title: A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome.
abstract: Sepsis and multiple organ dysfunction syndrome (MODS) are major causes of morbidity and mortality in the intensive care unit. Recently mitochondrial dysfunction has been proposed as a key early cellular event in critical illness. A growing body of experimental evidence suggests that mitochondrial therapies are effective in sepsis and MODS. The aim of this article is to undertake a systematic review of the current experimental evidence for the use of therapies for mitochondrial dysfunction during sepsis and MODS and to classify these mitochondrial therapies. A search of the MEDLINE and PubMed databases (1950 to July 2009) and a manual review of reference lists were conducted to find experimental studies containing data on the efficacy of mitochondrial therapies in sepsis and sepsis-related MODS. Fifty-one studies were included in this review. Five categories of mitochondrial therapies were defined-substrate provision, cofactor provision, mitochondrial antioxidants, mitochondrial reactive oxygen species scavengers, and membrane stabilizers. Administration of mitochondrial therapies during sepsis was associated with improvements in mitochondrial electron transport system function, oxidative phosphorylation, and ATP production and a reduction in cellular markers of oxidative stress. Amelioration of proinflammatory cytokines, caspase activation, and prevention of the membrane permeability transition were reported. Restoration of mitochondrial bioenergetics was associated with improvements in hemodynamic parameters, organ function, and overall survival. A substantial body of evidence from experimental studies at both the cellular and the organ level suggests a beneficial role for the administration of mitochondrial therapies in sepsis and MODS. We expect that mitochondrial therapies will have an increasingly important role in the management of sepsis and MODS. Clinical trials are now required.
authors.affiliation: Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand. anna.dare@gmail.com
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Dare
authors.forename: Anthony R J
authors.initials: AR
authors.lastname: Phillips
authors.forename: Anthony J R
authors.initials: AJ
authors.lastname: Hickey
authors.forename: Anubhav
authors.initials: A
authors.lastname: Mittal
authors.forename: Benjamin
authors.initials: B
authors.lastname: Loveday
authors.forename: Nichola
authors.initials: N
authors.lastname: Thompson
authors.forename: John A
authors.initials: JA
authors.lastname: Windsor
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003067:Coenzymes / Q000378:metabolism / Q000627:therapeutic use*; D004579:Electron Transport / Q000187:drug effects; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D051336:Mitochondrial Membranes / Q000187:drug effects; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D020127:Recovery of Function; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000975:Antioxidants; D003067:Coenzymes; D016166:Free Radical Scavengers