Stevens, Jia Liu; (2022) The roles of redox and bioenergetics in perioperative outcomes following major surgery. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Imbalances in oxidation/reduction (redox) reactions can lead to oxidative and nitrosative stress, and mitochondrial function is central to redox regulation. Quantitative information incorporating all these elements in humans is scarce. This thesis tests the hypothesis that major surgery generates a state of stress that leads to perturbations in redox and bioenergetic processes and that these changes are linked to postoperative outcomes. This is an observational study of patients undergoing major hepato-pancreatico-biliary surgery. Increased oxidative and nitrosative stresses were evidenced by thiobarbituric acid reactive substances (TBARS) and nitrosothiols respectively. Increased intraoperative levels of TBARS were associated with postoperative morbidity, supporting the idea that oxidative stress is harmful perioperatively. Compensatory responses were also witnessed. Total reductive capacity, protein-adjusted total free thiols and the ferric-reducing ability of plasma, increased. Levels of nitric oxide (NO) metabolites, cyclic guanosine monophosphate, nitrite and nitrate, decreased from baseline to 24 hours later. Greater perioperative reductions of nitrate were found in the minor than in the major morbidity group, with baseline nitrate levels higher in the minor morbidity group compared with the major. Simultaneously, increases in LEAK (uncoupled) respiration from the skeletal muscle mitochondria were observed postoperatively, particularly in aerobically fit individuals. These findings may correspond to potential protective mechanisms in an environment of oxidative stress, which are: (1) upregulation of antioxidant pathways; (2) a switch away from the classic L-arginine NO pathway, and activation of alternative pathways, in conjunction with possible superior vascular endothelial health; and (3) adaptive mitochondrial uncoupling. To reflect the interconnected nature of redox biology, these findings of oxidative/nitrosative stress and mitochondrial respiration can be better summarised using the novel concept of the reactive species interactome, in which a state of stress induced by major surgery leads to both signals of harm and protection within the interactome during the first 24 hours after injury.

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