Evaluating the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care: Protocol for the UK-ROX trial.

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes. Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation. Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation. Discussion: The UK-ROX trial has received ethical approval from the South Central - Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.

Perioperative oxygenation-what's the stress?

Oxygen is the most used drug in anaesthesia. Despite such widespread use, optimal perioperative oxygen administration remains highly controversial because of concerns about the competing harms of both hyperoxia and hypoxia. Notwithstanding a Cochrane review concluding that routinely administering a fractional inspired oxygen concentration (FiO2) >0.6 intraoperatively might increase postoperative morbidity and mortality, the World Health Organization (WHO) currently recommends all anaesthetised patients receive 0.8 FiO2 during and immediately after surgery to reduce surgical site infections. Results from the largest trial available at the time of these two reviews (suggesting long-term survival may be worse with high FiO2, particularly in patients with malignant disease) were considered 'biologically implausible' by the WHO's Guideline Development Group. In addition, the integrity of some perioperative oxygen studies has been challenged. Resolving these controversies is of fundamental importance to all perioperative clinicians. This narrative review is based on the inaugural BJA William Mapleson lecture delivered by the senior author (AC) at the 2023 annual meeting of the Royal College of Anaesthetists in Birmingham. We present the current evidence for perioperative oxygen administration and contrast this with how oxygen therapy is targeted in other specialties (e.g. intensive care medicine). We will explore whether anaesthetists follow the WHO recommendations and consider how oxygen administration affects the stress response to surgery. We reason that novel clinical trial designs in combination with targeted experimental medicine studies will be required to improve our understanding of how best to optimise individualised perioperative oxygenation-a cornerstone of anaesthesia.

Preoperative aerobic fitness and perioperative outcomes in patients undergoing cystectomy before and after implementation of a national lockdown.

Background: Lower fitness is a predictor of adverse outcomes after radical cystectomy. Lockdown measures during the COVID-19 pandemic affected daily physical activity. We hypothesised that lockdown during the pandemic was associated with a reduction in preoperative aerobic fitness and an increase in postoperative complications in patients undergoing radical cystectomy. Methods: We reviewed routine preoperative cardiopulmonary exercise testing (CPET) data collected prior to the pandemic (September 2018 to March 2020) and after lockdown (March 2020 to July 2021) in patients undergoing radical cystectomy. Differences in CPET variables, Postoperative Morbidity Survey (POMS) data, and length of hospital stay were compared. Results: We identified 267 patients (85 pre-lockdown and 83 during lockdown) who underwent CPET and radical cystectomy. Patients undergoing radical cystectomy throughout lockdown had lower ventilatory anaerobic threshold (9.0 [7.9-10.9] vs 10.3 [9.1-12.3] ml kg-1 min-1; P=0.0002), peak oxygen uptake (15.5 [12.9-19.1] vs 17.5 [14.4-21.0] ml kg-1 min-1; P=0.015), and higher ventilatory equivalents for carbon dioxide (34.7 [31.4-38.5] vs 33.4 [30.5-36.5]; P=0.030) compared with pre-lockdown. Changes were more pronounced in males and those aged >65 yr. Patients undergoing radical cystectomy throughout lockdown had a higher proportion of day 5 POMS-defined morbidity (89% vs 75%, odds ratio [OR] 2.698, 95% confidence interval [CI] 1.143-6.653; P=0.019), specifically related to pulmonary complications (30% vs 13%, OR 2.900, 95% CI 1.368-6.194; P=0.007) and pain (27% vs 9%, OR 3.471, 95% CI 1.427-7.960; P=0.004), compared with pre-lockdown on univariate analysis. Conclusions: Lockdown measures in response to the COVID-19 pandemic were associated with a reduction in fitness and an increase in postoperative morbidity among patients undergoing radical cystectomy.

The effect of conservative oxygen therapy on mortality in adult critically ill patients: A systematic review and meta-analysis of randomised controlled trials.

