h postoperative) blood loss, transfusion requirements, and percentage of transfused patients per treatment group were significantly smaller in the aprotinin group than in the placebo group (1935 +/- 873 vs 2809 +/- 973 mL per patient [P = 0.007]; 42 vs 95 packed RBCs per group [P = 0.001]; 40% vs 81% per group [P = 0.02]). Hematological assessments showed an identically significant (a) intraoperative increase in both thrombin-antithrombin III complexes (TAT) and in activated factor XII (XIIa) and (b) decrease in activated factor VII (VIIa), indicating a similar significant effect on coagulation in patients of both groups (P = 0.9 for intergroup comparisons of postoperative VIIa, XIIa, and TAT). Intraoperative activation of fibrinolysis was significantly less pronounced in the aprotinin group than in the placebo group (P < 0.0001 for intergroup comparison of postoperative D-dimer levels). No adverse drug effects (circulatory disturbances, deep venous thrombosis, alteration of serum creatinine) were detected. Although administered intraoperatively, aprotinin treatment dramatically reduced intraoperative and 24-h postoperative blood loss and autologous transfusion requirements but did not change homologous transfusion in posterior lumbar spine fusion.
                In our study, aprotinin therapy significantly decreased autologous, but not homologous, transfusion requirements in posterior lumbar spine fusion. Total arterial grafting is increasingly preferred in coronary artery bypass grafting, but it increases blood loss. Aprotinin (Trasylol; Bayer Corp, Leverkusen, Germany) reduces blood loss in cardiac surgery but has not been subjected to a randomized trial in total arterial grafting.
                A single-center, randomized, double blind, placebo-controlled trial of aprotinin administration in total arterial grafting was performed. The primary outcome variable was postoperative blood loss, and the secondary outcome variable was the number of units of donor blood or coagulant products transfused. The incidence of myocardial injury was determined from serial measurements of cardiac troponin T and creatine kinase-MB and renal injury from serum creatinine.
                The placebo group (n = 34) and aprotinin group (n = 36) were similar with respect to all preoperative and intraoperative comparisons. One patient in each group underwent reexploration for bleeding. Open-label aprotinin was administered to 9 patients in the placebo group (26%) and to 2 patients in the aprotinin group (6%). There was a highly significant reduction in the median (interquartile range) blood loss in the aprotinin group compared with the placebo group (785 mL [590-1025 mL] vs 1525 mL [1175-1920 mL], respectively). Similarly, the aprotinin group demonstrated a marked reduction in the need for blood transfusion (77% vs 39%; P =.0001), the mean number of transfused blood units (2.6 vs 0.8, P <.001), and the number of patients requiring coagulant products (24% vs 3%; P <.001). There was no difference in myocardial injury in the 2 groups. Four patients in the aprotinin group had persistently elevated creatinine levels in the postoperative period (3 of whom had elevated preoperative creatinine levels and perioperative complications).
                Aprotinin significantly reduces blood loss and the need for blood component transfusion in patients undergoing total arterial grafting without increasing the risk of myocardial injury. Aprotinin should be considered routinely in patients undergoing total arterial grafting but cautiously in patients with an elevated preoperative creatinine level. A projected increase in total hip arthroplasties, shortfalls in blood availability, and awareness of complications of transfusion make blood management in orthopaedic surgery important. In a multicenter, randomized, double-blind, placebo-controlled study, we hypothesized use of aprotinin would reduce blood transfusions (any and allogeneic) and blood loss in total hip arthroplasty. Using an intent-to-treat approach, we recruited 393 patients stratified by preoperative autologous blood donation or none and then randomized them to receive aprotinin (176 patients receiving a 10,000 kallikrein inhibitor units [KIU] test dose, 2 million KIU load, 0.5 million KIU per hour) or placebo (177 patients). We assessed patients at baseline; postoperative days 1, 2, 3, and 7 (or discharge); and 6 +/- 2 weeks. Primary efficacy was percentage of patients having blood transfusion through day 7 or discharge. We based safety on reported adverse events. Aprotinin reduced transfusions by 46% (30 of 176 versus 56 of 177 patients). Aprotinin reduced the total number of any blood units and the number of allogeneic blood units transfused relative to placebo (48 versus 109 units and 30 versus 72 units, respectively). Serious complications were similar in the two groups (placebo, 11%; aprotinin, 10%). Our data suggest full-dose aprotinin is safe and effective in decreasing blood transfusion in total hip arthroplasty. In addition to blood-sparing effects, aprotinin may have cardioprotective and anti-inflammatory effects during cardiopulmonary bypass-assisted cardiac surgery. In this study, the authors examined whether aprotinin had cardioprotective and/or anti-inflammatory effects in patients undergoing off-pump coronary artery bypass grafting.
                A prospective randomized clinical trial.
                University hospital.
                Fifty patients were randomized to control (n = 25) or aprotinin treatment (n = 25) groups.
                Aprotinin was given as a loading dose (2 x 10(6) KIU) followed by a continuous infusion at 5 x 10(5) KIU/h until skin closure.
                Blood samples for cardiac troponin I; interleukin-6, interleukin-8, and interleukin-10; tumor necrosis factor alpha; and elastase were taken after anesthesia induction, completion of revascularization, and 6 hours, 12 hours, and 24 hours after revascularization. Blood samples were taken to assess for apoptosis in polymorphonuclear cells. Baseline plasma levels for cardiac troponin I did not differ between groups but were significantly lower in aprotinin-treated patients at the time of revascularization (p = 0.03) and 6 hours (p = 0.004) and 24 hours (p = 0.03) later. Aprotinin significantly reduced apoptosis in polymorphonuclear cells compared with control-treated patients (p = 0.04). There were no differences in plasma cytokine or elastase levels between groups.
                The authors conclude that aprotinin reduces perioperative cardiac troponin I release and attenuates apoptosis in polymorphonuclear cells but has no significant effects on plasma cytokine levels in patients undergoing off-pump coronary artery bypass graft surgery. Aprotinin has been used to decrease blood loss with complicated cardiac surgery but has not been investigated in extrapleural pneumonectomy, an operation that does not use cardiopulmonary bypass. In this prospective, randomized, placebo-controlled, double-blind trial, the authors investigated whether aprotinin decreased blood loss in patients who underwent this operation.
                After appropriate statistical design and institutional review board approval, eligible patients who were scheduled for extrapleural pneumonectomy were randomized to receive either aprotinin or placebo during the operation. Blood loss and survival data were obtained from electronic medical records and surgical databases.
                Of 20 patients who were enrolled, 16 patients met criteria for blood loss analysis. Four patients were excluded from the blood loss analysis: Three patients were inoperable because of tumor spread and underwent limited surgery, and 1 patient died intraoperatively because of acute, massive hemorrhage. The mean blood loss was 769 mL with aprotinin versus 1832 mL with placebo (P = .05; Wilcoxon test). All 20 patients were included in survival analyses. All 9 patients who received placebo died. In contrast, 7 of 11 patients who received aprotinin remained alive at the time of the current report. Kaplan-Meier survival curves differed significantly between the 2 groups (P = .0004). A Bayesian multivariate survival analysis of 18 patients who had complete data available on 8 prognostic variables indicated a posterior probability of .99 that aprotinin was beneficial.
