DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL OF MONOCLONAL-ANTIBODY TO HUMAN TUMOR-NECROSIS-FACTOR IN TREATMENT OF SEPTIC SHOCK

Background Despite the availability of potent antibiotics and intensiv e care, mortality rates from septic shock are 40-70%, We assessed the safety and efficacy of murine monoclonal antibody to human tumour necr osis factor alpha (TNF alpha MAb) in the treatment of septic shock. Me thods In a randomised, multicentre, double-blind, placebo-controlled c linical trial in 105 hospitals in the USA and Canada, we randomly assi gned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949 ) or placebo (0.25% human serum albumin n=930). Our main outcome measu rement was the rate of all-cause mortality at 28 days. Findings 382 (4 0.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 93 0 who received placebo had died at 28 days (95% CI -0.02 to 0.07, p=0. 27). We found no association between therapy with TNF alpha MAb and in creased rapidity in reversal of initial shock or prevention of subsequ ent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb thera py. Coagulopathy but not other organ or system failures, was significa ntly decreased in the TNF alpha MAb group compared with placebo (day 7 , p < 0.001; day 28, p = 0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha M4b grou p. Interpretation We did not find an improvement in survival after sep tic shock with TNF alpha MAb. Therapy not solely dependent on TNF alph a blockade may be required to improve survival.