International consensus is needed on a core outcome set to advance the evidence of best practice in cancer prehabilitation services and research.

Prehabilitation aims to optimise patients' physical and psychological status before treatment. The types of outcomes measured to assess the impact of prehabilitation interventions vary across clinical research and service evaluation, limiting the ability to compare between studies and services and to pool data. An international workshop involving academic and clinical experts in cancer prehabilitation was convened in May 2022 at Sheffield Hallam University's Advanced Wellbeing Research Centre, England. The workshop substantiated calls for a core outcome set to advance knowledge and understanding of best practice in cancer prehabilitation and to develop national and international databases to assess outcomes at a population level.

Metabolic basis to Sherpa altitude adaptation.

The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.

Changes in muscle proteomics in the course of the Caudwell Research Expedition to Mt. Everest.

This study employed differential proteomic and immunoassay techniques to elucidate the biochemical mechanisms utilized by human muscle (vastus lateralis) in response to high altitude hypoxia exposure. Two groups of subjects, participating in a medical research expedition (A, n = 5, 19 d at 5300 m altitude; B, n = 6, 66 d up to 8848 m) underwent a ≈ 30% drop of muscular creatine kinase and of glycolytic enzymes abundance. Protein abundance of most enzymes of the tricarboxylic acid cycle and oxidative phosphorylation was reduced both in A and, particularly, in B. Restriction of α-ketoglutarate toward succinyl-CoA resulted in increased prolyl hydroxylase 2 and glutamine synthetase. Both A and B were characterized by a reduction of elongation factor 2 alpha, controlling protein translation, and by an increase of heat shock cognate 71 kDa protein involved in chaperone-mediated autophagy. Increased protein levels of catalase and biliverdin reductase occurred in A alongside a decrement of voltage-dependent anion channels 1 and 2 and of myosin-binding protein C, suggesting damage to the sarcomeric structures. This study suggests that during acclimatization to hypobaric hypoxia the muscle behaves as a producer of substrates activating a metabolic reprogramming able to support anaplerotically the tricarboxylic acid cycle, to control protein translation, to prevent energy expenditure and to activate chaperone-mediated autophagy.

Cardiopulmonary exercise testing, prehabilitation, and Enhanced Recovery After Surgery (ERAS).

PURPOSE: This review evaluates the current and future role of cardiopulmonary exercise testing (CPET) in the context of Enhanced Recovery After Surgery (ERAS) programs. PRINCIPAL FINDINGS: There is substantial literature confirming the relationship between physical fitness and perioperative outcome in general. The few small studies in patients undergoing surgery within an ERAS program describe less fit individuals having a greater incidence of morbidity and mortality. There is evidence of increasing adoption of perioperative CPET, particularly in the UK. Although CPET-derived variables have been used to guide clinical decisions about choice of surgical procedure and level of perioperative care as well as to screen for uncommon comorbidities, the ability of CPET-derived variables to guide therapy and thereby improve outcome remains uncertain. Recent studies have reported a reduction in CPET-defined physical fitness following neoadjuvant therapies (chemo- and radio-therapy) prior to surgery. Preliminary data suggest that this effect may be associated with an adverse effect on clinical outcomes in less fit patients. Early reports suggest that CPET-derived variables can be used to guide the prescription of exercise training interventions and thereby improve physical fitness in patients prior to surgery (i.e., prehabilitation). The impact of such interventions on clinical outcomes remains uncertain. CONCLUSIONS: Perioperative CPET is finding an increasing spectrum of roles, including risk evaluation, collaborative decision-making, personalized care, monitoring interventions, and guiding prescription of prehabilitation. These indications are potentially of importance to patients having surgery within an ERAS program, but there are currently few publications specific to CPET in the context of ERAS programs.

Systematic review and narrative description of the outcomes of group preoperative education before elective major surgery.

