High-dose Aprotinin Research Articles

Influence of low- and high-dose aprotinin on thromboelastography in coronary artery bypass grafting surgery

Influence of low- and high-dose aprotinin on thromboelastography in coronary artery bypass grafting surgery

Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass

Background. Aprotinin therapy is now widely used during cardiac surgery. This study examined the clinical and economic effectiveness of high-dose or low-dose aprotinin in comparison to placebo. Methods. In a double blind, randomized study, three groups of 50 patients received high-dose aprotinin costing AUS$614 per patient (AUS$ = Australian dollars), low-dose aprotinin costing AUS$220 per patient or placebo. Resource use influenced by aprotinin therapy was measured. Results. Both doses were effective in reducing chest drainage and postoperative transfusion requirements, high-dose being more effective than low-dose. Both doses reduced the rate of reoperations for hemostasis. A base case of statistically significant differences associated with the high-dose and low-dose aprotinin showed cost savings of AUS$77 and AUS$348 per patient, respectively. If the demonstrated less significant reductions in operating room and ward stay are included, these savings become AUS$463 and AUS$715, respectively. Alternately, if cross-matches are replaced by group-and-hold and cell savers are not used, the savings per patient would be AUS$196 and AUS$467, respectively. Conclusions. While high-dose aprotinin is clinically more effective than low-dose aprotinin, low-dose therapy demonstrates greater cost savings.

Platelet protection in coronary artery surgery: Benefits of heparin-coated circuits and high-dose aprotinin therapy

Objective: To examine the extent of platelet activation during extracorporeal circulation by using the combination of heparin-coated oxygenation systems and high-dose aprotinin therapy, and to examine the affinity and thereby the protective capacity of aprotinin to the glycoprotein (GP) receptors of the platelet membrane. Design: Experimental in vitro study. Setting: Research laboratory of a university hospital. Participants: Thirty-two volunteers (blood donors). Measurements and Main Results: Thirty-two oxygenation circuits of the same construction series (16 heparin-coated and 16 noncoated) were investigated in a closed system of a heart-lung machine model with fresh human whole blood. In each of these two groups, eight circuits with and eight without a high-dose aprotinin application (250 kallikrein inhibitory units [KIU]/mL) were investigated. In all four groups, the number of platelets declined continuously during the 90-minute recirculation period. Group I (no heparin coating, no aprotinin) showed the greatest reduction; group IV (heparin coating, aprotinin) had a significantly smaller decrease in platelet number ( p < 0.01). Platelet factor 4 (PF-4) levels, released from the a-granule, were in inverse proportion to the platelet loss. After 90 minutes of recirculation, the PF-4 values increased to 615.8% ± 559.5% and 237.2% ± 179.0% of the initial value for groups I and IV, respectively ( p < 0.01). Affinity chromatography and immunoblotting techniques were used to evaluate the affinity of aprotinin for the GP receptors of the platelet membrane. The affinity appeared in the following order: GPIIb < GPIIIa < GPIb. Conclusion: Heparin-coated oxygenation systems and additional aprotinin caused significantly less platelet damage in an in vitro cardiopulmonary bypass model. Chromatographic and immunologic methods could prove aprotinin's affinity for the platelet receptor proteins GPIb and GPIIb-Illa and therefore its probable role in diminishing the triggering of the platelet activation cascade.

Early and late outcome after elective cardiac surgery in patients with cirrhosis

Background. A prospective study was performed to evaluate the early and late outcome after elective cardiac surgery in patients with cirrhosis. Methods. All patients who underwent elective cardiac surgery between 1995 and 1997, and were suspected of having a history of cirrhosis, were followed in the intensive care unit (ICU), during hospitalization and after hospital discharge. All patients received high doses of aprotinin during surgery. Results. Ten patients of Child-Pugh class A and 2 patients of Child-Pugh class B were studied. All patients had signs of portal hypertension, and 11 of 12 patients had thrombocytopenia. In the first 24 h after operation, the median chest tube output was 810 mL (range 350 to 1,500 mL). Median ICU and hospital stays were 3 and 15 days, respectively (range 2 to 10 and 7 to 36 days, respectively). Seven patients experienced postoperative morbidity and 7 patients had significant complications after their hospital discharge. One death occurred in the ICU. Two deaths occurred after hospital discharge and were related to further hepatic damage. Conclusions. These results suggest that, in patients with mild or moderate cirrhosis, the incidence of significant complications was high after elective cardiac surgery, increasing the length of stay in ICU and overall hospitalization time and compromising the health status, even well after the operation.

