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 lead 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 the first postoperative day (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) at 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, with a concomitant increase in reductive capacity. Baseline nitrate was inversely associated with postoperative morbidity, and the hallmarks of poor postoperative outcome include changes in both oxidative stress and NO metabolism.

The Interplay between Perioperative Oxidative Stress and Hepatic Dysfunction after Human Liver Resection: A Prospective Observational Pilot Study

“…To the best of our knowledge, the present work represents the first human prospective study to evaluate serum and immunohistochemical markers for oxidative stress in regards to its correlation with hepatic function and potential to predict PHLF according to established criteria (the ISGLS) [23]. Previous evaluations in clinical settings were most commonly derived from liver transplantation rather than liver resection patients [5,14,19,38,39]. Representing one of the few human liver resection studies on oxidative stress, a previous work by Schwarz et al utilized static oxidation-reduction potential markers (sORPs) and antioxidant capacity (cORP) in the perioperative period through the application of the RedoxSYS ® diagnostic system [13].…”

“…They mainly focused on the (significant) association of oxidative stress and inflammation with overall outcome (severe complications) and did not specifically assess postoperative hepatic function. Similarly, another prospective observational study recently published by a British group evaluated perioperative redox changes in patients undergoing hepato-pancreatobiliary cancer surgery [14]. Their cohort was inhomogeneous as they included not only liver resections (55%) but also major pancreatic resections (32%) and even palliative surgery (13%).…”

“…Moreover, different levels of oxidative stress were reported depending on the surgical access used (open vs. minimally invasive) and the type of anesthesia applied [9,10]. On top of increased baseline ROS states in patients with chronic organ damage or cancer, [11,12] significant acute oxidative stress due to inflammation, blood loss, and ischemia can result in complications and impair patient recovery, with a potential impact on oncological outcomes [5,[13][14][15][16][17]. In the field of liver resection, in contrast to liver transplantation, only limited evidence exists on the perioperative dynamics of oxidative stress serum markers and their association with postoperative outcomes [5,[12][13][14]18,19].…”

“…The association between perioperative oxidative stress and hepatic function after liver resection remains unclear. A few publications have examined the connection with overall postoperative outcomes [5,13,14], but no study has so far assessed a direct link with pre-defined PHLF. Therefore, the aim of this pilot study was to investigate the perioperative dynamics of systemic and hepatic oxidative stress levels, their association with different patient-, disease-, and surgery-related factors, and a potential connection with PHLF.…”

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 – 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.…”