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What medication most effectively prevents acute mountain sickness?

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Manuscript Number: EMS7495

Full Title: What medication most effectively prevents acute mountain sickness?

Article Type: HDA

Section/Category: NV - Mike O'Callaghan Federal Medical Center/Nellis AFB FMR

Keywords: Prevention; Acute Mountain Sickness; Medication

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Prevention Mountain Sickness V1.docx

Title: Best Preventive Treatment for Acute Mountain Sickness

Word Count: 870

HDA Question: What medication most effectively prevents acute mountain sickness?

Evidence-Based Answer
In patients at risk, acetazolamide should be used as first-line pharmacological treatment for the
prevention of acute mountain sickness (AMS) (SOR: B, meta-analysis of RCTs). Budesonide is
less effective compared to acetazolamide for the prevention of acute mountain sickness (SOR: D,
Single RCT). While further studies are needed, ibuprofen should not be recommended over
acetazolamide for the prevention of acute mountain sickness (SOR: D, Single RCT).

Methods
This clinical question was developed as an HDA through a standardized, systematic
methodology (HDA Methods, Supplemental Digital Content) [production will hyperlink the
words “HDA Methods, Supplemental Digital Content” to the Methods SDC file].

Evidence Summary
A 2017 meta-analysis of 64 randomized controlled trials (RCTs) compared multiple
pharmacologic agents in the prevention of acute mountain sickness (most commonly using the
Lake Louise Acute Mountain Sickness Scale) in elevations above 2,500 meters1. The reviewers
included RCTs and cross-over trials, irrespective of publication status and length of follow-up.
Exclusion criteria included quasi-randomized studies and prospective observational studies, as
well as studies where medications were administered during or after ascent. Studies were
identified through an electronic search through the Cochrane library database, as well as
MEDLINE, Embase, and LILACS. Participants from the studies were males and females
between the ages of 16 and 65 (19 studies only included males however) and in most studies,
participants reached an average altitude of 4001-5000 meters (m) (though some studies were
conducted in a simulated, hypobaric pressure chamber). Eleven studies were performed on
higher-risk individuals for AMS, based on history of prior AMS or higher-risk medical
conditions, such as asthma. The medications reviewed included acetazolamide, budesonide, and
dexamethasone as well as other agents in the prevention of AMS. Acetazolamide (total dose 250-
500 mg/day) reduced risk for AMS compared to placebo (N=2301, RR=0.47, 95% CI, 0.39-
0.56). Budesonide (200 µg inhaled twice daily) reduced risk for AMS compared to placebo
(N=132, RR=0.37, 95% CI, 0.23-0.62). Dexamethasone (multiple dosages studied) did not
reduce the risk for AMS compared to placebo (N=176, RR=0.60, 95% CI, 0.36-1.0). Lower
quality of evidence was present for budesonide and dexamethasone due to limited number of
participants as well as increased heterogeneity, especially in the dexamethasone studies, and as
such overall benefits and harms of such are inconclusive. The meta-analysis also lacked
information on reported adverse events, however the reported adverse events included
paresthesias for acetazolamide groups, which is a well-known side effect of such.
A 2018 prospective, double-blind RCT (N=103) compared budesonide (180 cg, inhaled twice
daily) versus acetazolamide (125 mg oral twice daily) versus placebo (lactulose placebo pill
taken twice daily) in the prevention of AMS.2 Participants consisted of healthy volunteers in
Northern and Southern California between 18 and 65 years of age who resided below 1240m at
baseline and were able to complete a moderately strenuous hike. Exclusion criteria included
individuals who were outside of the age range, pregnant, residing at altitudes greater than 1240m
in the past week, taking conflicting medications in the past week (steroids, acetazolamide,
diuretics, or NSAIDs), or with high-risk medical conditions for altitude sickness and associated
complications (sickle cell anemia, severe asthma or chronic obstructive pulmonary disease,
severe coronary artery disease, or severe anemia). Participants were randomized in a computer
generated 1:1:1 fashion to inhaled budesonide (N=33), oral acetazolamide (N=35), and placebo
(N=35). Medications were dosed in the morning before ascending from 1240m to 3,810m.
During the course of the ascent, participants performed two separate hikes (total distance 3.2
miles) and they later spent the night on the same day at 3810m. AMS incidence was assessed
with the Lake Louise Questionnaire. Results found AMS incidence was lower in the
acetazolamide group (43% of participants) compared to the budesonide group (73% of
participants, with an odds-ratio (OR) 3.5, 95% CI, 1.3-10.1), as well as compared to the placebo
group (63% of participants, OR 0.5, 95% CI 0.2-1.2). The study concluded budesonide was less
effective than acetazolamide for the prevention of AMS, however the study was of lower quality
given its number of participants and decreased power.