High-dose aprotinin with gentamicin-vancomycin antibiotic prophylaxis increases blood concentrations of creatinine and cystatin C in patients undergoing coronary artery bypass grafting

Both aprotinin and gentamicin-vancomycin antibiotic prophylaxis have been used widely in cardiac surgery to prevent bleeding and infections, respectively. As the drugs are excreted almost entirely by glomerular filtration, we investigated their action on renal function when administered either separately or together. To increase consistency, we measured serum concentrations of creatinine and cystatin C, a new marker of glomerular filtration rate, that many recent studies have shown to be more sensitive than serum creatinine. One hundred patients undergoing coronary artery bypass surgery were allocated randomly to one of four groups: group A received antibiotic prophylaxis with cefamandole and no aprotinin; group B received cefamandole and high-dose aprotinin; group C received antibiotic prophylaxis with gentamicin and vancomycin, but no aprotinin; and group D received both high-dose aprotinin and gentamicin-vancomycin antibiotic prophylaxis. Data from 84 patients, for whom data collection was complete, were analysed. In the first week after operation, mean serum concentrations of cystatin C and creatinine either remained constant or decreased slowly in all groups, except for group D. In group D, both markers increased gradually from postoperative day 2 onwards. The increase in cystatin C was significant on postoperative day 5 (from mean 1.02 (SD 0.11) mg litre-1 before operation to 1.35 (0.32) mg litre-1; P < 0.05), reaching a peak on postoperative day 7 (1.45 (0.35) mg litre-1; P < 0.05), while the increase in creatinine concentration was significant on postoperative day 6 (from 1.05 (0.16) mg dl-1 before operation to 1.29 (0.34) mg dl-1; P < 0.05). We conclude that simultaneous administration of high-dose aprotinin and prophylactic use of gentamicin with vancomycin increased serum concentrations of cystatin C and creatinine in the first postoperative week in patients undergoing cardiac surgery.

APROTININ REDUCES BLOOD LOSS AND TRANSFUSION REQUIREMENTS IN ORTHOTOPIC LIVER TRANSPLANTATION: A PLACEBO-CONTROLLED MULTICENTER STUDY.

1015 Intraoperative activation of the fibrinolytic system has been shown to contribute to the bleeding tendency during orthotopic liver transplantation (OLT). Aprotinin is a serine anti-protease and a potent inhibitor of fibrinolysis. Although small, retrospective studies have suggested that aprotinin may reduce blood loss in OLT, its indication remains controversial. We initiated a prospective, double-blind, placebo-controlled multicenter study (EMSALT) to test the hypothesis that aprotinin reduces blood loss in OLT. Six European liver transplant centers (Leiden, Rotterdam, Bologna, Huddinge, Brussels, Helsinki) participated in this study. Perioperative patient management, including blood transfusion were standardized according to the study protocol. Patients were randomized to either high dose aprotinin (2×106 KIU loading dose, followed by 1×106 KIU/hr and an additional bolus of 1×106 KIU 20 min before reperfusion), regular dose (2×106 KIU loading dose, followed by 0.5×106 KIU/hr), or placebo. Randomization was performed per center. After obtaining informed consent, 137 adult patients, who underwent their first OLT and met the inclusion criteria, were randomized. There were no significant differences in demographic data or severity of disease between the three groups. Primary end-points are presented in the tableTableThrombo-embolic events were seen in 1 patient in the high dose group, none of the patients in the regular dose group, and in 3 patients in the placebo group (p=0.41). Mortality (30 days) was not different between the three groups (6.5%, 4.7% and 8.3%; p=0.79). Conclusions: This prospective study shows that aprotinin is an effective and safe drug to help reduce blood loss and transfusion requirements in patients undergoing OLT.

Does high-dose methylprednisolone in aprotinin-treated patients attenuate the systemic inflammatory response during coronary artery bypass grafting procedures?

