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To the Editor:

We appreciate the discourse from Drs Lipman and Hackett,¹ value their insights, and welcome the opportunity to discuss our study.² Their main concern is that we have overestimated the expected incidence of acute mountain sickness (AMS). We echo this concern and wish we could accurately know the true incidence of AMS at our study site. We attempted to estimate it as accurately as possible using available data. The studies they cited are not ideal for direct comparisons because they used different locations, elevations, ascent rates, methodologies, and inclusion/exclusion criteria than those in our study. Because of the site-specific variability of AMS incidence, it is important to compare only those studies that are nearly identical.

They state that there has been an “almost a 50% decline in AMS over the past 18 years, to 22% at the Himalayan Rescue Association clinic in Manang.” The studies conducted at 3519 m in Manang, Nepal, had a completely different trekking ascent profile and location. Our study was performed ∼300 km away at a ∼1000 m higher elevation, in Pheriche (4371 m) and Dingboche (4410 m), to Lobuche (4940 m). Although we agree with their inference that a lower incidence poses challenges tin studying altitude illness in Manang, Manang was not our study site, nor was our methodology similar to that in the study they cited.

The SLEEP-AID study³ cited did indeed originate in Pheriche and Dingboche. Unfortunately, this study was also not comparable with ours because AMS incidence was studied at different altitudes. The SLEEP-AID study was an overnight study while participants were staying in Pheriche and Dingboche. Our study and those we relied on for our power analysis followed participants for at least 2 days as they ascended over 500 m higher to Lobuje, where AMS incidence was then calculated. One would expect to find lower AMS incidence among subjects at a lower altitude for a shorter duration than in subjects trekking to a higher altitude followed over several days.

The authors argue that without a placebo arm one does not “know if these medications reduced the incidence of AMS at all.” We agree, but to identify or quantify the efficacy of these treatments relative to placebo was never the intent of our study. Rather, our study purpose was to compare the efficacy of 2 treatments (ibuprofen and acetaminophen) relative to each other in modifying AMS incidence. Questions examining the efficacy of these treatments relative to placebo have been addressed in numerous previous studies elsewhere. We did note that “combined group incidence of AMS was 19.1%, which is notably lower than the 33% averaged historical incidence” and surmised that this apparent decrease in AMS incidence in both treatment groups relative to historical placebo levels likely resulted in part due to both treatments reducing AMS. This hypothesized explanation was based on prior studies showing ibuprofen’s efficacy at AMS prevention.⁴ If indeed historical overall reductions of AMS incidence in trekkers at our study site are taking place, that too could provide an additional explanation for at least some of the reduced AMS incidence we observed. That said, we examined whether ibuprofen and acetaminophen differed in the resulting incidence of AMS. We found little evidence to suggest that they do and concluded that “acetaminophen performs similarly to ibuprofen in the prevention of AMS in partially acclimatized subjects.”

We concluded that there was no strong evidence of a difference. Our reported results specify the strength of that conclusion based on sample size. We calculated that the difference in AMS incidence between the two treatments was 7%, but concluded that in the population overall, the true difference might be anywhere between −4% and +16%. The uncertainly of our conclusion illustrates a limitation of sample size, but it does provide some likely bounds regarding what differences are likely, should any exist, between the medications. Recruiting a third “placebo” arm to the study would have required either fewer subjects in our treatment arms or necessitated extending the trial over multiple trekking seasons. Possible declines in AMS incidence are far from conclusive. Larger sample sizes of Nepal trekkers (including multiseason recruitment) may be necessary for more precise estimates. Regardless, neither of these potential concerns invalidates our conclusions or indicates that we used an inappropriate approach to examine differences between ibuprofen and acetaminophen for prevention of AMS.

Lipman and Hackett’s estimation of our power calculations for our test of equivalency needs slight correction. We anticipated an incidence of about 14% AMS in our treatment groups, but we wanted to be able to detect a difference as small as 11% between the 2 treatments, a difference that might be clinically relevant. For 80% power and α = 0.05, we estimated we would need at most 125 individuals in each arm. Although we recruited more than that number of subjects, exclusions and a slightly higher than expected incidence of AMS resulted in a less precise estimate of the magnitude of difference between treatment arms.

Finally, we would also like to make a small correction: Our manuscript stated an AMS incidence of 33% in our power calculation, not 32% as was cited. For the sake of openness and clarity, it must be stated that we conducted our power analysis before conducting the study, based on multiple studies^,5 ^–8 with the same location, elevation, ascent profiles, recruitment methodologies, and time course. To calculate the historical AMS incidence, we combined the results of these studies by dividing the number of subjects who developed AMS in the placebo arms by the total number of subjects in the placebo arms (omitting subjects who received interventions), or 44+16+40+20=120 divided by 109+53+119+81=362. The overall incidence of AMS in subjects taking placebo in these studies was 120/362, or 33%.

References

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Hackett

In response to ibuprofen vs acetaminophen in AMS prevention by Kanaan et al. Wilderness Environ Med 2017 Sept 21. [Epub ahead of print].

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Peterson

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et al. Study looking at end expiratory pressure for altitude illness decrease (SLEEP-AID). High Alt Med Biol 2015; 16, 154–161.

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et al. Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness. Wilderness Environ Med 2012; 23, 307–315.

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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, 236–243.

Gertsch

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et al. 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, 797–799.

Basnyat

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Yeh

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, 45–52.

In Reply to Drs Lipman and Hackett

References