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Three Part Question

In [adults] is [prophylactic acetazolamide] effective in [preventing or reducing the severity of acute mountain sickness] as compared with placebo?

Clinical Scenario

A 32 year old altitude-naïve man is planning to join a trek to Makalu Base Camp (5000m altitude). He is concerned about the possibility of altitude sickness and wants to know whether taking acetazolamide would reduce this risk.

Search Strategy

Medline via PubMed interface, last search 16th March 2009:
((acetazolamide OR diamox) AND placebo)) AND ((mountain sickness) OR altitude)

Cochrane Library issue 1 2009:
MeSH and search words: “acetazolamide”, “prophylaxis”; “altitude sickness”; “acute mountain sickness”

Search Outcome

Medline:
63 papers found, including three reviews. A review by Bartsch et al is qualitative rather than systematic and quantitative, and therefore not included in the table. The more recent of the two remaining reviews (Dumont) is a systematic quantitative review performed October 1999, and is included below. All identified relevant papers prior to October 1999 were included in this systematic review.
Of 26 papers found which were published subsequent to this review, 14 were of inadequate quality or relevance for inclusion. The remaining 12 papers are included below.

Cochrane Library:
8 reviews were found, of which only two were relevant; the more recent (Dumont) is the same review as identified above.
166 clinical trials were found: 89 were prior to date of the comprehensive review above, 68 of the remaining were not relevant, the 9 remaining papers were all already identified in Medline search and are included below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
van Patot MC et al, 2008 USA	44 healthy adult (18-48 yrs) volunteers from resident altitude of 1400 to 1600m transported to 4300m (Pikes Peak, Colorado). Randomised to receive either acetazolamide 125mg twice daily or placebo (starting 3 days prior to ascent, continuing for 24hrs at altitude).	PRCT, 1b	Incidence of AMS as diagnosed by AMS-C >0.7 and LLQS ≥3 including headache.	Incidence of AMS 3/22 in acetazolamide group and 10/22 in placebo group (p=0.021).	Small group sizes. Possible mild acclimatisation by subjects prior to ascent, only stayed at altitude for 24hrs. (Transported to altitude rather than trekking.) No mention made of compliance or side effect profile.
			Severity of AMS as shown by average AMS-C and LLQS, and by incidence of LLQS ≥5 including headache.	Mean scores compared and were “significantly different (p<0.05)”. LLQS ≥5 in 2/22 of acetazolamide group and 10/22 in placebo group (p=0.012).
Basnyat B et al, 2008 Nepal and USA	364 healthy non-Nepali adults (18-65yrs) trekking from Pheriche (4250m) or Dingboche (4350m) to Lobuje (5000m). Randomised to receive acetazolamide 250mg twice daily (n=187) or visually-matched placebo (n=177). 25 participants dropped-out.	PRCT, 1b	Incidence of AMS as diagnosed by LLQS ≥3 including headache and at least one other symptom.	Incidence of AMS 21.9% in placebo group compared to 10.2% in acetazolamide group (p<0.01).	Baseline above 4200m altitude, so likely to have selected a population relatively resistant to AMS. Possible further sample bias; many potential participants excluded as already taking acetazolamide.
Kayser B et al 2008 Switzerland, Netherlands and Tanzania	93 adult (23-60yrs) volunteers transported from sea-level to 1860m then trekking to summit of Kilimanjaro (5896m) and back. 44 chose to take acetazolamide 500mg daily, 18 refused participation, remaining 31 were randomised to receive placebo (n=16) or calcium carbasalate 380mg daily (n=15).	Mixed cohort design, 2b	Incidence of AMS as indicated by: 1) (Dutch translation) LLQS ≥3 including headache, OR 2) by headache with LLSS and clinical score of ≥4, OR 3) by headache with LLSS and clinical and functional score ≥4	No difference between carbasalate and placebo. 1) 24/44 (54.5%) in acetazolamide group compared to 26/31 (83.9%) in pooled carbasalate and placebo group (p<0.01). 2) 19/44 (43.2%) in acetazolamide group compared to 22/31 (71.0%) in pooled group (p<0.05). 3) 24/44 (54.5%) in acetazolamide group compared to 26/31 (83.9%) in pooled group (p<0.01).	Small sample sizes, with resultant poor statistical power. Uncontrolled acetazolamide treatment arm, by participant choice. Groups therefore may not have been comparable at baseline. AMS assessed in evening only, not morning. AMS not assessed at summit, only at 4740m evening prior to summit and 3780m evening after summit.
			Severity of AMS as shown by average LLQS.	No difference between carbasalate and placebo. “Scores are significantly lower in the acetazolamide group compared to the pooled group (p<0.05)”
