| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
© 2000 International Anesthesia Research Society
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Recombinant hirudin (r-hirudin) is being used increasingly in patients with heparin-induced thrombocytopenia type II. Renal failure has been demonstrated to prolong the half-life of r-hirudin and to cause bleeding in patients who have undergone cardiopulmonary bypass (CPB). We assessed the ability of different filter systems for modified ultrafiltration to eliminate r-hirudin in vitro using simulated CPB. r-Hirudin concentration was measured (chromogenic laboratory standard plus ecarin clotting time) before and after filtration, and its elimination was calculated using both controlled system flow and arterial inflow (separate pump). Four hemofilters (Renoflow II, Baxter; Arylane H4, Cobe; Ultraflux AV 600, Fresenius; and BCS 110 Plus, Iostra) and two plasmapheresis filter systems (ASAHI Plasmaflow OP, Diamed; and PF 2000 N, Gambro) were assessed (5 filters of each brand = 30 filters) in a closed in vitro CPB system applying conditions usually occurring during CPB. Ten plasmapheresis filters showed a greater ability than 20 hemofilters to eliminate r-hirudin (60%–70% vs 15%–42%) within the shortest time (80 vs 180 s). Among the four hemofilter systems, the Arylane H4 filter provided the most effective (42%) r-hirudin elimination. Elimination of r-hirudin was markedly improved using plasmapheresis systems, compared with hemofilter systems. Our findings may be relevant to patients with impaired renal function, who have been administered r-hirudin during CPB.
Implications: Modified ultrafiltration may enhance the elimination of recombinant-hirudin, although plasmapheresis systems provide the most rapid and complete elimination of recombinant-hirudin during simulated cardiopulmonary bypass. The decision to use a specific system will ultimately depend on the prevailing clinical situation and overall health of the patient.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Recombinant hirudin (r-hirudin) is being used increasingly as an alternative anticoagulant in patients with heparin-induced thrombocytopenia type II (HIT II) (1–7). It appears particularly suitable during cardiopulmonary bypass (CPB) for several reasons. First, its effect is achieved immediately, and, because of its protein structure, it does not cross-react with heparin-induced antibodies. This is a great advantage in emergency cases (2). Second, the anticoagulant effect of r-hirudin concentration can be monitored on-line via measurement of the ecarin clotting time (ECT) (2–7). Third, r-hirudin normally has a rapid renal elimination (biological half-life of 1–1.5 h), thus ensuring rapid restoration of coagulation (8).
Renal failure can prolong the half-life of r-hirudin to more than 300 h (9), with little effect of dialysis (10). A persistent anticoagulant effect of r-hirudin and bleeding complications has been described in patients with renal dysfunction who have undergone CPB using r-hirudin (5,6).
Hemofiltration or (zero-balanced) modified ultrafiltration (MUF) used in conjunction with CPB circuits are established procedures (11–15), and may be useful in accelerating the elimination of r-hirudin (2,4,5,14,15). The objective of the present study was to assess whether r-hirudin can be effectively eliminated by MUF and hemofiltration, and if the elimination depends on the filter system used.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
With approval of the local ethics committees and written informed consent, the study was performed in vitro simulating the conditions evident during CPB, with regard to the volumes, flow rates, and laboratory parameters.
Types of Filter Systems
Four hemofilter systems and two plasmapheresis filter systems, possessing different characteristics with regard to membrane material, pore size, and membrane surface area, were used (Table 1). Each of the six filter systems was tested in each of five identical single filters (4 hemofilter systems x 5 single filters and 2 plasmapheresis filter systems x 5 single filters). Thus, a total of 30 single filters was tested.
|
CPB Circuit
The CPB system consisted of a standard heart-lung machine ("S 3," Stoeckert, Munich, Germany), a current custom-made sterile closed-circuit tubing with a collapsible venous reservoir (HMT GmbH, Fuerstenfeldbruck, Germany), and a current separate custom-made tubing for MUF (Medos, Stollberg, Germany).
The CPB system was primed with two units of packed red blood cells, two units of fresh frozen plasma (FFP), and 400 mL of fresh warm whole blood (to provide platelets and labile coagulation factors) that was obtained from six healthy volunteers (4 male students; 2 female students; 31.3 ± 1.2 yr; all ASA physical status I) using our current hemodilution packages (450 mL). The procedure was repeated five times per each of the six filter systems (i.e., the five single filters of each of the six filter systems were analyzed in one sequence).
