Conclusion

Based on these results, we believe that danaparoid should not be used for anticoagulation during CPB. However, danaparoid is an option in HIT patients undergoing OPCAB surgery and in vascular surgery.

B. Recombinant Hirudin

Recombinant hirudin (r-hirudin), a direct thrombin inhibitor (DTI) naturally produced by the salivary gland of the leech (Hirudo medicinalis), is now approved in most countries for clinical use by the iv route. Hirudin is a single-chain polypeptide of 65 amino acids (7000 Da) that forms a tight 1:1 stoichiometric complex with thrombin, thereby occupying both the fibrinogen-binding site and also blocking access to its catalytic site. As a result, all of the thrombin-catalyzed procoagulant reactions, such as conversion of fibrinogen to fibrin, activation of coagulation factors V, VIII, and XIII, and thrombin-induced platelet activation, are inhibited. Although two hirudins are approved (lepirudin, desirudin), data on use in cardiac surgery are only available for lepirudin.

Because of its potent anticoagulant effect, r-hirudin has been studied as an anticoagulant for use in open heart surgery in both dogs (Walenga et al., 1991) and pigs (Riess et al., 1997). In both animal models, effective CPB anticoagulation could be achieved by administration of r-hirudin as a bolus injection (1 mg/kg b.w.) followed by a continuous infusion of 1 mg/kg b.w., started after initiation of CPB, and continuing until end of CPB. In humans, however, recovery of hirudin in the plasma following b.w.-adjusted dosing shows a high interindividual variability (Koza et al., 1993). Therefore, a fixed-dose protocol for r-hirudin in the CPB setting bears the risk of both inadequate anticoagulation and overdosing. Although the latter is complicated by excessive and potentially fatal postoperative bleeds, the former may result in the occurrence of thromboembolic complications while on pump, including catastrophic total pump occlusion.

To establish a treatment schedule that is adjusted to the individual's response to hirudin, we investigated different monitoring systems for hirudin plasma levels. Several in vitro and in vivo experiments demonstrated that the ACT and activated partial thromboplastin time (aPTT) were not sufficiently sensitive to monitor hirudin plasma levels (Potzsch et al., 1997). However, reliable results were obtained by using the whole blood ecarin clotting time (ECT) (Potzsch et al., 1997; Koster et al., 2000a).

Ecarin is a prothrombin-activating enzyme, derived from the venom of the snake, Echis carinatus, that activates prothrombin to an intermediate product, meizothrombin (Nishida et al., 1995). Meizothrombin expresses only moderate clotting activity, but is fully reactive toward, and thus inhibited by, hirudin. As a result, in r-hirudin-containing plasma, meizothrombin forms stable 1:1 complexes with r-hirudin. Only when hirudin is neutralized does clotting become initiated, either by meizothrombin or by subsequently generated thrombin. Ecarin is available from commercial sources.

Table 1 outlines the whole blood ECT method, which we perform using the KC10a coagulometer (Potzsch et al., 1997).

The method is easily adaptable to any other coagulometer. A calibration curve is constructed by using citrate-anticoagulated whole blood spiked with r-hirudin to achieve final concentrations of 0.5, 1.0, 1.5, 2.0, 3.0, and 4.0 mg/mL. A reliable ECT requires adequate prothrombin levels, which can be reduced in severely ill patients and/or by hemodilution after beginning CPB. This problem can be overcome by mixing patient blood with normal human plasma (1:1).

Critical levels of r-hirudin during CPB were established in an in vitro CPB setting and in a first series of HIT patients undergoing cardiac surgery

TABLE 1 Whole Blood Ecarin Clotting Time

50 mL citrate-anticoagulated whole blood to be analyzed + 50 mL standard normal human plasma

Incubate for 1 min at 37° C + 50 mL ecarin solution (20 U/mL) containing 0.025 M calcium chloride Determination of the clotting time

TABLE 2 Treatment Protocol for r-Hirudin (Lepirudin) Anticoagulation During CPB

Initial lepirudin dosing (pre-CPB)

Initial iv lepirudin bolus: 0.25 mg/kg body weight

Initiate continuous iv infusion:a 30 mL/h (0.5 mg/min.)