Moraga FA et al 2007 Chile	36 altitude-naïve healthy adult (mean age 22.5yrs) male volunteers transported from sea level to 3696m (Ollagüe). Randomised to receive ginkgo biloba extract 80mg/12hr (n=12), acetazolamide 250mg/12hr (n=12) or placebo (n=12) starting 24hrs before departure continuing for 3 days at altitude.	PRCT, 1b	Incidence of AMS as diagnosed by LLQS ≥3	Incidence of AMS 36% in acetazolamide group, 56% in placebo group (p<0.05).	Small numbers. No blinding of volunteers or investigators. (Transported to altitude rather than trekking.)
			Severity of AMS as shown by average LLQS.	Mean AMS score 2.47 in acetazolamide group, 3.75 in placebo group (p<0.05)
Hillenbrand P et al 2006 Nepal and UK	400 male Nepali porters trekking from Namche Bazaar (3440 m) to Lobuche (4930 m). Randomised to receive acetazolamide 250mg daily or placebo.	PRCT, 2b	Incidence of AMS as diagnosed by (Nepali translation) LLQS ≥3 including headache and at least one other symptom.	AMS occurred in 13 (11.9%) of 109 porters who completed the trial, 7 taking acetazolamide and 6 taking placebo (results not statistically significant).	Study under-powered due to extremely high drop-out rate (72.8% dropped out). Specific group of altitude-experienced subjects (highly homogenous) – results may not be generalisable.
Basnyat B et al 2006 Nepal	222 healthy non-Nepali adult (18-65yrs) volunteers trekking from Namche Bazaar (3440m) to Lobuje (4928m). Randomised to receive acetazolamide 125mg twice daily (n=74), acetazolamide 375mg twice daily (n=82) or visually-matched placebo twice daily (n=66). 18 participants lost to follow-up. 28 non-compliant subjects included in analysis.	PRCT, 1b	Composite incidence of AMS as diagnosed by LLQS ≥3 including headache and at least one other symptom.	Composite incidence of AMS 51% in placebo group, 24% in acetazolamide 125mg group (95% CI 8-46% compared to placebo) and 21% in acetazolamide 375mg group (95% CI 12-49% compared to placebo). No statistical difference between two difference acetazolamide groups seen (95% CI -12.6 to 19.8%).	Underpowered due to smaller sample sizes than required (though sample sizes bigger than most studies). Baseline 3440m altitude, so likely to have selected a population relatively resistant to AMS.
			Severity of AMS as shown by average LLQS.	“No statistical difference in the severity of AMS in the three groups”.
Chow T et al 2005 USA	57 unacclimatised adult (18-65 yrs) volunteers transported from Los Angeles (1230m) to nr. Bishop (3800m), staying at altitude for 24hrs. Randomised to receive ginkgo biloba extract 120mg twice daily, acetazolamide 250mg twice daily or placebo.	PRCT 1b-	Incidence of AMS as diagnosed by LLQS ≥3 including headache and at least one other symptom.	Incidence AMS 30% in acetazolamide group, 60% in placebo group (p=0.06)	Under-powered with small sample sizes. Not all raw data presented in paper, and so not possible to ascertain accuracy of statistics. Possible that not all study participants accounted for. Only stayed at altitude for 24hrs.
			Severity of AMS as shown by average LLQS.	Median score 2 in acetazolamide group and 4 in placebo group (p=0.01).
			Number of participant requests for analgesia for headache.	0 in acetazolamide group, 5 in placebo group (p=0.03).
			Number of participant requests for anti-emetics.	0 in acetazolamide group, 3 in placebo group (p=0.20)
			Cases of HAPE or HACE.	1 case of HACE, in participant taking placebo. No cases HAPE.
Carlsten C et al 2004 USA and Bolivia	33 healthy adult (18-60yrs) low-lander (<1600m) volunteers flying from Miami (sea level) to La Paz (3630m). Randomised within 2hrs of arrival at La Paz to receive acetazolamide 125mg (n=12), acetazolamide 250mg (n=10) or placebo (ascorbic acid) (n=11) for two doses 8 hours apart. 1 drop-out due to non-compliance with protocol.	PRCT, 1b-	Incidence of AMS at 24hrs as diagnosed by LLQS ≥3 including headache.	0% in all three groups.	Severely underpowered with small sample sizes. Rationale for restricting participant enrolment (e.g. weight and height) not given; randomisation not described, not stated whether groups comparable at baseline. Unusual dosing regimen, continued and followed up for only 24hrs. Unusual, (possibly inappropriate) choice of statistical methods; not all data presented clearly.
			Incidence of AMS at 24hrs as “liberally” diagnosed by LLQS ≥3 not including headache.	18% in placebo group, 27% in acetazolamide 125mg group, 0% in acetazolamide 250mg group (p-value not given).
			Change in LLQS between baseline and 24hrs.	Mean LLQS at 0 and 24hrs: 1.73 and 1.09 in placebo group (p=0.21), 1.45 and 1.36 in acetazolamide 125mg group (p=0.88) and 2.7 and 0.6 in acetazolamide 250mg group (p=0.008).
			Change in LLQS over time (linear regression of LLQS at 0, 6, 12 and 24hrs).	No statistically significant difference between placebo group and acetazolamide 125mg group (p=0.181), significant decline in LLQS in acetazolamide 250mg group compared to placebo (p=0.002).
