Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e6779 (Published 18 October 2012)
Cite this as: BMJ 2012;345:e6779

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Dear Editor,

We agree with the conclusion in the recently published meta-analysis of Low et al on the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness that this study provides evidence that acetazolamide at doses of 250 mg, 500 mg, and 750 mg daily are all effective in preventing acute mountain sickness at high altitudes. However in practice we still prefer to advice a daily preventive dose of 500 mg, as the study population of the 4 studies on the preventive effect of acetazolamide 250 mg daily included in this review, does not correspond with the population of clients in many travel clinics.

Basnyat and Gertsh enrolled participants at altitudes above 4000 m, after excluding those who developed acute mountain sickness in the past (1,2,3). Van Patot enrolled participants starting at 1600m, but they were residents at 1400-1600 m, already at least partly acclimatized (4).

Many clients in our travel clinics start at sea level and fly above 3000 m in one day. So our clients are more comparable with the participants in the Carlston study, which was excluded in this review as they did not compare the use of acetazolamide with placebo (5). Carlston compared a preventive dose of 250 mg daily with a preventive dose of 500 mg daily in travelers who flew from Miami (sea level) to La Paz (3,630 m). He found a protective effect of 500 mg daily but not of 250 mg daily.

In general we do not advice to take acetazolamide preventively, as the number needed to treat is quite high, 6-7 for a low dose according to this review. So for most travelers we advise to take acetazolamide along and to start taking it for a few days, as soon as symptoms of AMS appear. However we agree completely with the authors that further studies assessing the efficacy of a low dose of acetazolamide during rapid ascent to altitude would be useful, especially in non acclimatized climbers starting at sea level.

Reference List

(1) Basnyat B, Gertsch JH, Johnson EW, Castro-Marin F, Inoue Y, Yeh C. Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial. High Alt Med Biol 2003; 4(1):45-52.
(2) Basnyat B, Gertsch JH, Holck PS, Johnson EW, Luks AM, Donham BP et al. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol 2006; 7(1):17-27.
(3) Gertsch JH, Lipman GS, Holck PS, Merritt A, Mulcahy A, Fisher RS et al. Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT). Wilderness Environ Med 2010; 21(3):236-243.
(4) van Patot MC, Leadbetter G, III, Keyes LE, Maakestad KM, Olson S, Hackett PH. Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness. High Alt Med Biol 2008; 9(4):289-293.
(5) Carlsten C, Swenson ER, Ruoss S. A dose-response study of acetazolamide for acute mountain sickness prophylaxis in vacationing tourists at 12,000 feet (3630 m). High Alt Med Biol 2004; 5(1):33-39.

Competing interests: None declared

Mieke Croughs, MD, Public Health

Jef Van den Ende, Fons van Gompel, Roy Remmen

GGD Hart voor Brabant (Netherlands) and Institute of Tropical Medicine, Belgium , Vogelstraat 2, 5212 VL 's-Hertogenbosch, The Netherlands

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We thank Matiram Pun for these helpful and constructive comments.

We are pleased that our review (1) and other recent reviews (2-4) have put an end to much of the controversy regarding what dose of acetazolamide to use for the prevention of acute mountain sickness. This review came from a genuine question arising from clinical practice where one of us (Dr A J Avery, a GP) was finding it very difficult to decide what dose of acetazolamide to precribe to patients attending for advice on travel to altitude. While altitude medicine specialists would have known that evidence was available to support the use of 250mg daily (in divided doses), this was not the case for a generalist. Undertaking a systematic review and metaanalysis has been a helpful way of addressing the controversy.

We are interested in the point made about intolerance to acetazolamide given its sulfonamide moeity. Recently one of us (Dr Avery) saw a patient requesting medication for prevention of acute mountain sickness, who helpfully pointed out a previous adverse reaction (rash) to sulfonamide. As a result, acetazolamide was not prescribd.

The point about gingko biloba is well taken (it was not necessary for us to mention this ineffective preparation in the introduction).