Background: Oxygen is the commonest intervention provided to critically ill patients requiring mechanical ventilation. Despite this, it is unclear how much oxygen should be administered to patients in order to promote the best clinical outcomes and it has been suggested that a strategy of conservative oxygen therapy (COT) may be advantageous. We therefore sought to answer the question of whether COT versus usual or liberal oxygen therapy was beneficial to adult patients receiving mechanical ventilation on an intensive care unit (ICU) by performing a systematic review and meta-analysis. Methods: Studies were included if they were randomised controlled trials comparing COT to liberal or usual oxygen therapy strategies in acutely ill adults (aged ⩾18 years) admitted to an ICU, and reported an outcome of interest. Studies were excluded if they were limited to a specific single disease diagnosis. The review was registered on PROSPERO (CRD42022308436). Risk of bias was assessed using a modified Cochrane Risk of Bias assessment tool. Effect estimates were pooled using a random effects model with the between study variance estimated using restricted maximum likelihood and standard errors calculated using the method of Hartung-Knapp/Sidik-Jonkman. Between study heterogeneity was quantified using the I2 statistic. The certainty in the body of evidence was assessed using GRADE criteria. Results: Nine eligible studies with 5727 participants fulfilled all eligibility criteria. Trials varied in their definitions of COT and liberal or usual oxygen therapy. The pooled estimate of risk ratio for 90 day mortality for COT versus comparator was 0.99 (95% confidence interval 0.88-1.12, 95% prediction interval 0.82-1.21). There was low heterogeneity among studies (I2 = 22.4%). The finding that mortality was similar for patients managed with COT or usual/liberal oxygen therapy was graded as moderate certainty. Conclusions: In critically ill adults admitted to an ICU, COT is neither beneficial nor harmful when compared to usual or liberal oxygen therapy. Trials to date have been inconsistent in defining both COT and liberal or usual oxygen therapy, which may have had an impact on the results of this meta-analysis. Future research should focus on unifying definitions and outcome measures.

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

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.

Oxygen Targets During Mechanical Ventilation in the ICU: A Systematic Review and Meta-Analysis.

Patients admitted to intensive care often require treatment with invasive mechanical ventilation and high concentrations of oxygen. Mechanical ventilation can cause acute lung injury that may be exacerbated by oxygen therapy. Uncertainty remains about which oxygen therapy targets result in the best clinical outcomes for these patients. This review aims to determine whether higher or lower oxygenation targets are beneficial for mechanically ventilated adult patients. DATA SOURCES: Excerpta Medica dataBASE, Medical Literature Analysis and Retrieval System Online, and Cochrane medical databases were searched from inception through to February 28, 2021. STUDY SELECTION: Randomized controlled trials comparing higher and lower oxygen targets in adult patients receiving invasive mechanical ventilation via an endotracheal tube or tracheostomy in an intensive care setting. DATA EXTRACTION: Study setting, participant type, participant numbers, and intervention targets were captured. Outcome measures included "mortality at longest follow-up" (primary), mechanical ventilator duration and free days, vasopressor-free days, patients on renal replacement therapy, renal replacement free days, cost benefit, and quality of life scores. Evidence certainty and risk of bias were evaluated using Grading of Recommendations Assessment, Development and Evaluation and the Cochrane Risk of Bias tool. A random-effects models was used. Post hoc subgroup analysis looked separately at studies comparing hypoxemia versus normoxemia and normoxemia versus hyperoxemia. DATA SYNTHESIS: Data from eight trials (4,415 participants) were analyzed. Comparing higher and lower oxygen targets, there was no difference in mortality (odds ratio, 0.95; 95% CI, 0.74-1.22), but heterogeneous and overlapping target ranges limit the validity and clinical relevance of this finding. Data from seven studies (n = 4,245) demonstrated targeting normoxemia compared with hyperoxemia may reduce mortality at longest follow-up (0.73 [0.57-0.95]) but this estimate had very low certainty. There was no difference in mortality between targeting relative hypoxemia or normoxemia (1.20 [0.83-1.73]). CONCLUSIONS: This systematic review and meta-analysis identified possible increased mortality with liberal oxygen targeting strategies and no difference in morbidity between high or low oxygen targets in mechanically ventilated adults. Findings were limited by substantial heterogeneity in study methodology and further research is urgently required to define optimal oxygen therapy targets.

Dietary Nitrate Supplementation Does Not Alter Exercise Efficiency at High Altitude - Further Results From the Xtreme Alps Study.