A 2019 prospective, double-blind RCT (N=92) compared ibuprofen (600 mg, 3 times daily)
versus acetazolamide (125 mg, twice daily) in the prevention of AMS.4 Participants consisted of
healthy, non-pregnant volunteers between the ages of 18 and 65 that resided below 1240m.
Exclusion criteria was similar to the previous 2018 study, and included participants outside of
the age range, residence greater than 1240m of altitude (or living at such within the prior week),
allergies to involved medications, or recent history of similar medicines or steroids used in the
week prior to study. Participants were randomized in a computer-generated 1:1 fashion to take
ibuprofen (N=45) or acetazolamide (N=47) starting the night before ascending to 3810 m at
White Mountain, California. Participants completed two separate hikes at elevated altitude; the
first being 0.8 km at 3424m, and the second being 4.3 km at 3810m. They then spent the night at
3810m. Outcomes were assessed using the Lake Louise Questionnaire. These measurements
were performed the night before ascent at baseline, 6 hours after ascent, and at 18 hours after
ascent. AMS incidence was 62.2% in the ibuprofen group and 51.1% in the acetazolamide group
(95% CI, -11.1-33.5). The total scores from the Lake Louise Questionnaire however revealed no
statistically significant difference (p=0.8). Ibuprofen was not as effective as acetazolamide in the
prevention of AMS, however further studies may be needed to assess this intervention.
Currently, ibuprofen should not be recommended before acetazolamide for the prevention of
AMS.
References:
1. Nieto Estrada VH, Molano Franco D, Medina RD, Gonzalez Garay AG, Martí-Carvajal
AJ, Arevalo-Rodriguez I. Interventions for preventing high altitude illness: Part 1.
Commonly-used classes of drugs. Cochrane Database Syst Rev. 2017;6(6):CD009761.
Published 2017 Jun 27. doi:10.1002/14651858.CD009761.pub2. [LEVEL 1a].
2. Lipman GS, Pomeranz D, Burns P, et al. Budesonide Versus Acetazolamide for
Prevention of Acute Mountain Sickness. Am J Med. 2018;131(2):200.e9-200.e16.
doi:10.1016/j.amjmed.2017.05.034. [STEP 2b].
3. Burns P, Lipman GS, Warner K, et al. Altitude Sickness Prevention with Ibuprofen
Relative to Acetazolamide. Am J Med. 2019;132(2):247-251.
doi:10.1016/j.amjmed.2018.10.021. [STEP 2b].
Methods

Methods
The authors developed the clinical question, “What medication most effectively prevents acute
mountain sickness”, based on the clinical needs of their practice site. EBP editors approved the
question based on its relevance and applicability to practicing primary care clinicians. EBP
editors also verified the question does not duplicate other HelpDesk Answers written in the prior
three years.

The table includes the databases and search terms the authors used to find studies matching the
following study inclusion criteria: patients – individuals at risk of developing acute mountain
sickness; intervention – agents commonly used to prevent AMS: Carbonic anhydrase inhibitors,
Steroids, Bronchodilators, PDE5 inhibitors, Calcium channel blockers, NSAIDs, as well as other
less commonly used agents; comparison – the agents listed were compared against placebo, as
well as the other agents used to prevent AMS; and outcome –prevention of AMS. Authors
selected the most relevant, highest evidence level studies published within the last 56 years to
prepare the HDA manuscript (Figure).

Table: HDA Search Strategy

Search engine Search term or combination of Total number of
search terms records identified
PubMed Clinical Queries a) “acute mountain sickness” a) 705
filter: Therapy b) 204
scope: Broad c) 81
b) “acute mountain sickness”
filter: Therapy
scope: Narrow
c) “acute mountain sickness treatment
louise”
filter: Therapy
scope: Broad

Cochrane Library a) “acute mountain sickness” a) 5 reviews. 389

b) AND “prevention” trials.
c) OR “lake louise acute mountain b) 3 reviews. 214
sickness score” trials.
c) 3 reviews. 218
trials.
Trip Database a) “Acute mountain sickness” a) 975
(total results) b) 13
b) “Acute mountain sickness” c) 10
(systematic reviews)
c) “Acute mountain sickness
prevention”
(systematic reviews)
Figure: Literature Search Flow Diagram

Total number of records identified by all search

engines
(n = 1999)

Abstracts screened for relevance

(n = 73)

Full text articles identified through hand search of

Full text articles reviewed for eligibility and reference lists or through ‘Similar Articles’ in
quality PubMed
(n = 12) (n = N/A )
(n = )

Studies included as references

(n = 3)