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© 2001 International Anesthesia Research Society
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Abstract |
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Anticoagulation with recombinant hirudin (r-hirudin) (RefludanTM) has been suggested as an alternative to heparin for patients with heparin-induced thrombocytopenia requiring cardiac surgery. We sought to develop a modified activated coagulation time (ACT) that would allow quantification of the levels of r-hirudin required during cardiopulmonary bypass (CPB). Twenty-one patients scheduled for elective cardiac surgical procedures requiring CPB were enrolled in this IRB-approved study. R-hirudin was added to blood specimens obtained before heparin administration (before CPB) and 30 min after heparin neutralization with protamine (after CPB) to result in concentrations of 0, 2, 4, 6, 7, or 8 µg/mL. Kaolin/ACT and complete blood count measurements were assayed in native specimens (first 10 patients, Phase I) or in specimens mixed with equal volumes of commercial normal plasma (second 11 patients, Phase II). In Phase I, good (r2 = 0.83) linear relationships between ACT values and r-hirudin concentrations (
4 µg/mL) were observed in specimens obtained before CPB. However, ACT values were markedly prolonged (P < 0.0001) by r-hirudin in specimens obtained after CPB, with ACT values generally exceeding the ACT’s detection limit (>999 s) at hirudin concentrations >2 µg/mL. In patient specimens mixed with normal plasma (Phase II), ACT/hirudin relationships (i.e., hirudin/ACT slope values obtained with hirudin concentration 4 µg/mL) in the post-CPB period (0.022 ± 0.004 µg · mL-1 · s-1) were similar (P = 0.47) to those (0.019 ± 0.004 µg · mL-1 · s-1) obtained in the pre-CPB period. Accordingly, a significant relationship between normal plasma-supplemented ACT values and predilution hirudin concentration was obtained in the post-CPB (hirudin = 0.039ACT - 4.34, r2 = 0.91) period. Although our data demonstrate that the ACT test cannot be used to monitor hirudin during CPB, the addition of 50% normal plasma to post-CPB hemodiluted blood specimens yields a consistent linear relationship between hirudin concentration and ACT values up to a predilution concentration of 8 µg/mL. Plasma-modified ACT may be useful in monitoring hirudin anticoagulation during CPB.
Implications: A modified activated clotting time test system that may be helpful inmonitoring hirudin anticoagulation in patients with heparin-inducedthrombocytopenia during cardiac surgery with cardiopulmonary bypass isdescribed.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Systemic anticoagulation is required during cardiac surgery with cardiopulmonary bypass (CPB) to prevent clotting in the extracorporeal circuit and to preserve hemostatic system components. Heparin is the principle drug used for anticoagulation during cardiac surgery because it is effective, immediately reversible, inexpensive, and generally well tolerated (1). A serious complication of treatment with heparin is immune-mediated heparin-induced thrombocytopenia (HIT), which can lead to thrombocytopenia in 1.3%–10% of patients (2,3) or to thrombosis in 0.75% of patients (4).
Therefore, a previous history or current diagnosis of HIT poses a clinical dilemma in patients requiring cardiac surgery because the use of heparin during CPB may be contraindicated. Although a number of case reports in such patients indicate the successful use of alternative anticoagulant drugs such as ancrod (5), danaparoid (6), and argatroban (7), the direct thrombin inhibitor recombinant hirudin (r-hirudin) (RefludanTM; Hoechst Marion, Roussel, Kansas City, MO) seems to be the most suitable on the basis of several studies demonstrating its efficacy and safety (8–14).