The priming solution was increased to 2,000 mL by adding 800 mL of crystalloid solution ("Thomajodin," DeltaPharm, Pfullingen, Germany) and aprotinin ("Trasylol," Bayer AG, Leverkusen, Germany). Aprotinin was administered in a bolus (2 x 106 KIU), followed by a continuous infusion of 500,000 KIU/h, and the colloid osmotic pressure was set at 16–18 mm Hg by titration of FFP.
Values for hematocrit, hemoglobin concentration, electrolytes, oxygen partial pressure, pH, base excess, 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 multiwavelength Hem-oxymeter ("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 36.5–37.0°C.
r-Hirudin ("Refludan," Hoechst, Frankfurt, Germany) was added to achieve a baseline value of approximately 5 µg/mL, which corresponded to the upper limit of the concentration currently suggested for systemic anticoagulation during CPB (3.5–5 µg/mL) (1–7).
Ultrafiltration
The flowrate 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 addition of FFP, a baseline r-hirudin concentration of approximately 5 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 six filter systems.
Measurement of the Concentration for r-Hirudin
Measurements of blood r-hirudin concentration were obtained: (1) initially after the addition of 5 µg/mL of the drug to the prime (baseline measurement = cHir #1); (2) 20 min after the baseline measurement and circulation in the circuit, to identify a decrease in r-hirudin concentration (<5 µg/mL) because of binding of the drug to the artificial surfaces of the CPB circuit or to cellular components of the blood (i.e., control of the course of r-hirudin concentration without filtration = cHir #2); and (3) after filtration, refilling, and readjustment of the total volume of the priming solution (Table 2).
|
The r-hirudin 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, Manheim, Germany) (3). All measurements were performed in duplicate. Thus, a total of 180 plasma measurements was performed (2 measurements x 3 set-points x 5 filters x 6 filter systems). The results were corrected for hematocrit:
|
|
where c is concentration and hct is hematocrit.
The r-hirudin concentration was also evaluated in citrated whole blood using an online measurement of the ECT, which has been used safely and effectively during cardiac surgery in patients with HIT II (2,4,5,7). A standard curve was constructed to permit conversion of this ECT value (s) to a concentration for r-hirudin (µg/mL) and to allow for comparisons with the chromogenically-measured value before restarting the filtration process. According to departmental standards, ECT measurements were obtained using two identical devices in parallel ("TAS analyzer," Cardiovascular Diagnostics, Raleigh, NC) (actually distributed as "Rapidpoint Coag," Bayer, Mishawaka, IN), involving two measurements (duplicate) in each of the two devices. Twelve ECT measurements were obtained in each of the five single filters of the six different filter systems, providing a total of 360 ECT measurements (5 single filters x 6 filter systems x 3 set points x 2 measurements per device x 2 identical ECT analyzers).
Calculation of r-Hirudin Elimination and Statistical Analysis
Elimination for r-hirudin was obtained by calculation of the percentage decrease in r-hirudin concentration after the filtration and readjustment of the CPB volume (i.e., using the r-hirudin concentration [chir] and the circuit volume [v] prior [pf] and after [af] each filtration):
|
|
Statistical analysis in relation to the elimination characteristics of the different filter systems was performed using Student’s t test. The results of the hematocrit-corrected values of the chromogenic anti-IIa–based laboratory reference assay and the whole blood ECT were compared by Pearson’s correlation coefficient test. Between-group variations regarding the composition of the priming solutions and differences between the ECT analyzers were analyzed using a multifactorial analysis of variance, Wilcoxon test, and post-hoc analysis (Scheffé test). A value of P < 0.05 was considered to reflect a significant difference between values throughout the study.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Characteristics of the Priming Solution
There were no differences regarding volume, composition of the prime, and the flow rates in the 30 test runs.
