Metabolic Resuscitation Strategies to Prevent Organ Dysfunction in Sepsis.

Significance: Sepsis is the main cause of death among patients admitted to the intensive care unit. As current treatment is limited to antimicrobial therapy and supportive care, mortality remains high, which warrants efforts to find novel therapies. Recent Advances: Mitochondrial dysfunction is emerging as a key process in the induction of organ dysfunction during sepsis, and metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis. Critical Issues: Here, we review novel strategies to maintain organ function in sepsis by precluding mitochondrial dysfunction by lowering energetic demand to allow preservation of adenosine triphosphate-levels, while reducing free radical generation. As the most common strategy to suppress metabolism, that is, cooling, does not reveal unequivocal beneficial effects and may even increase mortality, caloric restriction or modulation of energy-sensing pathways (i.e., sirtuins and AMP-activated protein kinase) may offer safe alternatives. Similar effects may be offered when mimicking hibernation by hydrogen sulfide (H2S). In addition H2S may also confer beneficial effects through upregulation of antioxidant mechanisms, similar to the other gasotransmitters nitric oxide and carbon monoxide, which display antioxidant and anti-inflammatory effects in sepsis. In addition, oxidative stress may be averted by systemic or mitochondria-targeted antioxidants, of which a wide range are able to lower inflammation, as well as reduce organ dysfunction and mortality from sepsis. Future Directions: Mitochondrial dysfunction plays a key role in the pathophysiology of sepsis. As a consequence, metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis.