Low-dose Aprotinin Research Articles

Fibrinolysis-adjusted perioperative low-dose aprotinin reduces blood loss in bypass operations

Background. 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. Methods. 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. Results. 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 μg/L, respectively, versus 40 ± 21 μg/L; p < 0.05). Levels of plasmin–antiplasmin complexes were significantly decreased postoperatively in group A (607 ± 231 μg/L) versus group C (825 ± 225 μg/L) ( p < 0.05) but were increased in group TA (1,145 ± 394 μg/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). Conclusions. 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 and recombinant human erythropoietin reduce the need for homologous blood transfusion in cardiac surgery

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

Hematologic and economic impact of aprotinin in reoperative pediatric cardiac operations

Background. Aprotinin consistently reduces blood loss and transfusion requirements in adults during and after cardiac surgical procedures, but its effectiveness in children is debated. We evaluated the hemostatic and economic effects of aprotinin in children undergoing reoperative cardiac procedures with cardiopulmonary bypass. Methods. Control, low-dose aprotinin, and high-dose aprotinin groups were established with 15 children per group. Platelet counts, fibrinogen levels, and thromboelastographic values at baseline and after protamine sulfate administration, number of blood product transfusions, and 6-hour and 24-hour chest tube drainage were used to evaluate the effects of aprotinin on postbypass coagulopathies. Time needed for skin closure after protamine administration and lengths of stay in the intensive care unit and the hospital were recorded prospectively to determine the economic impact of aprotinin. Results. Coagulation tests performed after protamine administration rarely demonstrated fibrinolysis but did show significant decreases in platelet and fibrinogen levels and function. The thromboelastographic variables indicated a preservation of platelet function by aprotinin. Decreased blood product transfusions, shortened skin closure times, and shortened durations of intensive care unit and hospital stays were found in the aprotinin groups, most significantly in the high-dose group with a subsequent average reduction of nearly $3,000 in patient charges. Conclusions. In children undergoing reoperative cardiac surgical procedures, aprotinin is effective in attenuating postbypass coagulopathies, decreasing blood product exposure, improving clinical outcome, and reducing patient charges.

Aprotinin in pediatric cardiac operations: a benefit in complex malformations and with high-dose regimen only

Background. The benefits and the current indications of aprotinin in congenital operations are not well defined. At present there are only a few studies available that have investigated a small number of patients in several heterogeneous groups of malformations. Methods. We investigated efficacy and safety of aprotinin in three groups of children <15 kg, presenting with isolated ventricular septum defect (n = 60), tetralogy of Fallot (n = 52), and transposition of the great arteries (n = 56). Low-dose aprotinin regimen A1 (500,000 KIU in pump prime only) and high-dose aprotinin A2 (50,000 KIU/kg during induction of anesthesia, 50,000 KIU/kg in pump prime, and 20,000 KIU/h continuous infusion) were compared to a control group A0 (without aprotinin) regarding perioperative blood loss, transfusion requirements, and effects on the coagulation system. Results. The most common coagulation tests of aprotinin-treated patients and the platelet numbers were comparable with those of control patients preoperatively and 15 minutes after protamine administration. A significant dose-dependent reduction in fibrin–fibrinogen split products was observed at the end of cardiopulmonary bypass in the majority of aprotinin-treated patients with transposition. In patients with ventricular septum defect and Fallot, no significant difference in blood loss and transfusion requirements could be observed between patients with or without aprotinin and no difference was observed between low- and high-dose regimen. In transposition of the great arteries, high-dose aprotinin led to significant reduction of blood loss ( p = 0.02) and postoperative blood transfusion ( p = 0.003). Severe side effects as a result of administration of aprotinin were not observed. Conclusions. High-dose aprotinin reduces blood loss and transfusion requirement only in complex congenital cardiac operations; therefore aprotinin cannot be recommended as a blood conservation agent in routine pediatric operations.

