Intravenous Dabigatran Provides Adequate Anticoagulation for Cardiopulmonary Bypass Using a Rabbit Model

Abstract

Background– 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. Methods – 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. Results – 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. Conclusions – 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.

Dabigatran in Rabbit Cardiopulmonary Bypass: Reply

“…Erdoes, Koster, and Levy 1 for their very cogent and detailed analysis of our study. 2 We agree with many of the points they made, specifically the very limited effect dabigatran has on coagulation due to its specificity for thrombin. Most would agree, however, if only one enzyme in the coagulation system can be inhibited, thrombin is the obvious choice given its central place in the coagulation cascade, and its many indirect effects via feedback loops as indicated by Erdoes et al .…”

“…N adtochiy et al 1 report using intravenous dabigatran, a direct thrombin inhibitor (DTI), for anticoagulation in an animal model of simulated cardiopulmonary bypass (CPB). 1 Activated clotting time, thromboelastometric reaction time, and fibrin deposition in sections of the arterial line filters were analyzed to compare anticoagulation with dabigatran or heparin. In their CPB model, the authors suggest that dabigatran provides adequate anticoagulation similar to heparin for preventing thrombosis.…”

Dabigatran in Rabbit Cardiopulmonary Bypass: Comment

“…I read with interest the recent publication by Joo et al comparing posttetanic counts by accelerometry as compared with electromyography. 1 They demonstrated that accelerometry counted more twitches than did an electromyography system. However, while their work was meticulously conducted and analyzed, there is a slight but fundamental misstatement in their conclusion.…”

“…Nadtochiy et al 1 report using intravenous dabigatran, a direct thrombin inhibitor (DTI), for anticoagulation in an animal model of simulated cardiopulmonary bypass (CPB). 1 Activated clotting time, thromboelastometric reaction time, and fibrin deposition in sections of the arterial line filters were analyzed to compare anticoagulation with dabigatran or heparin. In their CPB model, the authors suggest that dabigatran provides adequate anticoagulation similar to heparin for preventing thrombosis.…”

Effect of bivalirudin on coagulation in neonatal (cord) and adult human blood in vitro

“…This study compared the in vitro anticoagulant effects of bivalirudin in neonatal blood from placenta‐cord units and adult human blood samples using commonly available whole blood point‐of‐care tests. We hypothesized that bivalirudin would have greater potency in cord blood compared with adult blood as measured by ACT and thromboelastography (TEG) in vitro, and in a simple model of CPB, the Chandler Loop 17 …”