Across the six experimental groups (involving 30 single filters), hematocrit averaged 37 ± 3%, hemoglobin concentration 11.3 ± 0.6 g/dL, pO2 143 ± 37 mm Hg, pH 7.351 ± 0.010; BEecf -0.1 ± 2.07 mmol/L, sO2 = 98 ± 0.6%, pCO2 = 41.6 ± 1.01 mm Hg, and platelets 122 ± 13 x 103/µL. Blood electrolytes showed normal values (sodium, 137 ± 2.3 mmol/L; potassium, 4.2 ± 0.3 mmol/L; magnesium, 0.83 ± 0.3 mmol/L; and calcium, 2.2 ± 0.2 mmol/L).
Colloid osmotic pressure averaged 17.2 ± 0.3 mm Hg, and filtration pressure 200 ± 17 mm Hg.
r-Hirudin Concentration and ECT Values
The overall mean concentration for r-hirudin before ultrafiltration across groups (Table 2) was 5.0 ± 0.2 µg/mL (range 4.7–5.2 µg/mL), which corresponded to a mean ECT value of 500 ± 0.6 s (range 470–522 s). The mean concentration for r-hirudin after ultrafiltration across groups was 2.6 ± 1.1 µg/mL (range 1.5–4.0 µg/mL), which corresponded to a mean ECT value of 258 ± 2.3 s (range 130–410 s). The correlation between the values obtained with the on-line ECT method and the chromogenic laboratory reference was excellent (r2 = 0.93). The difference between the duplicate ECT measurements obtained in a single analyzer or those obtained in two identical analyzers in parallel never exceeded 4% of the mean value.
Elimination Ability of the Different Filter Systems
All six filter systems reduced r-hirudin concentration from the baseline value of approximately 5 µg/mL to a range covering 1.7–4.2 µg/mL, which corresponds to an elimination of r-hirudin in the range of 15–70% (Table 2). The lack of change in r-hirudin concentration between measurements cHir #1 and cHir #2 indicated no binding of r-hirudin to artificial surfaces of the CPB circuit or cellular components of the blood (Table 2). The inline pressures covered the range of 190 ± 17 to 320 ± 31 mm Hg, and the time required for the filtration varied between 75 ± 32 and 197 ± 35 s (Table 2). The two plasmapheresis filter systems had equivalent effects, which were greater than the hemofilter systems (approximately 60%–70% vs 15%–40%), although achieved within less time (approximately 75–93 s vs 175–197 s) (Table 2). Among the hemofilter systems, the r-hirudin elimination was greatest for the COBE system and least for the BAXTER and FRESENIUS systems (Tables 1 and 2). The results for the five single filters of each of the six systems did not differ.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
r-Hirudin is a 65-unit amino acid peptide (molecular weight of 6,980 Da (16)), which is a highly potent and selective direct thrombin inhibitor. r-Hirudin shows 1:1 binding to both the active site region and the exocyte I region of thrombin (16). r-Hirudin has been proposed for use as an anticoagulant during CPB in patients with HIT II (1–7).
Because there is currently no reversal drug for r-hirudin (2–5,7), the reestablishment of normal blood coagulation depends on its elimination via the kidneys. The biological half-life of r-hirudin is approximately 1–1.5 h (8) in patients with normal renal function, but it can be prolonged more than 30-fold in patients with impaired renal function (10) and about 300 h in nephrectomized patients (8), leading to serious bleeding complications (2,5–7). This potential problem could be relevant to even simple cardiac surgery cases, which can be accompanied by acute renal dysfunction or overt failure secondary to post-bypass cardiac depression. Thus, the elimination of r-hirudin via the kidneys is always a major concern when this drug is used during cardiac surgery with CPB.
Previous studies on extracorporeal elimination of r-hirudin via dialysis in dogs demonstrated that large-flux hemodialyzers with a cutoff point of 50,000 Da were able to eliminate r-hirudin, whereas small-flux hemodialyzers (cutoff point 15,000 Da) were not. In a recent study (14), using an in vitro model, small-flux filters with a polysulfon membrane or regenerated cellulose were found nearly impermeable for r-hirudin, whereas other small-flux and large-flux filters decreased r-hirudin levels. These results are in contrast to findings during dialysis in patients with end-stage renal failure, in which a severe prolongation of the half-life of r-hirudin occurred despite the use of large-flux polysulfon filters (10). Because the r-hirudin molecule comprises a mass of 7,000 Da, which should result in easy penetration of filters with a pore size of 50,000 Da, protein tissue binding and/or the electrostatic charge were discussed as the underlying cause (10). However, in a recent investigation, a significantly improved elimination of r-hirudin was reported using hemofiltration with high-flux polysulfon filters, compared with other filter materials (15).
