Platelet function during cardiac surgery and cardiopulmonary bypass with low-dose aprotinin.

OBJECTIVE: To determine whether two low-dose regimens of aprotinin influence platelet function. DESIGN: Prospective, randomized, single-blinded trial. SETTING: University teaching hospital performing 600 cardiac operations per year. PARTICIPANTS: Fifty-nine patients scheduled for cardiac surgery undergoing cardiopulmonary bypass (CPB) of expected duration of 60 minutes or more. INTERVENTIONS: Patients were randomized into three groups. Group C (control) included 21 patients who did not receive aprotinin. In group A2, 17 patients received 14,286 kallikrein inhibitor units (KIU)/kg (2 mg/kg) of aprotinin before surgery, followed by a continuous infusion of 7,143 KIU/kg/h (1 mg/kg/h) until the end of surgery. In group A4, 19 patients received 28,572 KIU/kg (4 mg/kg) of aprotinin before surgery, followed by the same infusion. MEASUREMENTS AND MAIN RESULTS: Postoperative bleeding and transfusion requirements were significantly less in group A4. Changes in platelet number and function were similar in the three groups. Platelet aggregation was assessed in four periods: before CPB (T1), post-CPB (T2), and 2 hours (T3) and 4 hours (T4) after CPB. Platelet aggregation induced by adenosine diphosphate, 1 and 2 micromol/L; ristocetin, 1 mg/mL; and arachadonic acid (AA), 1.4 mmol/L, decreased at T2 (p < 0.001) in all groups, and for the ristocetin and AA groups, remained at less than baseline values at T3 and T4. In five patients from each group, platelet receptors for glycoprotein IIb-IIIa (GPIIb-IIIa) and expression of platelet activation markers, guanosine monophosphate 140 (GMP-140) and lysosomal protein, were measured by flow cytometry before and after CPB. Modifications in the expression of GPIIb-IIIa were always modest and without statistical significance. Platelet activation markers, GMP-140 or lysosomal protein, nearly doubled from baseline to post-CPB only in the A4 group, whereas they remained stable in both other groups (statistically not significant). CONCLUSION: The two regimens of aprotinin, both considered low dosage, did not exert a protective effect on platelet function. Neither dose produced changes in platelet GPIIb-IIIa or platelet activation markers. However, bleeding and transfusion needs were decreased.     

Aprotinin versus placebo in major orthopedic surgery: a randomized,double-blinded,dose-ranging study

We conducted a prospective, multicenter, double-blinded, dose-ranging study to compare the risk/benefit ratio of large- and small-dose aprotinin with placebo after major orthopedic surgery. Fifty-eight patients were randomized into three groups: Large-Dose Aprotinin (4 M kallikrein inactivator unit [KIU] bolus before surgery followed by a continuous infusion of 1 M KIU/h until the end of surgery), Small-Dose Aprotinin (2 M KIU bolus plus 0.5 M KIU/h), and Placebo. Bleeding was measured and calculated. Bilateral ascending venography was systematically performed on the third postoperative day. Measured and calculated blood loss decreased in the Large-Dose Aprotinin group (calculated bleeding, whole blood, hematocrit 30%, median [range], 2,023 mL [633-4,113] as compared with placebo, 3,577 mL [1,670-21,758 mL]). The total number of homologous and autologous units was also significantly decreased in the Large-Dose Aprotinin group (2 U [0-5 U] as compared with placebo, 4 U [0-42 U]). No increase in deep vein thrombosis or pulmonary embolism was observed in the aprotinin groups. Large-dose aprotinin was safe and effective in dramatically reducing the measured and calculated bleeding and the amount of transfused red blood cell units after major orthopedic surgery. IMPLICATIONS: Large doses of aprotinin decrease blood loss and transfusion amount in major orthopedic surgery.     

The impact of renal dysfunction on aprotinin pharmacokinetics during cardiopulmonary bypass.