                Aprotinin decreased blood loss. After accounting for covariate effects, there was a significant comparative benefit with aprotinin in postoperative survival. This finding was unexpected and could not be considered conclusive because of the small size of the current study. A confirmatory study may be warranted.
                (c) 2009 American Cancer Society. Risks and costs of allogeneic blood transfusions mandate strategies to reduce blood loss in surgery. The objective of this study was to assess the efficacy of antifibrinolytic treatment in reducing perioperative blood loss during total knee replacement.
                A double-blind, randomized and placebo-controlled clinical trial was carried out on 127 patients undergoing total knee replacement. Patients in the study group received tranexamic acid 10 mg kg(-1) i.v. just before the tourniquet was deflated and 3 h later, or epsilon-aminocaproic acid 100 mg kg(-1) before tourniquet deflation followed by continuous perfusion (1 g h(-1)) during 3 h. External perioperative blood loss was measured and total blood loss was calculated. The number of patients transfused and number of packed red cell (PRC) units transfused was recorded and possible postoperative thromboembolic complications were investigated.
                Total blood loss [mean (sd)] was 1099 ml (535) in the group that received antifibrinolytic agents and 1784 ml (660) in the control group (P<0.001). Five patients (7.5%) in the study group and 23 (38.3%) in the control group (P<0.001) received blood transfusions; the first group received a mean of 0.10 PRC unit per patient and the second, 0.58 (P<0.001). Mean reduction in haemoglobin levels (g dl(-1)) between preoperative and fifth day postoperative readings was 2.5 (0.9) in the study group and 3.4 (1.2) in the control group (P<0.001). Clinical assessment did not reveal any thromboembolic complications.
                Antifibrinolytic agents produce a significant decrease in blood loss in patients undergoing total knee replacement, reflected in a reduction in the number of blood transfusions required. Thrombin formation during cardiac surgery could result in disordered hemostasis and thrombosis. The aim of the study was to examine the effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic activity in patients undergoing cardiac surgery.
                Data were collected prospectively from 60 patients undergoing coronary artery bypass grafting using cardiopulmonary bypass (CPB). In a randomized sequence, 20 patients received aprotinin, 20 patients received tranexamic acid, and in 20 patients placebo was used.
                Significant thrombin activity was found in all the studied patients. Thrombin generation was less in the aprotinin group than in the tranexamic acid and the placebo group (thrombin/anti-thrombin III complexes 33.7 +/- 3.6, 53.6 +/- 7.0 and 44.2 +/- 5.3 microg/l 2 h after CPB and F1 + 2 fragment 1.50 +/- 0.10, 2.37 +/- 0.37 and 2.04 +/- 0.20 nmol/l 6 h after surgery, respectively). The inhibition of fibrinolysis was significant with both anti-fibrinolytic drugs (D-dimers 0.427 +/- 0.032, 0.394 +/- 0.039 and 2.808 +/- 0.037 mg/l 2 h after CPB, respectively). The generation of d-dimers was inhibited until 16 h after CPB in the aprotinin group. The plasminogen activation was significantly less in the aprotinin group (plasmin/anti-plasmin complexes 0.884 +/- 0.095, 2.764 +/- 0.254 and 1.574 +/- 0.185 mg/l 2 h after CPB, respectively).
                Thrombin formation is inevitable in coronary artery bypass surgery when CPB is used. The suppression of fibrinolytic activity, either with aprotinin or with tranexamic acid interferes with the hemostatic balance as evaluated by biochemical markers. Further investigations are needed to define the role of hemostatic activation in ischemic complications associated with cardiac surgery. Sixty patients (four groups of 15 patients) were entered in a randomized, controlled study to compare the efficacy of prophylactic treatment with dipyridamole, tranexamic acid, and aprotinin to reduce bleeding after elective coronary artery bypass grafting. Only patients with a preoperative platelet count of less than 246 x 10(9)/L were selected because a previous study showed that these individuals are at risk for increased postoperative bleeding. Compared to control subjects, postoperative blood loss 6 hours after operation was significantly reduced by tranexamic acid (674 +/- 411 versus 352 +/- 150 mL; p < 0.05) and by aprotinin (270 +/- 174 mL; p < 0.01). Dipyridamole did not reduce postoperative blood loss and was associated with complications in 3 patients. We conclude that hemostasis after cardiac operations can be improved with tranexamic acid and aprotinin. Dipyridamole appeared to be ineffective. To compare the efficacy of aprotinin (APR) and tranexamic acid (TRA) in reducing blood loss and transfusion requirements after cardiac surgery under extracorporeal circulation (ECC).
                Randomized controlled trial.
                One hundred and four adults undergoing either coronary artery bypass grafting (CABG) (n = 55), or aortic valve replacement (AVR) (n = 49), allocated into three groups.
                a) APR group (23 CABG and 20 AVR) received aprotinin, 2 x 10(6) KIU (280 mg) after induction, followed by an infusion of 0.5 x 106 KIU.h-1 (70 mg.h-1) until chest closure, with a supplement to the oxygenator prime of 2 x 10(6) KIU; b) TRA group (22 CABG and 19 AVR) received tranexamic acid, 15 mg.kg-1 between the injection of heparin (400 IU.kg-1) and the beginning of ECC, 15 mg.kg-1 after protamin injection (1.3 mg/100 IU of heparin); c) CTR group (10 CABG and 10 AVR), the control group, was not treated with an antifibrinolytic agent. The amount of blood collected from the chest tube drainage was measured at admission to ICU, as well as 4, 8 and 18 h after the insertion of drains and at the time of their removal. Packed red cells where given when the haematocrit was under 20% during ECC, 25% at the end of surgery and 30% after extubation.
                The blood loss was lower in APR group (834 +/- 448 mL) than in TRA group (1015 +/- 409 mL) (P = 0.009), and in CTR group (1416 +/- 559 ML) (P = 0.004). The rates of transfused patients in groups APR, ATR and CTR were 35, 37 and 60% respectively and the numbers of units administered per patient were 0.8, 0.8 and 1.7 respectively. In AVR cases, APR and TRA had a similar efficacy. In CABG cases, only aprotinin decreased postoperative bleeding. However there was no difference between APR and TRA concerning the transfusion requirements. In CABG cases the ECC was of shorter duration and blood loss was 1127 +/- 540 mL vs 894 +/- 422 mL in AVR cases (P = 0.03).
                Both APR and TRA decrease blood loss. APR is more efficient after CABG than TRA as far as blood loss is concerned, whereas the transfusion requirements are similar. As APR is about 100 times more expensive and carries a risk for allergic reactions, its use in a high dose regimen is only recommended for reoperations, in patients treated with salicylates and in case of sepsis. The objective of this study was to study the effect of low-dose tranexamic acid (TA) on postoperative bleeding and coagulation variables after coronary artery bypass grafting operation.