Pharmacoeconomics Analysis in a Pediatric Population

Background. Pharmacoeconomics is becoming increasingly important in the health-care environment, but pharmacoeconomic studies are fraught with problems. Pharmacoeconomics can be applied to analysis of the benefits of pharmacologic hemostasis.Methods. This article reviews the available methods of pharmacoeconomic analysis and their inherent methodologic concerns. It reviews pharmacoeconomic studies of pharmacologic hemostasis, with particular focus on the Pediatric Reoperative Open Heart Surgery study. In this study, patients were randomized to receive either high-dose aprotinin, low-dose aprotinin, or placebo. Results were analyzed from the viewpoint of cost-benefit, cost-effectiveness calculated with use of a roll-back decision tree, and cost-effective ratios.Results. Cost-benefit analysis showed low-dose aprotinin to have a greater cost-benefit than high-dose aprotinin, cost-effectiveness analysis and analysis of cost-effective ratios showed high-dose aprotinin to be more cost-effective than low-dose aprotinin, and all analyses showed aprotinin to be preferable to placebo.Conclusions. Aprotinin in pediatric repeat open heart operations not only has a cost-benefit but is cost-effective as well.

Influence of High- and Low-Dose Aprotinin on Activation of Hemostasis in Open Heart Operations

Background. The protease inhibitor aprotinin reduces hemostatic activation and blood loss after cardiac operations. The aim of the present study was to investigate the influence of two different aprotinin doses on hemostatic activation and to identify the most effective dose to reduce the postoperative bleeding tendency. Methods. In a prospective, randomized, double-blind clinical trial, 230 patients scheduled for routine open heart operations received either high-dose (group H) or low-dose (group L) aprotinin. Primary outcome measures were the level of F 1+2 prothrombin fragments as a marker of thrombin generation, the level of d-dimers as an indicator of fibrinolysis, and the amount of postoperative blood loss. Allogeneic blood transfusion was recorded as a secondary outcome measure. Results. Aprotinin plasma concentrations 5 minutes after the onset of cardiopulmonary bypass were 166 ± 45 kallikrein inactivator units per milliliter in group H and 118 ± 30 kallikrein inactivator units per milliliter in group L ( p < 0.05). Fibrinolytic activation was reduced significantly in group H compared with group L: the level of d-dimers at the end of CPB was 1,027 ± 781 ng/mL and 1,977 ± 1,001 ng/mL, respectively, in the two groups ( p < 0.05). However, thrombin generation (F 1+2 fragments) did not differ between the two groups (7.4 ± 3.5 nmol/L in group H and 8.6 ± 4.3 nmol/L in group L). Twenty-four–hour postoperative blood loss was 663 ± 461 mL in group H compared with 877 ± 513 mL in group L ( p < 0.05), and the corresponding allogeneic blood requirement was 1.3 ± 1.9 U in group H and 1.9 ± 2.3 U in group L ( p < 0.05). Conclusions. A high-dose aprotinin regimen was significantly more effective than a low-dose regimen in attenuating fibrinolysis and reducing the bleeding tendency and allogeneic blood requirements, but not in reducing F 1+2 prothrombin fragments. High-dose aprotinin therapy appears to be superior to low-dose therapy.

Operations on the thoracic aorta and hypothermic circulatory arrest: Is aprotinin safe?

Introduction: The safety of aprotinin, especially when used with profound hypothermic circulatory arrest, is still a matter of intense debate despite its presumed salutary effects on blood loss. Many investigators have reported toxic renal effects of high-dose aprotinin in such patients, but no prospective, randomized study has been conducted. To assess the potential detrimental effect of aprotinin on renal function and its putative reduction of blood loss, 50 patients undergoing thoracic aortic operations with the use of profound hypothermic circulatory arrest were randomly assigned to receive either low-dose aprotinin (1 × 10 6 kallikrein activation units) or placebo. Methods: The specific renal tubular markers β- 2-microglobulin and β- N -acetyl-<? check case >d<? check case >-glucosaminidase, as well as serum creatinine and blood urea nitrogen, creatinine clearance, sodium excretion, and potassium excretion, were measured to evaluate renal function preoperatively, immediately after the procedure, and 24 hours and 48 hours later. Results: No statistically significant difference was found in any measured renal parameter between the two groups (analysis of variance). Renal dysfunction, defined as an elevation of serum creatinine early postoperatively (≥1.5 times the preoperative value), occurred in two patients who received aprotinin and in one patient in the control group. Temporary dialysis (hemodialysis or continuous venovenous hemofiltration) was needed in two patients in the aprotinin group versus one in the control group. Furthermore, patients treated with aprotinin had significantly less total postoperative blood loss (718 ± 340 ml vs 920 ± 387 ml, p = 0.04). The aprotinin recipients also had a significantly lower transfusion requirement ( p <0.05). Conclusion: This controlled trial of low-dose aprotinin in patients undergoing thoracic aortic operations using profound hypothermic circulatory arrest demonstrated no detectable deleterious effects on renal function; moreover, the use of aprotinin was associated with significantly lower need for transfusion. (J Thorac Cardiovasc Surg 1998;115:220–5)

