Beneficial effects of recombinant human activated protein C in a ewe model of septic shock*
- 1 November 2007
- journal article
- Published by Wolters Kluwer Health in Critical Care Medicine
- Vol. 35 (11), 2594-2600
- https://doi.org/10.1097/01.ccm.0000287590.55294.40
Abstract
Objective: To investigate the effects of activated protein C (APC) in a clinically relevant animal model of septic shock. Design: Prospective, randomized, controlled study. Setting: University medical center research laboratory. Subjects: Eighteen female sheep (body weight, 27–35 kg). Interventions: Animals were fasted, anesthetized, invasively monitored, and mechanically ventilated before receiving 0.5 g/kg body weight of feces intraperitoneally to induce sepsis. Fluid resuscitation with Ringer lactate was titrated to maintain pulmonary artery occlusion pressure at baseline levels. No vasoactive agents or antibiotics were used. Two hours after the induction of sepsis, animals were randomized to receive an infusion of APC (24 μg·kg−1·hr−1, n = 9) or an equivalent volume of vehicle (n = 9) throughout the experimental period. Measurements and Main Results: The APC-treated animals had significantly higher arterial pressure, urine output, Pao2/Fio2 ratios, and thoracopulmonary compliance than the control animals. They had lower pulmonary arterial pressure and arterial lactate concentrations than the control animals. Plasma colloid oncotic pressure was better maintained in the APC-treated group than in the control group (p < .05). Prothrombin time and activated partial thromboplastin time were altered less, and plasma D-dimer concentrations were significantly lower in the APC-treated group than in the control group (p < .05). The blood protein C concentration and platelet count were maintained better in the APC-treated group than in the control group (p < .05). APC administration was associated with significantly longer survival (median, 27 hrs vs. 20 hrs; p < .05). At postmortem examination, the lung wet/dry ratio was significantly lower in the APC group than in the control group (6.3 ± 0.7 vs. 7.1 ± 1.2, p < .05). Conclusions: In this clinically relevant model of septic shock due to fecal peritonitis, administration of APC had beneficial effects on hemodynamic variables, gas exchange, lactic acidosis, and coagulation abnormalities. Higher colloid oncotic pressures and lower lung wet/dry ratios at autopsy suggest preserved endothelial integrity. APC administration resulted in prolonged survival.Keywords
This publication has 34 references indexed in Scilit:
- Sepsis in European intensive care units: Results of the SOAP study*Critical Care Medicine, 2006
- Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment*Critical Care Medicine, 2005
- Activated Protein C Mediates Novel Lung Endothelial Barrier EnhancementJournal of Biological Chemistry, 2005
- Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell protein C receptor and activation of protease-activated receptor-1Thrombosis and Haemostasis, 2005
- Inhibition of coagulation and inflammation by activated protein C or antithrombin reduces intestinal ischemia/reperfusion injury in ratsCritical Care Medicine, 2004
- Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia*Critical Care Medicine, 2004
- Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial*Critical Care Medicine, 2003
- Gene Expression Profile of Antithrombotic Protein C Defines New Mechanisms Modulating Inflammation and ApoptosisJournal of Biological Chemistry, 2001
- Efficacy and Safety of Recombinant Human Activated Protein C for Severe SepsisNew England Journal of Medicine, 2001
- Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.JCI Insight, 1987