Gertsch JH et al 2004 USA and Nepal	614 healthy non-Nepali adults (18-65 yrs) trekking from Pheriche (4280m) or Dingboche (4358 m) to Lobuje (4928 m). Randomised to receive ginkgo 120mg twice daily, acetazolamide 250mg twice daily, both drugs or placebo alone.	PRCT, 2b	Incidence of AMS as diagnosed by LLQS ≥3 including headache and at least one other symptom.	Incidence of AMS 12% in acetazolamide group, 34% in placebo group (odds ratio 3.76).	Baseline above 4200m altitude, so likely to have selected a population relatively resistant to AMS. High drop-out rate of participants (21%). Not all statistic results explicitly stated.
			Incidence of severe AMS as diagnosed by LLQS ≥5.	Incidence of severe AMS 3% in acetazolamide group, 18% in placebo group (odds ratio 6.46).
			Incidence and severity of headache.	Incidence of headache 19% in acetazolamide group, 53% in placebo group (odds ratio 4.77). Incidence of “severe headache” 2% in acetazolamide group, 13% in placebo group (odds ratio 9.01).
Wright AD et al 2004 UK	24 healthy adult (22-65 yrs) volunteers (22 men, 2 women) transported from Kathmandu (1300m) to Lukla (2800m) then trekked to Gorek Shep (5200m) over three days. Randomised to receive placebo (ascorbic acid 150mg) twice daily (n=6), medroxyprogesterone 30mg twice daily (n=6), acetazolamide 250mg twice and ascorbic acid 150mg twice daily (n=6), or acetazolamide 250mg twice daily and medroxyprogesterone 30mg twice daily (n=6); randomisation was stratified according to previous susceptibility to AMS.	PRCT, 1b-	Incidence of AMS as diagnosed by LLQS ≥3	Incidence of AMS 100% in placebo group, 60% in acetazolamide group. No further statistical analysis given.	Very small sample sizes. Acetazolamide treatment arm not blinded. “Placebo” has been shown to be effective prophylaxis for AMS. Process of randomisation not described in enough detail. Limited statistical analysis applied to AMS symptom scoring.
			Severity of AMS as shown by average LLQS.	“Total AMS score” 26.3 in acetazolamide group, 28.3 in placebo group; “not significantly lower”. No further statistical analysis given.
Basnyat B et al 2003 Nepal	197 healthy non-Nepali adult (18-70yrs) volunteers trekking from Pheriche (4243m) to Lobuje (4937m). Randomised to receive acetazolamide 125mg twice daily (n=96) or visually-matched placebo twice daily (n=101).	PRCT, 2b	Incidence of AMS as diagnosed by presence of headache plus one other symptom on LLQS.	Incidence of AMS 12.2% in acetazolamide group, 24.7% in placebo group (p= 0.043).	Baseline above 4200m altitude, so likely to have selected a population relatively resistant to AMS. High drop-out rate of participants (21%). Non-standard use of LLQS as diagnostic criteria for AMS. Participants assessed on evening of arrival at Lobuje (as opposed to 12-36hrs later).
			Incidence of severe AMS as diagnosed by LLQS ≥5.	Incidence of severe AMS 0% in acetazolamide group, 30% in placebo group (p= 0.14).
Hussain MM et al 2001 Pakistan	24 altitude-naïve low-lander (<500m) healthy adult (25-35yrs) male army personnel transported from Rawalpindi (515m) to 3800m then trekked to 4578m (Karakorum range). Randomised to receive; placebo (multivitamin) 12 hourly (n=6), acetazolamide 250mg 12 hourly (n=6), dexamethasone 4mg 12 hourly (n=6), or acetazolamide 250mg and dexamethasone 4mg together 12 hourly (n=6)	PRCT, 1b-	Presence and severity of AMS as categorised by score on 18 symptom 5 point Likert scale modified ESQ at 24 and 72 hours after arrival at 4578m altitude.	Mean ESQ score +/- SE at 24 hours: 11.83 +/- 1.58 in placebo group, 16.83 +/- 2.88 in acetazolamide group; not statistically significant. Mean ESQ score +/- SE at 72 hours: 9.33 +/- 2.42 in placebo group, 14.83 +/- 2.70 in acetazolamide group; not statistically significant.	Severely underpowered with very small group sizes. Not stated whether 4 groups comparable at baseline. Statistical methods not stated at all. Placebo may have included antioxidants, which have been shown to be effective prophylaxis for AMS.
Dumont L et al 2000 Switzerland and France	Systematic review of 33 trials, 9 of which studied prophylactic acetazolamide. Total 82 subjects received acetazolamide 500mg per day with 61 placebo controls, total of 71 subjects received acetazolamide 750mg per day with 81 placebo controls.	SR of RCTs, 1a	Only dichotomous results included (complete absence of AMS).	With 500mg acetazolamide: AMS prevented in 56/82 of treatment subjects and 33/61 in placebo (Relative risk 1.22; 95% C.I. 0.93 to 1.59). With 750mg acetazolamide: AMS prevented in 47/71 of treatment subjects and 26/81 in placebo (Relative risk 2.18; 95% CI 1.52 to 3.15).	Original trials reviewed subject to very small sample sizes. Some of original trials studied low risk ascents (e.g. high baseline). Only complete absence of acute mountain sickness considered, no review of effect on severity.