Aprotinin is a serine protease inhibitor that undergoes metabolism in the kidney. Because elimination is almost entirely renal, the clearance of aprotinin may be reduced in patients with renal insufficiency. Unfortunately, there are no data regarding aprotinin pharmacokinetics in cardiac surgical patients with renal insufficiency or end-stage renal disease (ESRD) undergoing cardiopulmonary bypass (CPB). We, therefore, determined the clearance (ApCl) and elimination half-life (T1/2) of aprotinin in 26 cardiac surgical patients with normal and abnormal renal function (creatinine clearance [CrCl] 0-122 mL/min) undergoing CPB. Subjects were given a 2 million kallikrein inhibiting unit (KIU) initial dose of aprotinin, followed by a 0.25 million KIU/h infusion. No aprotinin was added to the pump prime. Plasma aprotinin concentrations were sampled at 30 min after completion of the loading dose, 30 and 60 min after the onset of CPB, at the end of CPB, and at 8, 24, and 32 h after completion of the loading dose. ApCl was directly related and the elimination T1/2 inversely related to CrCl (r = 0.75 and 0.42, respectively). In patients with a CrCl >50 mL/min, the T1/2 and ApCl were 7.8 h and 53 mL/min, respectively, compared with 19.9 h and 25 mL/min (P < 0.05, P < 0.002, respectively) for patients with ESRD. In conclusion, ApCl is reduced, and T1/2 is prolonged in patients with renal insufficiency or ESRD undergoing CPB. Dosing modifications may be necessary for patients with abnormal renal function undergoing cardiac surgery. IMPLICATIONS: Because aprotinin is metabolized and eliminated in the kidney, its clearance may be reduced in patients with renal insufficiency. Our data suggest that aprotinin clearance is reduced, and aprotinin half-lives are prolonged in patients with renal insufficiency undergoing CPB. Dosing modification may therefore be indicated when aprotinin is administered to these patients for cardiac surgery.     

High-dose aprotinin reduces activation of hemostasis,allogeneic blood requirement,and duration of postoperative ventilation in pediatric cardiac surgery

BACKGROUND: Though multiple studies have affirmed the effectiveness of aprotinin in reducing blood loss in adult cardiac surgery, the possible benefit in pediatric cardiac surgery is controversial. METHODS: In a double-blind, randomized, and placebo-controlled study, the efficacy of aprotinin in attenuating the hemostatic and inflammatory activation during cardiopulmonary bypass in 60 patients weighing less than 10 kg was investigated. Secondary endpoints were the influence of aprotinin on the reduction of blood loss and allogeneic blood requirement, as well as postoperative oxygenation and length of mechanical ventilation. Aprotinin was administered in a high-dose of 3 x 10(4) KIU/kg plus a bolus of 5 x 10(5) KIU (not weight adjusted) added to the pump prime. RESULTS: Aprotinin plasma concentration at the end of cardiopulmonary bypass (CPB) was with 184 +/- 45 KIU/mL, within the targeted range of 200 KIU/mL. Coagulation and fibrinolysis were suppressed (F1.2 1 hour after CPB: 5.35 +/- 2.9 nmol/L vs 14.5 +/- 23.1 nmol/L; D-dimer 1 hour after CPB: 0.63 +/- 0.6 ng/mL vs 2.3 +/- 3.1 ng/mL; p < 0.05), inflammatory markers (interleukin [IL]-6, IL-8, IL-10) increased over time without significant differences between the groups, and only complement C3a activation was significantly attenuated at the end of CPB in the aprotinin group. Chest tube drainage was significantly reduced (24 hours: median 13.5 [IQR 12.2] mL/kg vs 19.4 [8.2] mL/kg; p < 0.05). All patients received one unit of packed cells to prime the heart lung machine. A second unit was needed significantly less often in the aprotinin group (13% vs 47%; p < 0.05). Postoperative oxygenation (pO2/FIO2 172 [IQR 128] mm Hg vs 127 [74]; p < 0.05) improved, and the time on ventilator was shorter in the aprotinin group (median 45 hours [IQR 94] vs 101 [IQR 74]; p < 0.05). No side effects were attributable to the use of aprotinin. CONCLUSIONS: High-dose aprotinin effectively attenuated hemostatic activation and reduced blood loss and transfusion requirement in pediatric cardiac surgery. Postoperative ventilation was also shortened in the aprotinin group.     