                Fifty patients undergoing primary coronary artery bypass grafting were randomly assigned to receive either placebo (0.9% NaCl; n = 25) or 10 mg/kg TA followed by infusion of 1 mg/kg per hour during the operation (n = 25). Data measured included blood loss, transfusion, reoperation, fibrinogen level, fibrinogen split products, platelet size, and platelet function. Measurements were made after induction of anesthesia, after heparin administration, during patient warming, after skin closure, and 24 hours after operation.
                Patients in the TA study group weighed less. Other demographic characteristics were similar between groups. Postoperative bleeding was less in the TA group (194 +/- 135 mL versus 488 +/- 238 mL, p < 0.001), whereas blood requirement was higher in the control group (1.68 +/- 1 versus 0.52 +/- 0.9 U of packed cells per patient, p < 0.001). The percent of patients exposed to blood products was significantly less in the TA group (36% versus 100%, p < 0.001). Fibrinogen split products were lower in the TA group during bypass (p < 0.001). Fibrinogen levels fell in both groups during cardiopulmonary bypass. Platelet number and function were reduced equally in both groups by cardiopulmonary bypass. Other test results were not different between groups.
                The use of low-dose TA during coronary artery bypass grafting significantly reduced the coagulopathy-induced postoperative bleeding and allogeneic blood products requirement. The low levels of fibrinogen split products during bypass in the study group reflect the inhibiting effect of TA in fibrinolysis. Tranexamic acid had no effect on platelet function during cardiopulmonary bypass. To examine pump-prime aprotinin action on coagulation and fibrinolysis in patients undergoing primary coronary revascularization.
                A prospective randomized study.
                A university hospital.
                Forty-three patients were randomly assigned to either group A, 21 patients treated with 2 x 10(6) kallikrein inhibitor units (KIU) of aprotinin in the cardiopulmonary bypass (CPB) prime, or group B, 22 patients, untreated.
                Patients, scheduled for elective coronary surgery, were treated with 2 x 10(6) KIU of aprotinin in the CPB prime. Markers of coagulation and fibrinolysis were evaluated.
                Surgical times, number of reopenings, and allogeneic blood requirements were collected for each patient. Blood samples were obtained before and after surgery for assessing coagulation (prothrombin time [PT], activated partial thromboplastin time [aPTT], ethanol test, factor VII, antithrombin III [AT III], thrombin-antithrombin III complex [TAT], fragment 1.2 of prothrombin [F1.2]) and fibrinolysis (fibrin degradation products [FOP], plasmin-antiplasmin complexes [PAP], D-dimers) markers variations. In group A surgical times were faster, there were fewer reopenings (0 v 3), and fewer blood transfusions (1 patient v 4 patients). The two groups did not differ for PT, aPTT, and fibrinogen measurements. Postoperative FDP (measurable in more patients of group B at the end of the operation), PAP, and D-dimers postoperatory levels (less increased in aprotinin group) show the antifibrinolytic properties of the drug. Regarding the coagulation markers, factor VII decreased, whereas TAT and F1.2 increased, all to a lesser extent in the aprotinin group compared with the untreated patients, at the end of operation.
                Pump-prime aprotinin minimized, even if not completely inhibited, the activation of coagulation and fibrinolysis during CPB, possibly ensuring a less complicated and safer postoperative recovery. It seemed to allow the maintenance of a correct balance of hemostatic systems, avoiding the risk of thrombotic phenomena. The serine proteinase inhibitor aprotinin significantly reduces postoperative blood loss in patients requiring cardiac surgery using cardiopulmonary bypass. This study compared two low-dose regimens with administration of high-dose aprotinin and a control protocol to determine whether the dose of aprotinin could be greatly decreased but still maintain efficacy after primary cardiac surgery. Some 100 patients were randomly assigned to one of four groups: control group (0.9 per cent saline placebo, n = 25); high-dose group (aprotinin 2 x 10(6) kallikrein inactivator (KI) units intravenous patient bolus and 0.5 x 10(6) KI units h-1 plus 2 x 10(6) KI units into pump prime, n = 25); prime group (aprotinin 2 x 10(6) KI units added to the pump prime, n = 24); and patient group (aprotinin 10(6) KI units intravenous patient bolus plus 10(6) KI units added to the pump prime, n = 26). Only patients from the high-dose and patient groups had reduced intraoperative blood loss, but patients from all three aprotinin-treated groups demonstrated a significant decrease in median postoperative blood loss compared with the control group (high-dose 350 ml, prime 420 ml, patient 340 ml versus control 780 ml; P < 0.001). There was an even greater reduction in measured median postoperative haemoglobin loss within the chest drains in the treated compared with the control patients (high-dose 15 g, prime 24 g, patient 14 g versus control 47 g; P < 0.001). These decreases were statistically the same for all the treated groups; it is possible to lower the dose of aprotinin to approximately one-third of the currently recommended dosage and still obtain significantly reduced postoperative blood loss in primary cardiac surgery. To evaluate the role of recombinant bovine aprotinin in reducing blood loss in coronary artery bypass graft surgery.
                An open-label, randomized, controlled study evaluating two dosage levels of recombinant aprotinin.
                Two acute care hospitals (Northwestern Memorial Hospital, Chicago, Ill., and the Scott & White Memorial Hospital, Temple, Texas).
                Patients undergoing primary and reoperation coronary artery bypass grafting were assigned to groups by means of a computer-generated table of random numbers. Treated (n = 48) and control (n = 36) patients did not differ significantly in age, sex, weight, number of grafts, or preoperative hemoglobin level.
                Recombinant aprotinin was given at two dosages. Dosage level 1 consisted of a bolus of 2 mg/kg intravenously immediately after the induction of anesthesia, 1 mg/kg added to each liter of the oxygenator prime, and 0.5 mg.kg-1.hr-1 infused continuously during operation. At dosage level 2, doses were doubled. Intraoperative monitoring of anti-factor Xa activity was performed, and additional doses of heparin were given on the basis of anti-factor Xa results.
                Preoperative and postoperative hemoglobin levels, amounts of autotransfusion device and chest tube drainage blood, and transfusions of allogeneic red blood cells. Adverse clinical events (alterations in renal function, graft thrombosis, myocardial infarction, and death) were recorded.
