Abstract
Septic shock in humans is characterized by a hyperdynamic circulation, elevated systemic mixed-venous O2 content and lactic acidosis. An apparent defect in O2 extraction along with increased anaerobic mechanism has prompted investigation of the role of hypoxia in the production of organ dysfunction and death. Although “classic” hypoxia, i.e. anemic, hypoxic, and stagnant hypoxia may be present at the level of the macro- or microcirculation, there is increasing evidence for “cytopathic hypoxia”, failure of oxygen utilization in the presence of adequate tissue pO2. The process of cellular energy production via oxidative phosphorylation is discussed, and the general mechanisms through which it may be perturbed are reviewed: 1) failure to deliver adequate substrate to the electron transport chain, 2) dysfunction of the electron transport chain, 3) failure of proper coupling between electron flux and ATP synthesis, (4) failure to deliver adequate O2 to the electron transport chain. The first three mechanisms define cytotopathic hypoxia and are discussed in-depth, with reference to possible relevance in human sepsis. Synergy between “classic hypoxia” and cytopathic hypoxia is hypothesized. The expanding role of nitric oxide and reactive nitrogen intermediates in this process is highlighted.
Published Version
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