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Departments for *Anesthesia and
Thoracic and Cardiovascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany;
Department of Cardiology, Flinders Medical Center, South Australia, Australia; and
Department of Cardiothoracic Anesthesia, Virginia Commonwealth University, Richmond, Virginia
Address correspondence and reprint requests to Dr. Andreas Koster, 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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IMPLICATIONS: Bivalirudin is a new, direct thrombin inhibitor. We investigated the extracorporeal elimination rate of different hemofilters and one plasmapheresis filter for bivalirudin. Our data show that bivalirudin can be effectively eliminated via hemofiltration and plasmapheresis, although there were significant differences in the elimination rates among the filter systems investigated.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bivalirudin, a small synthetic polypeptide with a plasma half-life of 25 min, is a new direct thrombin inhibitor with powerful anticoagulant activity conferred by bivalent binding to both the active site and the exosite 1 region of thrombin. The drug has been successfully used in large clinical trials during coronary angioplasty (2). The interesting feature of bivalirudin is that, apart from limited renal elimination, the component of the molecule that binds to the active site of thrombin is cleaved by the thrombin molecule itself, providing a degradation mechanism independent of specific organ function (3). This elimination pathway may increase safety in patients at high risk for the development of renal impairment. Therefore, bivalirudin represents an interesting option as an alternative anticoagulant in patients with heparin-induced thrombocytopenia.
In patients with nonimpaired renal function, approximately 20% of bivalirudin is cleared via the renal pathway whereas the remainder undergoes proteolysis (4). However, severe renal impairment increases the half-life from 25 to 57 min, whereas elimination in patients needing dialysis is increased to 210 min (5). In patients with renal impairment undergoing percutaneous transluminal coronary angioplasty (PTCA), this prolonged half-life is associated with increased bleeding that directly correlates with the degree of renal impairment (6). Therefore, after large dosages as used during PTCA or CPB, augmented elimination of the drug via hemofiltration may be necessary for enhanced reinstitution of coagulation. Furthermore, patients may require hemofiltration or hemodialysis after surgery. Therefore, rigorous knowledge about the elimination characteristics of bivalirudin with different filter systems seems highly desirable.
The present study was conducted to assess the elimination characteristics of bivalirudin with four different hemofilter systems and one plasma separator system.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Types of Filter Systems
Four hemofilter systems and one plasmapheresis filter system possessing different characteristics with regard to membrane material, pore size, and membrane surface area were used (Table 1). Five separate filters of each type were tested serially in the test circuit. Thus, a total of 25 single filters were tested.
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The CPB system was primed with 400 mL of packed red blood cells, 400 mL of fresh frozen plasma (FFP), and 400 mL of fresh warm whole blood (to provide platelets and labile coagulation factors), which were obtained from a healthy volunteer using our current citrated hemodilution packages (maximum 500 mL; Compoflex, Biotrans GmbH, Dreieich, Germany).
The priming solution was increased to 2000 mL by adding 800 mL of a balanced crystalloid solution (Thomajodin; DeltaPharm, Pfullingen, Germany), and the colloid osmotic pressure was measured by an oncometric method (BMT Onkometer 923; BMT, Berlin, Germany) and set at 16–18 mm Hg by titration of FFP.
Values for hematocrit, hemoglobin concentration, electrolytes, oxygen partial pressure, pH, base excess (BE), carbon dioxide partial pressure, oxygen saturation, and bicarbonate concentration were obtained in a blood gas analyzer (Stat Profile Ultra C; Nova Biomedical, Waltham, MA) and a multi-wavelength hemoxymeter (OSM 3; Radiometer, Copenhagen, Denmark). Platelet counts were obtained using an electronic particle counter (Sysmex K 1000 Hematological System; Digitana, Hamburg, Germany). Blood temperature was held at 36.5° to 37.0°C.