                Additional heparin was given to 48% patients in the aprotinin group and to 44% of control patients. Overall red blood cell loss (in milliliters, mean +/- standard deviation [SD]) was decreased with aprotinin at dosage level 1 for reoperations (1040 +/- 162 vs 1544 +/- 198, p < 0.01), and at dosage level 2 for all operations (primary operations, 886 +/- 362 vs 1333 +/- 618, p = 0.02; reoperations, 1191 +/- 560 vs 1815 +/- 1116, p = 0.2). Fewer patients in the aprotinin than in the control group had transfusions of donated blood (6/48 vs 12/36, p = 0.02) or reinfusion of chest tube drainage blood (12/48 vs 20/36, p < 0.01). Among patients receiving dosage level 1, there were no myocardial infarctions or deaths. At dosage level 2, one patient had profound bradycardia and died on day 12 and two patients had late graft closures. Two control patients had hypotension after bypass necessitating intraaortic balloon pumps, and one of these patients died. Postoperative increases in blood urea nitrogen and creatinine levels were small in both aprotinin and control groups. No hypersensitivity or other allergic reactions occurred.
                We conclude that, at the dosages given, recombinant bovine aprotinin decreases surgical blood loss and transfusion requirements in patients undergoing coronary artery bypass grafting, but its use requires appropriate monitoring of heparin use during bypass. Whether higher dosages of aprotinin increase the risk of graft thrombosis must be further assessed with a larger patient sample. Aprotinin reduces blood loss in operations done with cardiopulmonary bypass, whereas the use of desmopressin remains controversial. We compared aprotinin, desmopressin, and placebo in a double-blind, randomized trial to evaluate bleeding and transfusion requirements.
                One hundred forty-nine patients (48 received aprotinin, 50 desmopressin, 51 placebo) were included. Blood loss and transfusion requirements were recorded and levels of Factor VIII coagulant activity, von Willebrand's factor, thrombin-antithrombin complexes, and D-dimer were measured. Overall blood loss was 195 +/- 146 ml/m2 in the aprotinin group, 400 +/- 192 ml/m2 in the desmopressin group, and 489 +/- 361 ml/m2 in the placebo group (95% confidence intervals: difference between desmopressin and aprotinin 98 to 312 ml/m2, p < 0.001; difference between placebo and aprotinin 190 to 398 ml/m2, p < 0.001). Twenty-six percent of patients treated with aprotinin, 66% of those treated with desmopressin, and 56% of those treated with placebo were given transfusion (95% confidence intervals: difference between aprotinin versus placebo plus desmopressin 51% to 71%, p < 0.001). Fibrinolytic activation throughout cardiopulmonary bypass was markedly higher with placebo or desmopressin administration. D-dimer level correlated with overall blood loss in patients receiving desmopressin or placebo, but not in those receiving aprotinin.
                Aprotinin administration reduces blood loss and transfusion requirements in cardiopulmonary bypass. This benefit may be explained by a lower activation of fibrinolysis. Since excessive fibrinolysis during cardiac surgery is frequently associated with abnormal perioperative bleeding, many authors have advocated prophylactic use of antifibrinolytic drugs to prevent hemorrhagic disorders. We compared the effects of tranexamic acid (a synthetic antifibrinolytic drug) with aprotinin (a natural derivative product with antifibrinolytic properties) on perioperative bleeding and the need for allogeneic transfusions.
                In a single-center prospective randomized unblinded trial, 1040 consecutive patients undergoing primary, elective cardiac operations with cardiopulmonary bypass received either high-dose aprotinin or tranexamic acid. The aprotinin group (518 patients) received 280 mg in 20 minutes before the skin incision, 280 mg in the priming solution of the extracorporeal circuit, and a continuous infusion of 70 mg/h throughout the operation. The tranexamic acid group (522 patients) received 1 g in 20 minutes before the skin incision, 500 mg in the priming solution of the extracorporeal circuit, and a continuous infusion of 400 mg/h during the operation. Postoperative bleeding, perioperative transfusions, and hematologic variables were evaluated at fixed times. Postoperative thrombotic complications, intubation time, intensive care unit stay, and hospital stay were recorded.
                Postoperative bleeding was similar in the 2 groups: aprotinin 250 mL (150-400 mL) versus tranexamic acid 300 mL (200-450 mL) (median and 25th-75th quartiles), median difference of 50 mL (95% confidence intervals, 0-50 mL). The number of transfusions and the outcome did not differ.
                Tranexamic acid and aprotinin show similar clinical effects on bleeding and allogeneic transfusion in patients undergoing primary elective heart operations. Since tranexamic acid is about 100 times cheaper than aprotinin, its use is preferable in this type of patient. Perioperative bleeding following coronary artery bypass grafting (CABG) is associated with increased blood product usage. Although aprotonin is effective in reducing perioperative blood loss, excessive cost prohibits routine utilization. Epsilon aminocaproic acid (EACA) and tranexamic acid (TA) are inexpensive antifibrinolytic agents, which, when given prophylactically, may reduce blood loss. The present study was undertaken to compare the efficacy of TA and EACA in reducing perioperative blood loss.
                The study population consisted of first-time CABG patients. Patients were allocated in a prospective double-blind fashion: (1) group EACA (loading dose 15 mg/kg, continuous infusion 10 mg/kg per hour for 6 hours, N = 20); (2) group TA (loading dose 15 mg/kg, continuous infusion 1 mg/kg per hour for 6 hours, N = 20); (3) control group (infusion of normal saline for 6 hours, N = 19).
                Treatment groups were similar preoperatively. No significant difference in intraoperative blood loss or perioperative use of blood products was noted. D-dimer concentration was elevated in the control group compared to the EACA and TA groups (p < 0.05). Group TA had less postoperative blood loss than the EACA and control groups at 6 and 12 hours postoperatively (p < 0.05). TA had reduced total blood loss (600 +/- 49 mL) postoperatively compared to EACA (961 +/- 148 mL) and control (1060 +/- 127 mL, p < 0.05).
                TA and EACA effectively inhibited fibrinolytic activity intraoperatively and throughout the first 24 hours postoperatively. TA was more effective in reducing blood loss postoperatively following CABG. This suggests that TA may be beneficial as an effective and inexpensive antifibrinolytic in first-time CABG patients. Intraoperative administration of the proteinase inhibitor aprotinin causes reduction in blood loss and homologous blood requirement in patients undergoing cardiac surgery. To ascertain the blood-saving effect of aprotinin and to obtain further information about the mode of action, 40 patients undergoing primary myocardial revascularization were randomly assigned to receive either aprotinin or placebo treatment. Aprotinin was given as a bolus of 2 x 10(6) kallikrein inactivator units (KIU) before surgery followed by a continuous infusion of 5 x 10(5) KIU/h during surgery. Additionally, 2 x 10(6) KIU were added to the pump prime. Strict criteria were used to obtain a homogeneous patient selection. Total blood loss was reduced from 1,431 +/- 760 ml in the control group to 738 +/- 411 ml in the aprotinin group (P less than 0.05) and the homologous blood requirement from 838 +/- 963 ml to 163 +/- 308 ml (P less than 0.05). In the control group, 2.3 +/- 2.2 U of homologous blood or blood products were given, and in the aprotinin group, 0.63 +/- 0.96 U were given (P less than 0.05). Twenty-five percent of patients in the control group and 63% in the aprotinin group did not receive banked blood or homologous blood products. The activated clotting time as an indicator of inhibition of the contact phase of coagulation was significantly increased before heparinization in the aprotinin group (141 +/- 13 s vs. 122 +/- 25 s) and remained significantly increased until heparin was neutralized after cardiopulmonary bypass (CPB).(ABSTRACT TRUNCATED AT 250 WORDS) We evaluated the hemostatic effects of tranexamic acid, a synthetic antifibrinolytic drug, in patients undergoing beating-heart coronary surgery.
