Reference: Wilderness Environ Med. 2019 Mar;30(1):12-21
A patient presents to your clinic for travel advice as they are leaving soon for a mountain climbing expedition. Their outfitter has instructed them to see their physician for a medication to prevent Acute Mountain Illness (AMS). Your patient wants to know more about this condition and the medication.
AMS is a potentially deadly condition defined as headache plus one of the following: gastrointestinal upset, insomnia, dizziness, lightheadedness, fatigue, or weakness (High Alt Med Biol. 2018 Mar). The prevalence increases with speed of ascent and affects over 50% of climbers above 6,000 meters (Journal of Travel Medicine. 2012). In addition to supplemental oxygen and decreasing rate of ascent, acetazolamide has become widely accepted as the preferred medication for prevention of AMS (Journal of Travel Medicine. 2012). Previous studies found doses ranging from 250 mg daily to 750 mg daily, given in divided doses, to be effective for prevention of AMS (Journal of Travel Medicine. 2012). As adverse effects including paresthesia, urinary frequency, and dysgeusia have been shown to be dose dependent, determining the lowest effective dose is advantageous (JAMA. 2017).
The Reduced Acetazolamide Dosing in Countering Altitude Illness (RADICAL) trial was a double-blinded, randomized non-inferiority trial of 96 adult climbers (mean age 45 years, 35% women) ascending to Everest Base Camp in Nepal (Wilderness & Environmental Medicine. 2019). Climbers were randomized to acetazolamide 62.5 mg twice daily or 125 mg twice daily (standard dose), with therapy initiated prior to ascent. All climbers in the reduced and standard dose groups had similar baseline characteristics, rates of ascent, and peak altitudes. A history of AMS was reported in 10.1 % of climbers. The primary outcome was incidence of AMS with a secondary outcome of continuous Lake Louise Severity Score (LLS), with scores ranging from 0-12 and higher scores indicating more severe symptoms. Noninferiority for the reduced dose group was defined as incidence of AMS < 20% higher than standard dose and LLS score within 1.1 of the mean for the standard dose. Overall, 24% of climbers were excluded from the final analysis due to low adherence to the medication, multiple missing data points, or failure to ascend above 3,000 m.
At day 12, the overall incidence of AMS (mild or severe) was 55.3% in the reduced dose group compared to 60% in the standard dose group (p <0.05, non-inferiority met, p = 0.47 for superiority, not met). The overall mean LLS at day 12 was 1.014 for the reduced dose group compared to 0.966 for the standard dose group (difference 0.048, noninferiority criterion 95% CI upper limit 2.066, noninferiority met). There was no significant difference in the time to onset of symptoms between the two groups (6.0 days in reduced dose versus 4.5 days in standard dose, p=0.32). Adverse effects, such as urinary frequency and extremity tingling, were similar in both groups.
Limitations to this study include self-reported outcomes, high dropout rate, per-protocol analysis, and single peak sample. The overall rate of any AMS was higher than expected as compared to prior studies with standard dose acetazolamide (Cochrane Database Syst Rev. 2017). This study provides moderate quality evidence that acetazolamide 62.5 mg twice daily may be non-inferior to 125 mg twice daily. Given the similar rates of adverse events. There is promising indication for further study and if these findings are validated it may be practice changing for clinicians and climbers.
For more information, see the Acute Altitude Illnesses topic in DynaMed.
Scott Bland, DO is a second year Family Medicine resident at Cone Health in Greensboro, NC. He has degrees from Valencia Community College, University of Central Florida and Campbell University School of Medicine. His primary clinical interest is space and aviation medicine and he is currently assigned as a Flight Surgeon with the North Carolina Army National Guard.
Faculty contributions by Dr. Carina Brown, MD