Introduction: Nitrate supplementation in the form of beetroot juice (BRJ) ingestion has been shown to improve exercise tolerance during acute hypoxia, but its effect on exercise physiology remains unstudied during sustained terrestrial high altitude exposure. We hypothesized that performing exercise at high altitude would lower circulating nitrate and nitrite levels and that BRJ ingestion would reverse this phenomenon while concomitantly improving key determinants of aerobic exercise performance. Methods: Twenty seven healthy volunteers (21 male) underwent a series of exercise tests at sea level (SL, London, 75 m) and again after 5-8 days at high altitude (HA, Capanna Regina Margherita or "Margherita Hut," 4,559 m). Using a double-blind protocol, participants were randomized to consume a beetroot/fruit juice beverage (three doses per day) with high levels of nitrate (∼0.18 mmol/kg/day) or a nitrate-depleted placebo (∼11.5 µmoles/kg/day) control drink, from 3 days prior to the exercise trials until completion. Submaximal constant work rate cycle tests were performed to determine exercise efficiency and a maximal incremental ramp exercise test was undertaken to measure aerobic capacity, using breath-by-breath pulmonary gas exchange measurements throughout. Concentrations of nitrate, nitrite and nitrosation products were quantified in plasma samples collected at 5 timepoints during the constant work rate tests. Linear mixed modeling was used to analyze data. Results: At both SL and HA, plasma nitrate concentrations were elevated in the nitrate supplementation group compared to placebo (P < 0.001) but did not change throughout increasing exercise work rate. Delta exercise efficiency was not altered by altitude exposure (P = 0.072) or nitrate supplementation (P = 0.836). V̇O2peak decreased by 24% at high altitude (P < 0.001) and was lower in the nitrate-supplemented group at both sea level and high altitude compared to placebo (P = 0.041). Dietary nitrate supplementation did not alter other peak exercise variables or oxygen consumption at anaerobic threshold. Circulating nitrite and S-nitrosothiol levels unexpectedly rose in a few individuals right after cessation of exercise at high altitude. Conclusion: Whilst regularly consumed during an 8 days expedition to terrestrial high altitude, nitrate supplementation did not alter exercise efficiency and other exercise physiological variables, except decreasing V̇O2peak. These results and those of others question the practical utility of BRJ consumption during prolonged altitude exposure.

The Effect of Pre-operative Exercise Intervention on Patient Outcomes Following Bariatric Surgery: a Systematic Review and Meta-analysis.

This systematic review aimed to assess the effect of a pre-operative exercise intervention on short- and long-term health and clinical outcomes for adult patients undergoing bariatric surgery (BS). We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), SPORTDiscus and reference lists of relevant papers, through March 2021. Five randomised controlled trials were included (n = 199 patients). Modest increases in cardiorespiratory fitness (VO2max) were found at both pre-operative (0.73 mL kg-1 min-1, P ≤ 0.001) and maximum follow-up time points (0.98 mL kg-1 min-1, P ≤ 0.04). There was no significant effect of an exercise intervention on percentage total weight loss (%TWL). Pre-operative exercise can induce significant short- and long-term improvements in fitness in individuals with obesity. There is insufficient evidence to determine whether pre-operative training impacts other post-operative clinical outcomes.

Lifting the lid on perioperative goal-directed therapy.

The complex cellular interactions that underlie pathologies related to reduced oxygen delivery after surgery are poorly defined and difficult to measure. Heywood and colleagues explored the patterns of protein expression in skin biopsies taken from a subgroup of patients enrolled in a randomised trial designed to evaluate perioperative goal-directed therapy. One of their key findings was that a failure of participants to maintain preoperative systemic oxygen delivery was associated with an upregulation of intracellular proteins involved in counteracting oxidative stress. Their study highlights the importance of oxidative stress in the perioperative setting and suggests that maintenance of baseline oxygen delivery might be an important regulator of redox balance.

Physiological responses during ascent to high altitude and the incidence of acute mountain sickness.

Acute mountain sickness (AMS) occurs when there is failure of acclimatisation to high altitude. The aim of this study was to describe the relationship between physiological variables and the incidence of AMS during ascent to 5300 m. A total of 332 lowland-dwelling volunteers followed an identical ascent profile on staggered treks. Self-reported symptoms of AMS were recorded daily using the Lake Louise score (mild 3-4; moderate-severe ≥5), alongside measurements of physiological variables (heart rate, respiratory rate (RR), peripheral oxygen saturation (SpO2 ) and blood pressure) before and after a standardised Xtreme Everest Step-Test (XEST). The overall occurrence of AMS among participants was 73.5% (23.2% mild, 50.3% moderate-severe). There was no difference in gender, age, previous AMS, weight or body mass index between participants who developed AMS and those who did not. Participants who had not previously ascended >5000 m were more likely to get moderate-to-severe AMS. Participants who suffered moderate-to-severe AMS had a lower resting SpO2 at 3500 m (88.5 vs. 89.6%, p = 0.02), while participants who suffered mild or moderate-to-severe AMS had a lower end-exercise SpO2 at 3500 m (82.2 vs. 83.8%, p = 0.027; 81.5 vs. 83.8%, p < 0.001 respectively). Participants who experienced mild AMS had lower end-exercise RR at 3500 m (19.2 vs. 21.3, p = 0.017). In a multi-variable regression model, only lower end-exercise SpO2 (OR 0.870, p < 0.001) and no previous exposure to altitude >5000 m (OR 2.740, p-value 0.003) predicted the development of moderate-to-severe AMS. The Xtreme Everest Step-Test offers a simple, reproducible field test to help predict AMS, albeit with relatively limited predictive precision.

Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness.

BACKGROUND: Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. METHODS: To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. RESULTS: We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors' FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. CONCLUSION: Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies.

A feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients.

BACKGROUND: Despite oxygen being the commonest drug administered to critically ill patients we do not know which oxygen saturation (SpO2) target results in optimal survival outcomes in those receiving mechanical ventilation. We therefore conducted a feasibility randomised controlled trial in the United Kingdom (UK) to assess whether it would be possible to host a larger national multi-centre trial to evaluate oxygenation targets in mechanically ventilated patients. METHODS: We set out to recruit 60 participants across two sites into a trial in which they were randomised to receive conservative oxygenation (SpO2 88-92%) or usual care (control - SpO2 ≥96%). The primary outcome was feasibility; factors related to safety and clinical outcomes were also assessed. RESULTS: A total of 34 patients were recruited into the study until it was stopped due to time constraints. A number of key barriers to success were identified during the course of the study. The conservative oxygenation intervention was feasible and appeared to be safe in this small patient cohort and it achieved wide separation of the median time-weighted average (IQR) SpO2 at 91% (90-92%) in conservative oxygenation group versus 97% (96-97%) in control group. CONCLUSION: Whilst conservative oxygenation was a feasible and safe intervention which achieved clear group separation in oxygenation levels, the model used in this trial will require alterations to improve future participant recruitment rates in the UK.

Effects of perioperative oxygen concentration on oxidative stress in adult surgical patients: a systematic review.

BACKGROUND: The fraction of inspired oxygen (FiO2) administered during general anaesthesia varies widely despite international recommendations to administer FiO2 0.8 to all anaesthetised patients to reduce surgical site infections (SSIs). Anaesthetists remain concerned that high FiO2 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 FiO2 and SSIs have been inconsistent, but none have examined how FiO2 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 FiO2 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 FiO2 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 FiO2 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.

An anaesthetic and intensive care perspective on infection control measures for the prevention of airborne transmission of SARS-CoV-2.

Guidance regarding appropriate use of personal protective equipment in hospitals is in constant flux as research into SARS-COV-2 transmission continues to develop our understanding of the virus. The risk associated with procedures classed as 'aerosol generating' is under constant debate. Current guidance is largely based on pragmatic and cautious logic, as there is little scientific evidence of aerosolization and transmission of respiratory viruses associated with procedures. The physical properties of aerosol particles which may contain viable virus have implications for the safe use of personal protective equipment and infection control protocols. As elective work in the NHS is reinstated, it is important that the implications of the possibility of airborne transmission of the virus in hospitals are more widely understood. This will facilitate appropriate use of personal protective equipment and help direct further research into the true risks of aerosolization during these procedures to allow safe streamlining of services for staff and patients.

Human adaptation to hypoxia in critical illness.

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.

Effects of dietary nitrate supplementation on microvascular physiology at 4559 m altitude - A randomised controlled trial (Xtreme Alps).

Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate 'placebo'. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 µM) and at day 5 (D5) of high altitude (22.9 vs 84.3 µM, p < 0.001). Dietary nitrate supplementation also significantly increased both plasma nitrite (0.78 vs. 0.86 µM SL, 0.31 vs. 0.41 µM D5, p = 0.03) and total nitroso product (11.3 vs. 19.7 nM SL, 9.7 vs. 12.3 nM D5, p < 0.001) levels both at sea level and at 4559 m. However, plasma nitrite concentrations were more than 50% lower at 4559 m compared to sea level in both treatment groups. Despite these significant changes, dietary nitrate supplementation had no effect on any measured read-outs of sublingual or forearm blood flow, even when environmental hypoxia was experimentally reversed using supplemental oxygen. In conclusion, dietary nitrate supplementation does not improve microcirculatory function at 4559 m.

An Outpatient Hospital-based Exercise Training Program for Patients With Cirrhotic Liver Disease Awaiting Transplantation: A Feasibility Trial.