High-dose aprotinin modulates the balance between proinflammatory and anti-inflammatory responses during coronary artery bypass graft surgery

OBJECTIVE: To rule out the effect of high-dose aprotinin in respect to the balance of proinflammatory and anti-inflammatory mediators induced by cardiopulmonary bypass (CPB). DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: University-affiliated cardiac center. PARTICIPANTS: Twenty patients scheduled for coronary artery bypass graft surgery. INTERVENTIONS: In group A patients (n = 10), high-dose aprotinin was administered (2 x 106 KIU pre-CPB, 2 x 10(6) KIU in prime, 500,000 KIU/hr during CPB). In group C patients (n = 10), placebo was used instead. Proinflammatory interleukin (IL)-6, anti-inflammatory IL-1-receptor antagonist, and clinical parameters were measured 8 times perioperatively. The values are presented as mean +/- SEM. MEASUREMENTS AND MAIN RESULTS: Four hours after CPB, IL-6 concentration reached the maximum value, being significantly lower in group A patients as compared with group C patients (615 +/- 62 pg/mL v 1,409 +/- 253 pg/mL; p = 0.019). On the first postoperative day, the concentration of IL-6 in group A patients remained lower (219 +/- 24 pg/mL v 526 +/- 123 pg/mL; p = 0.015). In contrast, IL-1-receptor antagonist concentration was higher in group A patients as compared with group C patients after CPB (13,857 +/- 4,264 pg/mL v 5,675 +/- 1,832 pg/mL; p = 0.03). Total postoperative blood loss was lower in group A patients as compared with group C patients (648 +/- 64 mL v 1,284 +/- 183 mL; p = 0.002). CONCLUSIONS: High-dose aprotinin treatment reduced the inflammatory reaction and postoperative blood loss. The anti-inflammatory reaction was significantly enhanced in these patients, which suggests that the physiologic reaction of the organism to reduce the deleterious effects from CPB is more pronounced by using high-dose aprotinin.     

Variability of plasma aprotinin concentrations in pediatric patients undergoing cardiac surgery

OBJECTIVES: Infants and children undergoing cardiopulmonary bypass for repair of congenital heart defects are at substantial risk for excessive bleeding, contributing greatly to morbidity and mortality. Aprotinin significantly reduces bleeding and transfusion requirements in adults but is of indeterminate value for pediatric patients. The aim of this study was to determine plasma aprotinin concentrations in these patients with a functional aprotinin assay. METHODS: Thirty patients less than 16 years of age scheduled for cardiac surgery with aprotinin were enrolled. Aprotinin was administered as a 25,000 KIU/kg bolus, 35,000 KIU/kg cardiopulmonary bypass prime, and 12,500 KIU.kg(-1).h(-1) continuous infusion. Blood samples for aprotinin concentrations (kallikrein-inhibiting units/milliliter) were obtained before aprotinin; 5 minutes post-bolus; 5 minutes after cardiopulmonary bypass initiation; 30 and 60 minutes on cardiopulmonary bypass; on discontinuation of aprotinin; 1 hour after aprotinin discontinuation; and 4 hours after permanent separation from cardiopulmonary bypass. For analysis, patients were grouped according to weight (<10 kg, 10-20 kg, >20 kg). Differences between weight groups were assessed using an exact test for categoric variables and 1-way analysis of variance for continuous variables. RESULTS: Aprotinin concentrations differed significantly across weight groups. Five minutes after aprotinin bolus and initiation of cardiopulmonary bypass, there was significant correlation between weight and aprotinin concentration (r =.57, P =.003; r =.69, P =.001, respectively). CONCLUSION: A functional assay reveals significant variability in aprotinin concentration for pediatric patients using current weight-based aprotinin dosing. Additional investigation is necessary to determine target aprotinin concentration dosing regimens to provide better efficacy.     