Objective: To discover the possible effects of methylprednisolone on the systemic inflammatory response during aprotinin treatment. Design: Randomized, double-blinded study. Setting: University-affiliated heart center. Participants: Fifty-two patients scheduled for elective coronary artery bypass grafting. Interventions: In the methylprednisolone group (n = 26), 1 g of methylprednisolone was administered 30 minutes before cardiopulmonary bypass (CPB). The 26 control patients received a placebo instead. High-dose aprotinin was administered to all participants. Measurements and Main Results: After CPB, the concentration of the proinflammatory cytokines, interleukin-6 and interleukin-8, was significantly less in the methylprednisolone group. The anti-inflammatory interleukin-10 concentration was, in contrast, greater. After CPB, PaO 2 was greater in the methylprednisolone group (245 ± 17 v 195 ± 16 mmHg). Dynamic pulmonary compliance was also greater, whereas the alveolar-arterial oxygen difference was less (376 ± 17 v 428 ± 16 mmHg). On arrival in the intensive care unit, the oxygen delivery index was greater in the methylprednisolone group (62 ± 2.7 v 54 ± 2.3 mL/min/m 2) and the oxygen extraction rate was less (25% ± 0.02% v 30% ± 0.02%). After CPB, the cardiac index was significantly greater in the methylprednisolone group (4.1 ± 0.2 v 3.6 ± 0.2 L/min/m 2). These patients had less blood loss postoperatively (616 ± 52 v 833 ± 71 mL; p = 0.017) and a greater urine output (8,015 ± 542 v 6,417 ± 423 mL/24 h; p = 0.024). Conclusion: The use of methylprednisolone attenuates the systemic inflammatory response during aprotinin treatment and improves clinical outcome parameters.

ARE LIPID MEDIATORS IMPLICATED IN THE PRODUCTION OF PRO- AND ANTI-INFLAMMATORY CYTOKINES DURING CARDIOPULMONARY BYPASS GRAFT WITH EXTRACORPOREAL CIRCULATION?

In this study the authors assessed the sequential release of lipid mediators (TXB2, PGE2, 6-keto-PGF1α, LTB4, LTC4, PAF), pro-inflammatory cytokines (IL-6, IL-8, TNF-α) and anti-inflammatory cytokines (IL-4, IL-10) in 17 patients undergoing coronary artery bypass graft (CABG) with extracorporeal circulation (ECC). Time course of appearance of inflammatory mediators revealed the early and transient increase in lipid mediator plasma concentrations (6-keto-PGF1α, LTB4, LTC4, PAF) whereas cytokines (IL-6, IL-8, IL-10) were involved only in late pre- and post-operative periods. No variation of TXB2, PGE2, IL-4 and TNF-α levels were found. No correlation was documented between the levels of lipid mediators and pro- or anti-inflammatory cytokines suggesting that lipidic compounds are not implicated in the genesis of cytokines which appear much later involved. Despite the common use of high doses of aprotinin (a non-specific enzyme inhibitor) in hope to abrogate the inflammatory response to cardiopulmonary bypass procedure, this study reports the persistent release of several inflammatory compounds that might be involved in the post-CABG multiple organ failure syndromes.

Low-dose aprotinin half the cost of high-dose aprotinin in CABG

Low-dose aprotinin half the cost of high-dose aprotinin in CABG

High-dose aprotinin reduces systemic inflammatory response syndrome during CABG

High-dose aprotinin reduces systemic inflammatory response syndrome during CABG

Is epsilon-aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery?: a meta-analysis.