The activated partial thromboplastin time (APTT) may be used to monitor patients who receive small-dose (0.5–1.5 µg/mL) (15) hirudin for management of HIT in patients with venous thromboembolism (16) or acute coronary syndromes (17). However, the levels of r-hirudin recommended (18) for anticoagulation during CPB (3.5–4.5 µg/mL) exceed those that can be effectively monitored with either the APTT (11,19) or activated clotting time (ACT) (19). The ecarin clotting time assay, a clot-based method that uses a prothrombin-activating snake venom derivative and can be measured with the TAS instrument (Cardiovascular Diagnostics, Raleigh, NC) produced adequate dose-response curves with r-hirudin in eight patients during CPB (19). However, ecarin clotting time can be substantially prolonged by hemodilution (i.e., >30%) (19) or CPB-related reductions in procoagulant proteins (20), which may potentially lead to dosing errors. In this study, we examine the suitability of the ACT and a plasma-modified ACT (i.e., the addition of normal plasma [NP]) for monitoring hirudin concentrations that have been recommended for anticoagulation with CPB.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Twenty-one consecutive patients who were not receiving heparin or warfarin and who were scheduled for elective cardiac surgical procedures requiring CPB at Barnes Hospital/Washington University Medical Center, St. Louis, MO, were enrolled after approval of the study by the Institutional Human Studies Committee and after obtaining informed consent. Patients received an opioid-based anesthetic supplemented with inhaled anesthetics, muscle relaxants, and benzodiazepines. CPB was accomplished with a roller pump and a Cobe® membrane oxygenator (Cobe, Arvada, CO). The CPB system was routinely primed with 1.5–2 L of Plasmalyte® solution (Baxter Healthcare, Deerfield, IL), 50 mEq of sodium bicarbonate, 25 g of mannitol, and porcine heparin (5–10,000 U). During cardioplegia, systemic hypothermia was maintained at 32°C–33°C. Systemic anticoagulation for CPB was accomplished with porcine heparin according to a previously published protocol that was based on measurements of ACT and whole-blood heparin concentration. Specific triggers for additional heparin during CPB included an ACT <480 s and a heparin concentration less than the reference heparin concentration (i.e., reference concentration is the patient-specific concentration that is associated with a kaolin ACT of 480 s before initiation of CPB). After the patient was rewarmed to 37°C, extracorporeal circulation was discontinued, and heparin was neutralized with a protamine dose that was based on on-site measurements of residual whole-blood heparin concentration.
Blood specimens for hematologic analyses were obtained at two time points: before heparin administration (before initiation of CPB) and 30 min after discontinuation of CPB (after heparin neutralization with protamine). After separating an aliquot of blood for complete blood count analysis, additional specimens were divided into six aliquots, and r-hirudin was immediately added to each aliquot to result in the final following concentrations: 0, 2, 4, 6, 7, or 8 µg/mL. In the first 10 patients (Phase I), kaolin-activated ACT measurements (Hepcon instrument; Medtronic Perfusion Systems, Minneapolis, MN) were obtained. In the second group of 11 patients (Phase II), an equal volume of each aliquot of whole blood was added to citrated commercial normal plasma (Factor Assay Control plasma; George King, Kansas City, MO) and mixed (test tube inverted 10 times) before measurement of ACT to correct for the reduction of coagulation factors caused by CPB-related hemodilution. Calcium was not added to each mixture before test performance because the ACT reagent contains calcium (Medtronic Perfusion Systems). Hirudin/ACT dose-response curves were generated for each patient on all pre-CPB and post-CPB specimen mixtures. Complete blood count (i.e., hemoglobin, hematocrit, white cell, and platelet counts) measurements were determined electronically with the Coulter T540® (Coulter Electronics, Hialeah, FL) on all patient specimens and patient specimen/plasma mixtures.
Student’s paired or unpaired t-test and one-way analysis of variance with Bonferroni’s correction were used to compare hematologic test results. Ranked sum nonparametric analysis was used to compare results if either unequal variances or nonnormal distributions were apparent. P values <0.05 were considered significant.
