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Finally, an Effective New Treatment for Severe Sepsis?

Patients with severe sepsis have reduced levels of activated protein C, a substance with antithrombotic and anti-inflammatory properties. This observation led researchers to conduct an industry-sponsored, multicenter, randomized trial to compare a 96-hour infusion of recombinant activated protein C (drotrecogin alfa activated) and placebo in 1690 patients with severe sepsis.

Enrollment criteria were extensive, but basically, the trial included patients with known or suspected sources of infection, clinical findings of systemic inflammatory response syndrome, and 1 or more organs with sepsis-induced dysfunction. The lungs and the abdomen were the most common sources of infection; a third of the patients had positive blood cultures; and, among patients with identified pathogens, roughly equal numbers of infections with gram-positive and gram-negative organisms were noted.

The 28-day mortality rate was significantly lower in the protein C group than in the placebo group (24.7 percent vs. 30.8 percent, P=0.005). Levels of D-dimer and interleukin-6 -- markers for coagulopathy and inflammation, respectively -- fell significantly with protein C infusion compared with placebo infusion. The only adverse effect was serious bleeding (3.5 percent of patients treated with protein C vs. 2.0 percent with placebo, P=0.06).

Comment: Until now, the search for new therapeutic agents to reduce mortality from sepsis has been frustrating. An editorialist calls this trial a landmark in sepsis research and draws a straightforward conclusion: "Activated protein C should be given to patients who meet all the inclusion criteria [for this study]." However, the drug is not yet FDA-approved for use in the U.S.

— AS Brett

Published in Journal Watch General Medicine March 20, 2001

Citation(s):

Bernard GR et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001 Mar 8 344 699-709.

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• Medline abstract (Free)

Matthay MA. Severe sepsis -- A new treatment with both anticoagulant and antiinflammatory properties. N Engl J Med 2001 Mar 8 344 759-762.

• Original article (Subscription may be required)
• Medline abstract (Free)