Effects of Aprotinin During Cardiopulmonary Bypass in Patients Treated with Acetylsalicylic Acid

Of 35 acetylsalicylic acid (ASA)-treated patients undergoing coronary artery bypass surgery, 10 received a high dose of aprotinin (mean 5.2 x 10(6) KIU) during cardiopulmonary bypass (CPB); in 15 cases low-dose aprotinin (2 x 10(6) KIU) was added to the CPB priming solution, and 10 patients made up a control group without aprotinin. Median total blood loss was 52% less in aprotinin-treated patients, irrespective of dose, than in the controls. Fibrin-D dimer levels remained low in patients treated with high-dose aprotinin, but increased significantly in the control group. Platelet adhesion and platelet adenosine triphosphate secretion were reduced after CPB in all patients. Whole-blood aggregation after bypass was enhanced in aprotinin-treated patients. Aprotinin inhibited fibrinolysis and seemingly preserved platelet function despite ASA treatment. In view of the possible risks and relatively high cost of aprotinin, use of a high dose seems unnecessary, since a low dose was equally effective in reducing blood loss in ASA-treated patients.

11.7 Effects of a new low dose aprotinin regime on blood loss, hemostatic parameters and factor VIIa in CABG in comparison to low dose tranexamic acid and controls

11.7 Effects of a new low dose aprotinin regime on blood loss, hemostatic parameters and factor VIIa in CABG in comparison to low dose tranexamic acid and controls

Effects of minimal-dose aprotinin on coronary artery bypass grafting

Objective: To evaluate the effects of minimal-dose aprotinin in patients undergoing coronary artery bypass grafting, we conducted a prospective randomized study. Methods: A total of 167 patients were randomized to receive no aprotinin treatment (control, n = 57), minimal-dose aprotinin (1.0 × 10 6 KIU; n = 55), or low-dose aprotinin (2.7 ± 0.5 × 10 6 KIU; n = 55). Blood loss and transfusion requirements, parameters of clotting and fibrinolysis, renal function, and early graft patency rates were assessed. Results: 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 α 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, 98.5%; low-dose group, 92.3%; p = 0.25). Conclusions: 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 × 10 6 KIU added to the pump prime may be acceptably effective in reducing blood loss in patients undergoing primary coronary operations. J Thorac Cardiovasc Surg 1997;114:261-9

Aprotinin inhibits plasmin-induced platelet activation during cardiopulmonary bypass.

In the past few years, aprotinin has been used in cardiac surgery with impressive results of reducing blood loss, but several adverse effects of aprotinin also have been reported. One of the most likely mechanisms is the inhibition of plasmin by aprotinin, although this indirect effect has not been reproduced in all experimental studies. We evaluated the platelet function and fibrinolytic activity during human cardiac surgery, with or without aprotinin. During cardiopulmonary bypass (CPB) in humans without aprotinin (n=16), decrease of platelet aggregation induced by thrombin, increase of alpha-granule secretion of platelet and microparticle formation, and increase of plasmin/alpha2-antiplasmin complex (PIC) were observed. In contrast, low-dose aprotinin (1.0 x 10(6) KIU), which was administered only into the priming fluid of extracorporeal circuits (n=10), maintained platelet aggregation induced by thrombin and reduced alpha-granule secretion and microparticle formation of platelets during CPB. In vitro, plasmin (0.8 CU/mL) released alpha-granules of washed platelets, and this activation was completely inhibited by aprotinin (10 KIU/mL). Aprotinin has indirect effects to inhibit platelet activation, and this may partly explain the reduction of blood loss during cardiac surgery. To prevent the adverse effects, a single and minimal use of aprotinin is important. The results of in vivo and in vitro studies suggest that platelet preservation was demonstrated by the lower concentration of aprotinin (1.0 x 10(6) KIU per patient or 10 KIU/mL) compared with the concentration that inhibits plasma fibrinolysis.

