INTRODUCTION	Section 2 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Background: Altitude illness refers to a group of syndromes that result from hypoxia; the target organs are the brain and the lung. 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. Everyone traveling to altitude is at risk, regardless of level of physical fitness or previous altitude experience.

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 (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.

Pathophysiology:

Acclimatization

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 days 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, but concurrently, a lowered alveolar PCO₂ produces a respiratory alkalosis, acting as a brake on the respiratory center of the brain and limiting 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 somewhat 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 weeks 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 and pulmonary artery pressure at altitude.

Frequency:

• In the US: 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.

• Internationally: The reported incidence of HAPE varies from 0.01-15%, depending on the altitude, the ascent rate, and the population at risk.

Mortality/Morbidity: HAPE is rapidly fatal within a few hours unless treated by descent or oxygen, and it is the most common cause of death related to high altitude. As with HACE, recovery is usually complete, although even with proper treatment, a small percentage of patients will die. Patients who recover have rapid clearing of edema fluid and do not develop fibrosis or other long-term sequelae.

Race: Tibetan and Sherpa peoples appear to be genetically protected from HAPE, although it has been reported in these populations.

Sex: 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.

Age: 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.

	CLINICAL	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History: HAPE generally occurs 2-4 days after ascent to high altitude, often worsening at night. Decreased exercise performance is the earliest symptom, usually associated with a dry cough. The early course is subtle; as the illness progresses, the cough worsens and becomes productive; dyspnea can be severe, tachypnea and tachycardia develop, and drowsiness or other CNS symptoms may develop. Chest radiographs characteristically show patchy unilateral or bilateral fluffy infiltrates and a normal cardiac silhouette. The presence of a low-grade fever has led to misdiagnosis as pneumonia and to subsequent deaths.

HAPE varies in severity from mild to immediately life-threatening. It can be fatal within a few hours, and it is the most common cause of death related to high altitude. Differential diagnosis is sometimes problematic, but HAPE improves dramatically with descent or oxygen, whereas other diagnoses do not; these should be pursued in patients who do not fit this pattern.

The Lake Louise Consensus definition of HAPE requires at least 2 of the following symptoms (in the context of a recent elevation gain):

• Weakness or decreased exercise

• Cough

• Dyspnea at rest

• Chest tightness or congestion

Physical:

• In addition to 2 symptoms, the Lake Louise Consensus definition of HAPE requires at least 2 of the following signs:

• Rales or wheezing in at least one lung field

• Central cyanosis or arterial oxygen desaturation relative to altitude

• Tachycardia

• Tachypnea

• Fever and orthopnea are commonly present in HAPE; pink/frothy sputum is a late finding in severe HAPE.

Causes:

• Rapid ascent

• Higher altitudes are more risky

• Low hypoxic ventilatory response

• Congenital absence of a pulmonary artery or other vascular abnormalities that create a restricted pulmonary circulatory bed

• Pulmonary hypertension

• Physical exertion may precipitate or exacerbate HAPE (by raising pulmonary artery pressures).