Anesth Analg 2004;99:989-992
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000131509.94879.FB
CARDIOVASCULAR ANESTHESIA
Extracorporeal Elimination of Large Concentrations of Tirofiban by Zero-Balanced Ultrafiltration During Cardiopulmonary Bypass: An In Vitro Investigation
Andreas Koster, MD*,
Derek Chew, MD
,
Frank Merkle, ECCP
,
Marcus Gruendel, MD
,
Michael Jurmann, MD||,
Hermann Kuppe, MD*, and
Rainhard Oertel, MD¶
*Department of Anesthesia, Deutsches Herzzentrum Berlin, Berlin, Germany;
Department of Cardiology, Flinders Medical Centre, Bedford Park, Australia;
Department of Perfusion, Deutsches Herzzentrum Berlin, Berlin, Germany;
Department of Anesthesia and Intensive Care Medicine, Charite, Campus Virchow, Berlin, Germany;
||Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany; and
¶Institute of Clinical Pharmacology, Carl Gustav Carus Faculty of Medicine, University of Technology, Dresden, Germany
Address correspondence and reprint requests to Andreas Koster, MD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353, Berlin, Germany. Address e-mail to koster{at}dhzb.de
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Abstract
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The short-acting platelet glycoprotein IIb/IIIa antagonist tirofiban is beneficial when used in the context of cardiac surgery. Tirofiban has an elimination half-life of 2 h. Renal failure prolongs the half-life and continues inhibition of platelet aggregation refractory to transfusions of platelets. Extracorporeal elimination is necessary to prevent excessive hemorrhage in this condition. We assessed the elimination of tirofiban by hemofiltration in an in vitro model of cardiopulmonary bypass (CPB). Two hemofilters and one plasmapheresis filter were assessed. Three separate filters of each type were tested serially. The CPB circuit was primed with a total volume of 1000 mL. Tirofiban was added to a calculated concentration of 200 ng/mL. Portions of 50 mL of filtrate were retrieved from the dialyzer, and equal amounts of fluid were substituted in the circuit. After each filtration, the tirofiban blood level was analyzed. The procedure was repeated 16 times. Peak tirofiban concentrations ranged from 160 to 260 ng/mL. The elimination of tirofiban followed an exponential decay curve with fast clearance of the large therapeutic concentrations of 250 to 50 ng/mL. The subsidence coefficient b revealed no significant differences in elimination between the filter systems. These data suggest that ultrafiltration is an effective means for extracorporeal elimination of therapeutic levels of tirofiban.
IMPLICATIONS: Our data provide evidence that ultrafiltration is an effective method for extracorporeal elimination of high therapeutic levels of tirofiban. These results are of particular interest for the management of patients with impaired renal function or a high risk of developing perioperative renal failure who undergo cardiac surgery with the administration of tirofiban in the perioperative period.
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Introduction
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The role of platelet glycoprotein (GP)IIb/IIIa antagonists in the treatment of acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) is clearly established (1). However, these drugs, particularly the short-acting competitive platelet GPIIb/IIIa antagonist tirofiban, possess beneficial effects beyond the cardiology laboratory when they are used in the perioperative context of cardiac surgery. Bizzarri et al. (2) demonstrated a reduction of myocardial infarction and decreased hemorrhage and transfusion requirements in ACS patients undergoing urgent on-pump coronary artery bypass grafting surgery when tirofiban therapy was continued until the start of surgery. A recent study demonstrated reduced activation of the hemostatic/inflammatory system and a trend toward a decrease in blood loss when tirofiban was administered during cardiopulmonary bypass (CPB), suggesting that "platelet anesthesia" during the perfusion might be an indication beyond "bridging" to emergency surgery (3). Moreover, the administration of tirofiban and heparin is an established strategy for the management of patients diagnosed with heparin-induced thrombocytopenia (HIT) during CPB (4).