Comment(s)

There are only three prospective randomised controlled trials (Basnyat 2003 and 2008, Gertsch) of adequate sample size comparing prophylactic acetazolamide with placebo, and all of these are flawed by selecting participants relatively resistant to altitude sickness (i.e. recruiting at participants with no AMS and not on prophylaxis at altitudes of more than 4200m). However, despite the under-powering and resultant susceptibility to Type 2 errors, the majority of relevant studies have shown a statistically significant reduction in both the incidence and severity of AMS with acetazolamide prophylaxis compared to placebo. Only two randomised controlled trials (Wright, Hussain) studied the high-risk situation of unacclimatised (low-lander) adults exercising (trekking) at altitude. However, a further four trials (van Patot, Moraga, Chow, Carlsten) studied the high-risk situation of transporting unacclimatised adults to altitude. The systematic quantitative review by Dumont et al only considered the dichotomous outcome of complete absence of AMS. It was also limited by the small sample sizes of the original trials reviewed, and was therefore underpowered to show efficacy of lower doses of acetazolamide in prevention of AMS. While the optimal dose of acetazolamide is subject to on-going debate, it remains the generally accepted drug of choice for prevention of AMS (Bartsch). Further research is required in this area in the form of a sufficiently powered prospective randomised controlled trial examining efficacy of differing doses of acetazolamide in preventing and reducing the severity of AMS as compared to placebo.

