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Interleukin-1 Blockade Attenuates Mediator Release and Dysregulation of the Hemostatic Mechanism During Human Sepsis

Marja A. Boermeester, MD; Paul A. M. van Leeuwen, MD, PhD; Susette M. Coyle, RN; Gert Jan Wolbink, MD; C. Erik Hack, MD, PhD; Stephen F. Lowry, MD
Arch Surg. 1995;130(7):739-748. doi:10.1001/archsurg.1995.01430070061012.
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Objective:  To define the influence of interleukin-1 activity on coagulation and fibrinolytic system activation and the release of proinflammatory mediators in the early human response to severe infection.

Study Design:  All patients with severe sepsis syndrome who were enrolled from two surgical centers that were participating in a randomized, double-blind, placebo controlled, multicenter, multinational trial of recombinant human interleukin-1 receptor antagonist in the treatment of sepsis syndrome.

Population:  Twenty-six patients with sepsis syndrome received an intravenous loading dose of recombinant human interleukin-1 receptor antagonist (100 mg) or placebo followed by a continuous 72-hour 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:  Plasma levels of the anaphylatoxin C3a and thrombin-antithrombin III complexes were reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours (P<.05). Similarly, parameters of fibrinolysis, tissue-type plasminogen activator, and plasminogen activator inhibitor type 1 but not plasmin-α2-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–α1-antitrypsin complexes and phospholipase A2 levels were also significantly reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours.

Conclusions:  The results confirm that activation of the coagulation and fibrinolytic systems and release of soluble inflammatory mediators are consistently observed in patients with severe sepsis syndrome. Interleukin-1 activity contributes to activation of these processes as documented by the reduction in surrogate activation markers during recombinant human interleukin-1 receptor antagonist treatment.(Arch Surg. 1995;130:739-748)

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