EFFICACY AND PHARMACOKINETICS OF NEUTRALASE[trade mark sign] IN CABG
M Strong, JA Bennett, GP Gravlee, Barbara E. Tardiff, John M. Luber, Jochen Schneider, Thomas P. Barragry, DiSanto Ar, F. Carter, RL Broughton, NH Goldstein, DP Recker, JC Horrow · Anesthesia & Analgesia · 1998
Introduction. Neutralase[trade mark sign] (heparinase I) is a 42.5 kD enzyme which neutralizes heparin by cleaving it into primarily di- and tetrasaccharide fragments. [1] The activated clotting time (ACT) of heparinized volunteers returned to baseline after Neutralase administration, [2] leading to this phase II dose ranging study in elective coronary artery bypass graft (CABG) patients. Methods. Six institutions enrolled 49 patients with IRB approval into 3 sequential dosing groups in an open-label design: 5 mcg/kg (n=12), 7 mcg/kg (n=25) and 10 mcg/kg (n=12). Porcine mucosal heparin anticoagulation was reversed with bolus Neutralase at cardiopulmonary bypass (CPB) conclusion. Measurements included ACT (3 min prior to bolus and 3, 6, and 9 min thereafter), Neutralase blood concentrations, anti-Factor IIa and Xa activity (multiple timepoints) and chest tube drainage (CTD) over 24 hrs. An analysis-of-variance model with treatment as a main effect was used in assessing mean ACT and median (mean rank) chest tube drainage. Results. Figure 1 demonstrates a dose response relationship for ACT return to baseline at 9 min. Neutralase rapidly and completely eliminated anti-IIa activity, and decreased anti-Xa activity to 20% at 9 min and 6% at 12 hrs. Mean (SD) plasma half-life was 12.1 (2.9) min compared to 6.6 (2.1) min in volunteers. Figure 2 displays 12 hr CTD data.Figure 1Figure 2Discussion. The data support 7 mcg/kg as an appropriate dose for investigational clinical use after CPB: 5 mcg/kg yields more bleeding, while 10 mcg/kg yields an equivalent blood loss; and both 7 and 10 mcg/kg are clinically adequate for heparin reversal.