Lepirudin added to priming solution: 0.2 mg/kg body weight

Target lepirudin plasma levels:b >2.5 mg/mL before start of CPB

If <2.5 mg/mL, give additional bolus (10 mg)

Lepirudin dosing and monitoring while on CPB

Frequency of lepirudin level monitoring: Every 15 min using ECT

Intraoperative dose adjustments, based on ECT: Lepirudin plasma level Dosing modification

>4.5 mg/mL Reduce infusion rate by 10 mL/h

3.5-4.5 mg/mL No change in infusion rate

<3.5 mg/mL Increase infusion rate by 10 mL/h

Special steps toward end of CPB

Stop lepirudin infusion 15 min before anticipated end of CPB

After disconnection of CPB, administer 5 mg hirudin to the heart-lung machine to avoid clot formation a50 mg of lepirudin are dissolved in 50 mL 0.9% sodium chloride.

bThe target lepirudin level pre-CPB (>2.5 mg/mL) is lower than the ones sought during CPB (3.5-4.5 mEl/mL) because of the addition of lepirudin to the pump circuit volume (0.2 mg/kg body weight).

Abbreviations: CPB, cardiopulmonary bypass; ECT, ecarin clotting time; iv, intravenous.

(Potzsch et al., 1993; Riess et al., 1995, 1996). Clot formation in the CPB apparatus was seen at levels of r-hirudin below 1.8 mg/mL, and increasing levels of fibrino-peptide A (an indicator of thrombin-mediated fibrinogen cleavage) occurred at r-hirudin plasma levels less than 2.0 mg/mL. Based on these results, the therapeutic level of r-hirudin during CPB was set between 3.5 and 4.5 mg/mL. Higher intraoperative levels of r-hirudin could be complicated by a higher postoperative bleeding risk, especially because no antidote is available.

A treatment protocol based upon the ECT-monitoring of hirudin levels is given in Table 2. The data obtained from 10 patients with HIT, treated with r-hirudin for heart surgery, demonstrated that stable r-hirudin plasma levels in the range from 3.5 to 5.0 mg/mL could be obtained using the ECT-adjusted treatment schedule. Because of the relatively short half-life of r-hirudin of approximately 1 h, plasma levels of r-hirudin declined rapidly after stopping its infusion. However, in renally impaired patients, r-hirudin can accumulate, leading to postoperative bleeding (Koster et al., 2000b). In this situation, elimination can be augmented by the use of hemofilters, e.g., as modified ultrafiltration after termination of CPB (Koster et al., 2000c).

To date, the clinical data demonstrate that r-hirudin is a suitable alternative for anticoagulation of CPB in selected HIT patients. The ECT provides adequate monitoring and allows an adjusted treatment schedule with apparently minimal risk for thrombotic problems on pump. Because of the relatively short half-life, plasma levels of r-hirudin decline rapidly after stopping its infusion. However, there are two key aspects, which must be considered for safe management of CPB with r-hirudin. As no commercial point-of-care test for measurement of the ECT is available, care must be taken that reliable measurement of the ECT in the operating room can be provided. Moreover, due to the dramatic prolongation of the r-hirudin plasma half-life to >100 h in case of renal failure and associated risk of severe hemorrhage, only patients at low risk for postoperative renal impairment should be selected for this strategy.

The experience with the use of lepirudin for OPCAB surgery is limited to a small number of case reports. The dosages used varied from 0.2 to 0.4 mg/kg bolus followed by a continuous infusion of 0.15 mg/kg/h (Iqbal et al., 2005). Therefore, as no adequate dose finding study has been performed to date, this strategy should only be used if no other option is available. With regard to the use of lepirudin in vascular surgery, only one report describes the use for prosthetic replacement of an abdominal aneurysm. In this case a single bolus of 0.25 mg/kg was used which was not followed by a continuous infusion; this provided adequate anticoagulation during an aortic cross-clamp time of 65 min (Koster et al., 2000d). However, vascular surgery patients often have concomitant diabetes, with the potential for lepirudin accumulation due to renal impairment.

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