INTERLEUKIN-1 BLOCKADE ATTENUATES MEDIATOR RELEASE AND DYSREGULATION OF THE HEMOSTATIC MECHANISM DURING HUMAN SEPSIS

Objective: To define the influence of interleukin-1 activity on coagul ation and fibrinolytic system activation and the release of proinflamm atory mediators in the early human response to severe infection. Study Design: All patients with severe sepsis syndrome who were enrolled fr om two surgical centers that were participating in a randomized, doubl e-blind, placebo controlled, multicenter, multinational trial of recom binant human interleukin-1 receptor antagonist in the treatment of sep sis syndrome. Population: Twenty-six patients with sepsis syndrome rec eived an intravenous loading dose of recombinant human interleukin-1 r eceptor antagonist (100 mg) or placebo followed by a continuous 72-hou r infusion of recombinant human interleukin-1 receptor antagonist (1.0 [n=9] or 2.0 [n=8] mg/kg per hour) or placebo (n=9). Outcome Measure: Responses up to 72 hours after initiation of treatment. Results: Plas ma levels of the anaphylatoxin C3a and thrombin-antithrombin III compl exes were reduced in the high-dose recombinant human interleukin-1 rec eptor antagonist treatment group after 72 hours (P<.05). Similarly, pa rameters of fibrinolysis, tissue-type plasminogen activator, and plasm inogen activator inhibitor type 1 but not plasmin-alpha(2)-antiplasmin complexes, were also significantly reduced (P<.05) after 72 hours of treatment with a high dose of recombinant human interleukin-1 receptor antagonist. Neutrophil elastase-alpha(1)-antitrypsin complexes and ph ospholipase A(2) levels were also significantly reduced in the high-do se recombinant human interleukin-1 receptor antagonist treatment group after 72 hours. Conclusions: The results confirm that activation of t he coagulation and fibrinolytic systems and release of soluble inflamm atory mediators are consistently observed in patients with severe seps is syndrome. Interleukin-1 activity contributes to activation of these processes as documented by the reduction in surrogate activation mark ers during recombinant human interleukin-1 receptor antagonist treatme nt.