“Low-Dose” Aprotinin Modifies Hemostasis but Not Proinflammatory Cytokine Release

Background. 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. Methods. In a prospective, randomized study, 38 patients undergoing elective coronary artery bypass grafting were investigated. Nineteen patients received low-dose aprotinin (2 × 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 CPB. Results. Interleukin-1β was not detected in either group, whereas traces of tumor necrosis factor-α 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). Conclusions. Low-dose aprotinin fails to modify proinflammatory cytokine release, yet confers hemostatic improvement through reduced fibrinolysis in patients undergoing routine coronary artery bypass grafting. (Ann Thorac Surg 1997;63:68–73)

Postoperative use of aprotinin in cardiac operations: An alternative to its prophylactic use

Background: Aprotinin reduces blood loss after cardiopulmonary bypass. Although there can be little doubt about the efficacy of aprotinin, its safety has been questioned recently and is still under investigation. Because of the potential for complications and the high cost, a selective strategy limiting drug delivery to patients with established postoperative bleeding will be more reasonable. Methods: In a prospective, randomized, double-blind trial we studied the effect of postoperative low-dose (2 million kallikrein inactivator units) aprotinin on blood loss and transfusion requirements in patients undergoing cardiopulmonary bypass. Fifty-seven patients were randomly assigned to two groups: aprotinin or placebo. Results: The two groups were comparable in all demographic and surgical variables. Postoperative chest tube drainage was significantly less in the aprotinin group than in the placebo group (410 ml vs 696 ml, p < 0.01). The use of homologous blood products was significantly less in the aprotinin group than in the placebo group (0.4 ± 0.5 unit vs 1.7 ± 0.9 unit for packed red blood cells and 0.8 ± 1.3 unit vs 2.3 ± 1.6 unit for fresh frozen plasma). Conclusions: Our results suggest that postoperative aprotinin reduces blood loss and transfusion requirements and provides the opportunity to restrict its use selectively to patients with excessive postoperative bleeding. (J T horac C ardiovasc S urg 1996;112:1462-7)

Aprotinin in primary valve replacement and reconstruction: A multicenter, double-blind, placebo-controlled trial

Background: Patients having cardiac operations often require blood transfusions. Aprotinin reduces the need for blood transfusions during coronary artery bypass graft operations. To determine the safety and effectiveness of aprotinin in reducing the use of allogeneic blood and postoperative mediastinal chest tube drainage, we studied 212 patients undergoing primary sternotomy for valve replacement or repair. Methods: This study was multicenter, randomized, prospective, double-blind, and placebo-controlled. Patients received high-dose aprotinin ( n = 71), low-dose aprotinin ( n = 70), or placebo ( n = 71). The study medication was given as a loading dose followed by a continuous infusion and pump prime dose. Heparin administration was standardized. Transfusions, postoperative mediastinal shed blood, and adverse events were tracked. Results: Demographic profiles were similar among the treatment groups. Aprotinin did not decrease the percentage of patients receiving transfusions when compared with placebo (high-dose aprotinin, 63%, p = 0.092; low-dose aprotinin, 52%, p = 0.592; placebo, 48%). Aprotinin was associated with a reduction in the volume of mediastinal shed blood (high-dose aprotinin vs placebo, p = 0.002; low-dose aprotinin vs placebo, p = 0.017). Adverse events were equally distributed among the treatment groups except for postoperative renal dysfunction (high-dose aprotinin, 11%; low-dose aprotinin, 7%; placebo, 0%; p = 0.01). A disproportionate number of patients in the high-dose aprotinin group with postoperative renal dysfunction also had diabetes mellitus. Conclusions: Aprotinin treatment in this population did not reduce allogeneic blood use, although there were significant reductions in the volume of mediastinal shed blood. (J T HORAC C ARDIOVASC S URG 1996;112:1081-9)

Clotting and fibrinolytic disturbance during lung transplantation: Effect of low-dose aprotinin

