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. 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 microg x kg(-1) x 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.     

Hemodynamic effects of recombinant human activated protein C in patients with septic shock

Purpose

The aim of this study is to examine the effects of recombinant human activated protein C (rhAPC) on hemodynamic parameters in patients with septic shock.

Methods

This is a retrospective study of 2 university-hospital critical care units. Patients with septic shock with pulmonary artery catheterization or transthoracic thermodilution monitoring were studied. We matched patients with septic shock with at least 2 organ failures (18 treated with rhAPC and 18 controls) on sex, age, sequential organ failure assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II, and sepsis etiology. We recorded norepinephrine dose and hemodynamic parameters at baseline and 24, 36, and 48 hours after the real or theoretical start of rhAPC treatment.

Results

Mean arterial pressure remained stable in both groups. In rhAPC patients, norepinephrine requirements, initially higher than in controls, were significantly lower at 48 hours, and stroke volume at 24 and 48 hours improved (P < .05).

Conclusion

Recombinant human activated protein C use correlated with improved hemodynamic parameters and decreased norepinephrine requirements. The retrospective nature of the study limits the strength of these findings.     

Rapid and beneficial hemodynamic effects of activated protein C in septic shock patients

Objective Because recombinant human activated protein C (rhAPC) reduces NO production during sepsis, it could improve the vascular tone. We tested whether rhAPC reduces the dose of norepinephrine required to maintain mean arterial pressure (MAP) in septic shock patients.Design and setting Retrospective study in intensive care unit of two university hospitals.Patients Twenty-two septic shock patients with at least two organ failures were retrospectively investigated for MAP and the required dose of norepinephrine before and 24 h after rhAPC administration. A control group of 22 septic shock patients with at least two organ failures who did not receive rhAPC was matched on age, SAPS II, MAP, and norepinephrine dose at the time of the theoretical start of rhAPC.Measurements and results The MAP remained stable and similar in the two groups (86±16 vs. 89±9 mmHg at 24 h). The required dose of norepinephrine increased in the control group (+38%, from –41% to +38%) but decreased in the treated group (–33%, from –74% to +11%).Conclusions rhAPC rapidly improved the vascular tone in septic shock patients as assessed by a decrease in the norepinephrine dose required to maintain arterial pressure.     

Activated protein C

Summary.  Protein C is a vitamin K-dependent plasma protein zymogen whose genetic mild or severe deficiencies are linked with risk for venous thrombosis or neonatal purpura fulminans, respectively. Studies over past decades showed that activated protein C (APC) inactivates factors (F) Va and VIIIa to down-regulate thrombin generation. More recent basic and preclinical research on APC has characterized the direct cytoprotective effects of APC that involve gene expression profile alterations, anti-inflammatory and anti-apoptotic activities and endothelial barrier stabilization. These actions generally require endothelial cell protein C receptor (EPCR) and protease activated receptor-1. Because of these direct cytoprotective actions, APC reduces mortality in murine endotoxemia and severe sepsis models and provides neuroprotective benefits in murine ischemic stroke models. Furthermore, APC reduces mortality in patients with severe sepsis (PROWESS clinical trial). Although much remains to be clarified about mechanisms for APC's direct effects on various cell types, it is clear that APC's molecular features that determine its antithrombotic action are partially distinct from those providing cytoprotective actions because we have engineered recombinant APC variants with selective reduction or retention of either anticoagulant or cytoprotective activities. Such APC variants can provide relatively enhanced levels of either cytoprotective or anticoagulant activities for various therapeutic applications. We speculate that APC variants with reduced anticoagulant action but normal cytoprotective actions hold the promise of reducing bleeding risk because of attenuated anticoagulant activity while reducing mortality based on direct cytoprotective effects on cells.     

Activated protein C increases sensitivity to vasoconstriction in rabbit Escherichia coli endotoxin-induced shock

Introduction  

The aim of this study was to investigate the effects of activated protein C (aPC) on vascular function, endothelial injury, and haemostasis in a rabbit endotoxin-induced shock model.     

Comparative effects of recombinant human activated protein C and dexamethasone in experimental septic shock

Purpose  

To compare the effects of recombinant human activated protein C (APC) and glucocorticoids alone and in combination in non-anesthetized resuscitated septic shock induced by cecal ligation and puncture (CLP) on (a) survival, (b) hemodynamics, and (c) vascular reactivity. The effects of treatments on major cellular pathways likely implicated were also studied.