Anticytokine therapies in sepsis

The pro-inflammatory cytokines, tumor necrosis factor (TNF) and interleukin-1 (IL-1), are widely assumed to participate in the initial systemic manifestations of sepsis. While the toxicities of excessive cytokine activity have been well described in animal models, clinical evaluations often fail to detect circulating forms of these mediators in critically ill patients. It is now evident that a diverse array of host mechanisms serve to attenuate or block excessive cytokine influences. This homeostatic response includes the generation of natural antagonists, such as soluble receptors of TNF and an antagonist of IL-1 that prevents binding of the cytokine to its receptor. Recombinantly derived forms of these natural cytokine antagonists have proven effective in preventing many of the adverse consequences of sepsis. Prospective clinical trials of these agents are currently underway. While results of such trials are not fully available at present, it is likely that one or more therapies directed against TNF and IL-1 may prove effective in the management of septic shock.