Recombinant hirudin enhances cardiac output and decreases systemic vascular resistance during reperfusion after cardiopulmonary bypass in a porcine model.
OBJECTIVE
Cardiopulmonary bypass and surgical stress are accompanied by a systemic inflammatory response and activation of coagulation. Thrombin forms fibrin and activates platelets and neutrophils. Consequently, disseminated microthrombosis might increase capillary vascular resistance and thus impair reperfusion. We hypothesized that recombinant hirudin, a direct inhibitor of thrombin, could attenuate coagulation and enhance microvascular flow during reperfusion.


METHODS
Twenty pigs undergoing 60 minutes of aortic clamping and 75 minutes of normothermic perfusion were randomized in a blinded setting to receive an intravenous bolus of recombinant hirudin (10 mg, 0.4 mg/kg; n = 10) or placebo (n = 10) 15 minutes before aortic declamping and then continued with an intravenous 135-minute infusion of recombinant hirudin (3.75 mg/h, 0.15 mg/kg) or placebo. Thrombin-antithrombin complexes, activated clotting times, and several hemodynamic parameters were measured before cardiopulmonary bypass, after weaning from cardiopulmonary bypass, and at 30, 60, 90, and 120 minutes after aortic declamping. Intramucosal pH and Pco(2) were measured from the luminal surface of ileum simultaneously with arterial gas analysis at 30-minute intervals.


RESULTS
Recombinant hirudin inhibited thrombin formation after aortic declamping; at 120 minutes, thrombin-antithrombin complexes levels (microg/L, mean +/- SD) were 75 +/- 21 and 29 +/- 44 (P <.001) for placebo and pigs receiving recombinant hirudin, respectively. When compared with the placebo group, pigs receiving recombinant hirudin showed significantly higher stroke volume, cardiac output, and lower systemic vascular resistance at 60 and 90 minutes after aortic declamping (P <.05). Based on arteriomucosal Pco(2) and pH differences, progressive worsening of intestinal microcirculatory perfusion occurred in the placebo group but not in the recombinant hirudin group.


CONCLUSIONS
Infusion of thrombin inhibitor recombinant hirudin during reperfusion was associated with attenuated postischemia left ventricular dysfunction and decreased vascular resistance. Consequently microvascular flow was improved during ischemia-reperfusion injury. Control of thrombin formation during reperfusion may be a feasible approach to improve oxygen delivery to reperfused vascular beds.
Department of Cardiothoracic Surgery, Helsinki University Central Hospital, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland. mikko.jormalainen@hus.fi
Mikko
M
Jormalainen
Antti E
AE
Vento
Ulla
U
Wartiovaara-Kautto
Raili
R
Suojaranta-Ylinen
O Juhani
OJ
Rämö
Jari
J
Petäjä
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001784:Blood Gas Analysis; D002315:Cardiopulmonary Bypass; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics; D006629:Hirudins / Q000031:analogs & derivatives; D007422:Intestines / Q000503:physiopathology; D008297:Male; D008365:Manometry; D011183:Postoperative Complications / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000627:therapeutic use*; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects*
D000925:Anticoagulants; D006629:Hirudins; D011994:Recombinant Proteins; C083544:lepirudin