Anti-tumor necrosis factor therapy in sepsis: Update on clinical trials and lessons learned

Objective: Tumor necrosis factor (TNF) is an important mediator involved in the pathogenesis of sepsis, We review clinical studies investigating the efficacy of anti-TNF therapy in decreasing mortality rates in septic patients. Data Sources: We conducted a computerized bibliographic search of randomized, clinical, multicenter trials studying the effects of anti-TNF therapy in the treatment of sepsis, We included all primary studies, reviewed all published meta-analyses, and contacted primary investigators of multicenter trials where necessary. Data Synthesis, Almost all randomized studies targeting TNF during sepsis show a small, albeit nonsignificant, benefit in decreasing mortality, Strategies using monoclonal antibodies are more effective than are strategies using TNF receptor proteins. Analysis of randomized multicenter trials shows a small hut significant benefit with anti-TNF therapeutic strategies. Furthermore, a recent study in 2634 septic patients using a murine anti-TNF antibody shows a 3.6% significant benefit in reducing mortality. Conclusions: Anti-TNF strategies are only partially effective in patients with sepsis, Although individual studies show small, nonsignificant benefits, analysis of all trial data as well as data from a recent trial in a large population of septic patients show that anti-TNF strategies may confer a small survival benefit. Better characterization of patients and a more multimodal approach by concomitantly targeting other mediators involved in sepsis may be helpful in enlarging the clinical benefit of anti-TNF therapy.