Background: Group preoperative education is becoming standard care for patients preparing for surgery, alongside optimisation of exercise, diet, and wellbeing. Although patient education is essential, the effectiveness of group education programmes or 'surgery schools' as a means of delivery is unclear. This review examines whether attending group preoperative education improves patient outcomes. Methods: We systematically reviewed studies of group perioperative education before major elective surgery. Observational or intervention studies with a baseline group or control arm were included. All outcomes reported were collected and, where possible, effect estimates were summarised using random effects meta-analysis. Results: Twenty-seven studies reported on 48 different outcomes after group education. Overall, there was a 0.7 (95% confidence interval 0.27-1.13) day reduction in mean length of stay. The odds ratio for postoperative complications after abdominal surgery was 0.56 (95% confidence interval 0.36-0.85; nine studies). Patient-centred outcomes were grouped into themes. Most studies reported a benefit from group education, but only postoperative physical impairment, pain, knowledge, activation, preoperative anxiety, and some elements of quality of life were statistically significant. Conclusion: This review presents a summary of published evidence available for group preoperative education. While these data lend support for such programmes, there is a need for adequately powered prospective studies to evaluate the effectiveness of preoperative education on clinical outcomes and to evaluate whether behaviour change is sustained. Furthermore, the content, timing and mode of delivery, and evaluation measures of preoperative education require standardisation. Systematic review protocol: PROSPERO (166297).

Cardiopulmonary exercise variables and their association with postoperative morbidity and mortality after major oesophagogastric cancer surgery-a multicentre observational study.

Background: Outcomes after oesophagogastric cancer surgery remain poor. Cardiopulmonary exercise testing (CPET) used for risk stratification before oesophagogastric cancer surgery is based on conflicting evidence. This study explores the relationship between CPET and postoperative outcomes, specifically for patients undergoing neoadjuvant treatment. Methods: Patients undergoing oesophagogastric cancer resection and CPET (pre- or post-neoadjuvant treatment, or both) were retrospectively enrolled into a multicentre pooled cohort study. Oxygen uptake at peak exercise (VO2 peak) was compared with 1-yr postoperative survival. Secondary analyses explored relationships between patient characteristics, tumour pathology characteristics, CPET variables (absolute, relative to weight, ideal body weight, and body surface area), and postoperative outcomes (morbidity, 1-yr and 3-yr survival) were assessed using logistic regression analyses. Results: Seven UK centres recruited 611 patients completing a 3-yr postoperative follow-up period. Oesophagectomy was undertaken in 475 patients (78%). Major complications occurred in 25%, with 18% 1-yr and 43% 3-yr mortality. No association between VO2 peak or other selected CPET variables and 1-yr survival was observed in the overall cohort. In the overall cohort, the anaerobic threshold relative to ideal body weight was associated with 3-yr survival (P=0.013). Tumour characteristics (ypT/ypN/tumour regression/lymphovascular invasion/resection margin; P<0.001) and Clavien-Dindo ≥3a (P<0.001) were associated with 1-yr and 3-yr survival. On subgroup analyses, pre-neoadjuvant treatment CPET; anaerobic threshold (absolute; P=0.024, relative to ideal body weight; P=0.001, body surface area; P=0.009) and VE/VCO2 at anaerobic threshold (P=0.026) were associated with 3-yr survival. No other CPET variables (pre- or post-neoadjuvant treatment) were associated with survival. Conclusions: VO2 peak was not associated with 1-yr survival after oesophagogastric cancer resection. Tumour characteristics and major complications were associated with survival; however, only some selected pre-neoadjuvant treatment CPET variables were associated with 3-yr survival. CPET in this cohort of patients demonstrates limited outcome predictive precision. Clinical trial registration: NCT03637647.

Arterial blood gases and oxygen content in climbers on Mount Everest.

BACKGROUND: The level of environmental hypobaric hypoxia that affects climbers at the summit of Mount Everest (8848 m [29,029 ft]) is close to the limit of tolerance by humans. We performed direct field measurements of arterial blood gases in climbers breathing ambient air on Mount Everest. METHODS: We obtained samples of arterial blood from 10 climbers during their ascent to and descent from the summit of Mount Everest. The partial pressures of arterial oxygen (PaO(2)) and carbon dioxide (PaCO(2)), pH, and hemoglobin and lactate concentrations were measured. The arterial oxygen saturation (SaO(2)), bicarbonate concentration, base excess, and alveolar-arterial oxygen difference were calculated. RESULTS: PaO(2) fell with increasing altitude, whereas SaO(2) was relatively stable. The hemoglobin concentration increased such that the oxygen content of arterial blood was maintained at or above sea-level values until the climbers reached an elevation of 7100 m (23,294 ft). In four samples taken at 8400 m (27,559 ft)--at which altitude the barometric pressure was 272 mm Hg (36.3 kPa)--the mean PaO(2) in subjects breathing ambient air was 24.6 mm Hg (3.28 kPa), with a range of 19.1 to 29.5 mm Hg (2.55 to 3.93 kPa). The mean PaCO(2) was 13.3 mm Hg (1.77 kPa), with a range of 10.3 to 15.7 mm Hg (1.37 to 2.09 kPa). At 8400 m, the mean arterial oxygen content was 26% lower than it was at 7100 m (145.8 ml per liter as compared with 197.1 ml per liter). The mean calculated alveolar-arterial oxygen difference was 5.4 mm Hg (0.72 kPa). CONCLUSIONS: The elevated alveolar-arterial oxygen difference that is seen in subjects who are in conditions of extreme hypoxia may represent a degree of subclinical high-altitude pulmonary edema or a functional limitation in pulmonary diffusion.

Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp.

We postulated that changes in cardiac high-energy phosphate metabolism may underlie the myocardial dysfunction caused by hypobaric hypoxia. Healthy volunteers (n=14) were studied immediately before, and within 4 d of return from, a 17-d trek to Mt. Everest Base Camp (5300 m). (31)P magnetic resonance (MR) spectroscopy was used to measure cardiac phosphocreatine (PCr)/ATP, and MR imaging and echocardiography were used to assess cardiac volumes, mass, and function. Immediately after returning from Mt. Everest, total body weight had fallen by 3% (P<0.05), but left ventricular mass, adjusted for changes in body surface area, had disproportionately decreased by 11% (P<0.05). Alterations in diastolic function were also observed, with a reduction in peak left ventricular filling rates and mitral inflow E/A, by 17% (P<0.05) and 24% (P<0.01), respectively, with no change in hydration status. Compared with pretrek, cardiac PCr/ATP ratio had decreased by 18% (P<0.01). Whether the abnormalities were even greater at altitude is unknown, but all had returned to pretrek levels after 6 mo. The alterations in cardiac morphology, function, and energetics are similar to findings in patients with chronic hypoxia. Thus, a decrease in cardiac PCr/ATP may be a universal response to periods of sustained low oxygen availability, underlying hypoxia-induced cardiac dysfunction in healthy human heart and in patients with cardiopulmonary diseases.

Perioperative Risk Stratification and Modification.

This article discusses the important topic of perioperative risk stratification and the interventions that can be used in the perioperative period for risk modification. It begins with a brief overview of the commonly used scoring systems, risk-prediction models, and assessments of functional capacity and discusses some of the evidence behind each. It then moves on to examine how perioperative risk can be modified through the use of shared decision making, management of multimorbidity, and prehabilitation programs, before considering what the future of risk stratification and modification may hold.

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 effects of cancer therapies on physical fitness before oesophagogastric cancer surgery: a prospective, blinded, multi-centre, observational, cohort study.

Background: Neoadjuvant cancer treatment is associated with improved survival following major oesophagogastric cancer surgery. The impact of neoadjuvant chemo/chemoradiotherapy on physical fitness and operative outcomes is however unclear. This study aims to investigate the impact of neoadjuvant chemo/chemoradiotherapy on fitness and post-operative mortality. Methods: Patients with oesophagogastric cancer scheduled for chemo/chemoradiotherapy and surgery were recruited to a prospective, blinded, multi-centre, observational cohort study. Primary outcomes were changes in fitness with chemo/chemoradiotherapy, measured using cardiopulmonary exercise testing and its association with mortality one-year after surgery. Patients were followed up for re-admission at 30-days, in-hospital morbidity and quality of life (exploratory outcomes). Results: In total, 384 patients were screened, 217 met the inclusion criteria, 160 consented and 159 were included (72% male, mean age 65 years). A total of 132 patients (83%) underwent chemo/chemoradiotherapy, 109 (71%) underwent chemo/chemoradiotherapy and two exercise tests, 100 (63%) completed surgery and follow-up. A significant decline in oxygen uptake at anaerobic threshold and oxygen uptake peak was observed following chemo/chemoradiotherapy: -1.25ml.kg -1.min -1 (-1.80 to -0.69) and -3.02ml.kg -1.min -1 (-3.85 to -2.20); p<0.0001). Baseline chemo/chemoradiotherapy anaerobic threshold and peak were associated with one-year mortality (HR=0.72, 95%CI 0.59 to 0.88; p=0.001 and HR=0.85, 0.76 to 0.95; p=0.005). The change in physical fitness was not associated with one-year mortality. Conclusions: Chemo/chemoradiotherapy prior to oesophagogastric cancer surgery reduced physical fitness. Lower baseline fitness was associated with reduced overall survival at one-year. Careful consideration of fitness prior to chemo/chemoradiotherapy and surgery is urgently needed.

