Acute mountain sickness (AMS), characterized by headache, light-headedness, fatigue, nausea, and insomnia, occurs primarily at altitudes above 2,500 m in those poorly acclimatized to such conditions. If untreated, this symptom complex can progress to the life-threatening conditions of high altitude cerebral edema and high altitude pulmonary edema. It has been suggested that the carbonic anhydrase inhibitor acetazolamide is effective in the prevention of AMS when begun prior to ascent to altitude. However, for clinicians prescribing for those ascending to altitude, there has been a lack of clarity regarding the usefulness of acetazolamide, when and for whom it should be recommended, and the optimum dose. While guidelines published by the Wilderness Medical Society recommend acetazolamide for travelers under some circumstances, the Union Internationale des Associations d'Alpinisme does not make a similar suggestion. The side effect profile of acetazolamide includes paraesthesia, urinary frequency, and dysgeusia (taste disorder). As such unpleasant symptoms could affect compliance with treatment, it is desirable to determine the lowest effective dose in order to potentially minimize the harmful effects of acetazolamide.
Two systematic reviews of acetazolamide in the prevention of altitude-related symptoms have been published. The first, published in 1994, included trials measuring a diverse range of outcomes not limited to classic symptoms of AMS. This review found evidence of a benefit associated with acetazolamide but the heterogeneity in measured outcomes limits interpretation in a clinical context. The second systematic review was published in 2000 and had more restrictive inclusion criteria—including only studies reporting the incidence of AMS as an end point. The authors concluded that 750 mg/d of acetazolamide was effective in the prophylaxis of AMS but that there was no evidence of benefit from 500 mg/d. However, this review was limited by the small number of patients in the pooled analysis which significantly limited its power.
Since Dumont and colleagues published their review in 2000, a significant number of controlled trials have been reported, including several trials investigating doses of acetazolamide less than 750 mg/d. We decided to review the available evidence including these recent clinical trials. Our review was limited to trials with AMS as an end point. Since assessment of AMS is subjective and potentially prone to bias, we decided to include only randomized, placebo-controlled, double-blind studies which clearly defined the diagnosis of AMS.
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This systematic review synthesized data from rando-mized-controlled trials investigating the efficacy of acetazolamide prophylaxis in the prevention of altitude sickness. It found a significant benefit associated with acetazolamide treatment that was remarkably consistent across a range of heterogeneous trials. Overall, the meta-analysis suggested that taking acetazolamide prophylaxis is associated with a relative-risk reduction of around 48%. There was no evidence of any difference in efficacy between different doses of acetazolamide. This conclusion differs from that of Dumont and colleagues who concluded that while 750 mg/d was effective, lower doses were not. This difference is likely due to three principal factors: most importantly, there have been a significant number of new trials published since 2000, many of which examined lower doses of acetazolamide. Furthermore, the inclusion criteria of our study were different as we included only double-blind studies. Finally, while our primary end point was relative-risk reduction, in Dumont and colleagues it was NNT, which may have made comparison between trials difficult given the heterogeneity in risk of AMS between trials. It is of note that the two different types of study included, expedition-based and location-based studies, did not differ in their estimate of treatment efficacy despite marked differences in the design of the two study types. This supports the idea that the evidence of treatment benefit may be generalizable beyond the populations included in these studies.
The absolute risk reduction associated with acetazolamide prophylaxis was associated with the risk of AMS in the trial placebo group and with the rate of ascent but not the maximum altitude reached. The lack of association with maximum altitude is not surprising, as rate of ascent was variable and in all but two studies the maximum height reached was between 4,000 and 5,000 m. This does not exclude the possibility of an association if a greater range of maximum altitudes had been studied. There was an association between a study's representative rate of ascent and absolute benefit from acetazolamide. This means that as rate of ascent increases, the NNT from acetazolamide prophylaxis decreases. This finding is plausible but should be interpreted with caution. The rate of ascent is only approximate and particularly in the location-based studies is difficult to define. Furthermore, since the expedition-based studies had a higher rate of climb than the location-based studies, these differences could be confounded by other differences in the trial design rather than rate of ascent. The association between rate of climb and benefit from acetazolamide could only be definitively established by a properly controlled trial with randomized rates of ascent.
Adverse effects were not systematically described in the majority of studies and this made firm conclusions about the incidence of these adverse events difficult. Many studies reported only the lack of serious adverse events. It is clear, however, that adverse effects are common but generally mild. In the studies systematically reporting adverse effects, paraesthesia was most commonly reported. There were, however, insufficient data in this analysis to investigate any association between dose and adverse effects. This question was addressed in one of the studies, which concluded that adverse effects were more common in the 750 mg/d group.