                Forty consecutive patients were in a double-blind manner, prospectively randomized into two groups: 20 patients received tranexamic acid (bolus of 1 g before skin incision, followed by continuous infusion of 400 mg/hr during surgery), and 20 patients received saline. As primary outcomes, bleeding and allogeneic transfusions were considered. D-dimer and fibrinogen plasma levels were also evaluated to monitor the activation of fibrinolysis. Major postoperative thrombotic events, as a potential consequence of antifibrinolytic treatment, were recorded.
                The treatment group had significantly lower postoperative bleeding (median [25th to 75th percentiles]: 400 mL [337 to 490 mL] vs 650 ml [550 to 862 mL], p < 0.0001), lower need for allogeneic blood products (1,200 vs 5,300 mL, p < 0.001), and lower postoperative D-dimer plasma levels. No postoperative thrombotic complications were observed in either group.
                In this initial series of patients undergoing off-pump coronary surgery, tranexamic acid appears to be effective in reducing postoperative bleeding and the need for allogeneic blood products. We investigated the effect of a fibrinolytic inhibitor, tranexamic acid, on blood loss and blood transfusion in knee arthroplasty by a randomised, double-blind study of 86 patients. A dose of 10 mg/kg body-weight of either tranexamic acid or placebo was given intravenously shortly before the release of the tourniquet, and repeated three hours later. The mean total blood loss was 730 +/- 280 ml in the tranexamic acid group as against 1410 +/- 480 ml in the placebo group (p < 0.001). Both the number of patients receiving blood transfusion and the number of blood units transfused were reduced to one-third in the treated group, and mean postoperative Hb concentrations were significantly higher after prophylaxis. The number of thromboembolic complications was the same in both groups. Tranexamic acid should be given prophylactically in order to be effective. The effects of a fibrinolysis inhibitor (tranexamic acid, TA) and prostaglandin synthesis inhibitor (diclofenac sodium, DS) were compared in the reduction of excessive menstrual blood loss in 19 women with an intrauterine contraceptive device (IUCD). These women (mean blood loss before treatment to 135.1 +/- 18.9 SE ml, range 70-294 ml) were treated in random order with TA (1.5 g three times daily for 5 days starting on the first day of menstruation for two periods), and with DS (50 mg three times on the first day followed by 25 mg three times daily for 4 days, for two periods), or with placebo (one period) in a double-blind trial. The placebo treatment did not change menstrual blood loss (128.3 +/- 15.6 ml). The TA treatment decreased blood loss to 59.4 +/- 7.7 ml (P less than 0.001) and the DS treatment to 102.1 +/- 13.6 ml (P less than 0.01). Neither treatment abolished pelvic discomfort during menstruation or shortened its duration. Various side-effects were noted by 12 women during 19 TA treatments and by five women during six DS treatments. Thus, while TA is generally far more effective, DS gave pronounced decreases in menstrual bleeding in some women and had less frequent side-effects. Administration of aprotinin during extracorporeal circulation reduces blood loss and improves platelet function.
                To evaluate the protective effect of aprotinin on platelets, 50 patients undergoing cardiopulmonary bypass were randomized before surgery to one of three groups. Seventeen patients (group A) received continuous high-dose aprotinin (7 x 10(6) KIU) during cardiopulmonary bypass, 17 (group B) received a single bolus of aprotinin in the pump prime (2 x 10(6) KIU), and 16 (group C) received placebo. Scanning electron microscopy was used to evaluate platelet aggregation on extracellular matrix. The platelet function was graded from 1 to 4, with grade 4 being normal aggregation. Immediately after cardiopulmonary bypass, 16 patients in group A (94%) reached preoperative aggregation grade (mean grade, 3.4 +/- 0.7) compared with nine of 17 in group B (52%) (mean grade, 2.9 +/- 1.2), and none in group C (0%) (mean grade, 1.4 +/- 0.5; p < 0.001). Postoperative platelet count did not differ significantly among the three groups. After surgery, group A bled less than groups B and C (395 +/- 120 versus 488 +/- 135 and 780 +/- 408 ml, respectively; p < 0.01). Patients in the aprotinin groups received fewer red blood cell units (0.9 +/- 1.2 and 1.9 +/- 1.2 versus 3.4 +/- 1.9, respectively; p < 0.01) and were exposed to less homologous blood products (1.3 +/- 1.7 and 2.1 +/- 1.1 versus 6.1 +/- 5, respectively; p < 0.001).
                By preserving platelet function, aprotinin improves postoperative hemostasis in all patients who receive high dose and in most who receive low dose. Low-dose aprotinin inhibits hyperfibrinolysis in cardiac surgery. However, excessive postoperative bleeding and increased fibrinolysis may occur despite low dose-aprotinin administration. We investigated (i) whether fibrinolytic activity significantly rises under low-dose aprotinin administration, and (ii) whether this is associated with excessive postoperative bleeding (> or = 1000 ml/24 h). In a prospective single-blind trial, 120 consecutive patients were randomized to receive 280 mg aprotinin or no aprotinin before skin incision. D-dimer levels increased significantly to the end of surgery, reaching higher levels in the control group. The risk for excessive bleeding was lower in the aprotinin group (12 versus 37%, = 0.001). Fifteen minutes after heparin reversal, patients were at risk for excessive bleeding, when enhanced fibrinolysis was documented (aprotinin group, D-dimer > or = 1.0 micro g/ml, odds ratio = 9.1, = 0.047; control group, D-dimer > or = 3.0 micro g/ml, odds ratio = 4.6, = 0.014). Ninety-seven per cent of the aprotinin group and 81% of control group patients had no excessive bleeding when the D-dimer plasma level was below these values. We conclude that (i) fibrinolytic activity significantly rises under low-dose aprotinin administration, and (ii) plasma D-dimer levels at end of surgery may help to identify patients who are unlikely to develop excessive postoperative bleeding. High-dose aprotinin reduces bleeding after cardiac surgery, but has also evoked concern with regard to potential side effects and hospital costs. To evaluate the effects of reduced-dose aprotinin on blood loss and need for blood transfusion, 40 patients undergoing myocardial revascularization were studied (double-blind, placebo-controlled). Postoperative bleeding was reduced by 40% and erythrocyte infusion by 85% in the group given 3 x 10(6) KIU aprotinin (1 x 10(6) as a loading dose before cardiopulmonary bypass, 1 x 10(6) in the priming volume and 2.5 x 10(5)/hour intraoperatively) Aprotinin concentrations during the operation were monitored and maintained above the required level. There were no adverse effects of the drug. Hospital expenditure on blood products was reduced by 51% when aprotinin was used. Our study suggests that aprotinin in reduced dosage diminishes bleeding and requirements for blood products, and that it should be given before, during and after cardiopulmonary bypass. A high-dose regimen of aprotinin 5-6 million KIU is effective in reducing bleeding and the need for homologous blood products (HBP) associated with cardiopulmonary bypass (CPB). These high doses aim at achieving plasmin and plasma kallikrein concentrations which in vitro are inhibitory but, theoretically, smaller doses could suffice in vivo. Also, aprotinin is an expensive drug, so efficiency requires using the smallest effective dose. Therefore, the efficacy of prophylactic aprotinin 1 million KIU (the maximal dose approved currently) was evaluated in a patient population at high risk of bleeding and of being transfused. Forty-one patients undergoing reoperation or a complex surgical procedure were included in a prospective, randomized, placebo-controlled, double-blind study. Before skin incision, a bolus of 200,000 KIU aprotinin was administered in 20 min, followed by an infusion of 100,000 KIU.hr-1 over eight hours. Control patients received an equal volume of saline. Dryness of the operative field, chest drainage, transfusion of HBP, haemoglobin concentrations, and coagulation variables (including bleeding time) were compared. There were no differences between aprotinin and placebo-treated patients for all clinical and laboratory variables. The apparent ineffectiveness of aprotinin may be explained by the use of an insufficient dose, by a different protocol of administration (e.g., no bolus in CPB prime), or by the inability of aprotinin to decrease bleeding and transfusions any further. Also, the number of patients studied does not exclude the possibility of a Type II error.(ABSTRACT TRUNCATED AT 250 WORDS) To assess the effectiveness of two mechanical methods of blood conservation in reducing the need for allogeneic red blood cells or coagulation products during cardiac surgery.
