Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induce thrombocytopenia. Dabigatran provides anticoagulation for an in-vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits.
Nonlinear mixed effects models were used to estimate dabigatran parameters for a 2-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/mL was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy, and anticoagulated with intravenous dabigatran (6 animals) or heparin (4 animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 minutes. Measurement of activated clotting time, thromboelastometric reaction time (R), and blood gases were performed during CPB. Then, the animals were sacrificed and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy.
The observed dabigatran concentrations during CPB were above the target concentration, ranging from 137 ± 40 μg/mL at 5 min of CPB to 428 ± 150 μg/mL at 60 min, and 295 ± 35 μg/mL at 120 min. All rabbits completed 2 hours of CPB without visible thrombosis. In the two groups reaction time (R) values were elevated, reaching 10262 ± 4198 sec (dabigatran group) and 354 ± 141 sec (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran and heparin treated animals.
In this first-use, proof of concept study, we have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model.
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