Metabolic theory of septic shock

Figure 1 Septic shock begins with a systemic inflammatory reaction to an infection. A contemporaneous increase in metabolism is initiated, which can deplete reserves of critical nutrients such as glutathione. Glutathione is crucial for the neutralization of H₂O₂, a toxic, membrane-permeable oxidizing agent generated as a by-product of cellular metabolism. Depletion of cellular glutathione results in elevation of H₂O₂ which can diffuse out of organ parenchymal cells and into capillary endothelium before reaching the bloodstream. Once in the systemic circulation, excess H₂O₂ is distributed throughout the body resulting in systemic oxidative damage to plasma components, organs and blood vessels. The net result is H₂O₂ induced coagulopathy, immunocyte apoptosis and microvascular dysfunction leading to disseminated intravascular coagulation, immunosuppression, organ failure and septic shock respectively. H₂O₂ inhibits GPx and catalase, which are critical anti-oxidant enzymes required for H₂O₂ neutralization. This prevents restoration of normal plasma and tissue redox balance while exacerbating oxidative tissue damage. H₂O₂ can also activate nuclear factor-κB (NF-κB) contributing to the inappropriate activation of this master pro-inflammatory transcription factor observed in septic shock. The pathologic activation of NF-kB contributes to elevated tumor necrosis factor-alpha levels, another potent generator of intracellular H₂O₂. GPx: Glutathione peroxidase.

Figure 2 Pathologically elevated serum H₂O₂ levels can account for the general physiological, histological and clinical abnormalities observed in septic shock. Red blood cell glutathione accounts for a major portion of serum redox buffering capacity and is depleted in septic shock non-survivors vs. survivors. Brain neuron function is highly vulnerable to H₂O₂ oxidative stress and is manifested by electroencephalographic changes, which can appear before clinical encephalopathy is evident. Studies show that septic shock survivors upregulate serum antioxidant capacity (which decreases H₂O₂), while non-survivors are unable to do so. This suggests that elevated H₂O₂ is a necessary concomitant to the development of septic shock and recovery is preceded by decreasing H₂O₂. The individual clinical course, bookended by these extremes of H₂O₂, is influenced by parameters such as individual antioxidant capacity, susceptibility to oxidative stress, co-morbidities, age, general health and organ system involved.