Adam Sheperdigian and Edward Gilbert-Kawai
A distinct advantage of working in altitude, expedition or wilderness medicine is the chance to base your studies not in a lab, but in wild and exciting places. It is even better when your research gives insight not only to the extremes, but also to our day-to-day work back home. Hugely ambitious in their scope, the Xtreme Everest projects have taken the lab into the wild, using the slopes of Everest to shed light on the physiology of the critically-ill ICU patient. In this article, Adam Sheperdigian and Ned Gilbert-Kawai give Adventure Medic an overview of the projects, touching on some of the work done, as well as the sheer logistical effort involved. Want to know how to get three labs, fifteen tonnes of kit and three hundred yaks up Everest in the name of science? Then please, read on.
Xtreme Everest
In the spring of 2007 members of Caudwell Xtreme Everest (CXE) ventured up to the summit of Mount Everest as part of what was to become the largest high-altitude research expedition ever undertaken. Having recognised that oxygen levels in climbers at extreme altitudes may mimic those demonstrated in critically ill patients, the investigators decided to subject both themselves, and willing volunteers, to an array of physiological studies.
The objective – to identify the mechanisms responsible for successful acclimatisation and adaptation to hypobaric hypoxia, with the potential for translating these determinants into the hospital setting through the development of new treatments for critically ill hypoxic patients. Five years on, and building from the foundations of the work conducted on CXE, a second team from the University College London’s Centre for Altitude Space and Extreme Environment (CASE) Medicine set out for Nepal to continue exploring new realms of translational hypoxic research.
Led by Dr Daniel Martin (Expedition Leader) and Dr Edward Gilbert-Kawai (Research Leader), the Xtreme Everest 2 (XE2) research expedition departed from London on March 1st 2013. With them went an investigator team consisting of over 50 volunteer doctors and scientists, three field laboratories, and nearly 15 tonnes of equipment. Over the following three months spent in Nepal and the Solukhumbu valley some 45 different scientific studies were conducted on nearly 200 subjects.
Hypoxia
The unifying intervention for all the studies conducted on XE2 and the fundamental requirement to venture high up, was exposure to hypoxia – in this instance hypobaric hypoxia. Within medicine, the term hypoxia is invariably confused with hypoxaemia. Hypoxaemia refers to a decreased partial pressure of oxygen in the blood, whilst hypoxia refers to a decreased oxygen partial pressure at the tissue or cellular level. In a typical ascent to high altitude people attempt to normalise oxygen delivery by increasing, amongst other things, their ventilatory rate, cardiac output and haemoglobin concentration – a process known as acclimatisation.
In a similar manner in the intensive care setting, we may mimic the same process for critically ill patients through mechanical ventilation, inotropic medication and blood transfusions. Although these interventions can control a number of parameters, they do not explain apparent inter-individual responses to the same disease processes or hypoxic insult. Why do some individuals tolerate, and even thrive in a hypoxic environment, whilst others fail and fall? In an attempt to rationalise this discrepancy, the core research undertaken on XE2 looked into the human phenotype and genotype, and through the study of the physiological, biochemical and genetic biomarkers, we sought to find answers to this multifaceted and complex issue.
The Everest Research Model
The unifying intervention on XE2 was exposure to hypobaric hypoxia, and this was provided by a trek from Kathmandu to Everest Base Camp (EBC) (5300m). Using a matched ascent profile on each trek, every individual subject was exposed to an identically diminishing amount of oxygen, and could thus be compared. This ascent profile was exactly the same as that used for the CXE expedition in 2007 – a purposefully instigated slow ascent so as to minimise the incidence of acute mountain sickness and maximise successful ascent to EBC. Having had baseline normoxic testing conducted prior to their departure, subjects underwent identical testing at both Namche Bazaar (3400m) and Everest Base Camp (5300m). Unique to XE2 was the collection of descent data – further repeat testing on subjects return to Kathmandu in a environment of relative hyperoxia.
What did we study?
In total 45 individual studies were conducted on XE2. A general overview of the science conducted includes the following:
Upper Airway and Respiratory function / Ventilatory parameters, lung volumes and the hypoxic ventilatory rate were investigated. The latter of these provides us with an understanding of the central mediators behind what drives these processes. In addition, the well known but much despised “Khumbu-cough” was also studied along with the functioning of muco-cillary clearance.
