High Altitude Medical Research Expedition Himlung 2013 - a Study of Human Adaption to Hypoxia
Condition: Hypoxia
MeSH terms: Hypoxia
Study type: Observational

Summary: 
      The aim of the project "High Altitude Medical Research Expedition Himlung 2013" (HiReach2013)
      is to comprehensively investigate the cerebral, cardiovascular and pulmonary adaptation and
      the reactions of the human immune system during an ascent to extreme altitudes of over 7000
      m. A total of 44 healthy and trained volunteers will be included in the study after written
      informed consent has been obtained.Baseline sea level clinical examination will be performed
      in Bern, Switzerland (BE1) at 550 m 8 to 4 weeks before departure. High altitude research
      facilities will be available at the altitudes of 5000m, 6100m and 6900m. Post-expedition
      examination will be performed within 2 to 6 weeks after the end of the expedition in Bern. In
      the context of 3 sub-projects specific measurements and examinations are performed.

      These include: cMRI before and after the climb and neurovascular doppler examination during
      the climb; blood sampling for coagulation studies, cardiac and thoracic ultrasound, stress
      tests for assessment of cardiovascular performance.
    

Detailed description: 
      Background

      Altitude related medical problems are gaining more importance and attention as an ever
      increasing number of people travel to higher altitudes for work or pleasure. Resort towns in
      Europe and the Western United States at elevations in the 2000 m to 3000 m range attract
      millions of visitors annually. Many more visit cities in South America and Asia situated
      above 3000 m. In addition, tens of thousands of travelers, trekkers, and skiers worldwide
      ascend to elevations in the range of 3000 to 5500 m. An ever-increasing number of
      recreational climbers attempt ascents of summits of very high (3500 m to 5500 m) or extreme
      (>5500 m) altitudes. The Nepalese Ministry of Tourism and Civil Aviation and the Nepal
      Mountaineering Association reported having issued permits to 6032 climbers for peaks higher
      than 6000 m in the year 2010 alone. When considering that the number of people residing at
      high altitude is bound to increase, it is of importance to further deepen our understanding
      of the physiologic changes and dangers associated with exposure to high altitude. Oxygen
      homeostasis is essential for survival of healthy humans at high altitudes. Various
      physiological changes involving different organ systems occur during exposition and
      acclimatization to hypobaric hypoxia in the context of a high altitude sojourn. These include
      marked adaptations of pulmonary and systemic vascular function, changes in cerebral perfusion
      and metabolism, physiologic and metabolic adaptations of the immune system and innate defense
      mechanisms against infection. These changes are a consequence of tissue hypoxia per se or can
      be mediated by hypoxia induced activation of sympathoadrenal pathways. An example of
      important research activities in recent years is the discovery of hypoxia-inducible factor 1
      alpha (HIF1α) and its role in oxygen homoeostasis by regulation of multiple gene loci.
      Additionally, as a result of hypoxia induced increase in oxidative/reductive stress, enhanced
      generation of reactive oxygen (ROS) and nitrogen species (RNS), altered activity of
      antioxidant systems, and related oxidative damage to lipids, proteins, and DNA can occur as
      well as injury at the cellular, sub-cellular and molecular levels. These short-lived
      intermediates include among others superoxide anion (O2), hydrogen peroxide (H2O2), and
      hypochloride (HOCI. In addition, hydroxyl radicals (OH), hydroxide ions (OH) and superoxide
      radicals (O2-) are highly reactive members of the ROS family that accumulate under certain
      physiological and pathophysiological conditions. As a consequence, prolonged hypobaric
      hypoxia leads to systemic oxidative stress similar to severe inflammation.

      Tissue hypoxia and increased oxidative stress as well as adaptive or reactive changes in
      sympathoadrenal and neuroendocrine processes also occur in various disease states. Hypoxia
      per se plays an important role in the pathogenesis of major causes of mortality, including
      cancer, cerebral and myocardial ischemia, and chronic heart and lung disease. Global
      hypoxemia is a common problem in critically ill patients: In patients with pulmonary failure
      profound hypoxia can occur due to ventilation/perfusion mismatch or impaired diffusion
      capacity across the alveolo-capillary membrane despite best medical support including
      mechanical ventilation. Oxygen delivery to tissues might also be impaired due to low cardiac
      output or reduced oxygen carrying capacity in anemia. Microcirculatory dysfunction -
      occurring in the context of severe sepsis - can lead to local hypoxia on a cellular level
      even in patients with normal or increased arterial oxygen content and oxygen delivery.

