Association between mitochondrial dysfunction and severity and outcome of septic shock

doi:10.1016/S0140-6736(02)09459-X

The Lancet

Volume 360, Issue 9328, 20 July 2002, Pages 219-223

https://doi.org/10.1016/S0140-6736(02)09459-X Get rights and content

Summary

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).

Findings

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).

Interpretation

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.

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.

Section snippets

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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Mechanisms of DiseaseAssociation between mitochondrial dysfunction and severity and outcome of septic shock

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

GLOSSARY

Free Rad Biol Med

FEBS Lett

Arch Biochem Biophys

Chest

J Chromatogr

Neurosci Lett

Biochim Biophys Acta

Biochim Biophys Acta

Multiple organ failure: pathophysiology and potential future therapy

Ann Surg

Microcirculatory oxygenation and shunting in sepsis and shock

Crit Care Med