This Editorial refers to the articles by Ritchie et al., pp. 298–307 and Leshem et al., pp. 308–310 of this issue.
Although it is best to prevent acute mountain sickness (AMS) by gradual ascent without using any drugs, this may not always be an option in many settings. Rescuers may need to go up rapidly to high altitudes; or logistically, owing to a lack of camp site, it may not be possible for trekkers and climbers to spend the night at an optimal altitude. Furthermore, airports in places like Lhasa, Tibet (3,490 m) and La Paz, Bolivia (4,058 m) may cause travelers to arrive at high altitude without the ability to acclimatize en route. Some people who are predisposed to AMS may be protected by taking a prophylactic drug while ascending high altitudes. Many, such as pilgrims, often disregard strongly delivered advice about gradual ascent in their single-minded determination to ascend the sacred site. In addition, there is a fast-growing population of climbers in pursuit of a summit who are being advised by physicians to use prophylactic medicine to both improve performance and achieve summit success. Poor knowledge and lack of awareness of side effects may lead to widespread misuse of drugs. Finally, sudden military deployment to high altitude regions of the world, such as the Hindu Kush mountains in Afghanistan, may necessitate drug prophylaxis for the prevention of AMS. Two articles[3, 4] in the present issue deal with the use of acetazolamide at high altitude in the prevention of altitude illness.
In 1965, Cain and Dunn were the first to show that acetazolamide increased ventilation resulting in increased partial pressure of oxygen and decreased partial pressure of carbon dioxide. The findings of hyperventilation and increase in oxygen levels in the blood brought on by the drug were exploited in subsequent years in dealing with the effects of hypoxia of high altitude.[1, 6]
In this issue, the meta-analysis studying the prevention of AMS using acetazolamide covers 16 studies. No study protocols were available for the authors to independently review these. However, the meta-analysis was strengthened because only randomized, placebo-controlled trials were included in the study. Importantly, this meta-analysis included studies done after 2000. In a publication in 2000, Dumont and colleagues had arbitrarily shown that only 750 mg/day of acetazolamide would prevent AMS. By including many more studies [eg, see Refs [8-10]] since 2000, it was reassuring to note that a much lower dose (250 mg/day) was adequate for prevention.
Researching AMS can be difficult given the non-specific nature of the “hangover”-like symptoms on which the diagnosis is based. In addition, there are different questionnaires for assessing AMS including the most commonly used Lake Louise Symptoms score and the modified Environmental Systems Questionnaire. Although heterogeneity tests are not uniformly reliable, tests such as the funnel plots used by the authors did not show significant heterogeneity in the results of this meta-analysis using different questionnaires.
An interesting question is whether acetazolamide prevents high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE), both life-threatening complications of altitude sickness. There are no studies of acetazolamide to support its use in the prevention of HAPE and HACE, although intuitively HACE appears to be a continuum of AMS and preventing AMS arguably may prevent HACE. A randomized, placebo-controlled trial conducted at high altitude in the Everest region in 339 partially acclimatized trekkers to see if acetazolamide decreased pulmonary artery pressure (high pulmonary artery pressure being a sine qua non for the diagnosis of HAPE) using echocardiography revealed that acetazolamide failed to decrease pulmonary artery pressure.
The other high altitude study in this issue examined the efficacy of tadalafil in the prevention of severe high altitude illness (HAPE and HACE). One arm of the study consisted of acetazolamide and the other arm consisted of acetazolamide and tadalafil. Predictably, the acetazolamide–tadalafil arm did better because it reduced HAPE rates as tadalafil has been proven to prevent HAPE. However, as expected, an important difference between the two groups was the increase in headache and AMS scores in the tadalafil group at certain altitudes. This study also appears to suggest that acetazolamide may not be effective in the prevention of HAPE. An important drawback of this study was that it was a non-randomized trial.
Although acetazolamide is a sulfone, it has little cross reactivity with sulfa drugs and hypersensitivity reactions to acetazolamide are rare and more likely to occur in those who have severe, life-threatening reactions to sulfa drugs. Carbonic anhydrase is present in many tissues (red cells, lung, brain, chemoreceptors, and kidneys) where it may be relevant to high altitude acclimatization, but only renal carbonic anhydrase is inhibited at doses of about 3 mg/kg as a result of the drug's concentration in renal tissue and urine by tubular organic acid uptake and secretion. It appears that renal carbonic anhydrase inhibition is what is required for prophylaxis of AMS. In addition, the lower dosage is associated with lesser parasthesia, a common side effect of acetazolamide. By inhibiting renal carbonic anhydrase, there is bicarbonate diuresis which leads to metabolic acidosis which in turns drives ventilation and increases oxygenation. The metabolic acidosis begins within 1 hour of drug ingestion. Other potentially helpful effects of acetazolamide for acclimatization are that it decreases cerebrospinal fluid production in addition to inhibiting antidiuretic hormone secretion helping to counteract fluid retention at high altitude.
Other drugs including ginko biloba[8, 9] spironolactone, dexamethaosone, sumaptriptan and non-steroidal anti-inflammatory drugs have been tested in the prevention of AMS; and some of these have been shown to be efficacious.[18, 19] But acetazolamide continues to be the superior drug for AMS prevention due to its proven efficacy over the years in a large number of trials with an acceptable side-effect profile.
Another important use of acetazolamide in the mountains is in the prevention of periodic breathing at high altitude which is a very common problem sometimes triggering anxiety attacks. Acetazolamide decreases the hypoxemic spells during sleep and successfully treats this problem in most instances.
In conclusion, sojourners ascending high altitude need to be encouraged to go up gradually without the use of drugs, including acetazolamide to enhance acclimatization. However, in certain instances, acetazolamide may indeed be required. By publishing these two articles, the journal has given due importance to this commonly used drug for AMS.