BACKGROUND: Cancer treatments such as chemotherapy and radiotherapy given to people with oesophageal and gastric cancer (also known as cancer of the food pipe/stomach) before surgery can improve survival. However, the impact such treatments have on fitness and recovery after surgery is unclear. The aim of this research was to understand the impact cancer treatments has on fitness and any complications after surgery. METHODS: Patients with oesophageal and gastric cancer (also known as cancer of the food pipe/stomach) who were being treated by cancer treatment and surgery were recruited from different hospitals in the UK. All participants were asked to undertake an exercise test to measure fitness and fill out questionnaires to measure quality of life before and after cancer treatment. Complications patients experienced after surgery, the number of patients who had to be readmitted to hospital 30 days after surgery and one-year survival was recorded. RESULTS: A total of 160 consented to participate in this study and 159 were included in the study (72% male, average age 65 years). In total, 132 patients (83%) had cancer treatment, 109 (71%) had cancer treatment and the two exercise tests and 100 (63%) had surgery and were followed-up after surgery. Study findings show that fitness reduced after cancer treatment. Patient's fitness levels at the start of the study (or before cancer treatment) were linked to one-year survival. The fall in fitness after cancer treatment was not linked to death at the one-year follow-up. CONCLUSION: Cancer treatments before oesophageal and gastric cancer reduce fitness. Patients with a lower fitness level before cancer treatment had a reduced overall survival at one-year. Careful consideration of fitness prior to such cancer treatments and surgery is urgently needed.

Current Landscape of Nutrition Within Prehabilitation Oncology Research: A Scoping Review.

Background: Prehabilitation aims to improve functional capacity prior to cancer treatment to achieve better psychosocial and clinical outcomes. Prehabilitation interventions vary considerably in design and delivery. In order to identify gaps in knowledge and facilitate the design of future studies, we undertook a scoping review of prehabilitation studies to map the range of work on prehabilitation being carried out in any cancer type and with a particular focus on diet or nutrition interventions. Objectives: Firstly, to describe the type of prehabilitation programs currently being conducted. Secondly, to describe the extent to which prehabilitation studies involved aspects of nutrition, including assessment, interventions, implementation, and outcomes. Eligibility Criteria: Any study of quantitative or qualitative design that employed a formal prehabilitation program before cancer treatment ("prehabilitation" listed in keywords, title, or abstract). Sources of Evidence: Search was conducted in July 2020 using MEDLINE, PubMed, EMBASE, EMCARE, CINAHL, and AMED. Charting Methods: Quantitative data were reported as frequencies. Qualitative nutrition data were charted using a framework analysis that reflects the Nutrition Care Process Model: assessment, intervention, and monitoring/evaluation of the nutrition intervention. Results: Five hundred fifty unique articles were identified: 110 studies met inclusion criteria of a formal prehabilitation study in oncology. prehabilitation studies were mostly cohort studies (41%) or randomized-controlled trials (38%) of multimodal (49%), or exercise-only (44%) interventions that were applied before surgery (94%). Nutrition assessment was inconsistently applied across these studies, and often conducted without validated tools (46%). Of the 110 studies, 37 (34%) included a nutrition treatment component. Half of these studies provided the goal for the nutrition component of their prehabilitation program; of these goals, less than half referenced accepted nutrition guidelines in surgery or oncology. Nutrition interventions largely consisted of counseling with dietary supplementation. The nutrition intervention was indiscernible in 24% of studies. Two-thirds of studies did not monitor the nutrition intervention nor evaluate nutrition outcomes. Conclusion: Prehabilitation literature lacks standardized and validated nutritional assessment, is frequently conducted without evidence-based nutrition interventions, and is typically implemented without monitoring the nutrition intervention or evaluating the intervention's contribution to outcomes. We suggest that the development of a core outcome set could improve the quality of the studies, enable pooling of evidence, and address some of the research gaps identified.

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.

SafeFit Trial: virtual clinics to deliver a multimodal intervention to improve psychological and physical well-being in people with cancer. Protocol of a COVID-19 targeted non-randomised phase III trial.

