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Ann Thorac Surg 1998;65:70-77
© 1998 The Society of Thoracic Surgeons
Department of Anesthesiology, German Heart Center Munich, Munich, Germany
Department of Cardiovascular Surgery, German Heart Center Munich, Munich, Germany
Accepted for publication July 12, 1997.
Dr Dietrich, Department of Anesthesiology, German Heart Center Munich, Lazarettstrasse 36, D-80636 Munich, Germany (e-mail: dietrich@dhm.mhn.de).
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Abstract |
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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 F1+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 (F1+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 F1+2 prothrombin fragments. High-dose aprotinin therapy appears to be superior to low-dose therapy.
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Introduction |
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Although the blood-saving properties of aprotinin are generally well accepted [5], the most effective dose of this drug still is being discussed. The first publications on the use of aprotinin in open heart operations described a high-dose regimen with approximately 6 x 106 kallikrein inactivator units (KIU) (840 mg) of aprotinin per patient [6][7][8][9]. Modification of the initial dosing scheme by using a reduced dose of 2 x 106 KIU (280 mg) of aprotinin [10], or half-dose aprotinin [11], has been evaluated and shown to be more effective than placebo. This would be an important pharmacoeconomic finding. The expense of aprotinin makes it imperative that clinicians find the most efficacious and cost-effective dose. However, only a few studies have compared the efficacy of high-dose and low-dose aprotinin regimens [11][12][13].
Because aprotinin acts not only as an antifibrinolytic but also as an inhibitor of clotting activation [7], it prolongs clotting tests such as the celite-activated clotting time (CACT) or the activated partial thromboplastin time [14]. It is still a matter of discussion whether this represents an artificial in vitro effect, which may lead to inadequate heparinization, or whether it reflects true and effective anticoagulation [12][14][15][16][17][18]. Therefore, it is of interest to know whether there is a correlation between hemostatic activation, heparin requirements, and different plasma levels of aprotinin.
The aims of the present study were to investigate whether high-dose aprotinin treatment is more effective than low-dose treatment in reducing activation of hemostasis, to study the influence of different aprotinin doses on heparin-induced anticoagulation and heparin requirements during CPB, and to identify possible subgroups of patients who would benefit more from high-dose aprotinin treatment.
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Material and Methods |
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Study Design
Cohorts of 20 patients were randomized independently to receive either high-dose (group H) or low-dose (group L) aprotinin using a table of random numbers. On the basis of a presumed difference between high- and low-dose aprotinin of 1 standard deviation in the concentrations of D-dimers, as found in a previous study [19], we determined that a sample size of 120 patients (60 in each group) would provide 80% power with a type I statistical error of 5%. To identify possible subgroups of patients (eg, different procedures, influence of sex, redo operation), the total sample size was adjusted upward to 230 patients. To examine the influence of length of surgical procedure on hemostatic activation and blood loss, and to study the impact of different aprotinin doses on this activation, the patients were divided into groups according to whether the length of their surgical procedure was greater than or less than 240 minutes. This cutoff point was chosen because 240 minutes is the mean time for a coronary artery bypass grafting operation at our institution.
Study Protocol
Aprotinin and the appropriate placebo were provided by the manufacturer (Bayer AG, Leverkusen, Germany) in identical packages containing number-coded bottles. Each bottle of aprotinin contained 5 x 105 KIU (70 mg) of aprotinin in 50 mL of 0.9% saline solution, and the placebo bottles contained only saline solution. The dosage regimen of aprotinin was as follows: patients in group H received a loading dose of 2 x 106 KIU of aprotinin over a 15-minute period at the start of the operation, followed by a continuous infusion of 5 x 105 KIU/h throughout the operation. Patients in group L received equal volumes of placebo. In all patients, the oxygenator was primed with an additional bolus of 2 x 106 KIU of aprotinin. To identify possible adverse reactions to aprotinin, all patients received a test dose of aprotinin (10,000 KIU) 10 minutes before the first drug (or placebo) administration.
Anesthetic Technique
Anesthesia was induced with midazolam (0.1 mg/kg) and sufentanil (1 to 2 µg/kg). Neuromuscular blockade was initiated and maintained with pancuronium (0.1 mg/kg). Sufentanil and midazolam were given continuously during the operation to maintain anesthesia.
