Getting High With Salmeterol
Abstracts & Commentary
Synopsis: Prophylactic inhalation of salmeterol decreases the incidence of high-altitude pulmonary edema (HAPE).
Sources: Sartori C, et al. N Engl J Med. 2002;346:1631-1636; Voelkel NF. N Engl J Med. 2002;346:1606-1607.
HAPE is a life-threatening event. the mechanisms that lead to this physiologic insult have eluded investigators for years. Among the mechanisms that predispose to this condition is the absorption of liquid driven by active alveolar transepithelial sodium transport. Sartori and colleagues postulated that a defect in this mechanism might predispose patients to HAPE. Beta-adrenergic agonists up-regulate the clearance of alveolar fluid and attenuate pulmonary edema in animals.
In a double-blind, randomized, placebo-controlled study, Sartori et al assessed the effect of prophylactic inhalation of the beta-agonist salmeterol on the incidence of pulmonary edema during exposure to high altitudes (4559 m reached in less than 22 hours) in 37 subjects who were susceptible to HAPE. (Salmeterol, 125 µg, was started the morning of the day before the climb and every 12 hours thereafter.) They also measured the nasal transepithelial sodium and water transport in the distal airways, in 33 mountaineers who were prone to HAPE and 33 mountaineers who were resistant to this condition.
Prophylactic inhalation of salmeterol decreased the incidence of HAPE in susceptible subjects by more than 50%, from 74% in placebo to 33% in salmeterol-treated climbers. The nasal potential difference value under low altitude conditions was more than 30% lower in subjects who were susceptible to HAPE than in those who were not (P < 0.001).
Sartori et al concluded that inhalation of salmeterol reduces the risk of HAPE. Sodium-dependent absorption of liquid from the airways may be defective in patients susceptible to HAPE. Sodium driven clearance of alveolar fluid may have a pathogenic role in pulmonary edema in humans and, therefore, represents an appropriate target for therapy.
Comment by Ralph R. Hall, MD, FACP, FACSM
In 1991 in Summit County, Colorado, where Keystone Ski Resort is located and nearby Leadville, Colo, the incidence of acute mountain sickness was 22% at 7000-9000 ft and 42% at 10,000 ft.1 People living at these altitudes develop mountain sickness if they leave these altitudes for a few days and then return. High-altitude illness is a common problem in these and similarly located mountain areas.
In an editorial, Hackett and Roach beautifully describe the huge support needed to carry out this research.1 "It was carried out at the Capanna Regina Margherita, perched on the Punta Gnifetti (4559 m), one of the summits of Monte Rosa on the Italian-Swiss border. The mountain hut where this was done has a distinguished record in the annals of high altitude research. The great Italian physiologist Angelo Mosso (1846-1910) made Turin a center for exercise physiologist at the end of the 19th century." Most of the early studies on high altitude illness were accomplished there.
Salmeterol is now added to our tools for the prevention of HAPE. Since these climbers were susceptible to HAPE, the reduction in risk may be greater than with nifedipine or acetazolamide. It will be interesting to see if this can be confirmed when salmeterol is compared with other drugs used to treat high-altitude illness.
As pointed out by Voelkel in the accompanying editorial, it was noted that the placebo and the salmeterol groups had similar degrees of pulmonary hypertension after treatment. There are no data, however, regarding whether there were effects on pulmonary microvascular pressure.
It is interesting that Roncin et al, in a well-conducted study, found that a carefully compounded preparation of Ginkgo biloba markedly reduced the incidence of mountain sickness during ascent to 5000 m.2 This study noted that there was an improvement in pulmonary function that was not found with salmeterol or other preparations. Maakestad et al confirmed these observations in a subsequent study.3
The risk of HAPE is increased with rapid ascent, individual susceptibility, and the level of exertion. It was interesting to see in the log, kept near the top of Mt Kilimanjaro, that Sir Edmond Hillary was unable to reach the top of Kilimanjaro on his first attempt because he tried to summit in 1 day.4
For those interested in a recent review, including current treatments and prevention of high altitude illness, I recommend the review by Hackett and Roach.1
Dr. Hall, Emeritus Professor of Medicine, University of Missouri-Kansas City School of Medicine, is Associate Editor of Internal Medicine Alert.
References
1. Hackett PH, Roach RC. N Engl J Med. 2001;345: 107-114.
2. Roncin JP, et al. Aviat Space Environ Med. 1996;67: 445-452.
3. Maakestad K, et al. Wilderness Environ Med. 2001; 12:51.
4. Personal observation.
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