Anti-inflammatory therapies in sepsis and septic shock

Despite advances in supportive care, the morbidity and mortality rate resulting from sepsis and septic shock remain high (30-50%). A central hypothesis driving sepsis research in recent years is that this syndrome is the result of excessive inflammation. Therapies designed to inhibit the inflammatory response were first shown to be markedly beneficial in animal models of sepsis and then tested in numerous clinical trials involving thousands of patients. Three broad anti-inflammatory strategies have been investigated. First, glucocorticoids in high doses administered at the onset of sepsis were studied. This approach proved unsuccessful. More recently, however, glucocorticoids in lower doses have been found to have a beneficial effect in patients with septic shock. Whether the mechanism of this treatment benefit is through inhibition of inflammation, or by counteracting a relative steroid refractoriness occurring during sepsis, remains unknown. The next focus of research were agents active against the endotoxin molecule. However, as with the experience with glucocorticoids, this approach lacked a consistent pattern of efficacy. It is unclear if this lack of efficacy is the result of endotoxin being a poor therapeutic target, or from testing agents which lacked the appropriate biological activity. Most recently, clinical trials in sepsis have focused on inhibiting specific host pro-inflammatory mediators (e.g., TNF, interleukins). While individual trials of inhibitors of these pro-inflammatory mediators failed to show a convincing benefit, pooling the results of these trials suggest that this approach has a marginal effect, supporting a role for excessive inflammation in sepsis. An unanswered question is reconcilling the very favourable effects obtained with anti-inflammatory treatments in animal models with the marginal results in humans. Further clinical and laboratory research is needed and may provide insight into more effective ways to use the anti-inflammatory agents already tested, or to investigate other potentially more effective anti-inflammatory agents in this syndrome.