Acute Mountain Sickness Prevention: How Much Acetazolamide is Needed?

Abstract & Commentary

Synopsis: A recent study suggests that 250 mg doses of acetazolamide might be more effective than 125 mg doses in combating acute mountain sickness. Nonetheless, the applicability of these findings to travelers reaching high altitudes remains unclear.

Source: Carlsten C, et al. A Dose-Response Study of Acetazolamide For Acute Mountain Sickness Prophylaxis in Vacationing Tourists at 12,000 Feet (3630 m). High Altitude Medicine & Biology. 2004;5:33-39.

Acetazolamide is commonly used as a preventive therapy in travelers going to high altitude, in an effort to decrease the risk of developing acute mountain sickness. The dosing, however, remains controversial. Carlsten and colleagues compared acetazolamide (both 125 mg and 250 mg doses) with placebo for effectiveness in altering acute mountain sickness in visitors to Bolivia.

The 33 study participants were randomized to receive placebo or either 125 mg or 250 mg of acetazolamide twice daily. Therapy was initiated after arrival in La Paz, Bolivia (3630 meters above sea level). Symptoms of acute mountain sickness were reported and scored using the Lake Louise questionnaire. Symptom scores were significantly lower at 24 hours than on study entry, in subjects receiving 250 mg doses than in subjects receiving 125 mg doses or placebo.

Carlsten et al conclude that "the dosing of acetazolamide for acute mountain sickness prevention in non-mountaineering tourists at altitudes below 3700 meters should not be lowered below 250 mg twice daily." They acknowledge, however, that further studies would be needed before generalizing this recommendation to other populations of travelers.

Comment by Phillip Fischer, MD, DTM&H

Acute mountain sickness represents a condition of uncomfortable adaptation to high altitude that is characterized by headache, along with gastrointestinal upset, fatigue, dizziness, or sleep disturbances. It is not uncommon, and occurs in about 20% of travelers to 10,000 feet elevation, and among the majority of travelers to markedly higher altitudes. The Lake Louise scoring system was developed during the early 1990s to quantitatively assess the degree of symptoms, and it is quite useful in research studies such as that conducted by Carlsten et al.

Acetazolamide is a sulfonamide carbonic anhydrase inhibitor that alters the body’s acid-base, and carbon dioxide balances and stimulates some diuresis. It is widely used to prevent acute mountain sickness, and is usually given twice daily, beginning prior to ascent, and continuing for the first 3 days at altitude. Studies in travelers undergoing vigorous exercise at high altitude have documented the prophylactic value of this medication, but gastric discomfort and paresthesias have been reported. While controversial, there is some thought that lower doses (125 mg twice daily in adults) are as effective as the larger dose, and are associated with fewer side effects. Carlsten et al’s study provides one attempt to determine whether or not the lower dose is as good as the more traditional 250 mg twice daily dose.

Unfortunately, Carlsten et al did not provide conclusive data to support any changes in dosing recommendations. While the subjects who received the higher dose did subsequently have a greater decrease in the Lake Louise score, several concerns make the general applicability of the finding doubtful. First, this investigation is purported to be a prophylaxis study. However, it was not initiated until the subjects were already at high altitude. In addition, the results did not show a prevention of symptoms, but rather, a decrease in symptoms.

At study entry, a significant number of subjects already qualified as having acute mountain sickness, so the design and outcome of the study seem more to have looked at therapy, rather than at prophylaxis of mildly symptomatic disease. Second, the subjects who were randomized to be in the higher dose group were more symptomatic at study entry than were the subjects in the other groups. While the paper does not indicate if there was a statistical difference between groups at baseline, it is not clear that the subsequent decrease in symptom scores was related to a differential medication effect, as opposed to the pre-treatment levels of symptoms. Finally, 1 participant was dropped from the final analysis for lack of compliance with the protocol. The published report does not state whether this non-compliance was related to side effects, and/or whether inclusion of this subject’s outcome results would have altered the statistical significance of the findings.

Despite these limitations in Carlsten et al’s study, the report is useful. It appropriately raises the possibility that 250 mg of acetazolamide is more effective than 125 mg, and it provides suggestive data to this end. Clearly, more study is needed. Armed with these findings, inconclusive as they are, travel medicine practitioners who currently use a 250 mg dose of acetazolamide for prophylaxis should probably avoid changing that practice until there is better support for the adequacy of the lower dose regimen.

In addition, neither Ginkgo biloba, despite past optimism, nor theophylline, represents a reliably effective prophylactic agent.1

What else is new in the study of acute mountain sickness? The diagnosis of acute mountain sickness is based on clinically reported symptoms, and there is no accurate or objective test to predict or confirm the diagnosis. It is assumed that relative hypoxia is at the base of the pathophysiology underlying this condition, and some have used oxygen saturation as a clue to the presence of illness. O’Connor and colleagues attempted to quantify the relationship between oxygen saturation, heart rate, and acute mountain sickness in 169 hikers at 3080 meters on Mount Rainier in Washington.2 Mean oxygen saturation was 90%, and mean heart rate was 87 per minute. At the time of evaluation, 27% of participants reported symptoms compatible with a diagnosis of acute mountain sickness. The degree of oxygen saturation, however, was not associated with symptoms of acute mountain sickness. A diagnosis of acute mountain sickness was, on the other hand, associated with a higher heart rate. The heart rate differences, while significant, were not specific enough to accurately predict a diagnosis of acute mountain sickness.

The incidence of acute mountain sickness appears to be the same in individuals across the spectrum of age. A precise determination of the degree of symptoms, however, is more difficult in pre-verbal children. Yaron and colleagues used actigraphy, a measurement of movement, and presumed sleep in 30 children aged 4-33 months.3 Interestingly, a majority of study subjects were born prematurely, as the result of multiple gestations. Yaron et al showed that sleep disturbance was more common at high altitude (3109 meters) than at lower altitude (1601 meters), following similar travel and activity changes. The sleep pattern had returned nearly to baseline by the second night at altitude. Clearly, altered sleep seems common in infants during the first night at high altitudes.

Thus, acute mountain sickness continues to be a problem for travelers ascending to high altitudes.

Acetazolamide is the best-studied, safest, most effective medical agent for the prophylaxis of this condition, even though the optimal dose is yet to be conclusively determined. Measurements of oxygen saturation are not reliable in identifying subjects who actually have acute mountain sickness. Even young children are at risk of symptoms, and sleep disturbance is widespread in infants during the first night at altitude.

References

1. Bartsch P, et al. Acute Mountain Sickness: Controversies and Advances. High Alt Med Biol. 2004; 5:110-124.

2. O’Connor T, et al. Pulse Oximetry in the Diagnosis of Acute Mountain Sickness. High Alt Med Biol. 2004;5: 341-348.

3. Yaron M, et al. Sleep Disturbance After Rapid Ascent to Moderate Altitude Among Infants and Preverbal Young Children. High Alt Med Biol. 2004;5:314-320.

Philip R. Fischer, MD, DTM&H, Professor of Pediatrics, Department of Pediatric & Adolescent Medicine, Mayo Clinic, Rochester, MN, is Associate Editor for Travel Medicine Advisor.