High Altitude: Adaptations and Challenges

• This article addresses the physiological challenge of exposure to environmental hypoxia at high altitude and the adaptive and pathological responses.

Environmental Challenge

• Barometric pressure (PB) decreases non-linearly with altitude above Earth.
• Oxygen percentage in the atmosphere remains constant at 20.9%.
• Atmospheric partial pressure of oxygen (P02) reduces proportionally with PB.
• At Mount Everest's summit (8848 m), PB and atmospheric P02 are about one-third of sea-level values.
• Acute exposure to altitudes above 5500 m may cause loss of consciousness.
• Above 8000 m, loss of consciousness occurs reliably within 3 minutes.
• Acclimatization is the body's adaptive process to increasing altitude.
• Lowest documented arterial partial pressure of oxygen (Pao₂) in a healthy person was 2.55 kPa at 8400 m on Everest.
• Adequate acclimatization enables normal function with profound hypoxaemia.
• High altitude generally refers to altitudes over 2500 m.
• La Paz (Bolivia), the world's highest capital, is at 3500-4000 m.
• About 35 million people travel above 3000 m annually.

Acclimatization Response

• Reduced atmospheric P02 decreases alveolar partial pressures of oxygen (PAO₂) and Pao₂.
• This reduction leads to an initial decrease in oxygen delivery (DO2).
• Acclimatization increases DO2 through respiratory, haematological, and cardiac changes.

Respiratory Changes

• The oxygen cascade describes the decrease in oxygen partial pressure from atmosphere to mitochondria.
• Altitude and acclimatization influence the oxygen cascade.
• Climbers on Mount Everest (8400 m) had a mean Pao₂ of 3.3 kPa and Paco₂ of 1.8 kPa.
• The fraction of inspired O2 (Flo₂) is constant at 20.9%.
• At 8400 m, PB = 36.3 kPa, and atmospheric P02 = 7.6 kPa.
• Saturated vapor pressure of water is 6.3 kPa at body temperature.
• Respiratory humidification has a proportionally greater effect at altitude, reducing oxygen partial pressure in the airways.
• Partial pressure of inspired oxygen (Pio₂) = 6.3 kPa at 8400m.
• Alveolar partial pressure of oxygen (PAO2) differs from Pio, due to carbon dioxide (CO2) in the alveolar space.
• PAO2 is predicted by the alveolar gas equation: PAO2 = Pio2 - (PACO2/R).
• R, the respiratory quotient, averages 0.74 in climbers.
• Alveolar partial pressure of CO2 (PACO₂) is assumed equal to Paco.
• Oxygen is taken up from the alveolus by deoxygenated blood.
• Alveolar partial pressure of oxygen PAO2 =3.9 kPa (at 8400m).
• Alveolar ventilation (VA) is inversely proportional to Paco,.
• VA increases with ascent to altitude.
• At sea-level, mild hypoxia does not increase VA.
• Acclimatization inhibits the central response, increasing VA for any given Pao,.
• Mechanisms inhibiting the central response are associated with a decrease in cerebrospinal fluid (CSF) bicarbonate (HCO3).
• Increased VA produces respiratory alkalosis, compensated by renal loss of HCO3.
• Increased VA and decreased Paco₂ and PACO2 increase PAO2

Alveolar-arterial Gradient

• Ventilation-perfusion mismatch, shunting, or reduced diffusion capacity explain the A-a gradient.
• At sea-level, a normal A-a gradient is <1.3 kPa.
• In simulated ascent, the A-a gradient decreases with decreasing Pio,.
• Climbers' mean measured A-a gradient was 0.7 kPa.
• Increased gradient might be due to subclinical high-altitude pulmonary oedema (HAPE), functional diffusion limitation, or posture-related V-Q mismatch.

Haematological Changes

• Oxygen is primarily transported reversibly bound to haemoglobin Hb.
• Arterial oxygen content (CaO2) is measured in ml O2 100 ml-1 blood
• The climbers mean Sao₂ was calculated as 54% and the measured Hb was 19.3 g dl-1.
• CaO2 = (54×1.34×19.3×0.01)+(0.023×3.3) = 14.0 ml O2 100 ml-1 blood
• Arterial oxygen saturation (%) = Sao₂
• Huffner's constant (millilitres of oxygen carried by 1 g of Hb in vivo) = 1.34
• Constant = 0.023 = solubility coefficient of oxygen
• Hb increases during acclimatization, increasing CaO2.
• Acute: plasma volume is reduced by ~20%, producing haemoconcentration.
• Over time: erythropoietin is released in response to hypoxia.
• Red cell production increases occur within days and continue for weeks.
• Microcirculatory flow may be disrupted at altitude due to increased haematocrit.
• The oxygen dissociation curve describes the relationship between Pao2 and Sao2.
• Acutely, hyperventilation and respiratory alkalosis shifts the ODC to the left.
• Over days to a week, 2,3-diphosphoglycerate increases, returning the ODC to its sea-level position in fully acclimatized individuals.

