Cardiovascular function and tissue-type plasminogen activator kinetics during aortic cross-clamping or positive end-expiratory pressure ventilation. An experimental study in the pig

Abstract

Background: Aortic cross-clamping (AXC) and declamping (DC) are associated with homeostatic alterations, some of which are among the determinantsfor perioperative outcome. Myocardial and thromboembolic complications are predominant causes of perioperative morbidity and mortality. Impairmentof the fibrinolytic system has been postulated as the cause of the hypercoagulable state related to major surgery. We aimed to analyze: thepharmacological modulation by isoflurane (ISO), sodium nitroprusside (SNP) and milrinone (MIL) of the cardiovascular responses to AXC; the impact ofan acutely lowered cardiac output on the AXC-induced hemodynamic response pattern; the dynamic regulation of the endothelial derived tissue-typeplasminogen activator (t-PA, the key enzyme for initiation of fibrinolysis); and the impact of AXC and positive end-expiratory pressure ventilation(PEEP) on endogenous fibrinolysis. Methods: In multiple-organ porcine models, that included an infra-renal aortic snare and a system for graded pericardial infusion, we measured cardiacoutput, coronary sinus (antegrade and retrograde thermodilution, respectively), hepatic arterial, renal arterial and portal venous blood flows (perivascularultrasound ). Arterio-venous concentration gradients of both total and active t-PA, and respective plasma flows were obtained simultaneously for thecoronary, pulmonary, splanchnic and hepatic vascular beds, thereby allowing determinations of regional net release or uptake rates of t-PA . For precisequantifications of t-PA, a porcine standard was developed for the employed enzyme-linked immunosorbent assay. Results: Increases in mean arterial pressure induced by AXC were not attenuated by either ISO, SNP or MIL, although the AXC-induced increase insystemic vascular resistance was attenuated by 1.4% ISO. During a moderate decrease in stroke volume (produced by pericardial infusion), no regionalvasoconstriction was observed in response to AXC, while a more pronounced decrease in stroke volume totally abolished all circulatory responses toAXC. Plasma concentrations of both total and active t-PA differed among vascular regions, with the highest level in portal venous and the lowest level inhepatic venous blood. Marked differences in regional net fluxes of t-PA were found, with a high basal net release across the splanchnic vasculature, and aprominent net uptake across the liver. Although AXC did not induce significant alterations in regional net fluxes of t-PA, following DC, an acuteprofibrinolytic response occurred across preportal organs. However, hepatic t-PA net uptake was sufficient to preclude preportal t-PA net release toinfluence systemic plasma levels. With PEEP, a rapid increase in preportal net release of t-PA was induced. Despite a pronounced decrease in total liverblood flow, a significant increase in hepatic net uptake of t-PA was induced during PEEP, and hepatic venous t-PA plasma concentrations were thus notaltered. Notwithstanding, PEEP was associated with increased systemic levels of t-PA. Conclusions: AXC-induced cardiovascular responses are open to modulation through different pharmacological actions. The prevailing cardiac outputis decisive for circulatory adaption during AXC. The dynamic regulation of regional t-PA fluxes is organ- specific. The acute AXC/DC sequence and PEEPare associated with a profibrinolytic response in the splanchnic vascular bed.