The Xtreme-Everest program of investigation is based on 2 ideas: 1. “Investigating human adaptation to hypoxia is an important element of understanding the pathophysiology of critical illness and has the potential to lead to the development of new treatments” 2. “Healthy volunteers exposed to hypobaric hypoxia in field studies are a useful model for the study human adaptation to hypoxia” Hypoxia in critical illness Cellular hypoxia is a fundamental mechanism of injury in the critically ill.1 Hypoxia may occur as either a cause or consequence of, a variety of critical illnesses. For example hypoxia-mediated cell death may lead to the generation of an inflammatory response. Systemic inflammation is associated with microcirculatory dysfunction resulting in reduced oxygen delivery and thus the development of cellular hypoxia. Furthermore, critical illness is associated with deranged cellular oxygen utilisation. Investigating the physiology and pathophysiology of hypoxia Xtreme-Everest is a human healthy volunteer study investigating hypoxic adaptation. Hypoxic adaptive processes are likely to be common to tissue hypoxia whatever the cause, and studying healthy individuals progressively exposed to hypoxia through ascent to high altitude may inform the nature of the adaptive processes to hypoxia occurring in the critically ill. This approach offers the advantages of a relatively homogenous study population and environmental challenge, in contrast to those observed on Critical Care Units, as well as the availability of “pre-morbid” information and levels of function. It also offers an ethical alternative to hypoxia experimentation in patients; all involved are willing participants in climbing or trekking ventures, as a consequence of which they expose themselves to a hypoxic environment. Human physiology at altitude Xtreme-Everest is an observational cohort study with nested interventional sub-studies. A large cohort of healthy volunteers will be progressively exposed to hypoxia at a standardised rate expected to result in minimal altitude illness and provide time for acclimation (n=224). During the ascent, the adaptive response to hypoxia will be investigated, beneficial phenotypes will be identified and these will be related to underlying genotype. Baseline studies have been performed at sea level and these will be repeated at four laboratories in Nepal at altitudes of 1350m, 3400m, 4200m and 5300m (Everest Base Camp). A broad range of experimental protocols will be carried out investigating cellular oxygen utilisation, oxygen delivery, microcirculatory function, cerebral blood flow and oxygenation, neurocognitive function, sleep disturbance and metabolism. 15 climbers will ascend Mount Everest and a subset of these investigations will be performed at extreme altitudes, observing physiology at the limits of human endurance. I will present early data from the Xtreme-Everest Expedition including, I hope, an arterial blood gas from the summit.