Tirofiban is a short synthetic nonpeptide molecule with highly specific binding to the GPIIb/IIIa integrin. The protein binding is 65%, and the elimination half-life is approximately 2 h. Drug clearance is predominantly achieved via the renal pathway (5). In the event of renal failure, a common complication in the high-risk population of patients with acute myocardial infarction or HIT, prolongation of the drug half-life results in continued inhibition of platelet aggregation even if donor platelets are transfused. Therefore, extracorporeal elimination is the only option to prevent excessive hemorrhage in this condition. The current in vitro investigation was performed to assess the extracorporeal elimination of tirofiban by hemofiltration.
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Methods
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The study was conducted with the approval of the local ethics committees and written, informed consent. We simulated the conditions evident during CPB by using a standardized design for the CPB circuit, volumes, flow rates, and laboratory variables. Two hemofilter systems and one plasmapheresis filter system were used with different characteristics with respect to membrane material, pore size, and membrane surface area (Table 1). Three separate filters of each type were evaluated serially in the test circuit.
The CPB system consisted of a noncoated, closed adult circuit with a collapsible venous reservoir (Affinity VR 6081; Medtronic, Düsseldorf, Germany), 
-in. polyvinyl chloride tubing set with a 
-in. silicone arterial pump boot (Dideco, Mirandola, Italy), and a hollow fiber membrane oxygenator (Sorin Monolyth, Saluggia, Italy). Both the cardiotomy reservoir and the arterial line filter were excluded from the circulation to minimize the necessary priming volume. The circuit was mounted on a standard CPB machine (Stoeckert S 3; Stoeckert, Munich, Germany) with an arterial roller pump.
The system was primed with a total volume of 1000 mL, consisting of 450 mL of whole human blood (healthy volunteers), 50 mL of donor platelets, 50 mL of fresh frozen plasma, 450 mL of balanced electrolyte solution (Thomaejonin; Delta Pharma, Pfullingen, Germany), and 10,000 IU of unfractionated heparin (Liquemin; Roche, Grenzach-Wyhlen, Germany). Tirofiban (Aggrastat; MSD Sharp and Dohme, Haar, Germany) was added to the volume to achieve a calculated concentration of approximately 200 ng/mL. The priming volume was recirculated at room temperature at 2 L/min. A 
-in. polyvinyl chloride dialyzer circuit with a silicone pump boot (HMT, Fürstenfeldbruck, Germany) was connected to the circuit, with the dialyzer inlet downstream of the membrane oxygenator in the arterial line and the dialyzer outlet connected to the venous line of the CPB circuit. The flow rate in the dialyzer circuit was adjusted to 1 L/min. After 1 min of circulation, 50 mL of filtrate was retrieved from the dialyzer via a filtrate roller pump, and the same amount of volume was replaced in the CPB circuit (electrolyte solution when a hemofilter was used and fresh frozen plasma in the case of the plasmapheresis filter to maintain the oncotic pressure). After each filtration and readjustment of the CPB volume to the baseline of 1000 mL, the tirofiban blood level was analyzed. The procedure was repeated 16 times. For each filter tested, a new CPB system was used (n = 9).
Determination of tirofiban was performed with liquid chromatographic tandem mass spectrometry. The tirofiban was measured by using external calibrations and multiple reaction monitoring mode with two specific transitions on a Quattro Micro (Micromass) with an electrospray interface. The chromatographic separation was performed on a short RP-18e column. A steep mobile phase gradient was applied with a mixture of acetonitrile, ammonium acetate in water (0.002 mol/L), and formic acid. The retention time of tirofiban was approximately 3.3 min. It was demonstrated that by using 0.1 mL of biological samples, the analyte tirofiban can be determined accurately and precisely in the range of 2 to 250 ng/mL.