BACKGROUND: Time spent on the waiting list before liver transplantation (LT) provides an opportunity to optimize recipient fitness through prehabilitation, potentially reducing the physiological impact of major surgery. We assessed the feasibility and effectiveness of a 6-week exercise program in patients with cirrhotic liver disease awaiting LT. METHODS: This single-center, prospective cohort, feasibility study, enrolled patients awaiting LT to a 6-week period of thrice weekly, supervised exercise on a static bike. Cardiopulmonary exercise testing (CPET) was used to objectively assess cardiopulmonary fitness at baseline and after 6 weeks of exercise. A follow-up CPET was performed at 12 weeks. CPET-derived measures were used to guide prescription of the training program. A nonrandomized control cohort of LT patients were selected to match the exercise group based on specific demographic data. Allocation to study arms was primarily based on the distance participants lived from the hospital where training occurred. Both groups received structured nutritional advice. RESULTS: The exercise program was feasible, with 9 of 16 (56%) patients completing the full program of 6 weeks. Peak oxygen consumption (VO2peak) in the exercise group rose from a mean (SD) of 16.2 (±3.4) mL/kg/min at baseline to 18.5 (±4.6) mL/kg/min at week 6 (P = 0.02). In the control group, VO2peak decreased from a mean (SD) of 19.0 (±6.1) mL/kg/min to 17.1 (±6.0) at week 6 (P = 0.03). CONCLUSIONS: We have demonstrated that it is feasible to engage patients awaiting LT in an intensive aerobic exercise program with a signal of improvement in fitness being detected.

Perioperative Oxidative Stress: The Unseen Enemy.

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.

Ward-based Goal-Directed Fluid Therapy (GDFT) in Acute Pancreatitis (GAP) trial: study protocol for a feasibility randomised controlled trial.

INTRODUCTION: Acute pancreatitis is an inflammatory disease of the pancreas with high risk of developing multiorgan failure and death. There are no effective pharmacological interventions used in current clinical practice. Maintaining fluid and electrolyte balance is the mainstay of supportive management. Goal-directed fluid therapy (GDFT) has been shown to decrease morbidity and mortality in surgical conditions with systemic inflammatory response. There is currently no randomised controlled trial (RCT) investigating the role of GDFT based on cardiac output parameters in patients with acute pancreatitis in the ward setting. A feasibility trial was designed to determine patient and clinician support for recruitment into an RCT of ward-based GDFT in acute pancreatitis, adherence to a GDFT protocol, safety, participant withdrawal, and to determine appropriate endpoints for a subsequent larger trial to evaluate efficacy. METHODS AND ANALYSIS: The GDFT in Acute Pancreatitis trial is a prospective two-centre feasibility RCT. Eligible adults admitted with new onset of acute pancreatitis will be enrolled and randomised into ward-based GDFT (n=25) or standard fluid therapy (n=25) within 6 hours from the diagnosis and continuing for the following 48 hours. Cardiac output parameters will be monitored with a non-invasive device (Cheetah NICOM; Cheetah Medical). The intervention group will consist of a protocolised GDFT approach consisting of stroke volume optimisation with crystalloid fluid boluses, while the control group will receive standard care fluid therapy as advised by the clinical team. The primary endpoint is feasibility. Secondary endpoints will include safety of the intervention, complications, mortality, admission to intensive care unit, cost and quality of life. ETHICS AND DISSEMINATION: Ethics approval was granted by the London Central Research Ethics Committee (17/LO/1235, project ID: 221872). The results of this trial will be presented to international conference with interest in general surgery and acute care and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN36077283.

Enhanced flow-motion complexity of skin microvascular perfusion in Sherpas and lowlanders during ascent to high altitude.

An increased and more effective microvascular perfusion is postulated to play a key role in the physiological adaptation of Sherpa highlanders to the hypobaric hypoxia encountered at high altitude. To investigate this, we used Lempel-Ziv complexity (LZC) analysis to explore the spatiotemporal dynamics of the variability of the skin microvascular blood flux (BF) signals measured at the forearm and finger, in 32 lowlanders (LL) and 46 Sherpa highlanders (SH) during the Xtreme Everest 2 expedition. Measurements were made at baseline (BL) (LL: London 35 m; SH: Kathmandu 1300 m) and at Everest base camp (LL and SH: EBC 5,300 m). We found that BF signal content increased with ascent to EBC in both SH and LL. At both altitudes, LZC of the BF signals was significantly higher in SH, and was related to local slow-wave flow-motion activity over multiple spatial and temporal scales. In SH, BF LZC was also positively associated with LZC of the simultaneously measured tissue oxygenation signals. These data provide robust mechanistic information of microvascular network functionality and flexibility during hypoxic exposure on ascent to high altitude. They demonstrate the importance of a sustained heterogeneity of network perfusion, associated with local vaso-control mechanisms, to effective tissue oxygenation during hypobaric hypoxia.