Metabolic theory of septic shock

Abstract

Septic shock is a life threatening condition that can develop subsequent to infection. Mortality can reach as high as 80% with over 150000 deaths yearly in the United States alone. Septic shock causes progressive failure of vital homeostatic mechanisms culminating in immunosuppression, coagulopathy and microvascular dysfunction which can lead to refractory hypotension, organ failure and death. The hypermetabolic response that accompanies a systemic inflammatory reaction places high demands upon stored nutritional resources. A crucial element that can become depleted early during the progression to septic shock is glutathione. Glutathione is chiefly responsible for supplying reducing equivalents to neutralize hydrogen peroxide, a toxic oxidizing agent that is produced during normal metabolism. Without glutathione, hydrogen peroxide can rise to toxic levels in tissues and blood where it can cause severe oxidative injury to organs and to the microvasculature. Continued exposure can result in microvascular dysfunction, capillary leakage and septic shock. It is the aim of this paper to present evidence that elevated systemic levels of hydrogen peroxide are present in septic shock victims and that it significantly contributes to the development and progression of this frequently lethal condition.

Keywords: Hydrogen peroxide; Hypermetabolic; Sepsis; Septic shock; Systemic inflammatory response syndrome.

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.