Acute mountain sickness (AMS) is a constellation of symptoms including headache, sleep disturbance, fatigue, dizziness, and nausea, vomiting, or anorexia that commonly occurs in travelers ascending to altitudes above 2,500m. AMS incidence varies based on altitude and ascent profile with rates reported from 25 to 75% in tourists, trekkers, and mountaineers at North American altitudes. Symptom onset is typically six to twelve hours after arrival at high altitude. This self-limited disease can be debilitating when severe, and left unrecognized or untreated may progress to potentially fatal high altitude cerebral edema (HACE). While gradual ascent has proven effective in preventing AMS, this approach is often impractical to recreationists, search and rescue, disaster relief, and military operations.
Acetazolamide increases minute ventilation by 10-20% in subjects at altitude, and hastens acclimatization. It is well established that acetazolamide's main site of action is in the kidney, where it generates a metabolic acidosis through renal bicarbonate wasting and attenuates the effects of hypoxemic-induced respiratory alkalosis. Recommended dosing of acetazolamide for AMS prophylaxis has significantly decreased since early days of use in the 1960s. The current recommended dose of acetazolamide for this indication is 125 mg twice daily, as opposed to historical recommendations of 500mg or 750mg daily. Multiple meta-analyses have concluded that when compared with higher doses, 250mg of acetazolamide daily has been shown to be equally efficacious, with the added benefit of decreasing side effects including paresthesias and dysgeusia. A randomized controlled trial confirmed effectiveness of acetazolamide 125mg twice daily in prevention of AMS when started prior to ascent. In this study, it was found that 125mg twice daily corresponded to a range of 3-5mg/kg/day, depending on subject weight. Within this range, those on the lower dosing range did not have a greater incidence or severity of AMS. For subjects weighing between 50kg (110 lbs) - 83kg (183 lbs), a dose of 250mg/day acetazolamide would fall in this range. Interestingly, mountaineers and trekkers have anecdotally reported protection against AMS with 125mg/day of acetazolamide, a dose below 3-5mg/kg for anyone over 41kg (91lb).
Finding the lowest effective dose of acetazolamide for AMS prophylaxis is important because side effects of this medication can mimic AMS, decreasing the specificity of disease scoring on the validated Lake Louise Questionnaire (LLQ) and subsequent AMS diagnosis and chemoprophylactic effectiveness.Keeping in mind that LLQ is scored based on symptoms of headache, gastrointestinal symptoms, fatigue and weakness, and dizziness and lightheadedness, whatever effect acetazolamide has on AMS prevention may be obscured by its side effects that mimic the very same disease. Falsely positive LLQ scores in trekkers and mountaineers taking acetazolamide prophylaxis may lead to unnecessary pharmacologic treatment or even evacuation. From the perspective of high altitude research, participants randomized to or already taking acetazolamide may skew study results by decreasing LLQ specificity and potentially leading researchers to overestimate incidence of AMS.
