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.