Anti-inflammatory therapies in sepsis and septic shock

Despite advances in supportive care, the morbidity and mortality rate resul ting from sepsis and septic shock remain high (30 - 50%). A central hypothe sis driving sepsis research in recent years is that this syndrome is the re sult of excessive inflammation. Therapies designed to inhibit the inflammat ory 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 we re studied. This approach proved unsuccessful. More recently, however, gluc ocorticoids in lower doses have been found to have a beneficial effect in p atients with septic shock. Whether the mechanism of this treatment benefit is through inhibition of inflammation, or by counteracting a relative stero id 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 mediato rs (e.g., TNF, interleukins). While individual trials of inhibitors of thes e pro-inflammatory mediators failed to show a convincing benefit, pooling t he results of these trials suggest that this approach has a marginal effect , supporting a role for excessive inflammation in sepsis. An unanswered que stion is reconcilling the very favourable effects obtained with anti-inflam matory treatments in animal models with the marginal results in humans. Fur ther clinical and laboratory research is needed and may provide insight int o more effective ways to use the anti-inflammatory agents already tested, o r to investigate other potentially more effective anti-inflammatory agents in this syndrome.