Abstract
Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-infectious critically ill patients and healthy individuals (p = 0.001). TOS/TAC was associated with severity scores, procalcitonin, IL-6, -10, -27, IFN-γ, Hsp72, Hsp90, survivin protein, and survivin isoforms -2B, -ΔΕx3, -WT (p < 0.001). In a propensity probability (age-sex-adjusted) logistic regression model, only sepsis was independently associated with TOS/TAC (Exp(B) 25.4, p < 0.001). The AUCTOS/TAC (0.96 (95% CI = 0.93–0.99)) was higher than AUCTAC (z = 20, p < 0.001) or AUCTOS (z = 3.1, p = 0.002) in distinguishing sepsis. TOS/TAC, TOS, survivin isoforms -WT and -2B, Hsp90, IL-6, survivin protein, and repressed TAC were strong predictors of mortality (p < 0.01). Oxidant/antioxidant status is impaired in septic compared to critically ill patients with trauma or surgery and is related to anti-apoptotic, inflammatory, and innate immunity alterations. The unpredicted TOS/TAC imbalance might be related to undefined phenotypes in patients and healthy individuals.
Highlights
Oxidative stress is common in critical illness, as a result of the generation of oxygen and nitrogen-derived free radicals and disruption of redox signaling or antioxidant control systems, including the decline in key antioxidant compounds [1]
We showed that sepsis is independently associated with an increased total oxidative status (TOS)/total antioxidant capacity (TAC) imbalance compared to non-septic intensive care unit (ICU) patients
We showed that TOS/TAC changes are affected by various inflammatory biomolecules, the innate immune system alarmins Hsp72 and Hsp90, the anti-apoptotic protein survivin, and sepsis-related severity
Summary
Oxidative stress is common in critical illness, as a result of the generation of oxygen and nitrogen-derived free radicals and disruption of redox signaling or antioxidant control systems, including the decline in key antioxidant compounds [1]. Oxidative stress is defined as an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of an organism. Total oxidative status (TOS) represents the oxidizing state of patients and is usually estimated through direct measurement of relatively stable ROS family members, such as hydrogen peroxide (H2 O2 ), peroxyl radicals, and DNA damage markers. TOS may be estimated indirectly by examining the oxidative damage these radicals cause to lipids, proteins, or nucleic acids. An imbalance in cellular redox homeostasis is regulated by enzymatic or non-enzymatic antioxidant machinery systems, expressed by the total antioxidant capacity (TAC) [4]. Current research focuses on the evaluation of possible correlations between TOS or TAC, as well as clinical severity, in intensive care unit (ICU)
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