Statistical analysis of the elimination characteristics of the different filter systems was performed with analysis of variance with the Scheffé test for post hoc analysis. P < 0.05 was used to reflect a significant difference between values throughout the study. Data presented in Table 1 are mean values and SD calculated from the data of each of the three individual in vitro runs of a filter system. In Figure 1, the variables of the nonlinear regression curves (y = a–bx) according to the Marquardt-Levenberg algorithm were calculated separately for each filter system by using the mean tirofiban concentrations from the three individual in vitro runs. For statistical calculations, SigmaPlot 2000 for Windows, Version 6 (SPSS Inc., Chicago, IL), and Microsoft Excel 2000 (Microsoft, Redmond, WA) were used.
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Figure 1. Elimination of tirofiban in an in vitro cardiopulmonary bypass (CPB) model. The variables of the nonlinear regression curves (y = a–bx) according to the Marquardt-Levenberg algorithm were calculated separately for each filter system by using the mean tirofiban concentrations from the three individual in vitro runs. One sample point reflects the additional harvest of 50 mL from the CPB circuit and measurement of the tirofiban concentration after replacement of the filtrate volume to the baseline 1000-mL CPB circuit volume.
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Results
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There were no differences regarding volume, prime composition, or flow rates in the 9 in vitro test runs. Across the 3 experimental groups, the hematocrit averaged 33% ± 2.4%, the hemoglobin concentration was 10.4 ± 0.6 g/dL, and platelets were 210 ± 19 x 103/µL. Colloid osmotic pressure averaged 18.2 ± 0.7 mm Hg. Values for the arterial filtration pressures and filtration times are given in Table 1. The courses of the tirofiban concentration are given in Figure 1. As calculated by the subsidence coefficient b, there were no significant differences in elimination characteristics between the different filter systems (Figure 1, Table 1).
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Discussion
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Our results demonstrate that large blood concentrations of tirofiban can be effectively eliminated via hemofiltration. In contrast to previous studies assessing hemofiltration of small peptide drugs, there were no significant differences in the elimination characteristics observed among the different filters (6,7). In this investigation, large concentrations of tirofiban (150–250 ng/mL) were used as the baseline level, corresponding with the large bolus injection of tirofiban 25 µg/kg that has recently been suggested for coronary intervention (8). Successful use of this dosing regimen has been reported recently, and it can be expected that this dosage will be used increasingly in clinical practice (9,10). However, even under the conditions of the established dosage, renal impairment of the patient (and that is the target patient population of this investigation) may cause accumulation of the drug, with subsequent achievement of large tirofiban concentrations.
Therapeutic concentrations, which achieve almost complete inhibition of 20 µmol/L adenosine diphosphate-stimulated platelet aggregation, range from 100 to 60 ng/mL, whereas concentrations less than 40 ng/mL provide only incomplete inhibition (approximately 60%) of platelet aggregation (8). The current data reveal that elimination of tirofiban via hemofiltration follows an exponential decay curve, with a fast clearance of the large concentrations of 250 to 100 ng/mL and therapeutic concentrations between 100 and 50 ng/mL and a slower elimination at subtherapeutic concentrations less than 40 ng/mL (8). Therefore, ultrafiltration (with the standard filter systems currently used in cardiac surgery) appears to be an effective means for extracorporeal elimination of large and standard therapeutic concentrations of tirofiban. Our results are of particular significance for patients with perioperative tirofiban therapy.
