EFFECT OF A CHIMERIC ANTIBODY TO TUMOR-NECROSIS-FACTOR-ALPHA ON CYTOKINE AND PHYSIOLOGICAL-RESPONSES IN PATIENTS WITH SEVERE SEPSIS - A RANDOMIZED, CLINICAL-TRIAL

Objectives: Tumor necrosis factor (TNF)-alpha appears central to the p athogenesis of severe sepsis, but aspects of the cytokine cascade and the link to physiologic responses are poorly defined. We hypothesized that a monoclonal antibody to TNF-alpha given early in the course of s evere sepsis would modify the pattern of systemic cytokine release and , as a consequence, resuscitation fluid requirements, net proteolysis, and hypermetabolism would be reduced. Design: Randomized, double blin d, placebo-controlled trial. Setting: Critical Care Unit and Universit y Department of Surgery in a single tertiary care center. Patients: Fi fty six patients (from 92 eligible patients) with severe sepsis. Twent y eight patients were randomized to treatment, and were comparable wit h the placebo group for age, gender, race, Acute Physiology and Chroni c Health Evaluation II score, and site and type of infection. Interven tions: A 300-mg single dose of cA2 (a chimeric neutralizing antibody t o TNF-alpha) was given intravenously within 12 hrs of the onset of sev ere sepsis. Standard surgical and intensive care therapy was otherwise delivered. Measurements and Main Results: Plasma concentrations of TN F-alpha, interleukin (IL)-1 beta IL-6, IL-8, IL-10, soluble 75-kilodal ton TNF-alpha receptor (sTNFR-75), and IL-1 beta receptor antagonist ( IL-1ra) were measured by sandwich enzyme linked immunosorbent assay be fore cA2 infusion, 8 hrs later, and then daily for a minimum of 4 days . Sequential changes in total body protein, body water spaces, and res ting energy expenditure over 21 days were measured, as soon as patient s achieved hemodynamic stability, by in vivo neutron activation analys is, tritium and bromide dilution, and indirect calorimetry, respective ly. Twenty one patients died, ten having received cA2. Suppression of measurable TNF-alpha was observed at 8 hrs with subsequent rebound by 24 hrs after cA2 treatment. The concentrations of other cytokines were high, were not reduced by intervention, and decreased logarithmically over 5 days. Both groups reached hemodynamic stability at similar tim es (57.5 +/- 11.8 hrs in controls vs. 58.6 +/- 9.2 hrs in the cA2 grou p) and following similar volumes of infused fluids (29.1 +/- 3.4 L vs. 28.9 +/- 4.4 L). No differences in net proteolysis, resolution of bod y water expansion, or alteration in resting energy expenditure were de monstrated. Conclusion: A single dose of cA2 did not alter the overall pattern of cytokine activation or the profound derangements in physio logic function that accompany severe sepsis.