Cardiopulmonary Bypass
The extracorporeal circuit consisted of a bubble oxygenator (High Flex D 700 S; Dideco, Mirandola, Italy), nonocclusive roller pumps, a cardiotomy reservoir (Dideco D 742; Dideco), and polyvinyl tubing. The oxygenator was primed with 1,900 mL of crystalloid solution containing 5,000 U of heparin. Cardiopulmonary bypass was performed under moderate hypothermia of 30° to 32°C rectal temperature and a flow rate of 2.4 L · min-1 · m-2. Myocardial preservation was achieved by the infusion of 1,000 mL of cold crystalloid cardioplegic solution (Bretschneider HTG; F. Köhler Chemie, Alsbach, Germany) into the aortic root after aortic cross-clamping.
Control of Heparin-Induced Anticoagulation
Blood was anticoagulated for CPB using 375 U/kg of porcine mucosa heparin (La Roche, Basel, Switzerland) injected through the central venous catheter before aortic cannulation. Ten minutes later, the anticoagulation was monitored using the CACT as well as a kaolin-activated clotting time (Hemochron 800; International Technidine Corp, Edison, NJ). According to our protocol, the effect of heparin was monitored by the CACT: if the CACT did not reach 400 seconds after the first heparin bolus, or if it dropped below 400 seconds during CPB, an additional bolus of 125 U/kg of heparin was given. The activated clotting time measurements were performed every 30 minutes until the end of CPB. In high ranges, the activated clotting time does not correlate with the degree of anticoagulation; consequently, the measurement was discontinued when the CACT exceeded 1,500 seconds. After the completion of CPB, residual heparin was neutralized by protamine chloride given in a ratio of 1.5 mg per 125 units of the initial heparin dose. In the presence of aprotinin, the CACT still is prolonged after heparin antagonism by protamine; thus, a kaolin-activated clotting time of greater than 140 seconds 15 minutes after protamine administration was an indication for repeated protamine administration (0.5 mg/kg).
Transfusion Policy
The intraoperative bleeding tendency was assessed by the anesthesiologist and the surgeon using a five-grade rating scale: heavy, increased, normal, low, and remarkably low. This rating was assessed after chest closure. The postoperative indication for allogeneic blood transfusion was a hematocrit of 28%. The requirement for allogeneic blood and blood products was recorded during the entire hospital stay. Blood loss was recorded 6, 12, and 24 hours after operation and at the time of removal of the chest tubes. Blood loss of greater than 500 mL within the first 6 postoperative hours was defined as "high" blood loss. Blood loss of greater than 300 mL/h during the first 2 postoperative hours, or of more than 200 mL/h during the subsequent time, were indications for surgical reexploration. A cell separator (Haemonetics, Munich, Germany) was used to concentrate the remaining cellular contents of the oxygenator after the termination of CPB. The hard shell reservoir of the heart-lung machine was used for postoperatively shed mediastinal blood collection. The shed mediastinal blood was retransfused up to 6 hours after operation when at least 250 mL of blood had been collected.
Blood Sampling
Blood samples were taken from the radial artery or, during CPB, from the port of the oxygenator at the following times: (1) after the induction of anesthesia and before the infusion of aprotinin; (2) 5 minutes after the start of CPB; (3) 60 minutes after the start of CPB; (4) at the end of CPB; and (5) at the end of the operation. After the first 10 mL of blood was discarded, blood was drawn into ethylenediaminetetraacetic acid tubes for determinations of hematocrit and platelet count, or into tubes containing sodium citrate (1:9) for coagulation tests. After centrifugation for 10 minutes, all plasma samples were frozen immediately in aliquots at -40°C and were thawed only before testing.
Biochemical Measurements
The split products of the cross-linked fibrin were measured by an immunoassay based on monoclonal antibodies to D-dimers (Boehringer, Mannheim, Germany). Levels of F1+2 prothrombin fragments were determined by sandwich enzyme-linked immunosorbent assays (Behringwerke, Marburg, Germany). Plasma aprotinin concentrations were quantified by means of a competitive enzyme-linked immunosorbent assay. The aprotinin measurement was performed only in the first 100 patients. The activated partial thromboplastin time was determined before and 6 hours after operation using standard methods.
Data Analysis
Two-way analysis of variance was used to analyze normally distributed data. When the p value was less than 0.05, post hoc comparisons were performed with Tukey’s test. Parametric data are given as the mean plus or minus the standard deviation. When Shapiro’s test of normality revealed that data (activated clotting time, F1+2 prothrombin fragments, D-dimers, blood loss, and allogeneic blood transfusion) did not conform to a normal distribution, a nonparametric test (the Mann-Whitney U-test) was used. Linear regression analysis was used to examine the relation between the duration of CPB and the D-dimer concentrations at the end of CPB. The 
2 test was used for categorical data. A p value of less than 0.05 was considered statistically significant.
