LEVEL-RESPONSE RELATIONSHIP AND LIMITS OF HYPOXIA TOLERANCE
The physiological response to hypoxia involves a complex cascade of adaptive mechanisms aimed at restoring oxygen delivery to vital organs and maintaining cellular homeostasis. The time-dependent patterns of physiological responses to hypoxia observed during the acclimatization process at high altitude, are shown in Figure 2. The severity of hypoxia determines the intensity and extent of these physiological responses [33, 34].
In mild hypoxia, characterized by a modest decrease in oxygen availability, the body initiates several compensatory mechanisms to mitigate the impact of oxygen deficiency. These responses include activation of the sympathetic nervous system, increased ventilation to enhance oxygen uptake in the lungs, peripheral vasodilation to facilitate increased blood flow and oxygen delivery to organs, increased cardiac output to ensure adequate oxygen supply, and enhanced oxygen extraction by tissues.
As hypoxia worsens to a moderate level, additional physiological responses come into play. The body increases red blood cell production to enhance oxygen-carrying capacity, and cells increasingly rely on anaerobic (glycolytic) metabolism to generate energy. This shift leads to the production of lactate and subsequent metabolic acidosis. Furthermore, the activation of HIFs occurs, regulating the expression of genes involved in oxygen transport, angiogenesis, and metabolism.
In cases of severe hypoxia, where oxygen availability reaches critical levels, the physiological responses become more pronounced. Breathing becomes more labored with increased respiratory effort. Lactate production further increases as reliance on anaerobic metabolism intensifies, resulting in severe metabolic acidosis. Cognitive function becomes impaired, resulting in confusion, impaired judgment, and potential loss of consciousness. Cardiovascular disturbances may arise, including arrhythmias, decreased cardiac output, and increased pulmonary artery pressure, which can lead to organ failure.
The limits of hypoxia tolerance refer to the thresholds beyond which the body’s compensatory mechanisms are overwhelmed, resulting in critical physiological dysfunction and potentially irreversible damage. These limits can be conceptualized as a ”defense zone” or a range within which compensatory mechanisms can maintain cellular homeostasis despite reduced oxygen availability. It has been postulated that this defence zone lies around 35 mmHg of arterial oxygen partial pressure [35].
It is important to recognize that individuals have different thresholds of hypoxia tolerance, influenced by factors such as genetical background, age, health status, physical fitness, and acclimatization [36]. Prolonged exposure to severe hypoxia can exceed an individual’s tolerance, leading to severe complications, including organ failure and death. Furthermore, each organ exhibits a distinctive normoxic tissue oxygen partial pressure threshold, below which its physiological functions become compromised: 72 mmHg for kidneys, 58 mmHg for intestinal tissue, 41 mmHg for liver, 34 mmHg for brain, and 29 mmHg for skeletal muscle [10, 37].
Understanding the limits of hypoxia tolerance is crucial for assessing risks associated with high-altitude activities, occupational settings, and medical conditions involving hypoxia. Careful monitoring and assessment are necessary to ensure safety and mitigate potential health risks. However, the Operation Everest studies I - III, all performed in hypobaric laboratory chambers, have demonstrated safety and feasibility of exposing highly selected, healthy, young individuals, under well controlled conditions to prolonged exposure of extreme hypoxia spanning several weeks [38, 39]. In a series of current pilot trials, evidence has demonstrated the safety and feasibility of subjecting not only healthy, middle-aged individuals but also those with prior myocardial infarction to normobaric hypoxia approaching the human hypoxic limit [40-43]. Both kind of study series pave the way for pharmacological studies using human hypoxia models.