Although aprotinin is known to be effective in reducing postoperative hemorrhage after cardiac surgery, epsilon-aminocaproic acid, an alternative antifibrinolytic, is considerably less expensive. Because the results of 3 small randomized clinical trials comparing these 2 agents directly were inconclusive, we performed a meta-analysis to compare the relative effectiveness and adverse-effect profile of these 2 agents against placebo. Data from 52 randomized clinical trials published between 1985 and 1998 involving the use of epsilon-aminocaproic acid (n=9) or aprotinin (n=46) in patients undergoing cardiac surgery were abstracted. Our primary outcomes were total blood loss, red blood cell transfusion rates and amounts, reexploration, stroke, myocardial infarction, and mortality. The meta-analysis revealed substantial reductions in total blood loss with epsilon-aminocaproic acid and low-dose aprotinin (each with a 35% reduction versus placebo, P<0.001) and high-dose aprotinin (53% reduction, P<0.001). There were identical reductions in total postoperative transfusions with epsilon-aminocaproic acid (61% reduction versus placebo, P<0. 010) and high-dose aprotinin (62% reduction, P<0.001). The proportion of patients transfused was similarly reduced with epsilon-aminocaproic acid (OR, 0.32; 95% CI, 0.15 to 0.69) and high-dose aprotinin (OR, 0.28; 0.22 to 0.37). Although both drugs reduced rates of reexploration to similar degrees, this effect was statistically significant only with high-dose aprotinin (OR, 0.39; 0. 24 to 0.61). epsilon-Aminocaproic acid and aprotinin had no effect on risks of postoperative myocardial infarction or overall mortality. Because the 2 antifibrinolytic agents appear to have similar efficacies, the considerably less-expensive epsilon-aminocaproic acid may be preferred over aprotinin for reducing hemorrhage with cardiac surgery.

Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery.

Cardiopulmonary bypass (CPB) is associated with defective haemostasis which results in bleeding and the requirement for allogenic blood product transfusions in many patients undergoing open heart surgery (OHS) and/or coronary artery bypass graft surgery (CABG) with CPB. Conservation of blood has become a priority during surgery because of shortages of donor blood, the risks associated with the use of allogenic blood products and the costs of these products. Aprotinin is a serine protease inhibitor isolated from bovine lung tissue which acts in a number of interrelated ways to provide an antifibrinolytic effect, inhibit contact activation, reduce platelet dysfunction and attenuate the inflammatory response to CPB. It is used to reduce blood loss and transfusion requirements in patients with a risk of haemorrhage and has clear advantages over placebo or no treatment. High dose aprotinin significantly reduces postoperative blood loss compared with aminocaproic acid and desmopressin, and decreases transfusion requirements compared with desmopressin. Results are less consistent with tranexamic acid: high dose aprotinin either reduces blood loss significantly more than, or to an equivalent level to, tranexamic acid. A variety of other lower aprotinin dosage regimens consistently result in similar reductions in blood loss to aminocaproic acid or tranexamic acid. Data from clinical trials indicate that aprotinin is generally well tolerated, and the adverse events seen are those expected in patients undergoing OHS and/or CABG with CPB. Hypersensitivity reactions occur in <0.1 to 0.6% of patients receiving aprotinin for the first time. The results of original reports indicating that aprotinin therapy may increase myocardial infarction rates or mortality have not been supported by more recent studies specifically designed to investigate this outcome. However, a tendency to early vein graft occlusion with aprotinin has been shown and care with anticoagulation and vessel grafts is required. No comparative tolerability data between aprotinin and the lysine analogues, aminocaproic acid and tranexamic acid, are available. Comparative tolerability and cost-effectiveness data for aprotinin and the lysine analogues are required to more fully assess their individual roles in reducing blood loss and transfusion requirements in patients undergoing CPB during OHS and/or CABG. However, clinical evidence to date supports the use of aprotinin over its competitors in patients at high risk of haemorrhage, in those for whom transfusion is unavailable or in patients who refuse allogenic transfusions.

Reduced inotropic support after aprotinin therapy during pediatric cardiac operations