INTRODUCTION: The impact of the COVID-19 pandemic (caused by the SARS-CoV-2 virus) on individuals with cancer has been profound. It has led to increased anxiety, distress and deconditioning due to reduced physical activity. We aim to investigate whether SafeFit, a multimodal intervention of physical activity, nutrition and psychological support delivered virtually by cancer exercise specialists (CES), can improve physical and emotional functionings during the COVID-19 pandemic. METHODS AND ANALYSIS: A phase III non-randomised intervention trial, target recruitment of 1050 adults with suspected or confirmed diagnosis of cancer. All recruited participants will receive the multimodal intervention delivered by CES for 6 months. Sessions will be delivered 1-to-1 using telephone/video conferencing consultations. CES will work with each participant to devise a personalised programme of (1) physical activity, (2) basic dietary advice and (3) psychological support, all underpinned by behaviour change support. PRIMARY OUTCOME: Physical and emotional functioning as measured by the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ-C30). SECONDARY OUTCOMES: overall quality of life measured by EORTC-QLQ-C30 and EQ-5D-5L, health economics, patient activation, self-efficacy to self-manage chronic disease, distress, impact of COVID-19 on emotional functioning, self-reported physical activity, functional capacity and nutrition. Adherence to the intervention will also be measured and a process evaluation conducted. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Health Research Authority (reference number 20/NW/0254). Results of this trial will be disseminated through publication of peer-reviewed articles, presentations at scientific conferences, and to the public and people with cancer in collaboration with our patient and public involvement representatives and partners. TRIAL REGISTRATION NUMBER: NCT04425616.

Postoperative acute kidney injury in adult non-cardiac surgery: joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.

Variation in human performance in the hypoxic mountain environment.

Ascent to altitude is associated with a fall in barometric pressure, and with it a decline in the partial pressure of atmospheric (and thus alveolar) oxygen. As a result, a variety of adaptive physiological processes are engaged to mitigate the fall in tissue convective oxygen delivery which might otherwise occur. The magnitude and nature of such changes is also modified with time, a process known as acclimatization. However, other phenomena are at work; the ability to perform physical work at altitude falls in a manner which is not wholly related to changes in arterial oxygen content. Indeed, alterations in local skeletal muscle blood flow and metabolism may play an axial role. Thus, for those who are not native to high altitude, the ability to compete at altitude is likely to be impaired. The magnitude of such impairment in performance, however, differs greatly between individuals, and it seems that genetic variation underpins much of this difference. The identification of the relevant genetic elements is in its infancy in humans, but ongoing work is likely to help us gain an increasing understanding of how humans adapt to altitude and to develop mitigating interventions.

Changes in sublingual microcirculatory flow index and vessel density on ascent to altitude.

We hypothesized that ascent to altitude would result in reduced sublingual microcirculatory flow index (MFI) and increased vessel density. Twenty-four subjects were studied using sidestream dark-field imaging, as they ascended to 5300 m; one cohort remained at this altitude (n = 10), while another ascended higher (maximum 8848 m; n = 14). The MFI, vessel density and grid crossings (GX; an alternative density measure) were calculated. Total study length was 71 days; images were recorded at sea level (SL), Namche Bazaar (3500 m), Everest base camp (5300 m), the Western Cwm (6400 m), South Col (7950 m) and departure from Everest base camp (5300 m; 5300 m-b). Peripheral oxygen saturation (SpO2), heart rate and blood pressure were also recorded. Compared with SL, altitude resulted in reduced sublingual MFI in small (<25 microm; P < 0.0001) and medium vessels (26-50 microm; P = 0.006). The greatest reduction in MFI from SL was seen at 5300 m-b; from 2.8 to 2.5 in small vessels and from 2.9 to 2.4 in medium-sized vessels. The density of vessels <25 microm did not change during ascent, but those >25 microm rose from 1.68 (+/- 0.43) mm mm(-2) at SL to 2.27 (+/- 0.57) mm mm(-2) at 5300 m-b (P = 0.005); GX increased at all altitudes (P < 0.001). The reduction in MFI was greater in climbers than in those who remained at 5300 m in small and medium-sized vessels (P = 0.017 and P = 0.002, respectively). At 7950 m, administration of supplemental oxygen resulted in a further reduction of MFI and increase in vessel density. Thus, MFI was reduced whilst GX increased in the sublingual mucosa with prolonged exposure to hypoxia and was exaggerated in those exposed to extreme altitude.

Design and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptation to progressive environmental hypoxia.