      In critically ill patients cellular hypoxia induces oxidative stress which can deplete
      cellular antioxidative capacities and lead to impaired ability to use available oxygen.
      Depleted levels of reduced glutathione, an important intra-mitochondrial antioxidant, in
      combination with increased generation of ROS and RNS seem to inhibit oxidative
      phosphorylation and ATP generation. There is increasing interest in ROS-intermediates and
      their role in the progression and modulation of vascular dysfunction and remodelling seen in
      different chronic disease entities, such as diabetes mellitus, chronic heart failure or
      chronic obstructive pulmonary disease (COPD) and development of pulmonary hypertension (PHT).
      The mechanisms of ROS-generation are not fully understood. ROS are produced in leukocytes,
      but the generation of ROS might also occur through disruption of the electron transport chain
      in mitochondria. The resulting mitochondrial dysfunction has been described as an additional
      factor causing pulmonary vasoconstriction and remodelling in PHT. In hypoxic patients with
      respiratory failure an increase of pulmonary vascular pressure frequently occurs (WHO Class
      III - pulmonary hypertension) which may worsen hypoxemia by impairing lung perfusion. If this
      increase is caused by a direct vasoconstrictive effect of hypoxia on the pulmonary
      endothelial cells or by an increase in ROS is still not fully understood.

      Generally, the mechanisms leading to adaptation to prolonged hypoxic conditions in healthy
      humans and in critically ill patients are not well understood. In the context of critical
      illness these mechanisms are difficult to explore due to the heterogeneity of patients and
      precipitating illnesses. Furthermore, effects of hypoxia and concurring disease related
      processes are difficult or impossible to distinguish. Animal models of critical illness might
      have substantial limitations and often do not represent the human patient. It has been
      suggested that the physiological and pathophysiological responses to hypobaric hypoxia may be
      similar to responses seen in critical illness. In the context of a high altitude expedition
      human subjects can safely be submitted to prolonged hypoxia and oxidative stress and the
      resulting cerebral, cardiovascular and pulmonary adaptation and changes in mitochondrial
      function, inflammatory cascade, and coagulatory activity can be explored in a controlled
      fashion. The study of human responses to hypoxia occurring in a hypobaric environment in
      healthy volunteers ascending to high altitudes may therefore serve as a model of isolated
      hypoxia and might help to improve our understanding of the effects in critically ill
      patients.

      Objective

      The aim of the project "High Altitude Medical Research Expedition Himlung 2013" (HiReach2013)
      is to comprehensively investigate the cerebral, cardiovascular and pulmonary adaptation and
      the reactions of the human coagulation system during an ascent to extreme altitudes of over
      7000 m.

      Methods

      Cardiopulmonary exercise testing will be done using a testing system on a bicycle using a
      roller trainer for standardization and regulation of the work load. Static and dynamic lung
      volumes will be assessed at each study site. The measurements will include the assessment
      DLCO using a commercially available spirometer. Transthoracic Doppler echocardiography will
      be performed for assessment of systolic/diastolic cardiac function and pulmonary artery
      pressures. Lung ultrasound will be applied in each subject at each study site to quantify
      extravascular lung water by ultrasound lung comets. Microparticle measurements will be
      performed using an Annexin V based ELISA. Cerebral blood flow velocity will be measured from
      a middle cerebral artery using transcranial Doppler. Structural cerebral changes and cerebral
      volume will be assessed with MRI of the brain. At each study site extensive coagulation
      studies will be performed.
    

Intervention name(s): Hypobaric hypoxia
Intervention type(s): Other
Intervention description(s): Subjects are exposed to hypobaric hypoxia in the context of a high altitude expedition.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy and trained volunteers with basic mountaineering experience
      
Biospecimen description: 
      serum urine
    
Keywords: hypoxia hypobaric