Beneficial effects of recombinant human activated protein C in a ewe model of septic shock.
OBJECTIVE
To investigate the effects of activated protein C (APC) in a clinically relevant animal model of septic shock.


METHODS
Prospective, randomized, controlled study.


METHODS
University medical center research laboratory.


METHODS
Eighteen female sheep (body weight, 27-35 kg).


METHODS
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 microg x kg(-1) x hr(-1), n = 9) or an equivalent volume of vehicle (n = 9) throughout the experimental period.


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.
Wang
Zhen
Z
Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium.
Su
Fuhong
F
Rogiers
Peter
P
Vincent
Jean-Louis
JL
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012756:Sheep; D012772:Shock, Septic / Q000188:drug therapy*
D011486:Protein C; D011994:Recombinant Proteins