BACKGROUND: The physiological responses to hypoxaemia and cellular hypoxia are poorly understood, and inter-individual differences in performance at altitude and outcome in critical illness remain unexplained. We propose a model for exploring adaptation to hypoxia in the critically ill: the study of healthy humans, progressively exposed to environmental hypobaric hypoxia (EHH). The aim of this study was to describe the spectrum of adaptive responses in humans exposed to graded EHH and identify factors (physiological and genetic) associated with inter-individual variation in these responses. DESIGN: Observational cohort study of progressive incremental exposure to EHH. SETTING: University human physiology laboratory in London, UK (75 m) and 7 field laboratories in Nepal at 1300 m, 3500 m, 4250 m, 5300 m, 6400 m, 7950 m and 8400 m. PARTICIPANTS: 198 healthy volunteers and 24 investigators trekking to Everest Base Camp (EBC) (5300 m). A subgroup of 14 investigators studied at altitudes up to 8400 m on Everest. MAIN OUTCOME MEASURES: Exercise capacity, exercise efficiency and economy, brain and muscle Near Infrared Spectroscopy, plasma biomarkers (including markers of inflammation), allele frequencies of known or suspected hypoxia responsive genes, spirometry, neurocognitive testing, retinal imaging, pupilometry. In nested subgroups: microcirculatory imaging, muscle biopsies with proteomic and transcriptomic tissue analysis, continuous cardiac output measurement, arterial blood gas measurement, trans-cranial Doppler, gastrointestinal tonometry, thromboelastography and ocular saccadometry. RESULTS: Of 198 healthy volunteers leaving Kathmandu, 190 reached EBC (5300 m). All 24 investigators reached EBC. The completion rate for planned testing was more than 99% in the investigator group and more than 95% in the trekkers. Unique measurements were safely performed at extreme altitude, including the highest (altitude) field measurements of exercise capacity, cerebral blood flow velocity and microvascular blood flow at 7950 m and arterial blood gas measurement at 8400 m. CONCLUSIONS: This study demonstrates the feasibility and safety of conducting a large healthy volunteer cohort study of human adaptation to hypoxia in this difficult environment. Systematic measurements of a large set of variables were achieved in 222 subjects and at altitudes up to 8400 m. The resulting dataset is a unique resource for the study of genotype:phenotype interactions in relation to hypoxic adaptation.

Perioperative Quality Initiative (POQI) consensus statement on fundamental concepts in perioperative fluid management: fluid responsiveness and venous capacitance.

BACKGROUND: Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state. METHODS: The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting. DISCUSSION: We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties.

Changes in skeletal muscle oxygenation during exercise measured by near-infrared spectroscopy on ascent to altitude.

INTRODUCTION: We sought to quantify changes in skeletal muscle oxygenation during exercise using near-infrared spectroscopy (NIRS) in healthy volunteers ascending to high altitude. METHODS: Using NIRS, skeletal muscle tissue oxygen saturation (StO2) was measured in the vastus lateralis of 24 subjects. Measurements were performed at sea level (SL; 75 m), at 3,500 m, on arrival at 5,300 m (5,300 m-a; days 15 to 17) and at 5,300 m again (5,300 m-b; days 69 to 71). Amongst the subjects, nine remained at 5,300 m whilst 14 climbed to a maximum of 8,848 m. Exercise was 3 minutes of unloaded cycling followed by an incremental ramp protocol to exhaustion. The absolute StO2 at different stages of exercise along with the difference between StO2 at stages and the rate of change in StO2 were compared between altitudes. Resting peripheral oxygen saturation was recorded. RESULTS: NIRS data achieving predefined quality criteria were available for 18 subjects at 75 m, 16 subjects at 3,500 m, 16 subjects on arrival at 5,300 m and 16 subjects on departure from 5,300 m. At SL, mean StO2 declined from 74.4% at rest to 36.4% at maximal oxygen consumption (P < 0.0001) and then rose to 82.3% (P < 0.0001) 60 seconds after exercise had ceased. At 3,500 m-a and 5,300 m-b, the pattern was similar to SL but absolute values were approximately 15% lower at all stages. At 5,300 m-a, the resting StO2 was similar to SL and the change in StO2 at each exercise stage less marked. At 5,300 m-b, the rate of decline in StO2 during exercise was more rapid than SL (P = 0.008); here the climbers had a smaller decline in StO2 during exercise (41.0%) and a slower rate of desaturation (0.086%/second) than those who had remained at 5,300 m (62.9% and 0.127%/second) (P = 0.031 and P = 0.047, respectively). CONCLUSIONS: In most individuals, NIRS can be used to measure exercising skeletal muscle oxygenation in the field. During exercise the patterns of absolute oxygenation are broadly similar at altitude and SL. Following prolonged adaptation to altitude, the rate of muscle desaturation is more rapid than observed at SL but less so in those exposed to extreme hypoxia above 5,300 m.