Background. Several reports indicate that aprotinin treatment before and during cardiopulmonary bypass (CPB) might have a protective effect on the myocardium. We evaluated the hemodynamic effects of perioperative aprotinin treatment. Methods. We conducted a randomized, double-blind, placebo-controlled trial in 34 infants (mean age, 2.5 years) who had cardiac operations. Half of the patients received high-dose aprotinin therapy. There were no significant differences between the aprotinin and placebo groups with respect to age, weight, sex, aortic cross-clamp time, and CPB time. The following data were recorded at arrival in the intensive care unit 6, 12, 24, and 48 hours after termination of CPB: heart rate, blood pressure, left atrial pressure, central-peripheral temperature difference, arterial-central venous oxygen saturation difference, urine output, serum creatinine, lactate and neutrophil elastase levels, the Doppler echocardiographic factors shortening fraction and preejection period/left-ventricular ejection time, and cumulative doses of catecholamines (epinephrine), enoximone, and furosemide. Results. No hemodynamic variable showed any significant difference between aprotinin and placebo groups. Urine output, creatinine, lactate, and elastase levels, as well as the cumulative doses of furosemide and epinephrine were not significantly different. Twelve hours after CPB 10 patients in the placebo group and 4 in the aprotinin group had received enoximone ( p < 0.05). The placebo group had received significantly larger doses of enoximone than the aprotinin group at arrival in the intensive care unit (0.13 ± 0.05 versus 0 mg/kg), 12 hours after CPB (0.58 ± 0.14 versus 0.18 ± 0.09 mg/kg), 24 hours after CPB (1.11 ± 0.24 versus 0.42 ± 0.16 mg/kg), and 48 hours after CPB (1.61 ± 0.40 versus 0.86 ± 0.28). At 6 hours the difference did not reach statistical significance. Conclusions. Clinical and hemodynamic status of the aprotinin-treated patients was similar to that of the placebo-treated patients in the first 48 hours after CPB. The placebo group, however, required significantly more inotropic support by enoximone than the aprotinin group to achieve this goal.

Activation of the protein C system during cardiopulmonary bypass with and without aprotinin

Background. The protein C system is important in the regulation of hemostasis. We studied its behavior during coronary artery bypass grafting procedures with and without aprotinin treatment using assays sensitive for activation of the protein C system.Methods. In a prospective, double-blind, randomized study of 48 patients we investigated the levels of antigen to proteins C and S and of the complexes between activated protein C with its two major plasma inhibitors, protein C inhibitor and α1-antitrypsin in patients treated with placebo (n = 17), low-dose (n = 15), and high-dose (n = 16) aprotinin during elective coronary artery bypass grafting.Results. The levels of proteins C and S showed a rapid decrease after heparinization, decreased greatly after start of cardiopulmonary bypass, and remained stable during cardiopulmonary bypass. Activated protein C inhibitor complexes were markedly elevated at the start of the procedure. Activated protein C–α1-antitrypsin decreased greatly after the start of cardiopulmonary bypass and remained stable during cardiopulmonary bypass. A significant peak was observed at the intensive care unit. Activated protein C–protein C inhibitor levels showed a peak after heparinization in accordance with the accelerating effect of heparin on the complex formation but decreased thereafter. Treatment with aprotinin did not notably alter any of the measured patterns.Conclusions. In this study no evidence was found for increased activation of the protein C system during coronary artery bypass grafting. Administration of aprotinin did not result in different patterns of activation of the protein C system.

Central nervous system effects of cardiopulmonary bypass

Background. The spectrum of approaches to the issue of brain injury in cardiac surgical practice ranges from refusal to acknowledge that the problem exists to an overemphasis on cerebral risks that can unduly frighten patients. An appropriate approach to therapeutic and preventive strategies requires a fitting sense of proportion and an understanding of the mechanisms of cerebral injury. Methods. This article reviews the incidence and severity of cerebral injury during cardiopulmonary bypass, the identification of high-risk patients, and the mechanisms of injury, including hypoperfusion, microemboli, and inflammatory response. It discusses the influences of alpha-stat and pH-stat strategies on cerebral blood flow during cardiopulmonary bypass; the use of retinal angiography to image the retinal circulation, thus providing a window on the cerebral microcirculation during bypass; magnetic resonance imaging evidence of an inflammatory response in the brain during bypass; and current efforts to gain better understanding of the molecular mechanisms involved in the inflammatory response. Results. The current incidence of stroke during cardiopulmonary bypass is somewhat lower than in the 1980s but still remains a significant problem. Levels of cognitive impairment also are unacceptably high. Recognized predictors enable us to identify patients at particularly high risk of stroke. Hypertensive patients are particularly susceptible to ischemic injury during bypass and should be perfused at mean perfusion pressures higher than those for normotensive patients. Under conditions of hypothermia, a pH-stat strategy causes loss of cerebral blood flow autoregulation, and the cerebral blood flow becomes pressure-passive. With both the pH-stat and alpha-stat strategies, cooling of the patient greatly increases the flow to metabolism ratio of the cerebral blood flow; however, this luxury perfusion brings to the brain not just an excess supply of oxygen but also an increased quantity of microemboli. Current investigative efforts are focused on the endothelial cell–leukocyte adhesion cascade, attempting to characterize β 2 and β 1 adhesion molecule expression in patients undergoing cardiac surgery. Hammersmith Hospital is about to complete a study of the effects of high-dose aprotinin on the inflammatory response pattern and on cerebral infarction. Conclusions. Further progress in the development of therapeutic and preventive strategies with respect to cerebral injury during cardiac bypass depends on an increase in the understanding of the mechanisms involved. Current strategies should include optimizing cerebral perfusion and minimizing macroembolic and microembolic damage. The possibility of modifying the systemic inflammatory response is the most interesting challenge of the next few years.