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Results |
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There was no difference in the amount of red blood cells gained intraoperatively with the cell separator (801 ± 289 mL in group H and 870 ± 423 mL in group L; p = not significant). However, a significant difference existed in the amount of shed mediastinal blood that was retransfused after operation (143 ± 256 mL in group H versus 252 ± 288 mL in group L; p < 0.05). In group H, 34% of all patients received shed mediastinal blood compared with 54% in group L (p < 0.05). Excluding these patients from analysis, the amount of blood lost 6 hours after operation remained significantly different (243 ± 86 mL in group H and 295 ± 112 mL in group L; p < 0.05). Moreover, a positive correlation between the length of the operation and the amount of postoperative blood loss was noted (p < 0.05). This correlation did not differ significantly between the groups (ie, bleeding was not attenuated to a greater degree in longer-lasting operations in group H compared with group L).
Outcome and Complications
In 3 of 230 patients, the attending anesthesiologist noted a fall in blood pressure of greater than 20% from baseline during the infusion of the first drug bolus. All 3 patients recovered immediately after the injection of a vasopressor and the aprotinin infusion was continued. Two of the 3 patients received low-dose aprotinin, so the reaction occurred during the infusion of placebo. Three patients in group H and 5 in group L underwent repeated thoracotomy for surgical hemostasis (p = not significant). In 4 of these 8 patients, a surgical source of bleeding could be identified. Excluding the data of these patients from analysis did not alter the results. Renal insufficiency did not develop in any of the patients. No deaths occurred within 30 days of operation.
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Comment |
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Bleeding and Allogeneic Blood Requirements
The clinical effectiveness of aprotinin for improving hemostasis and consequently reducing bleeding in patients undergoing cardiac operations has been well documented in several studies [6][7][8][11][24]. However, the most effective dose of the drug has not been determined yet. In a study designed to investigate platelet protection during the initial phase of CPB by a pump-prime-only dose of 2 x 106 KIU and a full dose of 6 x 106 KIU, van Oeveren and colleagues [4] demonstrated improved hemostasis and platelet function with aprotinin treatment compared with placebo. A subsequent study confirmed these results [3]. Cosgrove and associates [12] examined 169 patients undergoing isolated reoperative myocardial revascularization and compared a full-dose aprotinin regimen (approximately 6 x 106 KIU) with a half-dose regimen and placebo. The total drainage volume was found to be 720 ± 753 mL in the high-dose group, 1,121 ± 683 mL in the placebo group, and an intermediate value of 866 ± 1,636 mL in the half-dose group. Only in the high-dose group was the reduction in allogeneic blood requirements significant. Levy and co-workers [11] studied four groups of patients: those who received full-dose or half-dose aprotinin, pump-prime aprotinin only, or placebo. Again, a dose-dependent effect of aprotinin was evident: the total drainage volume was reduced from 1,700 ± 140 mL in the placebo group to 1,420 ± 132 mL in the pump-prime-only group, to 1,040 ± 143 mL in the low-dose aprotinin group, and finally to 900 ± 135 mL in the high-dose aprotinin group. The allogeneic blood requirement also was reduced from 10.3 ± 1.4 U in the placebo group to 2.2 ± 0.4 U in the high-dose aprotinin group.
Recently, Lemmer and colleagues [13] investigated in a multicenter, randomized, placebo-controlled study 704 patients undergoing first-time coronary artery bypass grafting. Enrolled patients received one of four study drug regimens: high-dose aprotinin, low-dose aprotinin, pump-prime-only aprotinin, or placebo. Total drainage was dose-related: 786 ± 50 mL in the high-dose aprotinin group, 811 ± 51 mL in the low-dose aprotinin group, 899 ± 52 mL in the pump-prime-only group, and 1,286 ± 52 mL in the placebo group. One surprising result of this study was that the lowest aprotinin dose appeared to be associated with more frequent (but not statistically significant) possible perioperative myocardial infarctions (16% versus 9% in the placebo group). In an accompanying editorial, Smith and Muhlbaier [18] blamed this phenomenon on an altered balance of procoagulant and anticoagulant activation. In fact, it may be possible that with low plasma levels of aprotinin, fibrinolysis is inhibited but the coagulation side remains activated.
