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Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome
Andrew F Shorr1, Gordon R Bernard, Jean-Francois Dhainaut
1Department of Medicine, Section of Pulmonary and Critical Care Medicine, Washington Hospital Center, Washington, DC, USA. afshorr@dnamail.com
Insights
Early changes in Protein C levels predict sepsis survival. Improved Protein C (activated) levels correlate with reduced mortality in sepsis patients, regardless of initial levels.
Area of Science:
- Sepsis research
- Hemostasis and thrombosis
- Critical care medicine
Background:
- Protein C is crucial for hemostasis and the host response to infection.
- Protein C depletion is a hallmark of sepsis, predicting patient morbidity and mortality.
- Early directional changes in Protein C levels may correlate with sepsis outcomes.
Purpose of the Study:
- To investigate the correlation between early directional changes in Protein C levels and sepsis patient outcomes.
- To determine if baseline and Day 1 Protein C levels are independent risk factors for mortality in sepsis.
- To assess the impact of drotrecogin alfa (activated) on Protein C levels and sepsis outcomes.
Main Methods:
- Analysis of 1574 patients from the PROWESS trial, categorized by baseline Protein C activity (< or = 40%, 41-80%, >80%).
- Logistic regression analysis of 28-day mortality in placebo patients to evaluate baseline and Day 1 Protein C levels as risk factors.
- Assessment of drotrecogin alfa (activated) treatment effects on Protein C levels and mortality.
Main Results:
- Both baseline and Day 1 Protein C levels were independent predictors of mortality in placebo patients.
- Severely deficient patients (< or = 40% Protein C) with improved levels by Day 1 had significantly reduced mortality (OR=0.43, P=0.03).
- Drotrecogin alfa (activated) improved Day 1 Protein C levels and reduced mortality, particularly in severely deficient patients.
Conclusions:
- Baseline Protein C levels independently predict sepsis outcomes.
- Day 1 changes in Protein C levels, irrespective of baseline values, also predict sepsis outcomes.
- Improved Protein C levels with drotrecogin alfa (activated) treatment may partially explain enhanced survival in sepsis.
Introduction:
Protein C, because of its central role in hemostasis, plays an integral role in the host response to infection. Protein C depletion, resulting from increased consumption, degradation, and/or decreased synthesis, is characteristic of sepsis and has been shown to predict morbidity and mortality. The objective of this study was to determine whether early directional changes in protein C levels correlate with outcome.
Methods:
Patients in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) clinical trial were assessed and categorized by baseline protein C (n = 1574). Deficiency was categorized as: severe deficiency, protein C levels < or = 40% of normal protein C activity (n = 615, 39% of patients); deficient, protein C levels 41-80% of normal protein C activity (n = 764, 48.5% of patients); and normal, >80% of normal protein C activity (n = 195, 12.4% of patients). Logistic regression analysis of 28-day mortality for placebo patients was used to investigate whether baseline and day 1 protein C levels were independent risk factors for mortality. The impact of treatment with drotrecogin alfa (activated) (DrotAA) was also assessed.
Results:
Protein C levels at baseline and day 1 were independent risk factors in placebo patients. If baseline protein C levels of severely deficient placebo patients remained < or = 40% at day 1 their odds of death increased (odds ratio = 2.75, P < 0.0001), while if levels improved to >40% by day 1 their risk of death decreased (odds ratio = 0.43, P = 0.03). If baseline protein C levels of placebo patients were >40% but decreased by > or = 10% on day 1, their risk of death increased (odds ratio = 1.87, P = 0.02). DrotAA treatment improved protein C levels by day 1 compared with placebo (P = 0.008) and reduced the risk of death in severely deficient (< or = 40%) patients at baseline. Treatment also decreased the number of severely protein C deficient (= 40%) patients and decreased the number of deficient (41-80%) patients and normal (>80%) patients who had a > or = 10% decrease in protein C levels by day 1.
Conclusion:
Baseline protein C levels were an independent predictor of sepsis outcome. Day 1 changes in protein C, regardless of baseline levels, were also predictive of outcome. The association of DrotAA treatment, increased protein C levels, and improved survival may partially explain the mechanism of action.
