Altitude Illness - Pulmonary Syndromes

Updated: Oct 05, 2015
  • Author: N Stuart Harris, MD, MFA, FACEP; Chief Editor: Joe Alcock, MD, MS  more...
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Altitude illness refers to a group of syndromes that result from hypoxia. Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) are manifestations of the brain pathophysiology, while high-altitude pulmonary edema (HAPE) is that of the lung (see image shown below). Everyone traveling to altitude is at risk, regardless of age, prior medical history, level of physical fitness, or previous altitude experience. [1]

The high altitude environment generally refers to elevations over 1500 m (4900 ft). Moderate altitude, 2000-3500 m (6600-11,500 ft), includes the elevation of many ski resorts. Although arterial oxygen saturation is well maintained at these altitudes, low PO2 results in mild tissue hypoxia, and altitude illness is common. Very high altitude refers to elevations of 3500-5500 m (11,500-18,000 ft). Arterial oxygen saturation is not maintained in this range, and extreme hypoxemia can occur during sleep, with exercise, or with illness. HACE and HAPE are most common at these altitudes. Extreme altitude is over 5500 m; above this altitude, successful long-term acclimatization is not possible and, in fact, deterioration ensues. Individuals must progressively acclimatize to intermediate altitudes to reach extreme altitude.




Hypoxia is the primary physiological insult on ascent to high altitude. The fraction of oxygen in the atmosphere remains constant (0.21), but the partial pressure of oxygen decreases along with barometric pressure on ascent to altitude. The inspired partial pressure of oxygen (PiO2) is lower still because of water vapor pressure in the airways. At the altitude of La Paz, Bolivia (4000 m; 13,200 ft), PiO2 is 86.4 mm Hg, which is equivalent to breathing 12% oxygen at sea level.

The response to hypoxia depends on both the magnitude and the rate of onset of hypoxia. The process of adjusting to hypoxia, termed acclimatization, is a series of compensatory changes in multiple organ systems over differing time courses from minutes to weeks. While the fundamental process occurs in the metabolic machinery of the cell, acute physiologic responses are essential in allowing the cells time to adjust.

The most important immediate response of the body to hypoxia is an increase in minute ventilation, triggered by oxygen-sensing cells in the carotid body. Increased ventilation produces a higher alveolar PO2. Concurrently, a lowered alveolar PCO2 results in a respiratory alkalosis and so acts as to limit the increase in ventilation. Renal compensation, through excretion of bicarbonate ion, gradually brings the blood pH back toward normal and allows further increase in ventilation. This process, termed ventilatory acclimatization, requires approximately 4 days at a given altitude and is greatly enhanced by acetazolamide. Patients with inadequate carotid body response (genetic or acquired, eg, after surgery or radiation) or pulmonary or renal disease may have an insufficient ventilatory response and thus not adapt well to high altitude.

In addition to ventilatory changes, circulatory changes occur that increase the delivery of oxygen to the tissues. Ascent to high altitude initially results in increased sympathetic activity, leading to increased resting heart rate and cardiac output and mildly increased blood pressure. The pulmonary circulation reacts to hypoxia with vasoconstriction. This may improve ventilation/perfusion matching and gas exchange, but the resulting pulmonary hypertension can lead to a number of pathological syndromes at high altitude, including HAPE and altitude-related right heart failure. Cerebral blood flow increases immediately on ascent to high altitude, returning to normal over about a week. The magnitude of the increase varies but averages 24% at 3810 m and more at higher altitude. Whether the headache of AMS is related to this flow increase is not known.

Hemoglobin concentration increases after ascent to high altitude, increasing the oxygen-carrying capacity of the blood. Initially, it increases due to hemoconcentration from a reduction in plasma volume secondary to altitude diuresis and fluid shifts. Subsequently, over days to months, erythropoietin stimulates increased red cell production. In addition, the marked alkalosis of extreme altitude causes a leftward shift of the oxyhemoglobin dissociation curve, facilitating loading of the hemoglobin with oxygen in the pulmonary capillary.

Sleep architecture is altered at high altitude, with frequent arousals and nearly universal subjective reports of disturbed sleep. This generally improves after several nights at a constant altitude, though periodic breathing (Cheyne-Stokes) is normal above 2700 m.

Pathophysiology of HAPE

HAPE is a noncardiogenic, hydrostatic pulmonary edema, characterized by pulmonary hypertension and increased pulmonary capillary pressure. Left ventricular function is normal in HAPE. Patchy hypoxic pulmonary vasoconstriction and consequent localized overperfusion, combined with hypoxic permeability of pulmonary capillary walls, results in a high-pressure, high-permeability leak. In addition, alveolar fluid clearance may be altered in those susceptible to HAPE.

Hypoxic pulmonary vasoconstriction results in increased pulmonary artery pressures in all who ascend to high altitude, but it is exaggerated in those susceptible to HAPE, primarily due to genetically determined factors. This genetically based individual susceptibility is perhaps the greatest risk factor, although preexisting medical conditions associated with pulmonary hypertension or a restricted pulmonary vascular bed will greatly increase susceptibility to HAPE. Exercise increases the risk of HAPE because it increases cardiac output, severity of hypoxemia, and pulmonary artery pressure at altitude.

While it has long been held that HAPE and AMS/HACE do not share pathophysiologic basis, recent studies have noted increases in optic nerve sheath diameter (ONSD)—a measure of increased intracranial pressure—in patients with acute HAPE, which decreased as HAPE resolved.




United States

The true incidence is unknown, although HAPE is known to occur at high-altitude ski areas in Colorado at a rate of approximately 1 case per 10,000 skier-days.

Current research with the International HAPE Registry is working to better define the incidence and factors surrounding HAPE occurrence.


The reported incidence of HAPE varies from 0.01-15%, depending on the altitude, the ascent rate, and the population at risk. Studies have assessed high altitude illness in Denali, [2] Nepal, [3] and the South Pole. [4]


Prior reports of "genetic protection" from HAPE afforded to Tibetan and Sherpa peoples must be taken as limited in scope and may well not be true. Case series of patients with HAPE from indigenous groups previously reported as "protected" from HAPE exist.


Some studies have suggested that males are affected more frequently than females; however, these studies were retrospective and did not study the population at risk.


Occurrence of primary HAPE has no clear association with age, although reascent HAPE is more common in children who reside in high altitude who return to high altitudes after a lowland sojourn than in adults in the same circumstances.