Mechanisms of DiseaseAssociation between mitochondrial dysfunction and severity and outcome of septic shock
Introduction
Sepsis is the systemic inflammatory response associated with an infectious insult. It is the leading cause of death in critically ill patients, and the predominant cause of multiple organ dysfunction.1 However, precise mechanisms through which organ dysfunction develops remain unknown, as do reasons for its persistence long after cessation of the acute inflammatory phase. Although microvascular flow redistribution undoubtedly occurs,2 we and others have shown increased tissue oxygen tension in the organs of animals and patients with sepsis.3, 4 This finding suggests that the predominant defect might lie in cellular oxygen use (tissue dysoxia) rather than in oxygen delivery per se.
Mitochondrial oxidative phosphorylation is responsible for over 90% of total body oxygen consumption and ATP generation. The respiratory chain (electron-transport chain) includes four individual enzyme complexes (I–IV). These enzyme complexes, notably NADH-ubiquinone oxidoreductase (complex I) and cytochrome C oxidase (complex IV), can be inhibited by reactive oxygen and nitrogen species such as nitric oxide.5, 6, 7 These reactive species are produced in substantial excess during sepsis and are also generated by the mitochondria.8 Complex I inhibition by nitric oxide is facilitated, in vitro, by depletion of the intracellular antioxidant reduced glutathione.5, 6 Concentrations of this antioxidant are also known to decrease in septic states.9, 10
No study has yet addressed whether alterations in bioenergetic status in severe sepsis are associated with increased nitric oxide production, mitochondrial dysfunction, and antioxidant depletion, and whether these abnormalities relate to organ failure and to outcome. To address these questions, we undertook a systematic study of mitochondrial dysfunction in critically ill patients with sepsis admitted to intensive care.
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Patients
After obtaining approval from the ethics committee of the University College London Hospitals National Health Service Trust, patients were recruited from the intensivecare unit or from the orthopaedic department. Patients (or their next-of-kin) were asked for informed consent (or agreement) before enrolment.
Patients with recent-onset severe sepsis or septic shock (as defined by standard criteria11) were enrolled. Those with severe coagulopathies (platelet count <30×109/L or international
Results
Of the 28 patients with sepsis, 16 survived the septic episode (survivors). Non-survivors died in the intensivecare unit, with a median stay of 6 days. All patients had increased cardiac outputs and all but two were requiring norepinephrine to maintain a mean blood pressure in excess of 60 mm Hg. All were mechanically ventilated and 12 underwent haemofiltration. For patients who did not respond to high-dose norepinephrine (seven eventual survivors and two non-survivors), a 16 mg dose of
Discussion
We have shown, in patients with sepsis and multiple organ failure, a relation between shock severity (as gauged by norepinephrine requirements to maintain an adequate blood pressure), mitochondrial dysfunction, ATP depletion, intracellular antioxidant (reduced glutathione) depletion, and nitric oxide production (as gauged by nitrite/nitrate concentrations) in skeletal muscle. Despite being unable to distinguish clinically between eventual survivors and non-survivors, significant differences
GLOSSARY
- bioenergetic status
- Energy “stored” in a form (ATP) that is readily available for cellular metabolism.
- oxidative phosphorylation
- The coupling of energy released from substrate oxidation by the respiratory chain to the synthesis of ATP.
- respiratory chain
- Terminal pathway of oxidative phosphorylation, a series of mitochondrial oxidoreductive molecules including cytochromes responsible for the stepwise transfer of electrons from substrates to oxygen.
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