Reduced blood loss by aprotinin in thoracic surgical operations associated with high risk of bleeding. A placebo-controlled, randomized phase IV study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Aprotinin reduces the perioperative blood loss and the need for blood transfusion in thoracic surgical procedures in patients with an increased risk of bleeding.     

Kidney-specific proteins in patients receiving aprotinin at high- and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass

BACKGROUND AND OBJECTIVE: The aim was to determine whether the administration of aprotinin can cause deleterious effects on renal function in cardiac surgery with cardiopulmonary bypass (CPB). METHODS: Sixty consecutive patients with normal preoperative renal function undergoing elective coronary artery bypass surgery with CPB using the same anaesthetic; CPB and surgical protocols were randomized into three groups. Patients received placebo (Group 1), low-dose aprotinin (Group 2) or high-dose aprotinin (Group 3). Renal parameters measured were plasma creatinine, alpha1-microglobulin and beta-glucosaminidase (beta-NAG) excretion. Measurements were performed before surgery, during CPB and 24 and 72 h, and 7 and 40 days postoperatively. RESULTS: In the three groups, alpha1-microglobulin and beta-NAG excretions significantly increased during CPB, at 24 and 72 h, and 7 days postoperatively (P < 0.05) and had returned to preoperative levels at postoperative day 40. Plasma creatinine levels were within normal values at times recorded. In Groups 2 and 3, alpha1-microglobulin excretion during CPB was significantly higher than in Group 1 (P < 0.001), and 24h after surgery it still remained significantly higher in Group 3 compared to Groups 1 and 2 (P < 0.05). CONCLUSIONS: Aprotinin caused a significant increase in alpha1-microglobulin excretion but not in beta-NAG excretion during CPB, which may be interpreted as a greater renal tubular overload without tubular damage. This effect persisted for 24 h after surgery when high-dose aprotinin doses had been administered. Creatinine plasma levels were not sensitive to detect these prolonged renal effects in our study.     

Heparin-level-based anticoagulation management during cardiopulmonary bypass: a pilot investigation on the effects of a half-dose aprotinin protocol on postoperative blood loss and hemostatic activation and inflammatory response

Cardiac surgery involving cardiopulmonary bypass (CPB) leads to activation of the hemostatic/inflammatory system. We compared the influence of a half-dose aprotinin regimen on postoperative blood loss and the activation of the hemostatic/inflammatory system during CPB, when used during a heparin-level-based heparin management for cardiac surgery. Two-hundred patients (n = 100 in each group) were enrolled in this randomized prospective study. In Group I only heparin was given according to the results of the Hepcon HMS Plus. In Group II aprotinin was added with a bolus of 1 x 10(6) kallikrein inhibiting units (KIU) for the patient immediately before initiation of CPB, 1 x 10(6) KIU in the priming solution of the CPB, and a continuous infusion of 250,000 KIU/h during CPB. Postoperative blood loss was determined after 12 h. Heparin and antithrombin activity were evaluated by an anti-Xa assay and measurement of antithrombin III activity. Hemostatic activation was evaluated by adenosine diphosphate-stimulated platelet aggregometry and by measurements of the generation/release of beta-thromboglobulin (beta-TG), soluble P-selectin (sPS), thrombin (TAT), prothrombin 1 and 2 fragments (PTF1+2), factor XIIa (FXIIa), plasmin (PAP), and D-dimers. Inflammatory response was evaluated by measuring complement factors 5b-9 (C5b-9), interleukin (IL)-6, and neutrophil elastase (NE). There were no differences in the pre-CPB values or duration of CPB between the two groups. There were no differences in the post-CPB values for platelet count, platelet aggregation, beta-TG, sPS, TAT, PTF1+2, C5b-9, NE, or IL-6. The additional use of aprotinin resulted in a significant decrease of PAP, D-dimers, and 12 h postoperative blood loss, whereas generation of the contact factor XIIa was increased. The administration of aprotinin significantly reduced postoperative blood loss after cardiac surgery and CPB. This most likely has to be attributed to the antifibrinolytic effects of aprotinin. No effects on thrombin generation, platelet activation, inflammatory response, or clinical outcome were noted. IMPLICATIONS: The use of half-dose aprotinin and heparin-level-based anticoagulation management during cardiopulmonary bypass leads to a significant reduction of postoperative blood loss after cardiac surgery. This effect can most likely be attributed to the antifibrinolytic effects of aprotinin, as we did not observe effects on other variables of activation of the hemostatic/inflammatory system.     