Complement activation during major surgery: The effect of extracorporeal circuits and high-dose aprotinin

Objective: To assess the in vivo contribution to complement activation of an extracorporeal circuit and the use of high-dose aprotinin during major surgery. Design: Sequential samples were obtained from 8 patients undergoing thoracic surgery, 20 patients undergoing orthotopic liver transplantation (OLT) using venovenous bypass, and 19 patients undergoing cardiac surgery using cardiopulmonary bypass (CPB). Intervention: The latter two groups were part of a randomized controlled trial of high-dose aprotinin. Measurements: Total complement activation was measured with the hemolytic complement activity and the C3 activation-specific marker, C3d antigen. Main Results: Complement activation did not occur during thoracic surgery. During OLT, C3d antigen levels, expressed as mean ± standard deviation (SD), were elevated from baseline at skin closure (8.6 ± 2.5 v 13.0 ± 5.2 mg/L; p = 0.0082). During cardiac surgery, C3d antigen levels increased 10 minutes after the start of CPB (pre-CPB, 8.0 ± 1.9 v 14.2 ± 3.1 mg/L; p = 0.0001) and remained at greater than baseline values postoperatively (8.0 ± 1.9 v 11.8 ± 2.3 mg/L; p = 0.002). There was no difference in complement activation in those receiving high-dose aprotinin during OLT or cardiac surgery. Complement activation during cardiac surgery using extracorporeal circulation occurred to a greater extent than during OLT and thoracic surgery. Complement activation during cardiac surgery or OLT was not attenuated by the use of high-dose aprotinin.

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.

Activation of Hemostasis During Cardiopulmonary Bypass and Pediatric Aprotinin Dosage

Background. Cardiopulmonary bypass results in inappropriate activation of the coagulation and fibrinolytic systems. Factors such as a greater degree of hemodilution, use of deep hypothermic circulatory arrest, the impact of cyanosis on coagulation, and the immature coagulation system of the newborn will increase the risk of problematic perioperative bleeding.Methods. This article describes the characteristics of the hemostatic system in children undergoing cardiac operations and addresses the effect of aprotinin on hemostasis. Hemostatic parameters were measured in 96 pediatric patients using three different doses of aprotinin. The high-dose group (group 1) received 30,000 KIU/kg (4.2 mg/kg) of aprotinin after induction of anesthesia and an additional bolus of 30,000 KIU/kg (4.2 mg/kg) into the pump prime. In the low-dose group (group 2), both the initial bolus and the pump-prime dose of aprotinin were halved to 15,000 KIU/kg (2.1 mg/kg). Group 3 received the high dose with an additional bolus of aprotinin to the pump prime.Results. Plasma levels of aprotinin in both groups 1 and 2 were lower than the 200 KIU/mL (0.03 mg/mL) value usually reached in adults with high-dose aprotinin treatment. Group 3 patients had levels greater than 200 KIU/mL (0.03 mg/mL) throughout the procedure. Biochemical indices of fibrinolysis (fibrin[ogen] degradation products, d-dimers) revealed significant and dose-dependent inhibition at all three aprotinin concentrations. In contrast, significant changes in coagulation activation markers (prothrombin fragments F1.2, thrombin-antithrombin III complex, and fibrin monomers) were found only in group 3.Conclusions. The inverse relationship between a small patient’s blood volume and the large pump-prime volume requires additional aprotinin to be added to the prime to achieve plasma levels sufficient to inhibit activation of the coagulation cascade.