Excessive production of inflammatory mediators during invasive
infection plays a key role in the pathogenesis of
septic shock. In an attempt to improve survival of patients with this lethal syndrome, agents were developed to selectively inhibit mediators in this inflammatory response. Despite promising preclinical results, several different mediator-specific
anti-inflammatory agents failed to demonstrate significant benefit in patients. There was, however, a significant difference in mortality between preclinical and clinical trials. The median control mortality in preclinical trials, performed almost uniformly in highly lethal
sepsis models, was 88%. In clinical trials however, the median control mortality rate was much lower, at 41%. A recent meta-regression analysis of these preclinical and clinical trials in combination with prospective confirmatory studies demonstrated that risk of death as assessed by control group mortality rate significantly altered the treatment effect of these agents in both humans and animals. While
anti-inflammatory agents were very beneficial in groups with high control mortality rates, they were ineffective or harmful in groups with low control mortality rates. Thus, variation in the risk of death due to
sepsis provides a basis for the marked difference in the efficacy of these
anti-inflammatory agents in preclinical and clinical trials over the last decade. In contrast to mediator-specific
anti-inflammatory agents,
glucocorticoids and activated
protein C have recently demonstrated significant beneficial effects in individual clinical trials. However,
glucocorticoids were studied only in patients with vasopressor-dependent
septic shock, which is associated with a high control mortality rate (i.e. 61%) similar to the level at which mediator-specific agents would have been expected to be markedly beneficial. Furthermore, consistent with earlier findings for mediator-specific
anti-inflammatory agents, analysis of the activated
protein C study also demonstrated a relationship between risk of death and effect of treatment. Developing better methods to define high-risk septic populations for treatment with
anti-inflammatory agents will increase the efficacy of this therapeutic approach and minimize its potential for harm.