Platelet GPIIb/IIIa antagonists are widely used during PCI. In particular, many patients with ACS often require emergency surgery if this procedure does not result in adequate restoration of coronary perfusion. Use of the monoclonal antibody abciximab leads to a nearly irreversible high-affinity binding to the GPIIb/IIIa integrin, rendering platelets unable to aggregate for days. However, because abciximab is rapidly degraded by proteases within 30 minutes, transfusion of platelet concentrates is effective in reversing its action shortly after termination of the continuous infusion (5). Therefore, in patients treated with abciximab and who must undergo urgent cardiac surgery transfusion of platelets, it is the only effective option to prevent bleeding complications. In contrast, continuation of therapy with the short-acting reversible GPIIb/IIIa antagonist tirofiban until the start of cardiac surgery with CPB in ACS patients decreased bleeding and transfusion requirements without the need for platelet transfusions (2). However, this benefit of tirofiban therapy might reverse into the complication of uncontrollable bleeding if the patient develops perioperative renal failure secondary to low cardiac output. Under these conditions, prolongation of the drug half-life results in sustained inhibition of platelet aggregation, which cannot be antagonized by the transfusion of platelets because large quantities of unbound drug rapidly inhibit the new GPIIb/IIIa receptors. In this scenario, extracorporeal elimination appears to be the only choice for the prevention of hemorrhagic complications. Our data suggest that hemofiltration during CPB or zero-balanced modified ultrafiltration after the conclusion of CPB is an effective method for the reversal of large concentrations of tirofiban in this situation. The option of this procedure increases the safety profile of tirofiban and may stimulate interventional cardiologists to use this drug for high-risk PCI instead of irreversible platelet inhibitors, such as clopidogrel, which may be associated with severe bleeding and the need for platelet transfusions.
The management of patients with HIT during CPB currently remains a problem because no alternative anticoagulant has been approved for this indication. The combination of heparin with tirofiban to inhibit HIT-induced platelet aggregation has been successfully used in a larger series of patients with HIT, including complex perfusions and extended surgery (4,11). After treatment of approximately 100 patients at our institution, no complications were observed that could be attributed to the use of tirofiban for this indication. In five of our patients with end-stage renal failure and the preoperative need for dialysis, zero-balanced modified ultrafiltration after CPB was performed, although no data were available regarding the effects of ultrafiltration on the elimination kinetics of tirofiban. In these patients, no bleeding complications occurred. However, in two other German hospitals, two cases of severe hemorrhage in HIT patients after CPB with tirofiban and unfractionated heparin have been reported. This forced the manufacturers to discourage use of tirofiban in this off-label protocol (12). Review of the charts revealed that both patients were anuric after CPB and that bleeding stopped when hemofiltration was initiated in the postoperative period. It is conceivable that the persistence of therapeutic levels of tirofiban caused the hemorrhage refractory to platelet transfusions. Because therapeutic drug levels during CPB are necessary to prevent HIT-induced platelet aggregation, modified zero-balanced ultrafiltration after weaning from CPB shortly before protamine administration appears to be the most appropriate procedure in this situation. However, our data also imply that if this protocol is used, hemofiltration during CPB should be avoided to not decrease tirofiban concentrations critically with the subsequent risk of HIT-associated thromboembolic complications.
Our in vitro data show that high therapeutic levels of tirofiban can be effectively eliminated via hemofiltration with the use of standard hemofilters. These data suggest that the use of ultrafiltration during CPB or zero-balanced modified ultrafiltration after CPB is an effective means for elimination of high therapeutic levels of this drug in anuric patients who receive tirofiban in the immediate perioperative period. Additional clinical investigations are necessary for further validation of the clinical effectiveness of this strategy.
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Acknowledgments
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The study was supported by MSD Sharp and Dohme, Germany.
We would like to thank Anne M. Gale, ELS, of the Deutsches Herzzentrum Berlin for editorial assistance.
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References
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- Kong DF, Hasselblad V, Harringgton RA, et al. Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions. Am J Cardiol 2003; 92: 651–5.[ISI][Medline]
- Bizzarri F, Scoletta S, Tucci E, et al. Perioperative use of tirofiban hydrochloride (Aggrastat) does not increase surgical bleeding after emergency or urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001; 122: 1181–5.[Abstract/Free Full Text]
- Koster A, Chew DP, Kuebler W, et al. Effects of tirofiban on hemostatic activation and inflammatory response during cardiopulmonary bypass. Am J Cardiol 2003; 91: 346–7.[Medline]
- Koster A, Kukucka M, Bach F, et al. Anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II and renal impairment using heparin and the platelet glycoprotein IIb/IIIa antagonist tirofiban. Anesthesiology 2001; 94: 245–51.[ISI][Medline]
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Accepted for publication April 21, 2004.
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Abstract
Introduction