Editor Comment

Abbreviations: AMS, acute mountain sickness; AMS-C, cerebral ESQ III score; ESQ, Environmental Symptoms Questionnaire; HACE, high altitude cerebral oedema; HAPE, high altitude pulmonary oedema; LLSS, Lake Louise Symptom Score; LLQS, Lake Louise Questionnaire Score

Clinical Bottom Line

Current evidence shows that prophylactic acetazolamide is effective in reducing both incidence and severity of acute mountain sickness in adults.

References

1. van Patot MCT, 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.
2. Basnyat B, Hargrove J, Holck PS, et al. Acetazolamide fails to decrease pulmonary artery pressure at high altitude in partially acclimatized humans. High Alt Med Biol 2008; 9(3): 209-16.
3. Kayser B, Hulsebosch R, Bosch F. Low-dose acetylsalicylic acid analog and acetazolamide for prevention of acute mountain sickness. High Alt Med Biol 2008; 9(1): 15-23.
4. Moraga FA, Flores A, Serra J, Esnaola C, Barriento C. Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollagüe (3696 m) in northern Chile. Wilderness Environ Med. 2007; 18(4): 251-7. (Erratum in: Wilderness Environ Med. 2008; 19(1): 51.)
5. Hillenbrand P, Pahari AK, Soon Y, et al. Prevention of acute mountain sickness by acetazolamide in Nepali porters: a double-blind controlled trial. Wilderness Environ Med 2006; 17(2): 87-93.
6. Basnyat B, Gertsch JH, Holck PS, 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.
7. Chow T, Browne V, Heileson HL, Wallace D, Anholm J, Green SM. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial. Arch Intern Med 2005; 165(3): 296-301.
8. 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): 33-9.
9. Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck PS, and the Prevention of High Altitude Illness Trial Research Group. 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.. BMJ 2004; 328(7443): 797.
10. Wright AD, Beazley MF, Bradwell AR, et al. Medroxyprogesterone at high altitude. The effects on blood gases, cerebral regional oxygenation, and acute mountain sickness. Wilderness Environ Med 2004;15(1): 25-31.
11. 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.
12. Hussain MM, Aslam M, Khan Z. Acute mountain sickness score and hypoxemia. J Pak Med Assoc 2001; 51(5): 173-9.
13. Dumont L, Mardirosoff C, Tramèr MR. Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review. BMJ 2000; 321: 267-272.
14. Bartsch P, Bailey DM, Berger MM, Knauth M, Baumgartner RW. Acute mountain sickness: controversies and advances. High Alt Med Biol 2004; 5(2): 110-124.