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.

Keywords: Sepsis; Septic shock; Redox homeostasis; Thiosulfate; Hydrogen peroxide

Core Tip: Sepsis mortality remains unacceptably high because there is no specific treatment to prevent or reverse the multiple organ failure and refractory hypotension that develops in this condition. An evidence-based analysis suggests that impaired systemic redox homeostasis caused by the toxic accumulation of hydrogen peroxide has a causal role in the pathogenesis of this often fatal illness. The data imply that restoration of redox homeostasis by therapeutic reduction of hydrogen peroxide will significantly reduce the morbidity and mortality associated with sepsis. A therapeutic intervention to reduce systemic levels of hydrogen peroxide is presented.