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Results |
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Table 1 summarizes ACT, hematocrit, and platelet count values for pre-CPB and post-CPB specimens for each phase. In the pre-CPB period of Phase I, a good (r2 =0.83) linear relationship (hirudin = 0.017ACT - 2.3) was observed between ACT values and hirudin concentration when hirudin concentrations were
4 µg/mL (n = 20) ( Fig. 1, left panel). However, only 5 of 10 ACT values were within this test’s sensitivity limit at hirudin concentrations of 6 µg/mL. Furthermore, in the post-CPB period of Phase I, only 21 (42%) of all ACT values were within the detection limit of the Hepcon instrument (<999 s) at a hirudin concentration 
2 µg/mL, and only one ACT value was within the detection limit at a hirudin concentration of 6 µg/mL (Fig. 1, right panel). Post-CPB ACT/hirudin slope values (average post-CPB slope = 0.013 ± 0.006 µg · mL-1 · s-1) were similar (P = 0.17) to pre-CPB ACT/hirudin slope values (average slope = 0.016 ± 0.003 µg · mL-1 · s-1) at hirudin concentrations of 2 µg/mL.
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In the pre-CPB period, a good (r2 =0.91) linear relationship (hirudin = 0.017ACT - 1.9) was observed between ACT-NP values and hirudin concentration at hirudin concentrations
6 µg/mL (n = 44) ( Fig. 2, left panel). However, only 2 of 10 ACT-NP values were within the detection limit at hirudin concentrations 7 µg/mL. Similarly, in the post-CPB period, a good (r2 =0.91) linear relationship (hirudin = 0.020ACT - 2.17) was observed between ACT-NP values and hirudin concentrations at hirudin concentrations 4 µg/mL (n = 33) (Fig. 2, right panel). However, only 4 of 10 ACT-NP values were within the detection limit of this test at hirudin concentrations 6 µg/mL. Pre-CPB ACT-NP/hirudin slope values (0.023 ± 0.002 µg · mL-1 · s-1) were similar (P = 0.09) to pre-CPB Phase I slope values (slope = 0.020 ± 0.005 µg · mL-1 · s-1) when the analysis was limited to hirudin concentrations 4 µg/mL.
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When the analysis was limited to ACT-NP values obtained with hirudin levels
4 µg/mL (n = 33), similar linear relationships between hirudin concentration and ACT values were observed in both the pre-CPB (hirudin = 0.022ACT - 2.97, r2 = 0.94) and post-CPB (hirudin = 0.020ACT - 2.17, r2 = 0.91) periods. Accordingly, ACT-NP/hirudin slope values obtained in the post-CPB period (average slope = 0.022 ± 0.004 µg · mL-1 · s-1) were similar (P = 0.47) to ACT-NP/hirudin slope values (average slope = 0.019 ± 0.004 µg · mL-1 · s-1) obtained in the pre-CPB period at hirudin concentrations 4 µg/mL. Figure 3 illustrates the individual patient ACT responses at hirudin concentrations 4 µg/mL.
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Concentrations of hirudin used in both phases of the study (0–8 µg/mL) refer to final concentrations in solution. In Phase II, these concentrations (0, 2, 4, 6, 7, or 8 µg/mL) equate to in vivo concentrations that equal 0, 4, 8, 12, 14, or 16 µg/mL, based on a 50:50 dilution of blood specimens with reagent plasma. Therefore, Figure 4 depicts the relationship between plasma-supplemented ACT values and ex vivo hirudin concentrations before the effect of plasma dilution.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The identification and characterization of HIT in the cardiac surgical setting has led to several dilemmas for physicians managing patients with this diagnosis (3,4). The optimal strategy for managing patients with a history of HIT during cardiac surgery is a matter of controversy and continued investigation.
