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From the Department of Anesthesia, Deutsches Herzzentrum, Berlin, Germany
Address correspondence and reprint requests to Andreas Koster, MD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin. Address email to Koster{at}dhzb.de
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Abstract |
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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.
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Introduction |
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In a recent investigation we showed that a heparin-level-based heparin management, as compared with an activated-clotting-time (ACT) based heparin management, was associated with larger heparin concentrations during CPB, resulting in an improved attenuation of hemostatic activation and inflammatory response (5).
The protease inhibitor aprotinin, used in large variations of dosages, has been demonstrated to reduce postoperative blood loss and activation of the hemostatic/inflammatory system during CPB (6,7). However, there are scant data with regard to the effects of aprotinin when heparin management during CPB is performed according to a heparin-level-based protocol.
The current investigation was performed to evaluate the effects of aprotinin, administered according to a half-dose regimen, on activation of the hemostatic/inflammation system during CPB when used with heparin-level-based heparin management.
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Methods |
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Anesthesia was performed using a total IV technique with midazolam, propofol, sufentanil, and pancuronium bromide. Normothermic CPB was accomplished with a "closed" nonheparin-coated system and the use of membrane oxygenators and roller pumps. Priming of the CPB system was accomplished with 1500 mL Ringer’s solution. Additionally a cell saver reservoir was used to collect blood from the surgical site. This blood was processed (AutoLog; Medtronic) if the collected volume exceeded 400 mL.
A kaolin ACT of 480 s was determined as target value of the heparin-dose-response (HDR) cartridge for individual calculation of the heparin level necessary to achieve this ACT.
The HDR was performed before skin incision. However, as calculation of the blood volume of a patient according to body surface area is an approximation, particularly in cardiac surgery, the "pump" heparin was added to the patient bolus to create a safety window. The CPB circuit was primed with an additional 10,000 U of heparin. After administration of the heparin, an ACT (Hepcon HMS kACT) was obtained before initiation of CPB to determine the effect of the heparin bolus on inhibition of contact activation. If the ACT was not prolonged more than 480 s, an additional 10,000 IU heparin was given. The first determination of the heparin level was performed after 30 min using the six-channel heparin-protamine-titration (HPT) cartridge. If additional heparin had to be given to maintain the target level, double the required value was given to reach the target value from the "top" and to provide a wider window for further measurements that were then performed at intervals of 60 min.
After conclusion of CPB, the protamine dose necessary to reverse all administered heparin was calculated according to the results of the HPT measurement. After protamine administration and infusion of the total volume of the CPB circuit, residual free heparin was measured with a low range HPT cartridge and reversed with protamine.
Aprotinin (Trasylol, Bayer, Mannheim, Germany) was administered with a bolus of 1 x 106 kallikrein inhibiting units (KIU) for the patient immediately before initiation of CPB, 1 x 106 KIU in the priming volume of the CPB, and a continuous infusion of 250,000 KIU/h during the period of CPB.
In all patients, blood was collected intraoperatively with a cell saver and processed if the amount exceeded 400 mL. In both groups residual CPB blood was reinfused in the operating room. Postoperative blood loss was determined by the 12 h mediastinal drainage.
A hemoglobin level of <8.0 mg/dL was selected as the critical level for the intra- and postoperative transfusion of packed red blood cells. The trigger for the transfusion of fresh-frozen plasma and random donor platelet concentrates was based on the clinical decision of the anesthesiologist. A postoperative hemorrhage of >1500 mL within the first 12 h was considered an indication for surgical re-exploration in accordance with departmental standards.
