NEJM Volume 345:107-114,
July 12, 2001
Peter H. Hackett, M.D. and Robert C. Roach, Ph.D.
The term "high-altitude illness" is used
to describe the cerebral and pulmonary
syndromes that can develop in unacclimatized persons shortly after
ascent to high altitude.
Acute mountain sickness and high-altitude cerebral edema refer to the cerebral abnormalities, and high-altitude pulmonary edema to the pulmonary abnormalities. High-altitude pulmonary edema and high-altitude cerebral edema, though uncommon, are potentially fatal.
Whether high-altitude illness occurs is determined by the rate of ascent, the altitude reached, the altitude at which an affected person sleeps (referred to as the sleeping altitude), and individual physiology. In 1991 in Summit County, Colorado, the incidence of acute mountain sickness was 22 percent at altitudes of 1850 to 2750 m (7000 to 9000 ft)1 and 42 percent at altitudes of 3000 m (10,000 ft).
Clinical Presentation and Diagnosis
Acute mountain sickness
is a syndrome of nonspecific symptoms and is therefore subjective. The Lake Louise Consensus Group defined acute mountain sickness as the presence of headache in an unacclimatized person who has recently arrived at an altitude above 2500 m plus the presence of one or more of the following: gastrointestinal symptoms (anorexia, nausea, or vomiting), insomnia, dizziness, and lassitude or fatigue.
Rarely, acute mountain sickness occurs at altitudes as low as 2000 m. The symptoms typically develop within 6 to 10 hours after ascent, but sometimes as early as 1 hour. There are no diagnostic physical findings except in the few cases that progress to cerebral edema.
High-altitude cerebral edema
is a clinical diagnosis, defined as the onset of ataxia, altered consciousness, or both in someone with acute mountain sickness or high-altitude pulmonary edema. Clinically and pathophysiologically, high-altitude cerebral edema is the end-stage of acute mountain sickness. In those who also have high-altitude pulmonary edema, severe hypoxemia can lead to rapid progression from acute mountain sickness to high-altitude cerebral edema. Associated findings of high-altitude cerebral edema may include papilledema, retinal hemorrhage (a common incidental finding), and occasionally, cranial-nerve palsy as a result of elevated intracranial pressure. However, global encephalopathy rather than focal findings characterizes high-altitude cerebral edema. Drowsiness is commonly followed by stupor. Seizures are rare. Usually, the illness progresses over a period of hours or days. The cause of death is brain herniation.
Many conditions mimic acute mountain sickness and high-altitude cerebral edema. The onset of symptoms more than three days after arrival at a given altitude, the absence of headache, a rapid response to fluids or rest, and the absence of a response to descent, oxygen, or dexamethasone all suggest other diagnoses
In both the brain and the lungs, hypoxia elicits neurohumoral and hemodynamic responses that result in overperfusion of microvascular beds, elevated hydrostatic capillary pressure, capillary leakage, and consequent edema.
Treatment and Prevention
Management of acute mountain sickness or high-altitude cerebral edema follows three axioms:
Table 2 suggests management and prevention options for four common clinical scenarios.
Table 3 lists useful therapeutic agents.
Descent and supplementary oxygen are the treatments of choice. Remarkably, a descent of only 500 to 1000 m usually leads to resolution of acute mountain sickness; high-altitude cerebral edema may require further descent. Simulated descent with portable hyperbaric chambers, now commonly used in remote locations, is also effective. With the use of these chambers at a pressure of 2 psi (13.8 kPa), the equivalent altitude is roughly 2000 m lower than the ambient altitude.
When descent is not possible or supplementary oxygen is unavailable, medical therapy becomes crucial. A small, placebo-controlled study showed that the administration of acetazolamide reduced the severity of symptoms by 74 percent within 24 hours. Multiple studies have demonstrated that dexamethasone is as effective as or superior to acetazolamide and works within 12 hours. Whether the combination of acetazolamide and dexamethasone, because of their different mechanisms of action, is superior to the use of either agent alone is unknown. In two studies, a single dose of 400 mg or 600 mg of ibuprofen ameliorated or resolved high-altitude headaches. The success of sumatriptan for high-altitude headache has been inconsistent. Antiemetics are indicated for nausea and vomiting. For insomnia requiring treatment, acetazolamide, which reduces periodic breathing and improves nocturnal oxygenation, is the safest agent. Because of the risk of respiratory depression, sedative hypnotic agents should be avoided in those with acute mountain sickness unless they are combined with acetazolamide. Zolpidem does not depress ventilation at high altitudes and may therefore be a safe treatment for insomnia in persons with acute mountain sickness, but it has not been studied in clinical trials. After acute mountain sickness has resolved, any further ascent should be made with caution, perhaps with acetazolamide prophylaxis.
