Cytopathic Dysoxia Revisited

Most patients in septic shock die from the ensuing multi-organ dysfunction syndrome (MODS) rather than the acute inflammatory process per se. How systemic inflammation produces MODS remains unknown and many conundrums exist. It has been traditionally ascribed to tissue hypoxia secondary to microvascular shunting of blood away from nutrient capillaries. However, cell death, the expected corollary, is surprisingly absent in these failed organs despite gross biochemical and functional abnormality. With increasing severity of sepsis, tissue oxygen extraction falls with a decrease (relative or absolute) in tissue oxygen consumption. Nevertheless, tissue oxygen tensions rise, suggesting cellular availability but decreased utilisation, i.e. dysoxia. As mitochondrial oxygen consumption accounts for around 90% of total body oxygen utilisation, mitochondrial dysfunction leading to bioenergetic failure is a reasonable postulate to account for the biochemical and physiological perturbations witnessed in the septic patient. Importantly, nitric oxide and other reactive species, released in vast excess in sepsis, are potent inhibitors of mitochondrial oxidative phosphorylation. We review the increasing body of evidence derived from cell, animal and patient studies that implicate dysoxia as an important mechanism underlying the pathophysiology of multi-organ dysfunction.