Regionally differentiated fibrinolytic responses during volume-resuscitated acute endotoxemia in pigs

Background: Microcirculatory dysfunction and formation of microthrombi are common in sepsis as a result of a procoagulant state. A profibrinolytic change has however, been reported in early sepsis. This study investigates systemic and regional (pulmonary, preportal, hepatic, renal) fibrinolytic capacity as mirrored by fluxes of tissue-type plasminogen activator (t-PA) in response to acute endotoxemia and volume resuscitation. Methods: Eight anaesthetized, ventilated pigs (24-29kg) were instrumented for systemic and regional haemodynamic monitoring. Aortic, pulmonary arterial, portal, hepatic and renal venous blood samples were collected. Following baseline stabilisation, Escherichia coli endotoxin was infused for 120 min. During the last 30 min of infusion, volume resuscitation was initiated targeting baseline cardiac output, and animals were observed for 3 h. Total tPA was analyzed by ELISA calibrated for porcine tPA. Net organ tPA fluxes were calculated based on in/outflowing plasma concentrations and regional blood flows. Results: Preportal release and hepatic extraction of tPA was observed at baseline. Pulmonary and renal net fluxes of tPA were not significantly different from zero. Endotoxemia increased plasma tPA levels in all investigated vascular beds. Preportal tPA release increased approximately 10-fold and hepatic extraction increased approximately 12-fold in non-resuscitated acute endotoxemia. No significant changes in pulmonary or renal tPA fluxes were observed. Volume resuscitation restored net fluxes to baseline values while plasma levels remained elevated approximately twofold compared with baseline. Conclusion: Acute endotoxemia induces a prompt, marked and regionally differentiated pro-fibrinolytic response that cannot be discerned based on systemic levels of circulating tPA and that was normalized during volume resuscitation.