Research
Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated)
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* Corresponding author: Andrew F Shorr afshorr@dnamail.com
1 Washington Hospital Center, 110 Irving Street NW, Washington DC 20010, USA
2 Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Centre, 893 South Delaware Street, Indianapolis, Indiana 46285, USA
3 Critical Care Center, Sabadell Hospital, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Parc Taulí 1, 08208 Sabadell, Spain
4 Critical Care Medicine Research Group in Department of Intensive Care Medicine, Tampere University Hospital, Teiskontie 35, Tampere, 33521, Finland
5 Adult Intensive Care Unit, Guy's and St Thomas' NHS Foundation Trust, Lambeth Palace Road, London, SE1 7EH, UK
6 Service de Réanimation Polyvalente - CRICS group, Hopital Bretonneau-CHRU, 2 Boulevard Tonnellé, Tours, 37044, France
7 Service de Réanimation Polyvalente - CIC-P 0801 Inserm - CRICS group, CHRU Dupuytren, Limoges, 87042, France
8 Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
9 Department of Anesthesiology and Intensive Care, Friedrich-Schiller University, Erlanger Allee 101, Jena, 07743, Germany
Critical Care 2010, 14:R229 doi:10.1186/cc9382
See related commentary by Levi, http://ccforum.com/content/15/1/105
Published: 21 December 2010Abstract
Introduction
Serial alterations in protein C levels appear to correlate with disease severity in patients with severe sepsis, and it may be possible to tailor severe sepsis therapy with the use of this biomarker. The purpose of this study was to evaluate the dose and duration of drotrecogin alfa (activated) treatment using serial measurements of protein C compared to standard therapy in patients with severe sepsis.
Methods
This was a phase 2 multicenter, randomized, double-blind, controlled study. Adult patients with two or more sepsis-induced organ dysfunctions were enrolled. Protein C deficient patients were randomized to standard therapy (24 μg/kg/hr infusion for 96 hours) or alternative therapy (higher dose and/or variable duration; 24/30/36 μg/kg/hr for 48 to 168 hours). The primary outcome was a change in protein C level in the alternative therapy group, between study Day 1 and Day 7, compared to standard therapy.
Results
Of 557 patients enrolled, 433 patients received randomized therapy; 206 alternative, and 227 standard. Baseline characteristics of the groups were largely similar. The difference in absolute change in protein C from Day 1 to Day 7 between the two therapy groups was 7% (P = 0.011). Higher doses and longer infusions were associated with a more pronounced increase in protein C level, with no serious bleeding events. The same doses and longer infusions were associated with a larger increase in protein C level; higher rates of serious bleeding when groups received the same treatment; but no clear increased risk of bleeding during the longer infusion. This group also experienced a higher mortality rate; however, there was no clear link to infusion duration.
Conclusions
The study met its primary objective of increased protein C levels in patients receiving alternative therapy demonstrating that variable doses and/or duration of drotrecogin alfa (activated) can improve protein C levels, and also provides valuable information for incorporation into potential future studies.
Trial registration
ClinicalTrials.gov identifier: NCT00386425.