BACKGROUND: Acute mountain sickness results in symptoms such as headache, loss of appetite, nausea, fatigue, insomnia, and increased mortality in the first few days of exertion at high altitudes. Acetazolamide and dexamethasone have been recommended as treatments to prevent acute mountain sickness, although their efficacy and tolerability have not been well established.
DATA SOURCE: Thirty-three clinical trials comparing any pharmacologic treatment with placebo for the prevention of acute mountain sickness were identified through a comprehensive search of MEDLINE, EMBASE, the Cochrane Library, a high altitude bibliography Web site, and the bibliographies of retrieved reports and review articles. Of these trials, 18 reported complete prevention of acute mountain sickness as an outcome and as related to ascents to 4050 to 5890 meters (13300 to 19300 feet). These were included in a qualitative analysis of efficacy for any pharmacologic treatment (all 18 trials) and statistical meta-analyses for dexamethasone (8 trials representing 161 subjects) and acetazolamide (9 trials representing 295 subjects).
STUDY DESIGN AND VALIDITY: Only one author determined whether studies met inclusion criteria. All 3 authors read the included articles for validity, applying the 3-item 5-point Oxford score. The mean quality score was 3 (range=2-5). A total of 17 of the 33 trials used an adequate method of blinding. Validity was not a criteria for inclusion in the review. Following the qualitative analysis of efficacy, relative benefit (relative risk [RR] of prevention of mountain sickness) and numbers needed to treat (NNTs) were calculated for 2 interventions, dexamethasone and acetazolamide. Although the studies were rated for validity using previously tested criteria, no information on study limitations is given with which to judge the direction of effect. Using more than one author to determine eligibility would have minimized investigator bias. Although included studies varied in their definitions of acute mountain sickness, the results were homogenous. The investigators limited the outcome to complete prevention of symptoms. This conservative approach would underestimate the efficacy of the treatments making any significant benefit more likely to be real. Unfortunately, no information is provided on the subjects in the trials, including information such as age, sex, training, smoking status, and other risk factors for acute mountain sickness. This information would have helped generalize the study results.
OUTCOMES MEASURED: The primary outcome measured was complete prevention of acute mountain sickness according to the definition used in each of the original studies. Although reported for some of the studies, the reduction in symptom severity was not considered a criterion for efficacy in this study. Secondary outcomes included prevention of headache, nausea, insomnia, and dizziness, and the development of adverse drug reactions.
RESULTS: In 8 trials of dexamethasone (n=161) and 9 of acetazolamide (n=295), all with exposure above 4000 meters, single daily doses of dexamethasone 8 mg, 12 mg, and 16 mg or acetazolamide 750 mg were all more efficacious than placebo (NNT=3 for both). Smaller doses (dexamethasone 0.5 and 2 mg in one trial, acetazolamide 500 mg in 3 trials) did not prevent mountain sickness over placebo. Five trials of acetazolamide reported symptom end points including insomnia, headache, nausea, and dizziness; all results favored acetazolamide (NNT=3-6). Both dexamethasone and acetazolamide demonstrated a trend toward greater efficacy (lower NNT) with faster ascent rates. There was no relative benefit (RR for prophylaxis=1) for trials with ascent rates below approximately 500 meters per day; but there was a five- to six-fold relative benefit for prophylaxis at the highest ascent rates. Regarding adverse effects, subjects in 2 of 5 studies were more likely to experience depression on weaning of dexamethasone (overall RR=4.5). Acetazolamide was associated with polyuria (RR=4.2) and paraesthesia (RR=4.0).
Both dexamethasone 8 to 16 mg and acetazolamide 750 mg per day are effective for preventing acute mountain sickness. Despite US Food and Drug Administration approval, 500 mg per day of acetazolamide is not effective in preventing all symptoms. Side effects are mild for both drugs, but the potential for depression with abrupt cessation of dexamethasone may warrant weaning doses after exposure. There is no apparent benefit to therapy if ascension rates are less than 500 meters per day. Unfortunately, this study does not guide the clinician in selecting high- or low-risk patients in terms of demographics or lifestyle factors, and it does not it clarify how soon to start either medication before the ascent.