Our findings suggest that MUF in an extracorporeal circuit may be an effective means to eliminate r-hirudin when renal dysfunction is known or suspected, or in the case of an r-hirudin overdose. They suggest further that the type of filter system used in the circuit may have considerable influence on the elimination of r-hirudin. We found that the two ultra-large pore plasmapheresis filter systems were more effective than the conventional hemofilter systems in eliminating r-hirudin (Tables 1 and 2). Furthermore, our data indicated that the hemofilters were highly variable in their ability to eliminate r-hirudin (Table 2). Interestingly, the relatively small-pored Arylane H4 hemofilter (Table 1) was the most effective of the four hemofilter systems in eliminating r-hirudin (Table 2). Our findings are consistent with previous data suggesting that the filtering capability of these systems is determined more by the electrostatic charge of the material of the membranes rather than by pore size (10).
One potential disadvantage of the two plasmapheresis filters is their tendency to remove large amounts of plasma proteins (including a loss of procoagulant activity), which may necessitate the restoration of coagulation factors via administration of FFP. This may increase the risk of infection. In addition, an excessively rapid decrease in r-hirudin concentration during the filtration in vivo may lead to clotting in the CPB system, and the formation of pulmonary emboli (particularly when using the arterial cannula of the circuit as the inflow line to the patient).
In conclusion, our study provides evidence for effective extracorporeal elimination of r-hirudin from the blood via MUF. The use of this technique should reduce the risk of bleeding complications (including surgical reexploration) when r-hirudin is used in patients with HIT II who have undergone cardiovascular surgery with CPB, especially those with renal dysfunction.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Greinacher A, Völpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999;99:73–80.
[Abstract/Free Full Text] - Koster A, Kuppe H, Hetzer R, et al. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology 1998;89:777–80.[Web of Science][Medline]
- Poetzsch B, Madlener K, Seelig C, et al. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass: assessment of the whole blood ecarin clotting time. Thromb Haemost 1997;77:920–5.[Web of Science][Medline]
-
Koster A, Kuppe H, Crystal GJ, Mertzlufft F. Cardiovascular surgery without cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II using anticoagulation with recombinant hirudin. Anesth Analg 2000;90:292–8.
[Free Full Text] - Koster A, Kuppe H, Mertzlufft F. Cardiopulmonary bypass with recombinant hirudin in patients with heparin-induced thrombocytopenia type II: a synopsis of 19 cases. Br J Anaesth 1999;82 (Suppl 1):35(A116).
- Kwapisz MM, Schindler E, Müller M, Akinturk H. Prolonged bleeding after cardiopulmonary bypass with recombinant hirudin in heart transplantation. Eur J Cardiothorac Surg 1999;16:256–7.
- Koster A, Kuppe H, Hetzer R, Mertzlufft F. Bleeding complications associated with r-hirudin application for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II. Anesth Analg 1999;88:SCA 3.
- Nowak G, Bucha E, Goock T, et al. Pharmacology of r-hirudin in renal impairment. Thromb Res 1992;66:707–15.[Web of Science][Medline]
- Markwardt F, Nowak G, Sturzebecher J. Clinical pharmacology of recombinant hirudin. Haemostasis 1991;21 (Suppl 1):133–6.
- Vanholder R, Camez A, Veys N, et al. Pharmacokinetics of recombinant hirudin in haemodialyzed end-stage renal failure patients. Thromb Haemost 1997;77:650–5.[Web of Science][Medline]
- Journois D, Israel-Biet D, Pouard P, et al. High-volume, zero-balanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthesiology 1996;85:965–76.[Web of Science][Medline]
- Tassani P, Richter JA, Eising GP, et al. Influence of combined zero-balanced and modified ultrafiltration on the systemic inflammatory response during coronary artery bypass grafting. J Cardiothorac Vasc Anesth 1999;13:285–91.[Web of Science][Medline]
- Markwardt F, Nowak G, Bucha E. Hirudin as anticoagulant in experimental hemodialysis. Haemostasis 1991;21 (Suppl 1):149–55.