Patients undergoing lung transplantation are often confronted with a bleeding problem that may be due in part to the use of cardiopulmonary bypass and its activation of blood clotting and fibrinolysis. Objective: We performed a prospective study to determine whether and to what extent the clotting and fibrinolytic systems are being activated and whether low-dose aprotinin is effective in inhibiting blood activation during lung transplantation. Methods: Thirty lung transplantations performed on 29 patients were divided into a group with cardiopulmonary bypass alone ( n = 12), a group with cardiopulmonary bypass and 2 × 10 6 KIU aprotinin administered at the beginning of bypass in the pump prime ( n = 12), and a group without cardiopulmonary bypass ( n = 6). Serial blood samples were taken from the recipient before anesthesia, seven times during the operation, and 4 and 24 hours thereafter. Results: Results show that in the group having cardiopulmonary bypass alone, the concentration of the clotting marker thrombin/antithrombin III complex increased significantly during the early phase of the operation ( p < 0.01) and remained high until the end of the operation. Levels of tissue-type plasminogen activator, a trigger of fibrinolysis released by injured endothelium, also increased sharply in the early phase of the operation in the cardiopulmonary bypass group ( p < 0.01), followed by a significant increase in fibrin degradation products ( p < 0.01). In the aprotinin group, a significant reduction of thrombin/antithrombin III complex ( p < 0.05), tissue-type plasminogen activator ( p < 0.05), and fibrin degradation products ( p < 0.05) was observed in the early phase of the operation compared with levels in the bypass group, but these markers increased late during bypass associated with a significant drop ( p < 0.05) of plasma aprotinin level monitored by plasmin inhibiting capacity. In the nonbypass group, concentrations of thrombin/antithrombin III complex and tissue-type plasminogen activator also rose significantly ( p < 0.05) in the early phase of the operation, but the levels were significantly lower than those of the bypass group ( p < 0.05). Blood loss during the operation was 2521 ± 550 ml in the bypass group, 1991 ± 408 ml in the aprotinin/bypass group, and 875 ± 248 ml in the nonbypass group. Conclusion: These results suggest that clotting and fibrinolysis are activated during lung transplantation, especially in patients undergoing cardiopulmonary bypass. Aprotinin in a low dose significantly reduced activation of clotting and fibrinolysis in the early phase of the operation but not during the late phase of lung transplantation. (J T HORAC C ARDIOVASC S URG 1996;112:599-606)

Low-dose and high-dose aprotinin improve hemostasis in coronary operations

Prophylactic aprotinin therapy has become a popular method to reduce bleeding associated with cardiac operations. Today essentially two dose regimens are used, a high-dose regimen with administration throughout the complete operative procedure and a low-dose regimen with administration only during bypass. In unblinded studies both regimens were found to be equally effective. This double-blind placebo-controlled study in 115 patients undergoing elective coronary artery bypass grafting was done to confirm these results without potential investigator bias. Intraoperative hemoglobin loss was significantly reduced ( p < 0.01) by 42% in the high-dose group and by 17% in the low-dose group compared with loss in control subjects. Blood loss 6 hours after operation was 377 ml in the low-dose and 266 ml in the high-dose group compared with 630 ml in the placebo group ( p < 0.05 and p < 0.001, respectively). The average number of transfusions with packed red blood cells was reduced 31% in the low-dose group and 45% in the high-dose group, but the reductions were not significant. In a subgroup of patients, markers for coagulation and fibrinolysis were studied to investigate whether a different extent of activation existed. Fibrinolysis as measured by D-dimer levels was completely inhibited by the high-dose regimen, but was only partly suppressed in the low-dose group as compared with findings in the placebo group. Thrombin generation during cardiopulmonary bypass as reflected by F 1+2 levels was lower in patients treated with aprotinin, but the difference was not significant. Concentrations of thrombin inactivated by antithrombin III were not different between the groups. The observation that low-dose aprotinin significantly improved hemostasis but did not inhibit hyperfibrinolysis supports our previous finding that low-dose aprotinin mainly protects platelet adhesive function. The better result obtained with high-dose aprotinin may indicate the contribution of hyperfibrinolysis to bleeding after cardiopulmonary bypass. Because high-dose aprotinin is administered outside the period of full heparinization and might therefore increase the risk of thromboembolic complications, we propose a modification of the low-dose schedule to increase aprotinin levels sufficient for plasmin inhibition before release of the aortic crossclamp. (J T horac C ardiovasc S urg 1996;112:523-30)

