Antithrombin reduces pulmonary hypertension during reperfusion after cardiopulmonary bypass in a pig

Background: Antithrombin (AT) may alleviate many cardiopulmonary bypass (CPB) and ischemia-reperfusion (I/R)-related adverse effects. Using a porcine model of clinical cardiac surgery on CPB, we tested the effects of supplementary AT on myocardial and lung I/R injury. Methods: Twenty pigs undergoing 60-min aortic clamping and 75-min normothermic perfusion were randomized in a blinded setting to receive an intravenous (i.v.) bolus of AT (250 IU/kg) (AT group, n = 10) or placebo (n = 10) 15 min before aortic declamping. An additional group of five animals received 500 IU/kg AT in an open-label setting (AT+). Thrombin-antithrombin complexes (TAT), activated clotting times (ACT), AT and myeloperoxidase (MPO) activities, troponin T, and several hemodynamic parameters were measured before CPB and after weaning from CPB up to 120 min after aortic declamping. After 120 min of reperfusion, myocardial and lung biopsies were taken for histological examination. Results: AT effectively inhibited coagulation as assessed by ACT. In the AT and AT+ groups only, cardiac output (CO) and stroke volume (SV) showed a trend of post-ischemic recovery during the first 15 min after CPB. AT-attenuated reperfusion induced an increase in pulmonary arterial diastolic pressure (PAPD) but did not have significant effects on systemic or pulmonary vascular resistance. The effects of AT on SV, CO, and PAPD were fortified in the AT+ group. AT did not show effects on inflammatory changes in either myocardial or pulmonary tissue specimens. AT did not reduce post-ischemic troponin T release. Conclusion: Supplementary AT, in doses with significant anticoagulant effect, did not alleviate myocardial I/R injury in terms of histological inflammatory changes or post-ischemic troponin T release. Instead, however, AT-attenuated reperfusion induced an increase in pulmonary pressure after CPB. Mechanisms and clinical implications of these effects remain to be explored.