Cardiovascular Changes

• Increased sympathetic activity leads to an initial increase in cardiac output (Q).
• Increase primarily achieved by an increase in heart rate (HR).
• DO2 can be calculated by the product of Q and CaO2.
• Initial reduction in plasma volume with altitude reduces preload and SV.
• After several weeks, Q returns to sea-level values, but SV remains reduced with a consequential chronic elevation in HR.

Other Adaptations

• Capillary and mitochondrial densities were previously considered to increase with acclimatization.
• Microscopy demonstrates decreased muscle mass, producing apparent increased relative capillary densities, rather than neovascularization.
• Muscle biopsies have shown a 30% reduction in mitochondrial density.
• Acclimatization shows wide inter-individual variability.
• Changes in physical performance at altitude are unrelated to changes in oxygen content or delivery.

Acute High-Altitude Illness

• Acute high-altitude illness describes neurological or pulmonary syndromes in unacclimatized individuals ascending too rapidly.
• Acute mountain sickness (AMS) has been reported at altitudes as low as 2000 m.
• Incidence increases with altitude, reported in up to 40% of people at 3000 m.
• Potentially fatal HAPE and high-altitude cerebral oedema (HACE) are less common,.
• HAPE and HACE are diagnosed in <2% of individuals ascending above 4000 m.
• Faster ascent and higher altitudes reached increase the likelihood of high-altitude illness.
• Prevention through controlled ascent is the simplest means of reducing illness.

Pathophysiology of Acute High-Altitude Illness

• AMS and HACE may share the same pathophysiology and represent a spectrum of severity.
• Hypoxia induces neurohumeral and haemodynamic responses causing vasodilatation, hyperaemia, and microcirculatory changes, increasing capillary hydrostatic pressures, resulting in capillary leak and cerebral oedema.
• Sufferers of AMS have: reduced hyperventilatory response, impaired gas exchange, fluid retention, and increased sympathetic drive.
• The cardinal symptom of AMS and HACE is headache, due to increased volume of the intra-cerebral contents.
• Individuals may exhibit increased cerebral venous volume.
• HAPE is a result of an imbalance between forces driving fluid into and out of the alveolar space.
• Alveolar capillary leak is related to the level and heterogeneity of the pulmonary hypertension that occurs.
• HAPE appears to be a direct pressure effect with no evidence of inflammatory mediators in early bronchoalveolar lavage.
• Pulmonary capillary stress failure due to high transmitted pressures from some pulmonary arterioles has been demonstrated.
• An exaggerated pulmonary hypertensive response is demonstrated in susceptible individuals.
• Increased sympathetic drive is also present in HAPE.

Other Health Risks

• Remote travel is associated with diarrhoeal illness and other infections.
• Hypoxia and polycythaemia contribute to increased thrombotic events at altitude.
• High altitude is a hostile environment, remote from emergency services; trauma risk is increased.
• Reduced atmospheric protection from ultraviolet radiation and temperature extremes may result in thermal injuries or hypothermia and cold injury.
• At extreme altitudes above 5500 m, high-altitude deterioration occurs, characterized by lethargy, impaired cognitive function, anorexia, and weight loss.
• Deeper stages of sleep, rapid eye movement, and sleep quality are all reduced at altitude.

Acute High-Altitude Illness Management

• Controlled ascent prevents HACE and HAPE.
• Descent to a lower altitude should be the priority with all individuals suffering severe altitude illness and ascent should be discouraged when mild AMS is diagnosed.
• Controlled ascent profiles reduce the incidence of AMS.
• Considerations in diagnosis include: ruling out alternate diagnoses, evidence of HACE or HAPE, symptom severity, and treatment response.
• Exclusion of HACE includes a neurological examination/assessment of cognitive function and a heel-toe walk test.
• Mild AMS may be managed by resting at the same altitude.

Adjunctive Therapies

• Acetazolamide: prophylaxis or treatment.
• Dexamethasone: prophylaxis or treatment.
• Hyperbaric chamber
• Oxygen: prophylaxis or treatment