Chest
Volume 120, Issue 3, September 2001, Pages 915-922
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Clinical Investigations in Critical Care
Low Levels of Protein C Are Associated With Poor Outcome in Severe Sepsis

https://doi.org/10.1378/chest.120.3.915Get rights and content

Abstract

Study objective

To investigate whether protein C levels predict 30-day mortality rate, shock status, duration of ICU stay, and ventilator dependence in patients with sepsis.

Design

Retrospective analysis of a subset of a previously published, prospective, randomized, double-blind, placebo-controlled trial (“Effects of Ibuprofen on the Physiology and Survival of Patients With Sepsis” [ISS]).

Setting

A multicenter study performed in the United States and Canada (seven sites).

Patients

Seventy hospitalized patients with acute severe sepsis and failure in one or more organs at entry into the ISS trial.

Measurements and Main Results

Blood samples were obtained from all patients at baseline and at 20, 44, 72, and 120 h after the initiation of study drug (ibuprofen or placebo) infusion. Data obtained at these times included platelet count, prothrombin time, and partial thromboplastin time. The results described in this article are based on a subset of the total ISS population for whom additional coagulation assays were performed on the blood samples obtained at baseline and 44 h. These assays included protein C antigen, D-dimer, and fibrinogen levels. A total of 63 of the 70 patients (90%) studied in this report had acquired protein C deficiency at entry to the ISS trial (baseline). The presence and severity of acquired protein C deficiency were associated with poor clinical outcome, including lower survival rate, higher incidence of shock, and fewer ICU-free and ventilator-free days.

Conclusions

Acquired protein C deficiency may be useful in predicting clinical outcome in patients with sepsis. Clinical studies are warranted to determine whether the replacement of protein C in sepsis patients may improve outcome.

Section snippets

Materials and Methods

The ISS was a randomized, double-blind, placebo-controlled multicenter study of IV ibuprofen in 455 patients with severe sepsis. The study was approved by the institutional review board at each of the seven centers in the United States and Canada, and consent was obtained from each patient or their next of kin. Patient characteristics and the main study results have been reported elsewhere.16 Patients were enrolled into the study from October 1989 to March 1995.

Patients with a known or

Results

Table 2 displays baseline characteristics and results of the coagulation marker levels (ie, D-dimer, fibrinogen, protein C antigen, and platelets) of the seven subgroups of patients selected from the ISS trial as defined in the “Material and Methods” section. A total of 58 of the 70 patients (83%) included in this study received placebo, and the other 12 patients received ibuprofen in the ISS study. There were no statistically significant (ie, p≤ 0.05) differences between the two treatment

Discussion

Activated protein C is a serine protease that inhibits coagulation factors Va and VIIIa, subsequently blocking the generation of thrombin. Both plasminogen activator inhibitor (PAI)-1 and activated thrombin-activatable fibrinolysis inhibitor (TAFI) are inhibitors of the endogenous fibrinolytic system. TAFI is activated by thrombin. Activated protein C also exhibits profibrinolytic activity by neutralizing PAI-1 or by limiting the activation of TAFI by limiting thrombin generation.1920 Protein C

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    Drs. Yan, Helterbrand, and Wright are employees of Eli Lilly and Company. Dr. Hartman was an employee of Lilly during the collaboration of this study. This study is a scientific collaboration between Lilly and Dr. Bernard.

    Funds needed for conducting the coagulation assays at the University of Vermont were provided by Eli Lilly and Co. The ibuprofen clinical trial was supported by grant HL43167 from National Heart, Lung, and Blood Institute of the National Institutes of Health.

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