Argatroban

Argatroban is a synthetic, small-molecule (532 Da) DTI derived from L-arginine that binds reversibly to thrombin. Its half-life is about 40-50 min. The potential of argatroban to be an effective anticoagulant in patients with HIT has been documented by the studies of Lewis et al. (1997a,b, 2001, 2003) (see Chapter 15). Its feasibility for anticoagulation of HIT patients is after cardiac surgery, with dosing reduced to 0.5-1 mg/kg/min (Koster et al., 2006). However, only limited information (<20 patients) is available for use during cardiac surgery (Kawada et al., 2000; Furukawa et al., 2001; Edwards et al., 2003; Kieta et al., 2003; Ohno et al., 2003; Cannon et al., 2004; Gasparovic et al., 2004) and no standardized

TABLE 3 Treatment Protocol for Bivalirudin Anticoagulation During CPB and OPCAB Surgery

Dosing of bivalirudin

Initial iv bivalirudin bolus: 1.0 mg/kg body weight and initiate continuous iv infusion: 2.5 mg/kg/h

Bivalirudin added to pump circuit volume: 50 mg

ACT: A prolongation of >2.5-fold baseline ACT level (varies between different commercially available assays) indicates adequate anticoagulation with bivalirudin Bivalirudin dosing and monitoring while on CPB

Frequency of bivalirudin level monitoring: Every 30 min by ACT

A prolongation of >2.5-fold baseline ACT level (varies between different commercially available assays) indicates adequate anticoagulation with bivalirudin. Keep bivalirudin infusion rate constant, and only increase bivalirudin infusion rate if the ACT levels decrease below target (alternatively, maintain the same infusion rate but give repeat fractionated boluses of 0.25 mg/kg to maintain ACT in therapeutic range); do not reduce infusion rate if ACT exceeds target Performance of CPB

Due to the unique pharmacology of bivalirudin, stasis in the CPB circuit should be avoided/ minimized. This can be achieved by the following strategies: the use of closed systems whenever possible; the creation of shunting lines from the arterial filter to the cardiotomy reservoir; intermittent compression of the collapse venous reservoir with flushing back in the hard shell cardiotomy reservoir to provide flow of systemic blood in the cardiotomy reservoir and to maintain bivalirudin levels; storage of excessive blood in citrated bags instead of the hard shell cardiotomy reservoir; or processing excessive blood with the use of cell savers. The use of cardiotomy suction should be minimized whenever possible and replaced by the use of a cell saver to avoid aspiration and systemic infusion of "activated" blood from the operative field. If "blood cardioplegia" is used, constant flow should be provided in the lines to avoid clot formation and danger of thromboembolism of coronary arteries Temperature

Due to the enzymic metabolism of bivalirudin, hypothermia may lead to drug accumulation. Therefore, in the absence of a specific test to monitor bivalirudin levels, periods of hypothermia should be brief, and if possible only mild hypothermia (30-34°C.) should be instituted Extracorporeal elimination

Bivalirudin elimination can be enhanced after CPB by the use of modified ultrafiltration using standard commercially available hemofilters. However, due to the possibility of eliminating bivalirudin via hemofiltration, this procedure is discouraged during CPB (Koster et al., 2003b, 2004a)

Management of circuit after CPB

After cessation of CPB, the venous line should be infused into the patient, the system refilled with saline, the arterial and venous line reconnected, and circulation of the closed system started to avoid stasis and thrombosis of the system. With the beginning of recirculation, a bivalirudin bolus of 50 mg, followed by a continuous infusion of 50 mg/h, should be added to provide adequate bivalirudin concentrations. When it is definitively determined that CPB will not need to be reestablished, this volume has to be processed with a cell saver before reinfusion to avoid overdosage with bivalirudin Cell saver

A cell saver should be used with sodium citrate as anticoagulant for flushing line

II. OPCAB surgery Dosing of bivalirudin

Bolus: 0.75 mg/kg followed by continuous infusion of: 1.75 mg/kg/h (stop infusion approx. 20 min before end of grafting)

ACT: > 300 s when measured with the ACT+ device (Hemochrone Jr, NJ, USA) Considerations of graft handling

Assessments of grafts for patency and leakage should be performed with saline or, if bivalirudin-containing blood is used, grafts should thereafter be flushed with saline and "bulldogged" while applying pressure on the saline syringe. If a left or right internal thoracic artery is used for grafting, the vessel should be transected shortly before grafting in order to avoid stasis and potential risk of thrombus formation in the graft

Abbreviations: ACT, activated clotting time; CPB, cardiopulmonary bypass; OPCAB, off-pump coronary artery bypass.

dosing/monitoring protocol exists. Therefore, argatroban cannot be recommended for these indications. However, because of its short half-life and hepatobiliary excretion, argatroban can be expected to gain a pivotal role in peripheral vascular surgery where a large percentage of patients have renal impairment, thus precluding use of lepirudin. Studies to establish argatroban dosing protocols and to provide safety and efficacy data for this indication are desirable.

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