References

(1) Low EV, Avery AJ, Gupta V, Schedlbauer A, Grocott MP. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ 2012; 345.
(2) Seupaul RA, Welch JL, Malka ST, Emmett TW. Pharmacologic Prophylaxis for Acute Mountain Sickness: A Systematic Shortcut Review. Annals of emergency medicine 59[4], 307-317. 4-1-2012.
(3) Ritchie ND, Baggott AV, Andrew Todd WT. Acetazolamide for the Prevention of Acute Mountain Sickness - A Systematic Review and Meta-analysis. J Travel Med 2012; 19(5):298-307.
(4) Kayser B, Dumont L, Lysakowski C, Combescure C, Haller G, Tramer MR. Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis. High Alt Med Biol 2012; 13(2):82-92.

Competing interests: We are authors of the article

A J Avery, GP

Emma Low

University of Nottingham, Division of Primary Care, QMC, Nottingham, NG7 2UH

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Dear Editor,

The meta-analysis by Low et al on the prophylactic use of Acetazolamide for the prevention of acute mountain sickness (AMS) is impressive in a way it has moved up to tease out the minimum dosage of well tested and tried (actually proven) drug (1) as compared to many other contemporary meta-analyses (2-4). It has effectively put a controversy to rest on whether Acetazolamide is effective or needs higher dosage to prevent AMS (5).

While I agree with the lowest effective dosage (250mg per oral/day in two divided dosages) the analysis has come out, there are very limited trials on it especially in rapid and rigorous ascent profile as highlighted in the limitation. It is again unclear if it works in all ranges of body mass index especially in higher range. Alternative way of looking into efficacy of this lower dose would be to see if there is optimum physiological alteration in high altitude hypoxia. Is this low dose enough to facilitate hypoxic ventilator response or correct respiratory alkalosis?

The future researches should not only test rapid ascent, lower starting point and lower dose of Acetazolamide but also alternatives to it. Not all individuals can tolerate Acetazolamide due to its Sulfonamide moiety. Similarly, the dynamics of population who ascend to altitude is also changing (6;7) e.g. people with comorbid conditions, elderly, mining workers and pilgrims. Hence, the future studies should focus those population cohorts as well.

While alternatives to Acetazolamide is not the scope of the article, I am surprised to see an ineffective gingko biloba (8) as a first alternative while non-steroidal anti-inflammatory drugs have been tested more frequently lately and found effective (9;10).

References
(1) Low EV, Avery AJ, Gupta V, Schedlbauer A, Grocott MP. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ 2012; 345.
(2) Seupaul RA, Welch JL, Malka ST, Emmett TW. Pharmacologic Prophylaxis for Acute Mountain Sickness: A Systematic Shortcut Review. Annals of emergency medicine 59[4], 307-317. 4-1-2012.
(3) Ritchie ND, Baggott AV, Andrew Todd WT. Acetazolamide for the Prevention of Acute Mountain SicknessGÇöA Systematic Review and Meta-analysis. J Travel Med 2012; 19(5):298-307.
(4) Kayser B, Dumont L, Lysakowski C, Combescure C, Haller G, Tramer MR. Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis. High Alt Med Biol 2012; 13(2):82-92.
(5) Dumont L, Mardirosoff C, Tramer MR. Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review. BMJ 2000; 321(7256):267-272.
(6) West JB. A new approach to very-high-altitude land travel: the train to Lhasa, Tibet. Ann Intern Med. 2008 Dec 16;149(12):898-900.
(7) Yadav S. Urgent action is needed to prevent deaths among Himalayan pilgrims, says climbing federation. BMJ. 2009 Jun 29;338:b2628. doi: 10.1136/bmj.b2628.
(8) Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck PS. Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT). BMJ 2004; 328(7443):797.
(9) Gertsch JH, Lipman GS, Holck PS, Merritt A, Mulcahy A, Fisher RS et al. Prospective, Double-Blind, Randomized, Placebo-Controlled Comparison of Acetazolamide Versus Ibuprofen for Prophylaxis Against High Altitude Headache: The Headache Evaluation at Altitude Trial (HEAT). Wilderness & Environmental Medicine 2010; 21(3):236-243.
(10) Lipman GS, Kanaan NC, Holck PS, Constance BB, Gertsch JH. Ibuprofen Prevents Altitude Illness: A Randomized Controlled Trial for Prevention of Altitude Illness With Nonsteroidal Anti-inflammatories. Ann Emerg Med 2012; 59(6):484-490.

Competing interests: None declared

Matiram Pun, Graduate Student

Mountain Medicine and High Altitude Physiology, University of Calgary, Canada

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