Association between mitochondrial dysfunction and severity and outcome of septic shock.
BACKGROUND
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.


METHODS
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).


RESULTS
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).


CONCLUSIONS
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.
Bloomsbury Institute of Intensive Care Medicine, Wolfson Institute of Biomedical Research and Department of Medicine, University College London, London W1T 3AA, UK.
David
D
Brealey
Michael
M
Brand
Iain
I
Hargreaves
Simon
S
Heales
John
J
Land
Ryszard
R
Smolenski
Nathan A
NA
Davies
Chris E
CE
Cooper
Mervyn
M
Singer
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000145:classification / Q000378:metabolism* / Q000401:mortality; D015996:Survival Rate
D009569:Nitric Oxide; D000255:Adenosine Triphosphate