                Randomised controlled trial.
                Regional cardiac centre in a teaching hospital in Southampton.
                263 adults aged 18-80 years undergoing elective coronary artery bypass surgery entered the study, of whom 252 completed the trial. All patients received routine perioperative care. Patients were allocated to one of three treatment groups: intraoperative cell salvage, intraoperative cell salvage with acute perioperative normovolaemic haemodilution, or no mechanical blood conservation. There were 84 patients in each group.
                Numbers of patients who received allogeneic blood or coagulation products, and the mean number of units of blood transfused per patient.
                Of the patients in the intraoperative cell salvage group, 26 were given a transfusion of allogeneic blood, compared with 43 in the control group (odds ratio 0.43 (95% confidence interval 0.23 to 0.80)). The mean number of units of allogeneic blood transfused per patient in the intraoperative cell salvage group was 0.68 units (SD=1.55), compared with 1.07 (1.56) units in the control group. 32 of the patients in the intraoperative cell salvage group were given any blood product, compared with 47 in the control group (odds ratio 0.47 (0.25 to 0.89); P=0.019). Combining acute perioperative normovolaemic haemodilution with intraoperative cell salvage conferred no additional benefits.
                An intraoperative cell salvage device should be used in elective coronary artery bypass grafting. Pharmacological strategies may achieve further reductions in blood transfusions. Yet further reductions in blood transfusions could be achieved if the lower safe limit of haemoglobin concentration in patients undergoing cardiac surgery were known. Antifibrinolytic medications administered before skin incision decrease bleeding after cardiac surgery. Numerous case reports indicate thrombus formation with administration of epsilon-aminocaproic acid (epsilon-ACA). The purpose of this study was to examine the efficacy of epsilon-ACA administered after heparinization but before cardiopulmonary bypass in reducing bleeding and transfusion requirements after primary coronary artery bypass surgery.
                Seventy-four adult patients undergoing primary coronary artery bypass surgery were randomized to receive 125 mg/kg epsilon-ACA followed by an infusion of 12.5 mg x kg(-1) x h(-1) or an equivalent volume of saline. Coagulation studies, thromboelastography, and platelet aggregation tests were performed preoperatively, after bypass, and on the first postoperative day. Mediastinal drainage was recorded during the 24 h after surgery. Homologous blood transfusion triggers were predefined and transfusion amounts were recorded.
                One patient was excluded for surgical bleeding and five patients were excluded for transfusion against predefined criteria One patient died from a dysrhythmia 2 h postoperatively. Among the remaining 67, the epsilon-ACA group had less mediastinal blood loss during the 24 h after surgery, 529+/-241 ml versus 691+/-286 ml (mean +/- SD), P < 0.05, despite longer cardiopulmonary bypass times and lower platelet counts, P < 0.05. Platelet aggregation was reduced in both groups following cardiopulmonary bypass but did not differ between groups. Homologous blood transfusion was similar between both groups.
                Prophylactic administration of epsilon-ACA after heparinization but before cardiopulmonary bypass is of minimal benefit for reducing blood loss postoperatively in patients undergoing primary coronary artery bypass grafting. This study was designed to evaluate efficacy and tolerability of two different doses of aprotinin in patients receiving aspirin before undergoing coronary artery bypass grafting. Forty-two patients were randomized to receive either placebo (group I), or aprotinin in doses of 4,000,000 KIU (group II) or 6,000,000 KIU (group III). Drug efficacy was determined by measuring postoperative blood loss and transfusion of blood products. Both doses were effective in reducing blood loss and transfusion requirements. Blood loss through thoracotomy drainage was 450 +/- 224, 182 +/- 144, 142 +/- 98 ml, respectively, for control and treatment groups II and III (p = 0.0001). The numbers of patients with blood transfusions were seven (50%), two (17%) and two (17%) for group I and treatment groups II and III, respectively (p = 0.10). Tolerability was excellent and complications few and reversible. In conclusion, high and medium doses of aprotinin were well tolerated and reduced bleeding and transfusion requirements in patients submitted to coronary bypass surgery under the effects of aspirin. The proteinase inhibitor aprotinin is used in open heart surgery to reduce intraoperative and postoperative blood loss and transfusion requirements. To investigate a possible influence on graft patency, a randomized double-blind group comparison study was carried out in male patients elected for primary bypass surgery. One hundred ten (55/55) patients received either placebo treatment or aprotinin according to the Hammersmith scheme (2 Mio KIU as loading dose before sternotomy, followed by an infusion of 0.5 Mio KIU/h until the end of surgery; 2 Mio KIU added to the priming volume additionally). Graft patency was evaluated by angiography in 44 aprotinin and 35 placebo patients between the 18th and 35th days postoperatively. There was no difference in the overall graft occlusion: in the aprotinin group 89.5% (111/124) grafts were found patent compared to 87.2% (89/102) in the placebo group. Of the aprotinin patients 72.7% (32/44) and 71.4% (25/35) of the placebo patients had all grafts patent. Venous grafts were occluded in 16% (7/44) of aprotinin patients and in 29% (10/35) of placebo patients. On the other hand 5/27 patients in the aprotinin group vs 0/27 in the placebo group had occluded internal mammary artery (IMA) grafts (P = 0.0511%). Graft occlusions were not accompanied by signs of myocardial infarction in any case. Fifty-one patients in the aprotinin group and 47 patients in the placebo group were valid for parameters of clinical efficacy: blood loss within 6 h postoperatively was reduced by 58.5% in the aprotinin group (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) To evaluate and compare hemostatic effects of tranexamic acid vs. aprotinin vs. placebo in off-pump coronary artery bypass (OPCAB) surgery and, in addition, to assess the safety of fibrinolytic inhibitors therapies.