Platelet count was measured using the Cell Dyn 3500R (Abbott, Wiesbaden, Germany). Monitoring of platelet function was performed with 20 µmol/L adenosine diphosphate (ADP)-stimulated platelet aggregometry (Mölab, Bio-Data Corporation, Philadelphia, PA) in platelet-rich plasma (heparinized samples). Platelet-rich plasma was prepared by centrifugation at 800 r/min for 15 min and adjusted to a platelet count of approximately 200,000/µL, and aggregation was measured at a stir rate of 900 rpm at room temperature. ß-Thromboglobulin (ß-TG) was measured using the Asserchrom ß-TG ELISA (Roche Diagnostics, Mannheim, Germany). Heparin anti-Xa activity was determined using the STA-Rotachrom Heparin (Roche Diagnostics, Manheim, Germany). Antithrombin (AT) III was determined using the Coamatic LR Antithrombin Chromogenix (Hemochron Diagnostica, Essen, Germany). Thrombin was measured using the thrombin/antithrombin complex Enzygnost TAT micro (Dade Behring, Schwalbach, Germany). Prothrombin 1 and 2 fragments (PTF1 + 2) were assessed using the Enzygnost F1–2 micro assay (Dade Behring, Marburg, Germany). The factor XIIa ELISA (Progen, Heidelberg, Germany) was used to measure factor XIIa. D-dimers were measured using the STA-Liatest D-Di (Roche, Mannheim, Germany) and neutrophil elastase using a luminescent assay, Auto-ClinLumat LB 952 T (Berthold, Wildbad, Germany). Complement factors (C5b-9) were determined using the SC5b-9 complex ELISA (Innogenics, Heiden, Germany), interleukin (IL)-6 was measured using an ELISA (DPC Biermann, Nauheim, Germany), and soluble P-select using the soluble P-selectin ELISA (Biozol, Eching, Germany). The 12-h postoperative blood loss was also determined.
The calculation of sample size was based on the results of a previous investigation, supposing that the administration of half-dose aprotinin would have a similar effect on hemostatic activation as the variations in heparin management (5). Two-hundred patients were included in the study. Statistical analysis of the laboratory data and transfusion requirements were performed with analysis of variance using Duncan’s multiple range test. The re-exploration rates were analyzed using Fisher’s exact test. A P value of <0.05 was determined as significant. The values are expressed as mean ± SD. The Gaussian normal distribution of the obtained values was assessed using the Kolmogorov-Smirnov test (SPSS 10.0. for Windows; SPSS, Chicago, IL).
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Results |
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There were no significant differences between the data of the two groups before CPB. Results are given in Table 1.
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Discussion |
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The protease inhibitor aprotinin has been successfully used during CPB to reduce postoperative blood loss and activation of the hemostatic/inflammatory system. Basic mechanisms of aprotinin action discussed are antifibrinolytic effects, inhibition of the contact activation system, and, more recently, an inhibition of thrombin-induced platelet activation via inhibition of activation of the platelet protease-activated receptor 1 (PAR1) (7,8). However, although hundreds of original investigations, meta-analyses, and reviews have addressed this subject, it remains controversial at which dosages (full dose versus half dose versus small dose versus weight-adjusted dose) these effects are achieved and which protocol provides the optimal balance with regard to cost-effectiveness (6,9–14).
In addition to these variations during "standard perfusions" (ACT-based heparin management, uncoated CPB systems), the effects of aprotinin have also been investigated during CPB in combination with heparin-coated systems, which have been proposed to provide further attenuation of hemostatic activation (15). However, there are scant data with respect to the effects of aprotinin used during a heparin-level-based anticoagulation protocol during CPB, which itself, compared with an ACT-based management, reduces hemostatic activation and inflammatory response (5). Therefore, the current investigation was performed to assess the effects of aprotinin administered, in accordance with our departmental standard with a "half-dose regimen," on postoperative blood loss and activation of the hemostatic/inflammatory system during CPB under the condition of heparin-level-based heparin management.