A Comparison of the Effects of Tranexamic Acid and Low-Dose Aprotinin on Blood Loss and Homologous Blood Usage in Patients Undergoing Cardiac Surgery

A Comparison of the Effects of Tranexamic Acid and Low-Dose Aprotinin on Blood Loss and Homologous Blood Usage in Patients Undergoing Cardiac Surgery

Postoperative aprotinin: Effect on blood loss and transfusion requirements in cardiac operations

Aprotinin has been used increasingly to reduce postoperative blood loss in open heart operations. Although it was reported as safe in earlier studies, the overall safety of prophylactic use has been questioned recently. Because of the potential for complications and the high cost, it will be reasonable to use aprotinin more selectively in the postoperative period. We prospectively studied the effect of postoperative low-dose aprotinin (2 million kallikrein inactivator units [280 mg]) on blood loss and transfusion requirements in patients undergoing cardiopulmonary bypass. Seventy-five patients were randomly assigned to three groups: prophylactic high-dose aprotinin (group 1), postoperative aprotinin (group 2), or a nonmedicated control group (group 3). The three groups were comparable in all demographic and operative variables. Postoperative chest tube drainage was significantly decreased in both aprotinin groups compared with that in the control group (295 mL in group 1 and 325 mL in group 2 versus 411 mL in group 3; p < 0.05). No significant difference was seen between the two aprotinin groups. The use of homologous blood products was significantly less in group 1 and group 2 than in group 3 (1.15 +/- 1.13 U and 1.35 +/- 1.30 U versus 2.55 +/- 1.09 U; p < 0.05). Our results suggest that postoperative aprotinin reduces blood loss and transfusion requirements comparably with prophylactic high-dose aprotinin. Thus, one can restrict its use to patients with excessive postoperative bleeding.

Influence of low-dose aprotinin on the inflammatory reaction due to cardiopulmonary bypass in children

The serine protease inhibitor aprotinin inhibits trypsin, kallikrein, and plasmin and enhances the complement hemolytic activity of the first complement component C1. We tested whether low-dose aprotinin influences the inflammatory reaction related to cardiopulmonary bypass. In an open, randomized study, 25 children undergoing cardiac operations were investigated prospectively. The treated group comprised 11 patients receiving low-dose aprotinin (20,000 kIU/kg [2.8 mg/kg]), and the control group included 14 patients. Complement activation, cytokine production, and leukocyte stimulation were analyzed before, during, and after cardiopulmonary bypass. In all children, significant C3 conversion and C5a generation, interleukin-6 synthesis, and myeloperoxidase, eosinophil cationic protein, and histamine liberation occurred in relation to cardiopulmonary bypass. This was not influenced by aprotinin treatment. In contrast, neutrophil kinetic studies at the end of cardiopulmonary bypass showed a significantly lower increase in the aprotinin as compared with the control group. Our results suggest that low-dose aprotinin has little influence on the inflammatory reaction induced by cardiopulmonary bypass. Aprotinin affects neutrophil mobilization but not white blood cell degranulation related to cardiopulmonary bypass, and has no influence on complement activation and interleukin-6 synthesis.

冠動脈バイパス術におけるアプロチニンの術後出血軽減に対する効果

心臓手術においてアプロチニンの出血量軽減に対する有用性は広く認められている. 今回われわれは, 20人の少なくとも1本以上の動脈グラフトを用いた冠動脈バイパス術を行った患者のうち11人に1×106KIUのアプロチニンを体外循環時に使用し, 非使用患者群と比較しその効果を検討した. 術後出血による再手術はなく, グラフト開存率に有意差は認めなかった. また血栓症などの合併症も認めなかった. 血小板数, フィブリノーゲン, トロンポキサンB2, アンチプラスミンの術中および術後変化には, 2群間に有意差はなかった. 術後出血量はアプロチニン使用群が有意に少なかった(p<0.05). また術後輸血量も有意に少なかった (p<0.01). 以上の結果より, 血液生化学的検査では有用性を示唆する所見は得られなかったが, アプロチニンは術後出血軽減に有用であった.