Keep the evidence boundary beside acetazolamide dose advice

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Dear Editor,

Adhikari and colleagues recommend acetazolamide 125 mg every 12 hours for moderate-risk ascent and retain the conditional wording “consider doubling” to 250 mg every 12 hours for high-risk ascent.[1] We suggest that the evidence boundary for this higher-dose option should appear at the same prescribing decision point.

The 2024 Wilderness Medical Society (WMS) guideline recommends 125 mg every 12 hours as the adult prophylactic dose and states that 250 mg every 12 hours may be considered for high-risk ascent profiles up to 5000 m. Importantly, the same paragraph notes that 125 mg and 250 mg have not been directly compared in high-risk settings and that the appropriate dose above 5000 m has not been studied.[2]

WMS gives a strong, high-quality recommendation for considering acetazolamide prophylaxis in travellers at moderate or high risk of acute mountain sickness (AMS).[2] That recommendation, however, should not be interpreted as equivalent evidence for the incremental benefit of dose escalation, which WMS explicitly identifies as lacking direct comparison in high-risk settings.

Comparative evidence to date does not resolve this specific question. A 2025 Bayesian network meta-analysis of 28 randomised trials did not detect a statistically significant difference in AMS incidence among acetazolamide dosing regimens. Network meta-regression estimated a longer “time window” of benefit versus placebo for 250 mg twice daily, while the authors ultimately prioritised 125-250 mg twice daily as first-line prophylaxis.[3]

We suggest adding immediately after the dosing bullets: “For high-risk ascent, 250 mg every 12 hours may be considered, but its additional benefit over 125 mg every 12 hours has not been established by direct comparison in high-risk settings; the appropriate dose above 5000 m has not been studied.”

For a Practice Pointer intended to support prescribing decisions, keeping this qualification beside the dose would preserve the recommendation while making its evidential limits explicit.

References
1 Adhikari S, Zimmer R, Brugger H, et al. Prevention of altitude illness in adults: preparing people for travel to high altitude. BMJ. 2026;394:e100532. doi: 10.1136/bmj-2026-100532

2 Luks AM, Beidleman BA, Freer L, et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention, Diagnosis, and Treatment of Acute Altitude Illness: 2024 Update. Wilderness Environ Med. 2024;35:2S-19S. doi: 10.1016/j.wem.2023.05.013

3 Wang J, Lian N, Tang K, et al. Comparative effects of pharmacological interventions for the prevention of acute mountain sickness: A systematic review and Bayesian network meta-analysis. Travel Med Infect Dis. 2025;66:102868. doi: 10.1016/j.tmaid.2025.102868

No competing Interests: YesThe following competing Interests: Electronic Publication Date: Friday, September 18, 2026 - 02:31AI use: Yes I have used AIHighwire Comment Subject:

Prevention of altitude illness in adults: preparing people for travel to high altitude

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Keep the evidence boundary beside acetazolamide dose advice

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Prevention of altitude illness in adults: preparing people for travel to high altitude

Check this box if you would like your letter to appear anonymously:: Last Name: MaoFirst name and middle initial: LixinEmail:

lixinmao@stu.njmu.edu.cn

Address: 68 Gehu middle road, Wujin District, Changzhou, 213000, Jiangsu Province, ChinaOccupation: M.D. studentOther Authors: Shenglin GaoAffiliation: Department of Urology, the Third Affiliated Hospital of Nanjing Medical University, Nanjing Medical University BMJ: Additional Article Info: Rapid response