There are a number of limitations to our analysis. We decided to include in our analysis only studies involving acetazolamide. This study does not address the efficacy of other medications for the prophylaxis of AMS, such as dexamethasone, ibuprofen, and gingko balboa. A review on this broader question of the role of other pharmacological strategies has recently been published. Since many of the early studies of acetazolamide in AMS were carried out many decades ago, it is likely that we have not identified all the studies which could have potentially been included. We were also unable to obtain the text of one study. However, given that this study and any possible unidentified studies are likely to be small, it is unlikely that they would have significantly altered this analysis. Our inclusion criteria were intentionally narrow, resulting in the exclusion of a significant number of trials. However, the requirement for a randomized, double-blind design, and a clear definition of what constituted a diagnosis of AMS reduce the risk of systematic bias. The studies used a variety of methods of end-point assessment, most commonly the LLS and AMS-C/AMS-R. While these scores do correlate, they have been observed to identify different populations of patients with AMS.[48, 49] Furthermore, all the assessment tools for AMS suffer from having to apply an arbitrary cut-off to a complex clinical syndrome. These factors introduce a source of bias into our analysis; however, the lack of heterogeneity found in the assessment of the primary end point suggests that this effect is not large.
Our findings suggest that acetazolamide 250 mg/d is associated with a similar benefit compared to higher doses and that adverse effects are dose related. Therefore, a dose of acetazolamide 250 mg/d should be recommended in most instances based on current evidence. Future trials will clarify this understanding. Only one trial used a single daily dose of acetazolamide and this study, which was hampered by a low number of cases of AMS and a high dropout rate, failed to demonstrate a benefit of acetazolamide. Therefore, until further evidence emerges, divided daily dosing of acetazolamide should be suggested. This study could not address the interaction between dose and rate of ascent; further trials examining a range of doses in rapid ascent would be particularly helpful. In expedition-based trials, acetazolamide was started at low altitude whereas the location-based trials commenced treatment at moderate altitude. Both groups of trials demonstrated benefit from acetazolamide. However, since some patients in location-based studies were already experiencing altitude sickness when screened at moderate altitude, it would seem reasonable to commence acetazolamide at low elevations before ascending to a height where symptoms are likely. This analysis, however, provides limited evidence to assist prescribers in deciding which patients are likely to benefit most from acetazolamide treatment. Since studies with a high placebo risk and high ascent rate had a larger absolute risk benefit (Figure 5), this suggests that travelers judged to be at highest risk of AMS may benefit most from acetazolamide prophylaxis. The risk factors for AMS are well described and include not only altitude and rate of ascent but also personal factors such as history of AMS, young age, and a history of respiratory disease. Therefore, decisions on the prescribing of acetazolamide should be based on an individualized assessment of the risk of AMS weighed against the risk of adverse effects. This is the approach suggested by the Wilderness Medicine Society guidelines.
Many tourists visiting East Africa join expeditions ascending Mount Kilimanjaro. On typical tourist expeditions rates of ascent are much higher than those recommended by published guidelines and the incidence of AMS is high.[51, 52] While advice to tourists intending to embark on these expeditions should include advice regarding the dangers of this rapid ascent, in our experience many travelers elect to proceed with their expedition as planned despite this warning. On the basis of our analysis, in such cases the use of prophylactic acetazolamide would appear to be justified. Only one of the studies in our analysis attempted to capture the incidence of high altitude pulmonary edema as a primary end point and it failed to identify any cases during the trial, probably because subjects kept to modest rates of ascent. Our analysis is therefore unable to conclude anything about the efficacy of prophylactic acetazolamide in the prevention of the life-threatening complications of AMS. However, it is clear that many travelers continue to ascend even with symptoms of AMS. It is important that whether acetazolamide is prescribed or not, travelers receive clear advice about what to do if symptoms develop. In the UK, acetazolamide is not licensed for the prevention of AMS, so patients should be specifically informed of this when prophylactic therapy is prescribed. As acetazolamide is a sulfa drug there is a theoretical concern in patients with a history of allergy to sulphonamide antibiotics; however, other experts argue that it can safely be given to patients with a history of such allergy.
In conclusion, our systematic review has demonstrated strong evidence of a benefit of prophylactic acetazolamide in the prevention of AMS with a dose of 250 mg/d in divided doses offering similar efficacy to higher doses. Treatment is likely to be of greatest benefit to those at highest risk of developing AMS but prophylactic prescribing is no substitute for good pre-travel advice regarding altitude-related symptoms.