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Background: The fraction of inspired oxygen (FiO 2 ) administered during general anaesthesia varies widely despite international recommendations to administer FiO 2 0.8 to all anaesthetised patients to reduce surgical site infections (SSIs). Anaesthetists remain concerned that high FiO 2 administration intraoperatively may increase harm, possibly through increased oxidative damage and inflammation, resulting in more complications and worse outcomes. In previous systematic reviews associations between FiO 2 and SSIs have been inconsistent, but none have examined how FiO 2 affects perioperative oxidative stress. We aimed to address this uncertainty by reviewing the available literature., Methods: EMBASE, MEDLINE, and Cochrane databases were searched from inception to March 9, 2020 for RCTs comparing higher with lower perioperative FiO 2 and quantifying oxidative stress in adults undergoing noncardiac surgery. Candidate studies were independently screened by two reviewers and references hand-searched. Methodological quality was assessed using the Cochrane Collaboration Risk of Bias tool., Results: From 19 438 initial results, seven trials (n=422) were included. Four studies reported markers of oxidative stress during Caesarean section (n=328) and three reported oxidative stress during elective colon surgery (n=94). Risk of bias was low (four studies) to moderate (three studies). Pooled results suggested high FiO 2 was associated with greater malondialdehyde, protein-carbonyl concentrations and reduced xanthine oxidase concentrations, together with reduced antioxidant markers such as superoxide dismutase and total sulfhydryl levels although total antioxidant status was unchanged., Conclusions: Higher FiO 2 may be associated with elevated oxidative stress during surgery. However, limited studies have specifically reported biomarkers of oxidation. Given the current clinical controversy concerning perioperative oxygen therapy, further research is urgently needed in this area., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Reactive oxygen species (ROS) are essential for cellular signaling and physiological function. An imbalance between ROS production and antioxidant protection results in a state of oxidative stress (OS), which is associated with perturbations in reduction/oxidation (redox) regulation, cellular dysfunction, organ failure, and disease. The pathophysiology of OS is closely interlinked with inflammation, mitochondrial dysfunction, and, in the case of surgery, ischemia/reperfusion injury (IRI). Perioperative OS is a complex response that involves patient, surgical, and anesthetic factors. The magnitude of tissue injury inflicted by the surgery affects the degree of OS, and both duration and nature of the anesthetic procedure applied can modify this. Moreover, the interindividual susceptibility to the impact of OS is likely to be highly variable and potentially linked to underlying comorbidities. The pathological link between OS and postoperative complications remains unclear, in part due to the complexities of measuring ROS- and OS-mediated damage. Exogenous antioxidant use and exercise have been shown to modulate OS and may have potential as countermeasures to improve postoperative recovery. A better understanding of the underlying mechanisms of OS, redox signaling, and regulation can provide an opportunity for patient-specific phenotyping and development of targeted interventions to reduce the disruption that surgery can cause to our physiology. Anesthesiologists are in a unique position to deliver countermeasures to OS and improve physiological resilience. To shy away from a process so fundamental to the welfare of these patients would be foolhardy and negligent, thus calling for an improved understanding of this complex facet of human biology.

