Sepsis: Evidence-based pathogenesis and treatment

Figure 1 Krebs cycle derived reducing equivalents (NADH, FADH2) donate electrons that are processed by the electron transport chain during oxidative phosphorylation. Up to 5% of electrons (e^-) will normally escape the electron transport chain (ETC) into the mitochondrial matrix (electron leakage)[14-16]. These electrons combine with molecular oxygen (O₂) to form superoxide anion radical (O₂^-), which is metabolized by superoxide dismutase (SOD) to hydrogen peroxide (H₂O₂) that in turn is converted to glutathione disulfide (GS-SG) and water via glutathione peroxidase (GPX) and its reducing co-factor glutathione (GSH). Critical illness hypermetabolic states increase ETC activity leading to enhanced electron leakage and far greater H₂O₂ formation, which can deplete cellular GSH resulting in a build-up of H₂O₂ in cells and blood causing bioenergetic dysfunction and organ failure.

Figure 2 Confounding in Sepsis: The hypermetabolic state that accompanies a critical illness is a confounding factor in the relationship between systemic infection (exposure) and sepsis (effect). Hypermetabolism generates large amounts of hydrogen peroxide (H₂O₂), which is both a risk factor for the development of sepsis and is bilaterally associated (double arrow) with infection. Systemic infection triggers a hypermetabolic state accompanied by greatly amplified generation of H₂O₂, but non-infectious critical illness can also generate large amounts of H₂O₂ due to the accompanying hypermetabolic state. High levels of blood H₂O₂ can cause systemic lymphocyte apoptosis leading to significant lymphocytopenia, which predisposes to infection. Thus, systemic build-up of H₂O₂ can lead to sepsis. This can occur after an infectious or non-infectious insult. In the latter instance, infection may develop as a result of H₂O₂ induced systemic lymphocyte apoptosis and subsequent lymphocytopenia.

Figure 3 Sepsis and intervening variables: Hydrogen peroxide is an intervening variable between a critical illness (exposure), which triggers a systemic hypermetabolic response, and sepsis (effect). Hypermetabolism, characterized by the systemic inflammatory response syndrome, is the clinical manifestation of supraphysiological cellular H₂O₂ production. This will eventually lead to reductive depletion and sepsis (H₂O₂ toxicity, bioenergetic organ failure) if allowed to persist. Prolonged critical illness (hypermetabolism) and dietary restriction severely limit the body’s ability to re-establish and maintain redox homeostasis. Under these circumstances, direct acting reducing equivalents must be supplied to the patient to aid in neutralizing excess H₂O₂. A hypermetabolic response to critical illness or injury may continue for years after hospital discharge and contribute to increased inpatient and post-discharge morbidity and mortality (chronic critical illness and post sepsis syndrome respectively)[52-55].

Figure 4 H₂O₂ induced immune system failure. Sequences 4A and 4B illustrate the common hypermetabolic response in infectious and non-infectious critical illness leading to H₂O₂ toxicity induced organ failure and sepsis. Lymphocytes are highly sensitive to H₂O₂ induced apoptosis. Lymphopenia is thus a manifestation of H₂O₂ induced immune system failure secondary to a hypermetabolic response in both infectious and non-infectious critical illness. H₂O₂ induced lymphopenia will predispose to de-novo infection in otherwise sterile critical illness and may cause a super-infection in patients on appropriate antibiotics. H₂O₂ toxicity and/or super-infection may contribute to sepsis mortality despite appropriate antibiotics.