The present study corroborates the previous results. There was a significant difference between the high-dose aprotinin group and the pump-prime-only group with respect to bleeding tendency. The reduction in blood loss was 24%. Although this is less than the 35% to 50% reduction that has been described in several studies comparing the high-dose aprotinin regimen with placebo [1][25], it indicates that low-dose aprotinin treatment also causes a reduction in bleeding tendency [26]. Further, the number of patients who experienced blood loss exceeding 500 mL in 6 hours was significantly higher in group L, and the mean amount of shed blood, which was retransfused to the patients, was significantly lower in group H. Concomitant with this response was a significant reduction in allogeneic blood requirements in the high-dose aprotinin group. This difference in drainage volume corresponded well to the reduced fibrinolytic activity in group H. The difference in bleeding tendency even was directly observable: the rating on the bleeding scale at the time of chest closure was significantly different between the groups (ie, patients in the high-dose aprotinin group were identified as "low bleeders" on the basis of the judgments of the surgeon and the anesthesiologist).
Our study failed to identify any special subgroups of patients who would benefit more from a higher aprotinin dose, regardless of patient gender, primary versus redo operations, valve operations versus coronary artery bypass grafting, preoperative aspirin or heparin treatment, or length of surgical procedure.
Activated Clotting Time and Heparin Management
Aprotinin prolongs the activated clotting time, whereas kaolin does not [15]. The present data show that the influence of aprotinin on the CACT is dose-dependent: patients in group H had a significantly prolonged CACT compared with patients in group L. Moreover, because heparin management was based on the CACT, patients in group H received significantly less heparin whereas more patients in group L received an additional bolus of heparin. Nevertheless, clotting activation, measured as F1+2 prothrombin fragment concentrations, was not different between the two aprotinin dose groups. Despite a lower heparin dose, patients in group H demonstrated the same degree of thrombin generation. These findings support the hypothesis that aprotinin reduces clotting activation and has anticoagulant properties in vivo [14]. In addition, the prolonged activated partial thromboplastin time observed in group H 4 hours after operation supports this hypothesis. We could not identify laboratory or clinical signs of hypercoagulability in this study.
The heparin dose was not the primary end point of this study. We did not investigate the role of extrinsic activation of coagulation during CPB [27]. Only heparin is capable of inhibiting this pathway of activation. Therefore, our data do not justify recommendation of a reduced bolus of heparin for anticoagulation during CPB.
Side Effects
Aprotinin is derived from bovine lungs and possesses antigenic properties. Anaphylactic reactions, especially after short-term reexposure, have been described [28][29]. Because our protocol was blinded, a reaction to aprotinin could not be excluded during operation in 3 patients. However, in 2 of them, this reaction was noted during placebo infusion. This demonstrates the difficulty of distinguishing mild drug reactions from hemodynamic reactions induced otherwise. None of the patients in this study previously had been exposed to aprotinin. However, the widespread use of aprotinin will increase the risk of allergic reactions in the future. Renal insufficiency did not develop after operation in any of the patients.
Limitations of the Study
In the present study, we compared two doses of aprotinin that previously had been described as being effective [7][30]. Accordingly, we can only speculate about the effectiveness of other aprotinin doses. However, there is evidence that a lower dose, as used in the present study in group L, is not effective [31]. It is conceivable that a "half-dose" regimen, which has been shown to be effective in blood saving [11], may act similarly to our low dose because the total doses of aprotinin are comparable.
It was not the aim of the present study to demonstrate the efficacy of aprotinin treatment. This has been done with both doses in many subsets of cardiac surgical patients [11][12][13][24]. The aim was to investigate whether a higher dose is more effective than a lower one. For this type of study, a group of control patients would not provide new or additional information and, therefore, was not mandatory.
The amount of shed mediastinal blood retransfused after operation was significantly different between the groups. One might argue that the results may have been influenced by this difference. The primary end points of this study were intraoperative hemostasis and postoperative blood loss. The differences in activation of hemostasis were measured before retransfusion. By excluding all patients with retransfusion from analysis, the differences in postoperative blood loss remained significant. Therefore, it is not likely that bleeding tendency was influenced by shed mediastinal blood retransfusion, especially considering the relatively small amounts of retransfused blood [32].
Conclusion
In conclusion, aprotinin attenuated, in a dose-dependent manner, the activation of fibrinolysis during open heart operations. The present study failed to demonstrate a similar effect of different aprotinin doses on clotting activation. With a lower heparin dose, a comparable degree of anticoagulation was accomplished in group H compared with group L. In addition, the bleeding tendency and allogeneic blood requirements were reduced significantly with the higher aprotinin dose. Thus, a high dose of aprotinin was more effective than a reduced dose of the drug. Whether the higher dose also is more cost-effective should be investigated, but this may depend on the specific circumstances of each medical institution.
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This article has been cited by other articles:
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