Introduction: Oxygen is the most commonly administered drug to mechanically ventilated critically ill adults, yet little is known about the optimum oxygen saturation (SpO 2 ) target for these patients; the current standard of care is an SpO 2 of 96% or above. Small pilot studies have demonstrated that permissive hypoxaemia (aiming for a lower SpO 2 than normal by using a lower fractional inspired oxygen concentration (FIO 2 )) can be achieved in the critically ill and appears to be safe. This approach has not been evaluated in a National Health Service setting. It is possible that permissive hypoxaemia may be beneficial to critically ill patients thus it requires robust evaluation., Methods and Analysis: Targeted OXygen therapY in Critical illness (TOXYC) is a feasibility randomised controlled trial (RCT) to evaluate whether recruiting patients to a study of permissive hypoxaemia is possible in the UK. It will also investigate biological mechanisms that may underlie the links between oxygenation and patient outcomes. Mechanically ventilated patients with respiratory failure will be recruited from critical care units at two sites and randomised (1:1 ratio) to an SpO 2 target of either 88%-92% or ≥96% while intubated with an endotracheal tube. Clinical teams can adjust FIO 2 and ventilator settings as they wish to achieve these targets. Clinical information will be collected before, during and after the intervention and blood samples taken to measure markers of systemic oxidative stress. The primary outcome of this study is feasibility, which will be assessed by recruitment rate, protocol adherence and withdrawal rates. Secondary outcomes will include a comparison of standard critical care outcome measures between the two intervention groups, and the measurement of biomarkers of systemic oxidative stress. The results will be used to calculate a sample size, likely number of sites and overall length of time required for a subsequent large multicentre RCT., Ethics and Dissemination: This study was approved by the London - Harrow Research Ethics Committee on 2 November 2017 (REC Reference 17/LO/1334) and received HRA approval on 13 November 2017. Results from this study will be disseminated in peer-reviewed journals, at medical and scientific meetings, in the NIHR Journals Library and patient information websites., Trial Registration Number: NCT03287466; Pre-results., Competing Interests: Competing interests: DSM, MM and MPWG are directors of a company developing an oxygen delivery device (Oxygen Control Ltd). DSM has received honoraria and consultancy fees from Siemens Healthcare, Masimo, Deltex and Edwards Lifesciences. MPWG is the National Specialty Lead for Anaesthesia, Perioperative Medicine and Pain within the UK National Institute of Heath Research Clinical Research Network, an elected council member of the Royal College of Anaesthetists and serves on the board of the Evidence Based Perioperative Medicine (EBPOM) social enterprise and the medical advisory board of Sphere Medical Ltd. MPWG has received honoraria for speaking and/or travel expenses from Edwards Lifesciences, Fresenius-Kabi, BOC Medical (Linde Group), Ely-Lilly Critical Care, and Cortex GmBH. MPWG is executive chair of the Xtreme-Everest Oxygen Research Consortium and joint Editor-in-Chief of the journal Perioperative Medicine. MM is a consultant for Baxter, Edwards Lifesciences and Deltex; his University Chair is supported by Smiths Medical; Elected Council Member Royal College of Anaesthetsists; Editorial Board BJA and Critical Care; Founding Editor-in-Chief Perioperative Medicine., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Objectives: The mechanisms by which low oxygen availability are associated with the development of insulin resistance remain obscure. We thus investigated the relationship between such gluco-insular derangements in response to sustained (hypobaric) hypoxemia, and changes in biomarkers of oxidative stress, inflammation and counter-regulatory hormone responses., Methods: After baseline testing in London (75 m), 24 subjects ascended from Kathmandu (1,300 m) to Everest Base Camp (EBC;5,300 m) over 13 days. Of these, 14 ascended higher, with 8 reaching the summit (8,848 m). Assessments were conducted at baseline, during ascent to EBC, and 1, 6 and 8 week(s) thereafter. Changes in body weight and indices of gluco-insular control were measured (glucose, insulin, C-Peptide, homeostasis model assessment of insulin resistance [HOMA-IR]) along with biomarkers of oxidative stress (4-hydroxy-2-nonenal-HNE), inflammation (Interleukin-6 [IL-6]) and counter-regulatory hormones (glucagon, adrenalin, noradrenalin). In addition, peripheral oxygen saturation (SpO2) and venous blood lactate concentrations were determined., Results: SpO2 fell significantly from 98.0% at sea level to 82.0% on arrival at 5,300 m. Whilst glucose levels remained stable, insulin and C-Peptide concentrations increased by >200% during the last 2 weeks. Increases in fasting insulin, HOMA-IR and glucagon correlated with increases in markers of oxidative stress (4-HNE) and inflammation (IL-6). Lactate levels progressively increased during ascent and remained significantly elevated until week 8. Subjects lost on average 7.3 kg in body weight., Conclusions: Sustained hypoxemia is associated with insulin resistance, whose magnitude correlates with the degree of oxidative stress and inflammation. The role of 4-HNE and IL-6 as key players in modifying the association between sustained hypoxia and insulin resistance merits further investigation.

The syndrome of critical illness is a complex physiological stressor that can be triggered by diverse pathologies. It is widely believed that organ dysfunction and death result from bioenergetic failure caused by inadequate cellular oxygen supply. Teleologically, life has evolved to survive in the face of stressors by undergoing a suite of adaptive changes. Adaptation not only comprises alterations in systemic physiology but also involves molecular reprogramming within cells. The concept of cellular adaptation in critically ill patients is a matter of contention in part because medical interventions mask underlying physiology, creating the artificial construct of "chronic critical illness," without which death would be imminent. Thus far, the intensive care armamentarium has not targeted cellular metabolism to preserve a temporary equilibrium but instead attempts to normalize global oxygen and substrate delivery. Here, we review adaptations to hypoxia that have been demonstrated in cellular models and in human conditions associated with hypoxia, including the hypobaric hypoxia of high altitude, the intrauterine low-oxygen environment, and adult myocardial hibernation. Common features include upregulation of glycolytic ATP production, enhancement of respiratory efficiency, downregulation of mitochondrial density, and suppression of energy-consuming processes. We argue that these innate cellular adaptations to hypoxia represent potential avenues for intervention that have thus far remained untapped by intensive care medicine. [ABSTRACT FROM AUTHOR]

Ascent to high altitude is associated with a fall in the partial pressure of inspired oxygen (hypobaric hypoxia). For oxidative tissues such as skeletal muscle, resultant cellular hypoxia necessitates acclimatization to optimize energy metabolism and restrict oxidative stress, with changes in gene and protein expression that alter mitochondrial function. It is known that lowlanders returning from high altitude have decreased muscle mitochondrial densities, yet the underlying transcriptional mechanisms and time course are poorly understood. To explore these, we measured gene and protein expression plus ultrastructure in muscle biopsies of lowlanders at sea level and following exposure to hypobaric hypoxia. Subacute exposure (19 d after initiating ascent to Everest base camp, 5300m) was not associated with mitochondrial loss. After 66 d at altitude and ascent beyond 6400 m, mitochondrial densities fell by 21%, with loss of 73% of subsarcolemmal mitochondria. Correspondingly, levels of the transcriptional coactivator PGC-1 fell by 35%, suggesting down-regulation of mitochondrial biogenesis. Sustained hypoxia also decreased expression of electron transport chain complexes I and IV and UCP3 levels. We suggest that during subacute hypoxia, mitochondria might be protected from oxidative stress. However, following sustained exposure, mitochondrial biogenesis is deactivated and uncoupling down-regulated, perhaps to improve the efficiency of ATP production. [ABSTRACT FROM AUTHOR]