Mechanisms of Disease
The Lancet, Volume 360, Issue 9328, Pages 219 - 223, 20 July 2002 <Previous Article|Next Article>doi:10.1016/S0140-6736(02)09459-XCite or Link Using DOI

David Brealey MRCP a, Michael Brand PhD a, Iain Hargreaves PhD b, Simon Heales MRCPath b, John Land MRCPath b, Ryszard Smolenski PhD c, Nathan A Davies PhD d, Prof Chris E Cooper PhD d, Prof Mervyn Singer FRCP a

Sepsis-induced multiple organ failure is the major cause of mortality and morbidity in critically ill patients. However, the precise mechanisms by which this dysfunction is caused remain to be elucidated. We and others have shown raised tissue oxygen tensions in septic animals and human beings, suggesting reduced ability of the organs to use oxygen. Because ATP production by mitochondrial oxidative phosphorylation accounts for more than 90% of total oxygen consumption, we postulated that mitochondrial dysfunction results in organ failure, possibly due to nitric oxide, which is known to inhibit mitochondrial respiration in vitro and is produced in excess in sepsis.
We did skeletal muscle biopsies on 28 critically ill septic patients within 24 h of admission to intensive care, and on nine control patients undergoing elective hip surgery. The biopsy samples were analysed for respiratory-chain activity (complexes I-IV), ATP concentration, reduced glutathione (an intracellular antioxidant) concentration, and nitrite/nitrate concentrations (a marker of nitric oxide production).
Skeletal muscle ATP concentrations were significantly lower in the 12 patients with sepsis who subsequently died than in the 16 septic patients who survived (p=0·0003) and in controls (p=0·05). Complex I activity had a significant inverse correlation with norepinephrine requirements (a proxy for shock severity, p=0·0003) and nitrite/nitrate concentrations (p=0·0004), and a significant positive correlation with concentrations of reduced glutathione (p=0·006) and ATP (p=0·03).
In septic patients, we found an association between nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction, and decreased ATP concentrations that relate to organ failure and eventual outcome. These data implicate bioenergetic failure as an important pathophysiological mechanism underlying multiorgan dysfunction.