                In a prospective, randomized, double-blind study finally 91 patients undergoing OPCAB were investigated (group A, n=32, tranexamic acid 1g before skin incision and continuously 200mg/h; group B, n=29, aprotinin 1,000,000IU before skin incision and 250,000IU/h; group C, n=30, placebo).
                Highly significant inter-group differences were found in cumulative blood loss within 4h (geometric means [95% confidence intervals]-group A: 89.3 [72.7, 109.8] mL, group B: 72.3 [49.2, 106.3] mL and group C: 192.3 [151.8, 243.5] mL) (P<0.001), within 8h (group A: 152.1 [120.7, 191.6] mL, group B: 130.3 [88.1, 192.8] mL and group C: 283.8 [226.0, 356.3] mL) (P=0.001), and within 24h postoperatively (group A: 410.3 [337.6, 498.6] mL, group B: 345.8 [256.0, 398.2] mL and group C: 619.8 [524.3, 732.8] mL) (P<0.001). At all time points, placebo group C was significantly distinct from the groups treated with fibrinolytic inhibitors (groups A and B). However, no differences between groups A and B were found. Both mean hemoglobin and hematocrit values 24h postoperatively were different between the groups (P=0.018 and P=0.077, respectively), acheiving the lowest value in group C. Number of re-transfuzed patients was highest in group C, but without statistical significance (either packed red blood cells, P=0.119 or fresh-frozen plasma, P=0.118). We observed one postoperative myocardial infarction in aprotinin treated group B and one temporary postoperative myocardial ischemia in placebo group C, no cerebrovascular or pulmonary embolism was noticed. Treated groups A and B did not demonstrate postoperative increase in mean levels of myocardial enzymes, compared with group C. Significantly higher mean values of D-dimer were found in group C 24h postoperatively (P<0.001).
                Both tranexamic acid and aprotinin seem to be similarly effective in the reduction of postoperative blood loss in OPCAB. Tranexamic acid appears to be cost-effective and safe alternative to aprotinin. A randomized, placebo-controlled, double-blind trial (n= 15 in each group) showed that patients given aprotinin intravenously (200 ml, [2000000 kallikrein inactivator units] before the operation and then 50 ml per h until the end of the operation) during simultaneous maxillary Le Fort 1 and mandibular sagittal split osteotomies, lost 52% less blood than controls (calculated by subtracting the volume of saline irrigant used from the volume of blood collected in the aspirator bottle and surgical drains). Patients given aprotinin lost a mean (SD) of 473 (190) ml compared with 986 (356) ml in controls. They also required significantly less transfused blood (1 was given 2 units in the aprotinin group compared with 9 given a mean of 1.5 units (range 1-4) in the control group). There were no complications attributable to this drug.
                Copyright 2001 The British Association of Oral and Maxillofacial Surgeons. Aprotinin, a proteinase inhibitor, has been reported to reduce blood loss significantly during cardiac surgery. The mechanisms of this effect remain unclear. We studied the effect of aprotinin on blood loss and transfusion requirement during total hip replacement. Potential mechanisms of action and side effects also were investigated.
                Forty patients scheduled for primary total hip replacement were randomized to receive, in double-blind fashion, either aprotinin given as a bolus of 2 x 10(6) kallikrein inactivator units (KIU) followed by an infusion of 5 x 10(5) KIU/h until the end of surgery or an equivalent volume of normal saline. Anesthesia and surgical techniques were standardized and systematic deep venous thrombosis prophylaxis was used. Peri- and postoperative blood loss and transfusion were measured. Fibrinolysis, coagulation pathways, and platelet function were assessed. Renal and hepatic function as well as the incidence of deep venous thrombosis also were assessed.
                Aprotinin reduced total blood loss from 1,943 +/- 700 ml to 1,446 +/- 514 ml (P < 0.05). This reduction of blood loss occurred during surgery (P < 0.05) and postoperatively (P < 0.001). Total amounts of blood transfused were 3.4 +/- 1.3 units/patient in the control group and 1.8 +/- 1.2 units/patient in the aprotinin group (P < 0.001). The activated partial thromboplastin time was significantly prolonged by aprotinin immediately after surgery, at 50.6 +/- 12.4 versus 32.3 +/- 4.6 s in control patients (P < 0.001), but results of the other coagulation tests were not different between the two groups. No side effects were observed in the aprotinin group. The incidence of deep venous thrombosis in the two groups was not significantly different.
                The use of high-dose aprotinin during total hip replacement results in a reduction in both blood loss and the amount of blood transfused. Aprotinin's mode of action, however, remains to be elucidated. The effects of epsilon-aminocaproic acid (EACA) and tranexamic acid (TA) on bleeding and allogeneic transfusions, and the cost of pharmacological and transfusional treatment were compared to aprotinin (AP).
                We randomized 210 patients subjected to elective cardiac surgery. Of these, 68 patients received EACA (a bolus of 5 g, an infusion of 2 g/h, and 2.5 g in the priming), 72 patients received TA (a bolus of 1 g, an infusion of 400 mg/h, and 500 mg in the priming), and 70 patients received AP (a bolus of 280 mg, an infusion of 70 mg/h, and 280 mg in the priming). Postoperative blood loss and homologous transfusions were collected and the cost of pharmacological treatment and homologous transfusions were calculated.
                Bleeding but not allogeneic transfusions was significantly higher in the EACA group (467+/-234 versus TA, 311+/-231 versus AP, 283+/-233; p < 0.001). Costs of pharmacological and transfusional treatment were significantly lower in the TA group ($58.10+/-$105.10) versus the EACA group ($100.70+/-$158.60) versus the AP group ($432.60+/-$118.70) (p < 0.0001).
                Compared to AP, TA has the same effects on bleeding and transfusions, but with a significant reduction of costs. Patients treated with EACA showed a significantly higher postoperative bleeding with an increased trend of transfusion requirement. Total knee arthroplasty is associated with major postoperative blood loss of approximately 800 to 1200 milliliters, and blood transfusion is frequently required. With the increased concern about the risks of blood transfusion, various methods of blood conservation in orthopaedic surgery have been studied. The most appropriate solution, however, is to reduce the loss of blood during and after an operation. The present prospective, controlled, randomized study was designed to evaluate the hemostatic efficacy of the use of fibrin tissue adhesive in patients managed with total knee arthroplasty.