Prevention of high-altitude illness
For the prevention of high-altitude illness, the best strategy is a gradual ascent to promote acclimatization. The suggested guidelines are that once above an altitude of 2500 m, the altitude at which one sleeps should not be increased by more than 600 m in 24 hours and that an extra day should be added for acclimatization for every increase of 600 to 1200 m in this altitude.
For example, as compared with ascent to an altitude of 3500 m in a one-hour period, a gradual ascent over a period of four days reduced the incidence and severity of acute mountain sickness by 41 percent. Most experts recommend prophylaxis for those who plan an ascent from sea level to over 3000 m (sleeping altitude) in one day and for those with a history of acute mountain sickness.
Acetazolamide is the preferred drug, and dexamethasone is an alternative; both are unequivocally effective; the dosages vary. The combination was more effective than either alone. Although controversial, small doses of acetazolamide (125 mg twice a day in adults) appear empirically to be as effective as larger doses, with fewer side effects; the minimal effective dose remains uncertain.
In two controlled trials, Ginkgo biloba prevented acute mountain sickness during a gradual ascent to 5000 m and reduced both the symptoms and the incidence of acute mountain sickness by 50 percent during an abrupt ascent to 4100 m. With respect to headache, prophylactic aspirin (325 mg every four hours for a total of three doses) reduced the incidence from 50 percent to 7 percent. Reports suggest various Chinese herbal preparations might prevent high-altitude illness, but controlled studies are lacking. The notion that overhydration prevents acute mountain sickness has no scientific basis.
High-altitude pulmonary edema is a noncardiogenic pulmonary edema associated with pulmonary hypertension and elevated capillary pressure.
Clinical Presentation and Diagnosis
High-altitude pulmonary edema accounts for most deaths from high-altitude illness. As is the case for acute mountain sickness, the incidence of high-altitude pulmonary edema is related to the rate of ascent, the altitude reached, individual susceptibility, and exertion; cold, which increases pulmonary-artery pressure by means of sympathetic stimulation, is also a risk factor. Abnormalities of cardiopulmonary circulation increase the risk of high-altitude pulmonary edema. High-altitude pulmonary edema commonly strikes the second night at a new altitude and rarely occurs after more than four days at a given altitude, owing to adaptive cellular and biochemical changes in pulmonary vessels.
Early diagnosis is critical.
Treatment and Prevention of High-altitude pulmonary edema
Increasing alveolar and arterial oxygenation is the highest priority in patients with high-altitude pulmonary edema.
Patients with severe high-altitude pulmonary edema, indicated by the failure of arterial oxygen saturation to improve to more than 90 percent within five minutes after the initiation of high-flow oxygen, and those with concomitant high-altitude cerebral edema must be moved to a lower altitude and possibly hospitalized. If supplemental oxygen is unavailable, then descent, the use of a portable hyperbaric chamber, or both become lifesaving. Medication (nifedipine) is necessary only when supplemental oxygen is unavailable or descent is impossible (Table 2 and Table 3 ). In clinical studies, nifedipine reduced pulmonary-artery pressure approximately 30 percent but barely increased the partial pressure of arterial oxygen.
A recent study suggested that inhaled beta-agonists might be useful in the prevention of high-altitude pulmonary edema, and by extension, for treatment as well.
Positive end-expiratory pressure delivered by means of a mask helps improve gas exchange and can be a temporizing measure.
Endotracheal intubation, mechanical ventilation, and pulmonary-artery catheterization are rarely necessary.
Prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo twice daily
during ascent and stay at 4559 m.
Results: Two participants who received tadalafil (Cialis) 10 mg developed severe AMS (Acute Mountain Sickness) on arrival at 4559 m and withdrew from the study; they did not have HAPE (High Altitude Pulmonary Edema) at that time. High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone (Decadron). Eight of 9 participants receiving placebo, 7 of 10 receiving tadalafil, and 3 of 10 receiving dexamethasone had AMS. At high altitude, systolic pulmonary artery pressure increased less in participants receiving dexamethasone (16 mm Hg [95% CI, 9 to 23 mm Hg]) and tadalafil (13 mm Hg [CI, 6 to 20 mm Hg]) than in those receiving placebo (28 mm Hg [CI, 20 to 36 mm Hg]). Ann Intern Med Oct. 3, 2006;145 497-506