Metabolic and Mitochondrial responses / Prolonged exposure to hypoxia is known to alter muscle mass and mitochondrial function. Muscle biopsies were taken from a select number of individuals and the resultant specimens allowed us to preform real time respirometry. Individual constituents of the Kreb’s cycle were analysed allowing us to assess the efficiency and capacity of these organelles in periods of hypoxia.
Nitric Oxide production and metabolism / Nitric oxide is a key mediator of endothelial function and central to understanding the vascular responses to hypoxemia. Through comprehensive examination of production, excretion and utilisation we hoped to better understand its involvement in the acclimatisation process.
Microcirculation and Cardiac responses / Using real-time microscopic imaging and laser doppler flowmetry subjects underwent detailed assessment of their microcirculation – potentially the key component of oxygen delivery. Continuous 24hr ECG monitoring was also used to identify changes in heart-rate variability and arrhythmias.
Cardiopulmonary Exercise testing / This provides us with an indicator of the impact of hypoxia on performance at altitude. Furthermore it allows detailed analysis of exercise capacity, efficiency, and oxygen kinetics.
Daily testing / Additionally throughout the ascent participants completed a daily diary that included a Lake Louise score and basic physiological parameters (heart rate, respiratory rate, oxygen saturations and blood pressure) before and after a mild, validated exercise test. These simple parameters offered a daily insight into each individual’s subjective and objective experiences of an ascent to high-altitude. Data obtained in the field for each individual subject will be compared to their own baseline normoxia values, and with five different cohorts on the expedition, inter-cohort variability will also be assessed for. These distinctive cohorts included; Lowlanders, Sherpas, Identical twins, Children and Investigators. As the latter of these were stationed at Everest Base Camp for six weeks, this data set provides a unique insight into physiological changes over time.
Sherpas
A central aspect of the research was the inclusion of a Sherpa Cohort. Throughout history Sherpas have been intimately involved in all expeditions and assaults on Everest, with their continued performance at altitude mesmerising their western counterparts.
Since migrating from the highland Tibetan plateau thousands of years ago, this somewhat isolated population has evolved over time to live and thrive amongst the daily hypoxic insult encountered at altitude. Undoubtedly natural selection has moulded their phenotype-genotype to enable survival, but what is it physiologically that explains their apparent indifference to the hypoxic environment? Through the comparison of a Sherpa cohort, as compared to a Lowlander cohort, XE2 aims to identify possible mechanisms utilised by Sherpas – characteristics that could help direct new treatment strategies and therapeutic interventions for critically ill patients in the hospital setting.
Preparation
XE2 took two years to organise and implement. Preparing for field work in a high up, cold and isolated environment was certainly not without its difficulties. Prior to our departure, all the scientific equipment had to be tested and validated in extremes of temperatures and pressures, as fluctuations of temperature from minus 20C to plus 20oC is normal at 5300 meters. Computers had to be adapted to incorporate solid-state drives, and an electricity grid manufactured to provide the necessary output to support a fully functioning laboratory at each location.
High up on our list of priorities was the realisation that Everest Base Camp was effectively isolated from the outside world, thus unless it ascended with us at the start of the expedition, we would not have it at our disposal. Consequently every individual piece of equipment required for each study was checked and rechecked down to the last plaster.
In the six months prior to departure nearly twenty tonnes of equipment was acquired, inventoried and safely packed, and without the unrelenting work of the logistical team and on-going support of sponsors this could not have been accomplished. Once in the country, a team of nearly 300 Yaks, and 100 porters was utilised to carry the equipment to EBC.
What the future holds
Having returned from Nepal, the team now faces a task perhaps more monumental than their efforts in Nepal, the processing, analysing and publishing of this gigantic data set. Alongside their collaborators from around the world, CASE Medicine’s work on Xtreme Everest 2 has only just begun.
If you are interested in following their developments please visit the website or follow us on Twitter.
- Levett D, Martin D, Grocott MPWet al. Design and Conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptaion to progressive environmental hypoxia. BMC Medical Research Methodology, 2010 Octo 21; 10(1):98
- High Altitude Medicine and Physiology, 4th Edition. West, Schoene and Milledge
- Levett D, Radford E, Murray A et al. Acclimatization of skeletal muscle mitochondria to high altitude hypoxia during ascent of Everest. FASEB Journal, 2011 Dec 20
- Levett D, Fernandez B, Feelish M et al. The role of nitrogen Oxides in human adaptation to hypoxia. Scientific Reports 2011;1:109
- Martin D, Goedhart P et al. Changes in Sublingual Microcirculatory flow index and vessel density on ascent to altitude, Experimental Physiology 2010;95:880-891