Randomized, Placebo-Controlled, Double-Blind Study of an Ultra-Low-Dose Aprotinin Regimen in Reoperative and/or Complex Cardiac Operations

A bstract Background and aim of the study : 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. Methods : 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. Results : 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). Conclusions : 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.     

Removal of aprotinin from low-dose aprotinin/tranexamic acid antifibrinolytic therapy increases transfusion requirements in cardiothoracic surgery

This retrospective study investigated whether withdrawal of aprotinin from combined low-dose aprotinin/tranexamic acid (TXA) antifibrinolytic therapy altered postoperative blood loss and transfusion requirements in patients undergoing cardiothoracic surgery employing cardiopulmonary bypass (CPB). The study included data from patients receiving a combination of low-dose aprotinin (2×10(6)?KIU in CPB prime; n=615) and 2000?mg TXA or patients receiving TXA only (n=587). In both groups, TXA was given after protamine administration. Study endpoints were blood loss, transfusion requirements and reoperation. There were no differences in EuroSCORE, CPB time, antiangial medication and baseline coagulation parameters between groups. There were more males in the TXA group (85%) as compared to the TXA+aprotinin group (77%; P=0.02). Postoperative blood loss (0.80±0.69 vs. 0.66±0.52?l; P=0.001) and transfusion of fresh frozen plasma (0.6±0.7 vs. 0.4±0.6?U; P<0.001), packed cells (3.9±5.5 vs. 2.7±3.3?U; P<0.001) and platelets (0.7±0.6 vs. 0.5±0.6?U; P<0.001) was higher in the TXA group than in patients receiving combined therapy, respectively. There were more reoperations for bleeding in the TXA group (53 vs. 34, respectively; P=0.03) with similar mortality and deterioration in glomerular filtration rate. In conclusion, withdrawal of aprotinin from combined antifibrinolytic therapy is associated with increased blood loss, transfusion requirements and reoperations.     

Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization.

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)     

The effects of aprotinin on platelet function in blood exposed to eptifibatide: an in vitro analysis

The preoperative use of platelet inhibitors has increased the risk of bleeding during cardiac surgery. Aprotinin has been shown to preserve hemostatic function in patients undergoing CPB. The purpose of this study was to investigate the effect of aprotinin on coagulation in blood exposed to eptifibatide. Freshly collected bovine blood was used in an in vitro model of extracorporeal circulation. Blood was separated into two groups: activated (60 minutes exposure to bubble oxygenation) and nonactivated. Within each group there were four subgroups: control (n = 3), eptifibatide (2.8 microg/mL, n = 3), aprotinin (250 KIU/mL, n = 3), and eptifibatide with aprotinin (2.8 microg/mL, 250 KIU/mL, n = 3). Twenty-four modified extracorporeal circuits utilizing a hard-shell venous reservoir and cardioplegia heat exchangers were used. Blood flow was maintained at a rate of 1.25 L/min for a total of 170 minutes, at 37 +/- 1 degree C. Samples were collected at 0, 20, 50, and 110 minutes with the following variables measured: thromboelastograph (TEG), activated clotting time (ACT), and hematocrit (Hct). Results demonstrated that at 110 minutes, the TEG index (TI) was decreased by four-fold in the activated group compared to the nonactivated group (-4.6 +/- 1.2 vs. 1.4 +/- 1.5, p < .05). The administration of aprotinin resulted in preservation of the TI as compared to eptifibatide-treated blood (-4.9 +/- 1.2 vs. -7.9 +/- 1.2, p < .05). Aprotinin combined with eptifibatide reduced coagulation derangements when compared to eptifibatide alone (-5.2 +/- 1.2 vs. -7.9 +/- 1.2, p < .05). In conclusion, aprotinin attenuated the platelet inhibition effect of eptifibatide during in vitro CPB, resulting in improved coagulation.     

