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. Everyone traveling to altitude is at risk, regardless of age, prior medical history, 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 (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.
Frequency: 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.
HAPE can be rapidly fatal within a few hours unless treated by descent or oxygen. HAPE is the most common cause of death related to high altitude.
Given appropriate treatment, recovery from HAPE is usually complete and can occur rapidly (1-2 d). This noted, 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.
A recent report describes a case series of HAPE treated successfully at more than 14,000 ft when emergent descend was not a viable option. Importantly, while these cases had good outcomes, they were being treated by physicians with expertise in treating HAPE who had full access to advanced treatment modalities. Rapid descent remains a critical treatment for most cases of HAPE.
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.
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
Dyspnea at rest
Chest tightness or congestion
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
Fever and orthopnea are commonly present in HAPE; pink/frothy sputum is a late finding in severe HAPE
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
Physical exertion may precipitate or exacerbate HAPE (by raising pulmonary artery pressures).
The mainstay of treatment is descent for anything other than mild HAPE. Descent to an altitude below that where symptoms started is always effective treatment, but it may not be practical or possible given the topography, weather, the patient's ultimate trekking or climbing goals, or group resources. Accordingly, a descent of 500-1000 m is usually sufficient. As noted above, while case series of treatment of even severe HAPE under expert care in well-equipped settings have been reported, descent for other than mild HAPE cases remains clearly indicated. Selected cases of reascent HAPE and mild HAPE at moderate altitude may be treated with oxygen and strict bedrest. If patients worsen, they must descend.
All of the following treatments are used as an adjunct to descent. Oxygen, if available, is lifesaving and should be administered at 4 L/min by mask or nasal cannula. Nifedipine should be used if descent or oxygen is not available. Nifedipine may help prevent exertional worsening in patients being evacuated on foot. Portable hyperbaric chambers can effect a physiologic (simulated) descent when actual descent is not possible or practical. End-positive pressure masks are useful in treating HAPE but are poorly tolerated.
The role of acetazolamide in the treatment of HAPE remains ill-defined but may prove beneficial. Additionally, recent reports give evidence that dexamethasone might have beneficial effect in HAPE as well. While not clearly established, there is little apparent downside risk to using either acetazolamide and dexamethasone in severe HAPE.
Inhaled salmeterol (a beta-agonist) has been demonstrated to help prevent acute HAPE in HAPE-susceptible populations. Salmeterol is thought to act by increasing alveolar fluid clearance through pulmonary sodium channels. Although its use in HAPE treatment has not been proven, it is often used in this indication.
Phosphodiesterase inhibitors have also been demonstrated to help prevent acute HAPE in HAPE-susceptible populations. These agents are thought to act by increasing availability of nitric oxide in pulmonary arterial vessels and so result in decreased pulmonary arterial tone and reduced pulmonary hypertension. Although its use in HAPE treatment has not been proven, it is often used in this indication.
Only limited studies provide any evidence that furosemide may be useful with acute HAPE, and it is not without downside risk. Furosemide should be used with substantial caution, if at all, as many patients are intravascularly depleted. Most authors discourage use of furosemide in treating HAPE.
Depending on the elevation, a physiologic (simulated) descent of about 2000 m (7000 ft) may be achieved within minutes. Intermittent pumping is necessary to flush carbon dioxide from the system, unless a chemical scrubber system is used. Patients with severe HAPE may need to have their head elevated to tolerate lying down. Elevation can be accomplished by placing the bag on a rigid surface, such as boards or a wooden bed, and propping up the head end by 0.3-0.5 m (12-20 inches).
In practice, most patients with moderate HAPE tolerate lying flat after reaching the physiologic lower elevation of the pressurized bag. Patients typically are treated in 1-hour increments and then are reevaluated, with additional treatments as indicated. Closely monitor patients for rebound signs and symptoms, which may occur soon after removal from the hyperbaric environment, or they may develop over a period of hours.
Portable hyperbaric chambers (eg, Gamow, CERTEC, PAC) are widely used among adventure travel/trekking groups and climbing expeditions. These chambers are lightweight, coated fabric bags about 2 m in length and 0.7 m in diameter. The patient is placed inside the bag, which is sealed shut and inflated with a manually operated pump, pressurizing the inside to 105-220 mm Hg above ambient atmospheric pressure. This pressure gradient is regulated by pop-off valves set to the target pressure, and it is fixed depending on the brand of bag in use.
MEDSCAPE General Abstract