HypothesisMultiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation
Introduction
Patients with overwhelming infection, major trauma, or other critical illness often develop clinical and biochemical signs of multiple organ dysfunction, even though the affected organs might not have been directly damaged by the original insult. This failure is traditionally ascribed to the effect of inflammatory mediators that induce circulatory changes with resulting tissue hypoxia and cell damage. However, if this were the case, then failure should be irreversible, especially in organs such as liver and kidney whose constituent cells have poor regenerative capacity. Yet fulminant hepatic failure is exceedingly rare, survivors with so-called acute tubular necrosis seldom require long-term renal replacement therapy,1 and overall survival rates are roughly 50–60%. Especially remarkable is the fact that the histological appearances of the failed organs are often normal, with minimum or no apoptosis or necrosis, even in those who die.2
This finding suggests that the defect is principally functional rather than structural, and potentially reversible. Since increasing severity of sepsis is associated with a progressive fall in tissue oxygen consumption3 but with a rise in tissue oxygen tension,4 the problem is probably one of reduced cellular use of oxygen rather than tissue hypoxia per se. This finding is compatible with the coexisting decrease in perfused microvessels in sepsis,5 since similar changes are reported with hyperoxia.6
Tissue ATP concentration represents the balance between local supply and demand. We have shown that preservation of ATP concentrations in patients with sepsis is associated with eventual survival, despite concurrent inhibition of mitochondrial complex I of the electron transport chain.7 The fact that increased glycolytic generation of ATP is unlikely to compensate fully for reduced mitochondrial production suggests that cells are able to reduce their metabolism, and thus their ATP turnover. We propose that multiorgan failure is an attempt by the body to ensure cell survival in the face of sustained critical illness, with affected cells entering a dormant state analogous to hibernation or aestivation. This response enhances the chances of recovery of organ function should the patient survive. We further suggest that that this state of metabolic dormancy is induced via cytokine-mediated and hormone-mediated effects on cellular energy production, and might have evolved as a mechanism that increases the chances of survival in animals in which an external insult is potentially overwhelming.
Section snippets
The endocrine response to critical illness
The acute-phase response to critical illness is well recognised, with abrupt and massive release of stress hormones, including adrenocorticotropic hormone (and cortisol), catecholamines, vasopressin, glucagon, and growth hormone.8 These hormones help to maintain effective circulation and thus tissue oxygenation; increase generation of energy substrate in the form of glucose, fatty acids, and aminoacids from body stores, including liver and muscle; and heighten synthesis of both mitochondrial
Effects on respiration
The mitochondrial respiratory chain uses electrons liberated from oxidation of food, and traps free energy through the phosphorylation of ADP. The final reaction in this pathway, in which oxygen is reduced to water, uses over 90% of body VO2. ATP is produced mainly by this process of oxidative phosphorylation, though lesser amounts are generated via glycolysis. Availability of ATP can be regarded as the rate-limiting step of cellular metabolism.
In laboratory models, mitochondrial respiration is
Testing the hypothesis
To provide evidence for the role of mitochondria in the development of multiorgan failure, a temporal relation between rises in ATP concentrations, reduction in ATP turnover, and changing clinical status needs to be identified. Clinical improvement and restoration of organ function should also be associated with an increase in bioenergetic and metabolic activity. Proof of principle would be confirmed by use of bioenergetic modulators that hasten recovery. Direct measurement of ATP turnover in
Clinical implications
The principles of intensive-care medicine are essentially supportive, yet many interventions in the critically ill patient—including sedation, immunonutrition, mechanical ventilation, liberal blood transfusion, inotropes, and endocrine supplementation—have been associated with adverse outcomes. A more sophisticated understanding of the temporal and reactive sequence of hormonal, metabolic, inflammatory, and immunological changes during the acute and later phases of severe illness would promote
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