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Altitude Illness - Pulmonary Syndromes

  • Author: N Stuart Harris, MD, MFA, FACEP; Chief Editor: Joe Alcock, MD, MS  more...
Updated: Oct 05, 2015


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.

Contributor Information and Disclosures

N Stuart Harris, MD, MFA, FACEP Chief, Division of Wilderness Medicine, Massachusetts General Hospital (MGH). Fellowship Director, MGH Wilderness Medicine Fellowship. Attending Physician, MGH. Assistant Professor in Surgery, Harvard Medical School.

N Stuart Harris, MD, MFA, FACEP is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Massachusetts Medical Society, International Society for Mountain Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Eddy S Lang, MDCM, CCFP(EM), CSPQ Associate Professor, Senior Researcher, Division of Emergency Medicine, Department of Family Medicine, University of Calgary Faculty of Medicine; Assistant Professor, Department of Family Medicine, McGill University Faculty of Medicine, Canada

Eddy S Lang, MDCM, CCFP(EM), CSPQ is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine, Canadian Association of Emergency Physicians

Disclosure: Nothing to disclose.

Chief Editor

Joe Alcock, MD, MS Associate Professor, Department of Emergency Medicine, University of New Mexico Health Sciences Center

Joe Alcock, MD, MS is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Samuel M Keim, MD, MS Professor and Chair, Department of Emergency Medicine, University of Arizona College of Medicine

Samuel M Keim, MD, MS is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Public Health Association, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.


Thomas E Dietz, MD Consulting Staff, Department of Emergency Medicine, Providence Hood River Memorial Hospital

Disclosure: Nothing to disclose.

Sara W Nelson, MD Resident Physician, Harvard Affiliated Emergency Medicine Residency, Brigham and Women's Hospital and Massachusetts General Hospital

Sara W Nelson, MD is a member of the following medical societies: American College of Emergency Physicians, Emergency Medicine Residents Association, and Phi Beta Kappa

Disclosure: Nothing to disclose.

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High-altitude pulmonary edema (HAPE). Image courtesy Dr Matthew Cushing.
Hyperbaric treatment at 4250 m in a Gamow bag.
Thoracic ultrasonography: comet tail sign. Patient with acute high-altitude pulmonary edema (HAPE). Note wedge-shaped forms extending from pleural lining. In contrast, normal thoracic sonogram (below) reveals only diffuse, "snow storm" appearance. Courtesy of Dr Peter Fagenholz, et al.
Thoracic ultrasonography. Normal thoracic sonogram reveals only diffuse, "snow storm" appearance without comet tail sign. Courtesy of Dr Peter Fagenholz, et al.
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