Sepsis: Current treatment modalities and future therapeutic targets

Despite many years of extensive research and increasing knowledge about the pathophysiological pathways and processes involved in the septic cascade, the mortality rates from severe sepsis (documented infection-induced organ dysfunction or hypoperfusion abnormalities) and septic shock (hypotension not reversed with fluid resuscitation) in most centres remain unacceptably high. Ongoing research continues to provide new information on the management of sepsis. Importantly, there is increasing awareness that the syndrome is common, lethal and expensive and that it therefore warrants an organised, expert-provided approach to care. The treatment of severe sepsis and septic shock consists of prompt identification of the infection site, early and aggressive antimicrobial therapy, supportive protocols based on "early-goal directed therapy" and adjunctive therapies. In addition, a large number of immunomodulatory agents continue to be studied in both experimental and clinical settings in an attempt to unearth efficacious agents that reduce mortality. Eventhough initial preclinical results have been often promising, the majority of these trials failed to have any significant effect on septic patients when compared to other critically ill intensive care patients. Indeed cytokine orchestration, especially anti-tumour necrosis factor (TNF) and anti-interleukin-1 (IL-1) agents, has uniformly failed to lower the mortality rates of critically ill septic patients. In this review, we address promising research efforts that target blocking potential novel therapeutic agents including apoptosis, migratory inibitory factor (MIF), the complement split product C5a, ethyl pyruvate, bacterial lipoprotein tolerance and DAMPs (damage associated molecular patterns) including high-mobility group box 1 (HMGB1), heat shock proteins (HSP) and myeloid related proteins (Mrps). Notwithstanding previous disappointments with novel strategies, these inflammatory mediators show significant potential for the development of new experimental targeted therapies for the treatment of severe sepsis. We discuss in depth the reasons why successful in-vivo models and results do not automatically translate into in-vitro studies and deliberate why these newer agents should engender cautious optimism.