Cytopathic hypoxia - Is oxygen use impaired in sepsis as a result of an acquired intrinsic derangement in cellular respiration?

Accumulating data support the view that sepsis is associated with an acquired intrinsic derangement in cellular respiration, a phenomenon that might be called cytopathic hypoxia. Several different biochemical mechanisms have been postulated to account for cytopathic hypoxia. in sepsis, including reversible inhibition of cytochrome oxidase by nitric oxide, irreversible inhibition of one or more mitochondrial respiratory complexes by peroxynitrite. Perhaps the most important mechanism underlying the development of cytopathic hypoxia is activation of the nuclear enzyme, poly-(ADP-ribosyl)-polymerase (PARP), which catalyzes the formation of homopolymers consisting of repeating adenosine nucleotide subunits and leads to depletion of cellular stores of nicotinamide adenine dinucleotide (NAD+/NADH). If cytopathic hypoxia is pathophysiology of sepsis and multiple organ dysfunction syndrome, then clinical strategies designed to improve tissue perfusion and oxygen delivery are doomed to failure. Rather, efforts in the future will need to focus on pharmacologic interventions designed to preserve normal mitochondrial function and energy production in sepsis.