Direct thrombin inhibitors, such as argatroban (7) and hirudin (16), have been used successfully as substitutes for heparin in hospitalized patients with venous thromboemboli and HIT. Hirudin has also been used in several small series of cardiac surgical patients during CPB, without apparent complications (8–12). Although it seems that hirudin may be an alternative for patients with HIT undergoing cardiac surgery because of its shorter half-life (i.e., 60 minutes), it has several important limitations, including an unknown but probably narrow therapeutic window, accumulation in patients with renal dysfunction (21), and lack of a neutralizing agent. Although minimal blood loss has been described in several small series of cardiac surgical patients treated with hirudin during CPB (8–10), other reports indicate that blood loss may be substantial when hirudin is used (11,14); these reports highlight the critical importance of laboratory monitoring of hirudin to achieve and maintain therapeutic hirudin levels. The therapeutic range for hirudin in patients undergoing cardiac surgery is likely to be substantially larger than the 0.5–1.5 µg/mL (yielding APTT values two to three times those of control) (15) that is used in the treatment of patients with venous thromboembolism and acute coronary syndromes (17). Thus, on the basis of experience with very limited numbers of patients, some authors have recommended that hirudin be maintained at levels of 3.5–4.5 µg/mL during CPB (18).
However, the optimal range has yet to be determined for prevention of clot formation in the CPB circuit and thrombotic complications and for effective suppression of excessive activation of the hemostatic system by using several sensitive markers of thrombin generation or activity (e.g., prothrombin fragment 1.2, fibrinopeptide A), platelet activation (e.g., ß thromboglobulin), and fibrinolysis (D-dimers). Concurrent use of a platelet inhibitor may be required because hirudin and other direct thrombin inhibitors do not directly inhibit platelets; this is reflected by the marked platelet dysfunction that was observed at the end of CPB in two patients who received hirudin (8,9).
In the absence of a readily available, practical assay of hirudin concentration, the APTT has been used to monitor its anticoagulant effect in patients who receive hirudin (8,9). However, a poor correlation between hirudin concentration and either APTT (11,19) or ACT (19) values was recently observed. The ecarin clotting time assay correlates (r2 = 0.63) with r-hirudin levels up to 8 µg/mL (19); however, test results can also be substantially prolonged by hemodilution (i.e., >30%) (19) and reductions in procoagulant proteins (20), which may lead to dosing errors. In addition, the ecarin reagent/test system is currently not approved for clinical use in the United States. The results from this study confirm that a standard ACT cannot be used to maintain hirudin levels during CPB because of prolongation to terminal times with hirudin concentrations 2 µg/mL, most likely secondary to the effects of hemodilution. Hemodilution during CPB results in substantial (i.e., as much as a 70%) decreases in coagulation factors (22–24) and platelets, leading to prolongation of ACT values with standard unfractionated heparin anticoagulation. Thus, previous studies have demonstrated that ACT values do not correlate with heparin levels during CPB (25,26). Our data also clearly demonstrate that the ACT test cannot be used to monitor hirudin during CPB.
However, our findings indicate that blood specimen mixing with 50% ACT-NP results in the maintenance of a consistent linear relationship between ACT values and hirudin concentration up to 8 µg/mL. This is likely because of a correction of coagulation factor deficiencies, as well as a reduction in platelet count (Table 1), which reduces the effects of platelets on the ACT (27). The ACT-NP technique also facilitates the monitoring of larger hirudin concentrations, because a 50% dilution with normal plasma effectively extends the monitoring range to 8 µg/mL.
One limitation of the method described in our study involved the mixing technique, which can potentially be simplified by adding blood specimens to ACT cartridges prefilled with normal plasma. In addition, our study did not assess the potential effect of heparin/protamine complexes on this test system; however, the effect of these complexes is probably negligible on the basis of their rapid clearance (i.e., 20 minutes) by the reticuloendothelial system. Further studies are needed to evaluate the reliability of the ACT-NP technique in monitoring hirudin concentrations in patients receiving hirudin during CPB and to determine the optimal therapeutic range of hirudin in these patients.
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Acknowledgments |
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Supported in part by Medtronic Perfusion Systems.
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References |
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