Bivalirudin (AngiomaxTM; The Medicines Company, Parsippany, NJ) was added to achieve a baseline concentration of approximately 15 µg/mL (calculated for the final volume of the circuit) before the addition of the fresh blood.
Ultrafiltration
The flow rate of the arterial pump was maintained at 2 L/min. The pump in the filtration circuit was set at 1 L/min. After initial filtration of 1 L, the volume of the CPB circuit was increased to 2 L by adding crystalloid alone in the hemofilter group, and equal volumes of FFP and crystalloid in the plasmapheresis filter group. The oncotic pressure of 16–18 mm Hg was readjusted by the addition of FFP, a baseline bivalirudin concentration of approximately 15 µg/mL was reestablished, and the filtration procedure was performed, again using a second single filter (of the same type of filter system) in the same system. This protocol was followed for all five single filters and each of the five filter systems.
Measurement of the Concentration for Bivalirudin
Measurements of blood bivalirudin concentration were obtained: 1) initially after the addition of 15 µg/mL of the drug to the prime, 2) 20 min after the baseline measurement and circulation in the circuit, to exclude a decrease in bivalirudin concentration because of binding of the drug to the artificial surfaces of the CPB circuit or to cellular components of the blood, and 3) after filtration, refilling, and readjustment of the total volume of the priming solution.
The bivalirudin concentration (µg/mL) was measured in citrated plasma using the chromogenic anti-IIa-based laboratory reference assay (COBAS MIRA analyzer; Behringwerke, Marburg, Germany), which contained the standard S-2238 substrate (Chromogenix, Essen, Germany) and thrombin reagent (Boehringer, Mannheim, Germany). All measurements were performed in duplicate. The bivalirudin concentration was also evaluated in citrated whole blood using an on-line measurement of the ecarin clotting time as described before (7). A standard curve was constructed to permit conversion of the ecarin clotting time value(s) to a concentration for bivalirudin (µg/mL), and to allow for comparison of concentrations before restarting the filtration process.
Calculation of Bivalirudin Elimination
All data were presented as mean ± SD. The elimination for bivalirudin was obtained by calculation of the percentage decrease in bivalirudin concentration after the filtration and readjustment of the CPB volume. Statistical analysis of the elimination characteristics of the different filter systems was performed with analysis of variance using the Scheffé test for post hoc analysis. A value of P < 0.05 was used to reflect a significant difference between values throughout the study.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Across the 5 experimental groups (involving 25 single filters), hematocrit averaged 33% ± 2.4%, hemoglobin concentration 10.4 ± 0.6 g/dL, PO2 138 ± 32 mm Hg, pH 7.341 ± 0.010, BEecf -0.1 ± 2.1 mmol/L, sO2 = 98% ± 0.5%, PCO2 = 42.6 ± 1.01 mm Hg, and platelets 85 ± 9 x 103/µL. Blood electrolytes showed normal values (sodium 141 ± 3.1 mmol/L, potassium 4.3 ± 0.3 mmol/L, magnesium 0.77 ± 0.3 mmol/L, calcium, 2.1 ± 0.2 mmol/L).
Colloid osmotic pressure averaged 16.2 ± 0.3 mm Hg. Filter characteristics, elimination (in percentage), arterial filtration pressures, and the filtration time are given in Table 2.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In clinical practice, however, the elimination of bivalirudin via hemofiltration (or hemofiltration with the use of bivalirudin) may be required in different situations: 1) severe hemorrhage, for example after CPB or PTCA, with the need of augmented elimination of bivalirudin, 2) urgent surgery in a patient under anticoagulation with bivalirudin for continuous hemofiltration, or 3) elective use of bivalirudin in a patient receiving continuous hemofiltration. Whereas the first and second scenarios require the fast elimination of bivalirudin, in the third scenario, a reduced elimination might be preferred to save drug costs. Therefore, in view of our data, it is conceivable that choice of hemofilter systems may be important depending on the clinical situation when bivalirudin is used. These in vitro findings require confirmation by further in vivo studies.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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