-
Bucha E, Kreml R, Nowak G. In vitro study of r-hirudin permeability through membranes of different haemodialysers. Nephrol Dial Transplant 1999;14:2922–6.
[Abstract/Free Full Text] - Frank RD, Farber H, Stefanidis I, et al. Hirudin elimination by hemofiltration: a comparative in vitro study of different membranes. Kidney Int Suppl 1999;72:S41–5.
-
Rydel TJ, Ravichandran KG, Tulinsky A, et al. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 1990;249:277–80.
[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
 |
|
  A. Koster, T. Hentschel, T. Groman, H. Kuppe, R. Hetzer, S. Harder, and K.-G. Fischer Argatroban anticoagulation for renal replacement therapy in patients with heparin-induced thrombocytopenia after cardiovascular surgery J. Thorac. Cardiovasc. Surg., May 1, 2007; 133(5): 1376 - 1377. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Benz, M. A. Nauck, J. Bohler, and K.-G. Fischer Hemofiltration of Recombinant Hirudin by Different Hemodialyzer Membranes: Implications for Clinical Use Clin. J. Am. Soc. Nephrol., May 1, 2007; 2(3): 470 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Gurbuz, W. G. Elliott, and A. A. Zia Heparin-induced thrombocytopenia in the cardiovascular patient: diagnostic and treatment guidelines Eur. J. Cardiothorac. Surg., January 1, 2005; 27(1): 138 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Koster, D. Chew, F. Merkle, M. Gruendel, M. Jurmann, H. Kuppe, and R. Oertel Extracorporeal Elimination of Large Concentrations of Tirofiban by Zero-Balanced Ultrafiltration During Cardiopulmonary Bypass: An In Vitro Investigation Anesth. Analg., October 1, 2004; 99(4): 989 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Koster and T. Fischer Management of Patients with Heparin-Induced Thrombocytopenia During Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2003; 7(4): 411 - 416. [Abstract] [PDF]
|
|
|
|
 |
|
 T. E. Warkentin and A. Greinacher Heparin-induced thrombocytopenia and cardiac surgery Ann. Thorac. Surg., December 1, 2003; 76(6): 2121 - 2131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Warkentin and A. Greinacher Heparin-induced thrombocytopenia and cardiac surgery Ann. Thorac. Surg., August 1, 2003; 76(2): 638 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Koster, D. Chew, M. Grundel, H. Hausmann, O. Grauhan, H. Kuppe, and B. D. Spiess An Assessment of Different Filter Systems for Extracorporeal Elimination of Bivalirudin: An In Vitro Study Anesth. Analg., May 1, 2003; 96(5): 1316 - 1319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Nuttall, W. C. Oliver Jr, P. J. Santrach, R. D. McBane, D. B. Erpelding, C. L. Marver, and K. J. Zehr Patients with a History of Type II Heparin-Induced Thrombocytopenia with Thrombosis Requiring Cardiac Surgery with Cardiopulmonary Bypass: A Prospective Observational Case Series Anesth. Analg., February 1, 2003; 96(2): 344 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Frank, H. Farber, R. Lanzmich, J. Floege, and H. P. Kierdorf In vitro studies on hirudin elimination by haemofiltration: comparison of three high-flux membranes Nephrol. Dial. Transplant., November 1, 2002; 17(11): 1957 - 1963. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Lowentritt, M. J. Kahn, and V. Batuman Use of recombinant hirudin as an anticoagulant in plasmapheresis in a patient with heparin-induced thrombocytopenia Nephrol. Dial. Transplant., August 1, 2002; 17(8): 1533 - 1534. [Full Text] [PDF]
|
|
|
|
 |
|
 E. Muhl, H.-J. Siemens, P. Kujath, and H.-P. Bruch Therapy and Monitoring of Heparin-Induced Thrombocytopenia Type II in Critically Ill Patients During Continuous Venovenous Hemodiafiltration: Comparison of aPTT and Ecarin Clotting Time for Monitoring of r-Hirudin Therapy J Intensive Care Med, January 1, 2002; 17(1): 34 - 40. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
