Denny Levett

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.

Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia—an ultrasound and MRI study

Transcranial Doppler is a widely used noninvasive technique for assessing cerebral artery blood flow. All previous high altitude studies assessing cerebral blood flow (CBF) in the field that have used Doppler to measure arterial blood velocity have assumed vessel diameter to not alter. Here, we report two studies that demonstrate this is not the case. First, we report the highest recorded study of CBF (7,950 m on Everest) and demonstrate that above 5,300 m, middle cerebral artery (MCA) diameter increases (n = 24 at 5,300 m, 14 at 6,400 m, and 5 at 7,950 m). Mean MCA diameter at sea level was 5.30 mm, at 5,300 m was 5.23 mm, at 6,400 m was 6.66 mm, and at 7,950 m was 9.34 mm (P<0.001 for change between 5,300 and 7,950 m). The dilatation at 7,950 m reversed with oxygen. Second, we confirm this dilatation by demonstrating the same effect (and correlating it with ultrasound) during hypoxia (FiO2 = 12% for 3 hours) in a 3-T magnetic resonance imaging study at sea level (n = 7). From these results, we conclude that it cannot be assumed that cerebral artery diameter is constant, especially during alterations of inspired oxygen partial pressure, and that transcranial 2D ultrasound is a technique that can be used at the bedside or in the remote setting to assess MCA caliber.

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). 31P 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.—Holloway, C. J., Montgomery, H. U., Murray, A. J., Cochlin, L. E., Codreanu, I. Hopwood, N., Johnson, A. W., Rider, O. J., Levett, D. Z. H., Tyler, D. J., Francis, J. M., Neubauer, S., Grocott, M. P. W., Clarke, K., for the Caudwell Xtreme Everest Research Group. Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp. FASEB J. 25, 792–796 (2011). www.fasebj.org

The Effect of High-Altitude on Human Skeletal Muscle Energetics: 31P-MRS Results from the Caudwell Xtreme Everest Expedition

Many disease states are associated with regional or systemic hypoxia. The study of healthy individuals exposed to high-altitude hypoxia offers a way to explore hypoxic adaptation without the confounding effects of disease and therapeutic interventions. Using 31P magnetic resonance spectroscopy and imaging, we investigated skeletal muscle energetics and morphology after exposure to hypobaric hypoxia in seven altitude-naïve subjects (trekkers) and seven experienced climbers. The trekkers ascended to 5300 m while the climbers ascended above 7950 m. Before the study, climbers had better mitochondrial function (evidenced by shorter phosphocreatine recovery halftime) than trekkers: 16±1 vs. 22±2 s (mean ± SE, p<0.01). Climbers had higher resting [Pi] than trekkers before the expedition and resting [Pi] was raised across both groups on their return (PRE: 2.6±0.2 vs. POST: 3.0±0.2 mM, p<0.05). There was significant muscle atrophy post-CXE (PRE: 4.7±0.2 vs. POST: 4.5±0.2 cm2, p<0.05), yet exercising metabolites were unchanged. These results suggest that, in response to high altitude hypoxia, skeletal muscle function is maintained in humans, despite significant atrophy.

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

BackgroundThe 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.MethodsDesign: Observational cohort study of progressive incremental exposure to EHH.SettingUniversity 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.Participants198 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 measuresExercise 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.ResultsOf 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.ConclusionsThis 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.

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  , heart rate and blood pressure were also recorded. Compared with SL, altitude resulted in reduced sublingual MFI in small (<25 μm; P < 0.0001) and medium vessels (26–50 μm; 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 μm did not change during ascent, but those >25 μm 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.

Cardiopulmonary Exercise Testing for Risk Prediction in Major Abdominal Surgery

Reduced exercise capacity is associated with increased postoperative morbidity. Cardiopulmonary exercise testing variables can be used to risk stratify patients. This information can be used to help guide the choice of surgical procedure and to decide on the most appropriate postoperative care environment. Thus CPET can aid collaborative decision making and improve the process of informed consent. In the future, CPET may be combined with other risk predictors to improve outcome prediction. Furthermore early evidence suggests that CPET can be used to guide prehabilitation training programs, improving fitness and thereby reducing perioperative risk.

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

PurposeThis review evaluates the current and future role of cardiopulmonary exercise testing (CPET) in the context of Enhanced Recovery After Surgery (ERAS) programs.Principal findingsThere 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.ConclusionsPerioperative 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.RésuméObjectifCette étude évalue le rôle actuel et dans le futur des tests d’efforts cardiopulmonaires (CPET) dans le contexte des programmes de récupération rapide après la chirurgie (RRAC).Constatations principalesIl existe une abondante littérature confirmant les rapports entre la forme physique et l’évolution générale du patient en période périopératoire. Les quelques petites études menées avec des patients subissant une chirurgie dans un programme de RRAC indiquent que les individus les moins en forme ont une plus grande incidence de morbidité et mortalité. Il existe des données probantes sur l’adoption croissante du CPET périopératoire, en particulier au Royaume-Uni. Bien que des variables tirées du CPET aient été utilisées pour guider les décisions cliniques sur le choix de la procédure chirurgicale et le niveau de soins périopératoires, ainsi que pour dépister des comorbidités rares, la capacité des variables tirées du CPET pour guider le traitement et, par conséquent, améliorer ses résultats reste incertaine. Des études récentes ont décrit une baisse de la forme physique (définie par le CPET) après des traitements néoadjuvants (chimio et radiothérapie) précédant une intervention chirurgicale. Les données préliminaires suggèrent que cela peut être associé à un effet secondaire sur les résultats cliniques des patients ayant la moins bonne condition physique. De premiers rapports suggèrent que les variables tirées du CPET peuvent être utilisées pour guider la prescription d’interventions d’entraînement à l’effort et, par conséquent, améliorer leur condition physique avant la chirurgie (c’est-à-dire, préadaptation). L’impact de telles interventions sur les résultats cliniques reste incertain.ConclusionsLe CPET périopératoire connaît une plage croissante d’utilisations, notamment pour l’évaluation du risque, la prise de décision collaborative, les soins personnalisés, l’évaluation du bénéfice des interventions et le guidage de la prescription de préadaptation. Ces indications sont potentiellement importantes pour les patients devant subir une chirurgie dans le cadre d’un programme de RRAC, mais il n’y a actuellement que peu de publications portant spécifiquement sur le CPET dans le contexte de programmes de RRAC.

Caudwell Xtreme Everest expedition

The Caudwell Xtreme Everest (CXE) expedition involved the detailed study of 222 subjects ascending to 5300 m or higher during the first half of 2007. Following baseline measurements at sea level, 198 trekker-subjects trekked to Everest Base Camp (EBC) following an identical ascent profile. An additional group of 24 investigator-subjects followed a similar ascent to EBC and remained there for the duration of the expedition, with a subgroup of 14 collecting data higher on Everest. This article focuses on published data obtained by the investigator-subjects at extreme altitude (>5500 m). Unique measurements of peak oxygen consumption, middle cerebral artery diameter and blood velocity, and microcirculatory blood flow were made on the South Col (7950 m). Unique arterial blood gas values were obtained from 4 subjects at 8400 m during descent from the summit of Everest. Arterial blood gas and microcirculatory blood flow data are discussed in detail.