In the patients studied, there was no difference in thrombin generation/activation with comparable levels of heparin anti-Xa activity and AT III, as evaluated by the measurement of TAT and PF1 + 2, between the two groups. Only FXIIa, a marker of contact activation, was absolutely increased in the patients treated with aprotinin, although the relative increase in activation of FXII was comparable (62% versus 57%). Similar to these minor effects on the activation of the plasmatic coagulation system, we did not observe any differences in platelet activation when aprotinin was given as observed by the ADP-induced platelet aggregation. One explanation for this observation might be that inhibition of thrombin-induced platelet activation does not affect in vitro ADP-induced aggregation of platelets (8). However, attenuation of thrombin-induced platelet activation should have translated as a reduced plasma concentration of ß-TG, a protein that is released from the 
-granulae of activated platelets, larger plasma concentrations of soluble P-selection (a marker of platelet activation), and higher post-CPB platelet count in the aprotinin group. As these effects were not observed in our patients, it is conceivable that aprotinin did not inhibit thrombin-induced platelet activation to a clinically relevant extent. One explanation for this observation might be the use of only the half-dose regimen of aprotinin. However, Landis et al. (8) reported potent inhibition of PAR1 even under the condition of a half-dose protocol. It may be that the underlying mechanism of our observation is that a heparin-level-based heparin management during CPB itself reduces thrombin generation to an extent where it has only minor effects on PAR1. Further investigations are necessary to verify this hypothesis.
In contrast to these minor effects on coagulation and platelet activation, the use of aprotinin was associated with a significant reduction of the levels of plasmin and D-dimers, which are both key markers of the fibrinolytic system. Therefore it is conceivable that "pure" antifibrinolytic effects contributed to the reduced blood loss in the patients treated with aprotinin.
The kinin-kallikrein pathway plays a pivotal role in the inflammatory systems, and large effects of the use of the protease inhibitor aprotinin during CPB in this regard have been discussed (7). However, the clinical data remain controversial. Although Greilich et al. (15) observed a significant reduction of IL-10 and IL-6 using a large-dose aprotinin regimen, Defraigne et al. (16) did not observe any differences in the release of key markers of the inflammation system and leukocyte activation using the same protocol in patients undergoing CPB with heparin-coated and noncoated systems. These results were confirmed in a recent investigation by Schmartz et al. (17), demonstrating that neither "high-dose" nor "half-dose" aprotinin had significant effects on key variables of inflammatory response to CPB. In the present investigation, the administration of half-dose aprotinin had no effects on the levels of IL-6 and neutrophil elastase, which are key markers of leukocyte activation. Moreover, no effect on the plasma concentration of C5b-9, the complement membrane attack complex, were observed, suggesting minor effects on this system. Again, as thrombin is one of the most powerful in vivo activators of leukocytes (partly via a regulation of platelet activity), effective reduction of thrombin generation using heparin-level-based heparin management during CPB might be responsible for this observation (18–20).
Level-based heparin management is more cost-intensive than a conventional ACT-guided regimen. The concept behind our anticoagulation strategy was to use a more sophisticated heparin management and also to reduce costs by reducing the dosages of aprotinin. We conclude that using a heparin-level-based anticoagulation strategy, the benefits of aprotinin given according to a half-dose regimen are "reduced" to the antifibrinolytic effects.
However, the significant reduction of intraoperative and postoperative blood loss with administration of half-dose aprotinin is an important finding of the current investigation. Further studies will show whether similar results can be achieved with the use of a heparin-level-based heparin management and "pure" antifibrinolytics such as tranexamic acid or 
-aminocaproic acid.
Additionally, larger, adequately powered clinical studies are necessary to address the impact of individual calculated level-based heparin management and modern weight-adjusted (large-dose) aprotinin protocols on the activation of the hemostatic/inflammatory system and on clinical outcome.
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Acknowledgments |
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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-aminocaproic acid as effective as aprotinin in reducing blood loss with cardiac surgery: a meta analysis. Circulation 1999; 99: 81–9.-aminocaproic acid decreases interleukin-10 after cardiac surgery with extracorporeal circulation. Circulation 2001; 104 (Suppl I): I265–9.
This article has been cited by other articles:
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  M. D. McEvoy, S. T. Reeves, J. G. Reves, and F. G. Spinale Aprotinin in Cardiac Surgery: A Review of Conventional and Novel Mechanisms of Action Anesth. Analg., October 1, 2007; 105(4): 949 - 962. [Abstract] [Full Text] [PDF]
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 J. R. Brown, N. J.O. Birkmeyer, and G. T. O'Connor Meta-Analysis Comparing the Effectiveness and Adverse Outcomes of Antifibrinolytic Agents in Cardiac Surgery Circulation, June 5, 2007; 115(22): 2801 - 2813. [Abstract] [Full Text] [PDF]
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