                Fifty-eight patients who were scheduled to have a total knee arthroplasty were randomly divided into two groups: a control group, in which the standard means of hemostasis were applied, and a treatment group, in which the standard means to control local bleeding were applied and a fibrin tissue adhesive was sprayed on the internal aspects of the operative field before skin closure. All operations were performed in a bloodless field with use of a pneumatic tourniquet. All patients received low-molecular-weight heparin as thromboprophylaxis twelve hours before the operation and every twelve hours postoperatively. Blood loss during the operation was evaluated by measuring the volume in the suction apparatus and by estimating the amount of lost blood in the swabs at the end of the operation. The apparent postoperative lost blood was determined by measuring the volume in the suction-drain bottles. All blood transfusions were recorded.
                The mean apparent postoperative blood loss (and standard deviation) in the fibrin-tissue-adhesive group was 360+/-287.7 milliliters compared with 878+/-403.0 milliliters in the control group, with a mean difference of 518 milliliters (p<0.001). The decrease in the level of hemoglobin was 25+/-10 grams per liter in the treatment group compared with 37+/-12 grams per liter in the control group (p<0.001). Sixteen patients (55 percent) in the control group required a blood transfusion and eight (28 percent) required two units of blood, whereas only five (17 percent) of the patients in the fibrin-tissue-adhesive group required a blood transfusion and only one (3 percent) required two units (p = 0.004). The number of adverse events was comparable between the two groups. None of the adverse events were considered to be related to the use of fibrin tissue adhesive. One death, which was due to massive pulmonary embolism, was reported in the control group. No seroconversion was reported at three and six months after the operation.
                The use of fibrin tissue adhesive in total knee arthroplasty seems to be an effective and safe means with which to reduce blood loss and blood-transfusion requirements. Furthermore, the importance of these findings was enhanced by a significant reduction in blood loss, in the postoperative decrease in the level of hemoglobin, and in blood-transfusion requirements despite preoperative thromboprophylaxis with low-molecular-weight heparin. We evaluated the blood conservation effects of tranexamic acid (TA) or aprotinin administered before and during cardiopulmonary bypass (CPB) in a prospective, randomized, double-blind study of 150 adult patients undergoing primary coronary artery bypass grafting surgery. Patients received either TA (2 g) or large-dose aprotinin (7 million KIU). Thirty additional untreated patients otherwise managed in a similar fashion were included from a recently completed study for comparison of outcomes. Demographic, medical, surgical, laboratory, mediastinal chest tube drainage (MCTD), transfusion, and outcome data were collected. Allogeneic blood product administration was tightly controlled. The demographic, medical, and surgical characteristics did not significantly differ between the two therapy groups. The median postoperative MCTD loss in the TA group did not significantly differ from that in the aprotinin-treated group (708 vs 600 mL). The percentage of patients that received no allogeneic blood products was 25% for the TA group and 27% for the aprotinin group (P = not significant). The median number of allogeneic blood products administered to the TA group (0 U) did not significantly differ from that administered to the aprotinin group (0 U). The percentage of patients with excessive MCTD (>1000 mL/24 h) did not significantly differ between groups (19% and 17%, respectively). In comparison, the control group had a significantly greater (P < 0.05) median MCTD (1020 mL), median allogeneic blood product exposure (4.5 U), and incidence of excessive MCTD (66%) and transfusion therapy (66%). These data help to support the use of pharmacologic methods to improve clinically relevant indicators of blood conservation for primary CPB procedures. Furthermore, the data show that TA is equivalent to aprotinin for blood conservation in patients at risk of excessive post-CPB bleeding and transfusion therapy. Implications: In a randomized, blind trial, we evaluated the effects of tranexamic acid or aprotinin on blood conservation after primary cardiopulmonary bypass surgery. Both drugs were equally effective in reducing blood loss, the incidence of transfusion, and the amount of blood products transfused compared with placebon. Extracorporeal circulation induces a systemic inflammatory response, which may adversely affect organ function. One manifestation of this response is increased fibrinolysis. Antifibrinolytic drugs such as aprotinin and epsilon-aminocaproic acid have been effective in reducing fibrinolysis and blood loss after extracorporeal circulation; however, the effects of antifibrinolytic drugs on proinflammatory and anti-inflammatory mediators are not known. This study examined the effects of aprotinin and epsilon-aminocaproic acid on plasma levels of proinflammatory [interleukin-6 (IL-6)] and anti-inflammatory [interleukin-10 (IL-10)] cytokines during and after extracorporeal circulation.
                Seventy-two patients undergoing coronary artery bypass grafting with extracorporeal circulation were randomly assigned in a double-blind study to receive high-dose aprotinin, epsilon-aminocaproic acid, or saline placebo. Plasma levels of IL-6 and IL-10 were measured at 5 time points before, during, and after extracorporeal circulation. In all 3 groups, both IL-6 and IL-10 rose significantly after institution of extracorporeal circulation and remained elevated through the first postoperative day. Compared with saline, aprotinin significantly reduced IL-10 (P=0.02) and peak IL-6 (P=0.02) after extracorporeal circulation. In contrast, none of the reductions in IL-6 and IL-10 by epsilon-aminocaproic acid achieved statistical significance. Both aprotinin and epsilon-aminocaproic acid decreased blood loss compared with saline, but there was no significant difference in the number of patients receiving blood products among the treatment groups.
                These data suggest that aprotinin and epsilon-aminocaproic acid differ in their effects on the inflammatory response to extracorporeal circulation. Aprotinin but not epsilon-aminocaproic acid appears to attenuate the rise in the proinflammatory and anti-inflammatory cytokines IL-6 and IL-10. Further studies will be required to determine if these cytokine alterations translate to changes in clinical outcomes. To determine the effect on aorta-coronary bypass grafts of high-dose aprotinin, a drug known to be effective in reducing bleeding after all forms of heart operations, a prospective double-blind study was performed. Graft patency was assessed noninvasively 7 to 12 days (median 9 days) postoperatively in 90 patients. In the aprotinin group, 38 of 43 patients had all grafts patent compared with 43 of 47 in the placebo group. In each group, respectively, 126 of 131 grafts versus 134 of 138 grafts were patent. Neither difference was statistically significant (p > 0.05). Blood loss and homologous blood use were significantly reduced in the aprotinin-treated patients. In this study, high-dose aprotinin did not result in early saphenous vein graft occlusion after aorta-coronary bypass operations. This is further evidence that aprotinin reduces hemostatic derangement during cardiopulmonary bypass without creating a "prothrombotic" situation.
Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the receipt of allogeneic red cell transfusion. Aprotinin appears to be slightly more effective than the lysine analogues in reducing blood loss and the receipt of blood transfusion. However, head to head comparisons show a lower risk of death with lysine analogues when compared with aprotinin. The lysine analogues are effective in reducing blood loss during and after surgery, and appear to be free of serious adverse effects.