大剂量抑肽酶对体外循环心内直视手术病人心肌的保护作用

目的：观察体外循环（ＣＰＢ）心内直视手术中使用大剂量抑肽酶对心肌保护的影响。方法：１２０例心脏瓣膜置换手术病人,随机分成两组：Ａ组（抑肽酶组,ｎ＝６０）,Ｂ组（对照组,ｎ＝６０）,ＡＢ两组均在主动脉阻断后行冷晶体停跳,至开放关作末次温血灌注。     

Postoperatively administered aprotinin or epsilon aminocaproic acid after cardiopulmonary bypass has limited benefit

BACKGROUND: Intraoperative antifibrinolytic treatment with aprotinin and epsilon aminocaproic acid (EACA) has been shown to be effective prophylaxis in the reduction of excessive bleeding after cardiopulmonary bypass operations. This study investigated the effectiveness of both drugs when used as a postoperative treatment of patients showing early signs of increased bleeding. METHODS: In a double-blind, randomized study, 69 patients with chest drainage of 100 mL or more 1 hour after bypass were treated with aprotinin, EACA, or placebo. RESULTS: In the first 24 hours postoperatively, neither drug significantly reduced chest drainage or blood transfusion requirements compared with placebo. Median (interquartile) cumulative chest drainage volumes for the first 24 hours postoperatively for the aprotinin, EACA, and placebo groups were 525 (340, 750), 575 (450, 762), and 650 (550, 800) mL, respectively. Among the study patients, 4 undergoing valve operation and treated with aprotinin showed a trend toward less bleeding during the first 12 hours postoperatively compared with 5 valve operation patients who received placebo (p = 0.06). Among all patients, the treatment with aprotinin or EACA failed to reduce levels of D-dimer compared with placebo after treatment, indicating that fibrinolysis was not significantly inhibited. CONCLUSIONS: Aprotinin or EACA administered in the early postoperative period was ineffective in reducing postoperative bleeding with the exception of a small group of patients having valve operations in whom aprotinin treatment may have shown some benefit.     

Low-dose aprotinin infusion is not clinically useful to reduce bleeding and transfusion of homologous blood products in high-risk cardiac surgical patients

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. However, based on the small differences observed, we conclude that low-dose aprotinin infusion is not useful clinically to reduce chest drainage and transfusions in a patient population at high risk of being exposed to HBP.     

The effect of aprotinin on risk of acute renal failure requiring dialysis after on-pump cardiac surgery

The use of aprotinin in cardiac surgery to reduce perioperative bleeding and transfusion is controversial. We assessed the effect of aprotinin on the risk of acute renal failure in 423 patients who underwent on-pump cardiac surgery between January 1, 2005 and December 31, 2006. Of these 423 patients, 318 (75.2%) received aprotinin (median dose=3.0 million KIU, standard deviation=2.8 million KIU; interquartile range: 2 million KIU to 4 million KIU). Aprotinin was more likely to be used in patients who did not cease aspirin before surgery, in urgent or emergency surgery, who had impaired left ventricular function, a longer period of bypass and aortic cross-clamp time, and with both coronary artery bypass graft and valvular surgery performed. The overall incidence of acute renal failure requiring dialysis was 2.8%. The use of aprotinin was not associated with a reduction in transfusion nor an increased risk of renal failure requiring dialysis, atrial fibrillation, cerebrovascular accident or mortality in the univarate analyses. In the multivariate analysis, only preoperative serum creatinine concentration (odds ratio [OR] 1.06 per 10 micromol/l increment in creatinine, 95% confidence interval [CI]: 1.01 to 1.14, P=0.029) and urgency of the surgery (urgent vs. scheduled surgery: OR 12.8, CI: 2.3 to 70.8, P=0.004; emergency vs. scheduled surgery: OR 23.1, CI: 3.0 to 180.2, P=0.003) were significantly associated with an increased risk of acute renal failure requiring dialysis. The use of low-dose aprotinin did not significantly reduce perioperative transfusion requirements and was not a significant risk factor for acute renal failure requiring dialysis in our patients.     

