In 2007, UCL researchers pulled off an incredible feat- sending a research team to the top of Mount Everest, Braving the harsh and barren surroundings, they performed groundbreaking studies that have greatly informed our understanding of hypoxia and critically ill patients.
History is rife with stories of brave people putting their bodies on the line for the advancement of science. Take Marshall and Warren, for example: these two Australian doctors famously ingested H. pylori to prove that peptic ulcer and gastric cancer could be caused by bacterial infection. Last year marked the tenth anniversary of a similarly heroic endeavour – the first Caudwell Xtreme Everest (CXE) expedition, organised by the UCL Centre for Altitude, Space and Extreme Environment Medicine (CASE).
Critically ill patients are predisposed to hypoxaemia (low oxygen levels in the blood), often resulting in tissue hypoxia. Organ failure and death frequently ensue. Treatment is centered on maintaining cellular oxygenation, but in the past, there was little evidence regarding optimal inspired oxygen levels. There was also no explanation for the individual variation in that response. In some patients, increasing oxygen delivery has no effect and may even be harmful. At altitude, people react differently to reduced oxygen levels – counter-intuitively, this has little to do with age or fitness. The CXE team believed such variation in the ability to adapt to hypoxia could be explained by individual variations in metabolic efficiency. To test this theory, investigators could look to animal models as a starting point, as it is commonly done with studies of human diseases. Owing to the complexity of human physiology in acute illness, however, highly simplified animal models may not be valid.
How about studying human patients, then? In a hospital environment, patients become critically ill for myriad reasons, making it impossible to tease apart the effects of hypoxia from a whole host of other pathophysiological events. Coincidentally, oxygen levels at the summit of Everest are the lowest tolerable by humans. The inhospitable heights of Everest – “death’s door”, truly – therefore presented the perfect opportunity to study healthy volunteers at various oxygen levels as they made their way up.
To be sure, medical studies on Everest has been done before. While previous studies contributed greatly to our understanding of adaptation to chronic hypoxia, CXE’s aim was to investigate how that adaptation differs among individuals. At the same time, the CXE team hoped to establish links between individual genes and environmental factors. Compared to previous similar studies, CXE has a much larger subject cohort and better field research infrastructure. Importantly, all subjects adhered to a strictly consistent ascent profile and hence identical levels of hypoxia. This allowed the team to study individual variation solely due to physiological differences without interference from environmental differences.
The research team recruited a large cohort of 222 volunteers, divided into two groups: trekkers (comprised of member of the public) and investigators (including doctors, scientists, allied health professionals and medical students). Such a large undertaking, unsurprisingly, required a gargantuan effort to ensure the logistics were in place for field testing. Most equipment had been tested in three pilot expeditions to the Alps and the Himalayas in the 2 years leading up to the CXE expedition. As baseline studies were being performed on the participants back in London, Sherpas and yaks carried about 25 tonnes of equipment and 80 tents up to Everest Base Camp. Field laboratories were set up in Sherpa lodges, specialised field shelters and high-altitude tents at multiple locations such as Kathmandu, Namche Bazaar, Pheriche, Everest Base Camp and beyond.
When the time came for the actual expedition, all 222 participants were flown in to Khumbu and made their way to Everest Base Camp on foot. Both study groups completed the journey to Everest Base Camp in slightly under two weeks. Along the way, they stopped at each field laboratory for a battery of tests: expired gas analysis and near-infrared spectroscopy on brain and skeletal muscle at rest and during exercise; plasma samples for inflammatory markers; nitric oxide metabolites and organ injury markers; and various neurological tests. Some investigators were subject to more invasive tests such as arterial cannulation and skeletal muscle biopsies. After testing, the trekker group returned to Kathmandu whereas the investigator group remained at Everest Base Camp, 14 of whom ascended to the summit that May for further testing and blood sample collection.
The expedition was not without its fair share of drama. On 22nd May 2007, Usha Bista, a 22-year-old Nepalese climber, was found unconscious near the summit by another group of climbers. She had been abandoned by her own team after falling ill and collapsing. The climbers who found Usha brought her to the CXE lab at South Col, where she was diagnosed with hypoxia-induced cerebral oedema. Thanks to the care she received and subsequent treatment in Kathmandu, Usha made a full recovery and went on to conquer the summit later that year.
The first CXE expedition was a resounding success, completing more than 90% of planned tests and generating a wealth of unprecedented data concerning microcirculation, nitric oxide and mitochondria. The team was able to assemble epigenetic profiles of the participants, which provided valuable insight into the interplay between genes and environment in the context of hypoxic adaptation. Data generated during the expedition informed many subsequent studies. For instance, Tibetan highlanders display enhanced nitric oxide formation, leading to the belief that this is a unique genetic trait borne by evolutionary forces. Findings from a CXE study dispelled this notion: when lowlanders climb to high altitudes, more nitric oxide forms, suggesting that nitric oxide formation is an innate physiological response to hypoxia.
These findings and the resulting questions spawned a second CXE expedition. Data from the first CXE expedition had demonstrated higher erythropoietin, nitric oxide and cGMP levels in experienced climbers compared to inexperienced climbers, suggesting that previous exposure to high altitudes improves adaptation to hypoxia via epigenetic mechanisms. This time, the team recruited volunteers living close to sea level and Sherpas. The latter, with their long ancestry in the mountains, may have developed adaptive mechanisms not seen even in experienced climbers. The second expedition allowed a direct comparison of these two populations, as well as a large biobank and phenotype database for translational research.
Xtreme Everest is a celebration of human ingenuity and collaboration. Such an astounding feat could not have been achieved without the hard work of the CXE team and the volunteers who gave up their holidays to take part. It is also a prime example of how expedition medicine can lead directly to personal fulfilment outside of medicine. Professor Monty Mythen, who led the field laboratory at Namche Bazaar, urges medical students who are considering a career in expedition medicine: “Go for it! If you want to do it then don’t overthink it. Life is too short. Find a good team with a great safety record – ideally the Xtreme Everest Research Consortium and the UCL CASE.”
We would like to thank Professor Michael (Monty) G Mythen for taking the time to contribute to this piece.
By Ian Tan