Can acetazolamide make high-altitude travel safer for COPD patients? Probably yes, but that doesn’t necessarily mean it is particularly advisable.
It is no secret that some travelers die at high altitudes as a result of acute mountain sickness (AMS), and the risk is highest for those with underlying conditions, especially chronic lung diseases. Many doctors, therefore, would advise against COPD patients going on a hiking tour in, say, the Nepalese Himalayas, at least when the COPD is more than only mild. But not everybody listens to their doctor, so the question remains whether something can be done to reduce the individual risk – beyond proper acclimatization, which is often easier said than done.
Two recent randomized trials offer help in counseling situations like these. The trials evaluated a drug that is used by many high altitude travelers anyway: acetazolamide as a prophylactic. It is approved for the prevention of AMS and its most severe complication, high-altitude cerebral edema, in the US. But many say that the agency is moving on thin ice with this approval – especially regarding effects in chronically ill patients.
The two recent placebo-controlled trials, published in NEJM Evidence, evaluated acetazolamide taken twice daily in a dose of 125 mg in the morning and 250 mg at night. The medication was started 24 hours before staying at 3.100 m for 2 days, after having stayed at below 800 m the days before. All participants traveled by minibus to a high altitude clinic at 3.100 m, a ride of 3 to 5 hours. The first trial was comprised of 176 patients with moderate COPD, at a mean age of 57 years. The second one evaluated drug or placebo in 345 healthy lowlanders at 40 years or older, at a mean age of 53 years.
In the COPD trial, all patients had oxygen saturation of 92 % or greater at low altitude, and none had arterial partial pressure of carbon dioxide of 45 mm Hg or more. Forced expiratory volume in 1 second was 63 % on average. Primary outcome of this trial was altitude-related adverse health effects or ARAHE, meaning AMS or symptoms OR findings relevant to COPD well-being like severe hypoxemia. AMS was self-assessed using the Lake Louise questionnaire, which is a symptom scale ranging from 0 to 15. It was assumed in persons with an LLS sum score of 3 or more including headache.
Regarding the primary endpoint, the COPD trial was a success: 76 % of participants in the placebo group, but only 49 % in der acetazolamide group experienced ARAHE (HR 0,54; 95 % CI 0,37–0,79; p < 0,001). This translates into a number needed to treat of 4, with a confidence interval of 3 to 8. Interestingly, the most common subtype of ARAHE in the COPD trial was severe hypoxemia, which was observed in 44 % of placebo patients and 16 % of acetazolamide patients. This translates into a number needed to treat of only 3. Most ARAHE events – 9 out of 10 – occurred early, within 20 hours of arrival at high altitude.
The healthy volunteer trial was similar in design, but the primary endpoint was slightly different in that a Lake Louise AMS score of 3 or more including headache was its only component. 32 % of placebo patients and 22 % of acetazolamide patients experienced AMS according to this definition, which again was statistically significant. The number needed to treat was 10 in the healthy setting, with a broad confidence interval of 5 to 141.
The COPD trial is relevant for daily routine because it is among the first randomized trials to focus on prevention in COPD patients travelling to high altitudes. Before that, two other randomized trials have examined preventative measures in this context. In one of those trials, nocturnal oxygen therapy reduced the incidence of ARAHE from 26 % in the placebo group to 4 % in the treatment group. Dexamethasone, in contrast, did not reduce ARAHE compared to placebo in a second trial, but did improve oxygenation and pulmonary hemodynamics.
So should doctors be more courageous in sending acetazolamide-shielded COPD patients to high altitudes, or should they at least object less often when patients desire this kind of recreation? It seems clear that, even with acetazolamide, high altitude traveling remains a risky endeavor. In fact, a relevant proportion of patients in the COPD trial developed an oxygen saturation of below 85 % during the first evening at 3.100 m – 25 % in the placebo group and 8 % in the acetazolamide group. And in spite of taking an acetazolamide treatment, half of all COPD patients still developed ARAHE with substantial symptoms that required descending to a lower level.
Commenting on the trials, Dr. Thomas L. Schwenk from the University of Nevada School of Medicine, considers this too high a risk: “In my experience practicing at altitude, these results would not reassure me in advising patients with moderate-to-severe COPD about vacationing at high altitude, even with acetazolamide.”
Image source: Rohit Tandon, Unsplash