Plasma aprotinin concentrations during cardiac surgery: full- versus half-dose regimens

Aprotinin is an effective but expensive drug used during cardiac surgery to reduce blood loss and transfusion requirements. Currently, aprotinin is administered to adults according to a fixed protocol regardless of the patient's weight. The purpose of this study was to determine aprotinin levels in patients receiving full- and half-dose aprotinin regimens by a simple functional aprotinin assay and to design a more individualized aprotinin dosage regimen for cardiac surgical patients. The mean plasma aprotinin concentration peaked 5 min after the initiation of cardiopulmonary bypass (full 401 +/- 92 KIU/mL, half 226 +/- 56 KIU/mL). The mean plasma aprotinin concentration after 60 min on cardiopulmonary bypass was less (full 236 +/- 81 KIU/mL, half 160 +/- 63 KIU/mL). There was large variation in the aprotinin concentration among patients. A statistically significant correlation was found between aprotinin concentration and patient weight (r(2) = 0.67, P < 0.05). Implications: The current dosing schedule for aprotinin results in a large variation in aprotinin plasma concentrations among patients and a large variation within each patient over time. We combined the information provided by our study with that of a previous pharmacokinetic study to develop a potentially improved, weight-based, dosing regime for aprotinin.     

Effects of epsilon-aminocaproic acid and aprotinin on leukocyte-platelet adhesion in patients undergoing cardiac surgery

BACKGROUND: The administration of aprotinin during cardiopulmonary bypass (CPB) is hypothesized to decrease activation of leukocytes and platelets and possibly reduce their adhesion. Although epsilon-aminocaproic acid (EACA) shares the ability of aprotinin to inhibit excessive plasmin activity after CPB, its effect on leukocyte and platelet activation and leukocyte-platelet (heterotypic) adhesion is largely unknown. This study was performed to determine the relative effectiveness of the antifibrinolytics, aprotinin and EACA, at reducing leukocyte and platelet activation and leukocyte-platelet conjugate formation in patients undergoing CPB. METHODS: Thirty-six patients scheduled to undergo cardiac surgery with CPB were randomized in a double-blind fashion to receive EACA, aprotinin, or saline (placebo). Markers of plasmin activity (D-dimer concentrations), platelet activation (CD62P), leukocyte activation (CD11b), and leukocyte-platelet adhesion (monocyte- and neutrophil-platelet conjugates) were measured before, during, and after CPB. RESULTS: Platelet CD62P (P-selectin), monocyte CD11b, and monocyte-platelet conjugates were all significantly increased (compared with baseline) in the saline group during and after CPB. Despite equivalent reductions in D-dimer formation in patients receiving EACA (P < 0.0001) and aprotinin (P < 0.0001), decreases in platelet CD62P and monocyte CD11b expression were incomplete (not significantly different from saline control). In contrast, peak monocyte-platelet conjugate formation was significantly reduced by both EACA (P = 0.026) and aprotinin (P = 0.039) immediately after CPB. CONCLUSIONS: EACA seems to be as effective as aprotinin at reducing peak monocyte-platelet adhesion after CPB. Furthermore, inhibition of excessive plasmin activity seems to influence monocyte-platelet adhesion. The findings suggest that monocyte-platelet conjugate formation may be a useful marker of monocyte and platelet activation in this clinical setting.     

The effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic response after cardiac surgery

Background: 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. Methods: 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. Results: 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 µg/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). Conclusion: 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.