title: Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues.
abstract: Human sepsis is thought to be systemic inflammatory response syndrome (SIRS) that is activated by invasive infection. The multiple organ dysfunction syndrome (MODS) is the identified failure of critical organ function in patients that have sustained SIRS. Because SIRS and MODS are consequences  of the excessive activation of inflammation, extensive research and numerous clinical trials have pursued treatments that would modify the inflammatory response. This presentation reviews the normal local mechanisms of inflammation and provides a theoretical framework for the transition of  the inflammatory process to a systemic level. Clinical trials with biomodulators to block or inhibit inflammation have generally failed to improve the outcomes in patients with severe sepsis, septic shock, and MODS. The role of counter-inflammatory signaling and the newer concept of the cholinergic  anti-inflammatory pathway are being investigated, and newer hypotheses are focusing upon the balancing of proinflammatory and counter-inflammatory mechanisms as important directions for newer therapies. It is concluded that failure to define novel and effective treatments reflects fundamental  gaps in our understanding of inflammation and its regulation.
authors.affiliation: Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. dfry@consultmpa.com
authors.forename: Donald E
authors.initials: DE
authors.lastname: Fry
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000503:physiopathology*; D018046:Protein C Inhibitor / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology*; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D018046:Protein C Inhibitor; D014409:Tumor Necrosis Factor-alpha