Perioperative redox changes in patients undergoing hepato-pancreatico-biliary cancer surgery

Abstract

Background Tissue injury induces inflammation and the surgical stress response, which are thought to be central to the orchestration of recovery or deterioration after surgery. Enhanced formation of reactive oxygen and nitrogen species accompanies the inflammatory response and triggers separate but integrated reduction/oxidation (redox) pathways that leads to oxidative and/or nitrosative stress (ONS). Quantitative information on ONS in the perioperative period is scarce. This single-centre exploratory study investigated the effects of major surgery on ONS and systemic redox status, and their potential associations with postoperative morbidity. Methods Blood was collected from 56 patients at baseline, end of surgery (EoS), and on day-1. Postoperative morbidity was recorded using the Clavien-Dindo classification and further categorised into minor, moderate and severe. Plasma/serum measures included markers of lipid oxidation (thiobarbituric acid-reactive substances; TBARS, 4-hydroxynonenal; 4-HNE, 8-iso-prostaglandin F2⍺; 8-isoprostanes). Total reducing capacity was measured using total free thiols (TFTs) and ferric reducing ability of plasma (FRAP). Nitric oxide (NO) formation/metabolism, was measured using cyclic guanosine monophosphate (cGMP), nitrite, nitrate and total nitroso-species (RxNO). Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-⍺) were measured to evaluate inflammation. Results Both oxidative stress (TBARS) and nitrosative stress (total nitroso-species) increased from baseline to EoS (+ 14%, P = 0.003 and + 138%, P < 0.001 respectively), along with an increase in overall reducing capacity (+ 9%, P = 0.03) at EoS and protein-adjusted total free thiols (+ 12%, P = 0.001) day-1 after surgery. Nitrite, nitrate and cGMP concentrations declined concomitantly from baseline to day-1. Baseline nitrate was 60% higher in the minor morbidity group compared to severe (P = 0.003).The increase in intraoperative TBARS was greater in severe compared to minor morbidity (P = 0.01). The decline in intraoperative nitrate was more marked in the minor morbidity group compared to severe (P < 0.001), whereas the cGMP decline was greatest in the severe morbidity group (P = 0.006). Conclusion In patients undergoing major HPB surgery, intraoperative oxidative and nitrosative stress increased, whilst reductive capacity also increased. Baseline nitrate was inversely associated with postoperative morbidity, and the hallmarks of poor postoperative outcome include changes in both oxidative stress and NO metabolism.

Uncoupled redox stress: how a temporal misalignment of redox-regulated processes and circadian rhythmicity exacerbates the stressed state

“…He suggested a direct equivalence in the recognition and treatment of perturbations of E h . While it is already possible to 'redox phenotype' individual patients along their disease trajectory for research purposes [58][59][60], relevant measures need to be developed for clinical practice. Exploration of how these might be applied in understanding the drivers for E h in different disorders at different stages of the hysteresis curve would make it possible to identify relatively simple interventions.…”