Source: 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 of Systematic Reviews 2017, Issue 6. Art. No.: CD009761. DOI: 10.1002/14651858.CD009761.pub2.
Study Population: Approximately 2,300 patients across 16 studies with recent ascent to altitude at 4,001-5,000 meters
Efficacy Endpoints: Development of AMS, defined by Lake Louise score or other study-specific criteria from arrival to 24 hours later
Harm Endpoints: Report of paresthesias from arrival to 24 hours later
Narrative: Above 2,500 meters, the partial pressure of oxygen in the atmosphere drops, requiring the human body to adapt. In the acute stage, these adaptations include hyperventilation, tachycardia and an increase in blood pressure. If ascent occurs rapidly, and physiologic adaptation is insufficient, Acute Mountain Sickness (AMS) can result. The symptoms AMS include headache, nausea, anorexia, vomiting, lightheadedness, insomnia and fatigue. If the condition persists, in the right individual and the right circumstances, these symptoms can progress to potentially fatal High Altitude Cerebral Edema (HACE) and/or High Altitude Pulmonary Edema (HAPE).
Prophylaxis is often attempted using the carbonic anhydrase inhibitor acetazolamide. Although the exact mechanism of action is unclear, one theory is that acetazolamide inhibits carbonic anhydrase in the kidneys, increasing bicarbonate excretion, resulting in a metabolic acidosis that offsets the hyperventilation-induced alkalosis experienced at altitude. However, acetazolamide likely has multiple effects throughout the body that help to prevent AMS. Both patients and providers should be aware that relief of AMS can come at the expense of side effects, most commonly paresthesias, but also polyuria, rash, and dysgeusia.
It should also be noted that the doses of acetazolamide used in these studies are higher than doses that have been shown to be as effective at preventing AMS. The incidence of adverse effects also increases as the dose of acetazolamide increases. This review may therefore overstate the risk of paresthesias. Although the frequency of paresthesias when taking this medication is high, this side effect is not life threatening and there is clear benefit in the reduction of debilitating AMS that may progress to life-threatening HACE if untreated. For this reason, we have given this treatment a rating of green.
Caveats: The trials included in this systematic review were heterogeneous in regard to number of days before starting the ascent that the intervention was started, method of ascent (trekking, gondola, etc.), altitude ascended to, dose of acetazolamide provided, and predisposition of patients to AMS as per prior history and comorbidities (asthma, chronic obstructive pulmonary disease, diabetes, etc.). Nonetheless, they were deemed homogeneous enough for comparison after a statistical analysis of heterogeneity showed differences between studies to be non-significant. Of note, the authors of the review point out that 70% of studies do not clearly describe the method of randomization. Furthermore, this review included studies in which patients were evaluated for symptoms up to 24 hours after ascent. Onset of symptoms (and side effects of medication) could first be noted beyond 24 hours, usually within the first few days. Treatment with acetazolamide would likely extend past 24 hours, further complicating the picture and possibly the likelihood of side effects.
Studies that evaluated paresthesias were frequently unclear in specifying if symptoms were elicited or spontaneously reported. Drop-out rates for acetazolamide arms specifically secondary to paresthesias are difficult to assess from the data gathered. It seems that most of the included studies did not report on how many people dropped out secondary to paresthesias alone. Authors of this review attempted to use an intention-to-treat analysis in order to address any break from experimental protocol secondary to any side effects of medication.
The definition of AMS was also variable. Authors note that 35% of trials use the Lake Louise score, which is specifically designed to evaluate AMS. In 30% of the studies the categorization of AMS was “unclear,” and in the remainder the diagnostic criteria were not commented on. The variability of the definition of AMS across studies could significantly affect the interpretation of data.
Benefit from arrival to 24 hours later (prevention of AMS):
2301 participants over 16 studies
Placebo group: 252/1046 (24.1%)
Acetazolamide group: 139/1255 (11.1%)
RR for acetazolamide group: 0.47 (95% CI, 0.39 to 0.56)
Absolute risk reduction: 13%
Harm Outcome (paresthesias experienced from arrival to 24 hours later):
789 participants over 5 studies
Placebo group risk: 32/351 (9.1%)
Acetazolamide group: 222/438 (50.6%)
RR for acetazolamide group: 5.53 (95% CI, 2.81 to 10.88)
Absolute risk increase: 41%
Author: Kyle Kelson, MD and Carlo Canepa, MD
Published/Updated: November 16, 2017
The title bar is color-coded with our overall recommendation.