Sepsis: Evidence-based pathogenesis and treatment.

Abstract

Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure, irreversible shock, and death. Sepsis has been vexing health care providers for centuries due to its insidious onset, generalized metabolic dysfunction, and lack of specific therapy. A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness. A hypermetabolic response requires supraphysiological amounts of energy, which is mostly supplied via oxidative phosphorylation generated ATP. A by-product of oxidative phosphorylation is hydrogen peroxide (H2O2), a toxic, membrane-permeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state. Continued production of mitochondrial H2O2 can overwhelm cellular reductive (antioxidant) capacity leading to a build-up within cells and eventual diffusion into the bloodstream. H2O2 is a metabolic poison that can inhibit enzyme systems leading to organ failure, microangiopathic dysfunction, and irreversible septic shock. The toxic effects of H2O2 mirror the clinical and laboratory abnormalities observed in sepsis, and toxic levels of blood H2O2 have been reported in patients with septic shock. This review provides evidence to support a causal role for H2O2 in the pathogenesis of sepsis, and an evidence-based therapeutic intervention to reduce H2O2 levels in the body and restore redox homeostasis, which is necessary for normal organ function and vascular responsiveness.