The following was excerpted from Modern nutrition in health and disease (Tenth Edition), edited by Maurice E Shils et al. It's a heavy, hefty and impressive tome that's worth checking out.
Septic shock has been characterized as a modern disease, a consequence of improved critical care for normally fatal injuries. Advancements in wound treatment, fluid replacement, and cardiorespiratory support give patients a better chance of surviving an initial trauma. However, these patients can be at an increased risk of severe infection, especially if the protective barrier of the skin is breached to a significant extent (e.g., severe burn injuries). A massive release of TNF-a, IL-lp, and other cytokines can occur, triggering widespread vascular permeability, vasodilation, and intravascular coagulation. This can ultimately lead to shock, organ failure, and death.
Anticytokine strategies have included intravenous infusion of IL-IRa, monoclonal antibodies directed against TNF-a, and chimeric constructs of sTNFR fused to the Fc region of immunoglobulin G. Although phase II trials have been promising, larger phase III trials have often failed to demonstrate increased survival for patients treated with anticytokine regimens (43). Some of the problems may be related to timing (relative to onset of infection): Treatment after IL-1 [3 and TNF-a have been released may be too late if these cytokines have already triggered the multiple kinin, eicosanoid, and cellular effector mechanisms involved in shock.
Other reasons for phase III trial failures may have been related to patient selection. Post hoc analyses of some trials have indicated that perhaps anticytokine therapy was beneficial for subsets of patients, that is, protecting the most severe cases and/or those with high circulating cytokine concentrations from cardiovascular collapse. How¬ever, anticytokine treatment may have inhibited important antimicrobial mechanisms in patients who had a moderate cytokine response and therefore increased their risk of fatality through infection. If this is true, then one challenge for future anticytokine therapy is to devise very rapid cytokine analyses that can identify the appropriate patients for treatment.