Application of goal-directed therapy for the use of concentrated antithrombin for heparin resistance during cardiac surgery

Abstract

The maintenance of anticoagulation in adult patients undergoing cardiopulmonary bypass is dependent upon a number of factors, including heparin concentration and adequate antithrombin activity. Inadequate anticoagulation increases the risk of thrombosis and jeopardizes both vascular and extracorporeal circuit integrity. The purpose of this study was to evaluate a goal-directed approach for the use of antithrombin in patients who were resistant to heparin. Following institutional review board approval, data were obtained from quality improvement records. A goal-directed protocol for antithrombin was established based upon heparin dosing (400 IU kg−1 body weight) and achieving an activated clotting time of ⩾500 seconds prior to cardiopulmonary bypass. Two groups of patients were identified as those receiving antithrombin and those not receiving antithrombin. Outcome measures included activated clotting time values and transfusion rates. Consecutive patients (n = 140) were included in the study with 10 (7.1%) in the antithrombin group. The average antithrombin dose was 1,029.0 ± 164.5 IU and all patients had restoration to the activated clotting time levels. Patients in the antithrombin group were on preoperative heparin therapy (80.0% vs. 24.6%, p = 0.001). Prior to cardiopulmonary bypass the activated clotting time values were lower in the antithrombin group (417.7 ± 56.1 seconds vs. 581.1 ± 169.8 seconds, p = 0.003). Antithrombin patients had a lower heparin sensitivity index (0.55 ± 0.17 vs. 1.05 ± 0.44 seconds heparin−1 IU kg−1, p = 0.001), received more total heparin (961.3 ± 158.5 IU kg−1 vs. 677.5 ± 199.0 IU kg−1, p = 0.001), more cardiopulmonary bypass heparin (22,500 ± 10,300 IU vs. 12,100 ± 13,200 IU, p = 0.016), and more protamine (5.4 ± 1.2 vs. 4.1 ± 1.1 mg kg−1, p = 0.003). The intraoperative transfusion rate was higher in the antithrombin group (70.0% vs. 35.4%, p = 0.035), but no differences were seen postoperatively. Utilization of a goal-directed algorithm for the administration of antithrombin for the treatment of heparin resistance is effective in patients undergoing cardiac surgery.

Heparin Resistance During Cardiopulmonary Bypass in Adult Cardiac Surgery

“…Thirdly, AT is supplemented via AT concentrate, and the last option is to accept the subtherapeutic ACT and commence CPB without any additional treatment. 6,8,[82][83][84] The additional dosing of heparin to counter heparin resistance is a commonly used practice for cardiothoracic anesthesiologists. 8 Heparin usually is administered at 300-to-500 U/kg in an attempt to achieve an ACT of 400-to-480 seconds.…”

“…Recombinant AT (rAT) is produced from transgenic goats and procured from milk. 83 Hence, rAT should not be given to patients with a known sensitivity to goat milk proteins. 8 Both forms of AT concentrates are similar and exhibit equivalent activity for in vitro thrombin and factor Xa inhibition assays.…”

“…This is despite a 4-fold increase in heparin-binding affinity in rAT, as well as a shorter half-life (10.49 § 7.19 hours for rAT compared with 56.8-68 hours for hAT), thus necessitating an infusion if rAT is to be used for extended periods.95 Antithrombin concentrate usually is dosed at 500-to-1000 IU (equivalent to 1-2 vials of hAT). 58,83,96,97 Patnik et al recommended a formula to estimate the initial dose of AT: AT dose (IU) = (desired minus current AT level as % of normal level) X weight (kg) divided by 1.4. 95 However, this formula requires a laboratory AT level that may not be timely enough before CPB.…”

“…In another study by Stammers et al, the average dose of AT concentrate required for the treatment of heparin resistance was found to be 1,029.0 § 164.5 IU or 14.1 § 3.4 IU/kg when normalized to body weight. 83 Each vial is reconstituted with water for injection to 10 mL of solution, which obviates the need for the large volumes required to replenish plasma AT levels seen with plasma transfusions. .…”

“…Although studies have shown that AT concentrate does not necessarily improve postoperative outcomes of bleeding as compared to treatment with FFP or no treatment at all, 58,[96][97][98] the majority of the evidence suggests that AT concentrate is a safe and effective method of restoring an adequate ACT for CPB. 58,82,83,85,87,90,91,93,96,97 One prohibitive factor would be its cost, which can be 8 times that of 2 units of FFP, 91 and another would be its lack of availability in certain institutions. 6 In the circumstances in which cost is a concern, the authors' recommendation would be to administer 1 vial (500 IU) first, followed by a second vial should the repeat ACT be inadequate for CPB.…”