From The Archives: Does Acetazolamide Prevent Altitude Sickness?

March 31, 2011

Please enjoy this post from the Clinical Correlations archives first posted May 7, 2009

Seema Pursnani, MD

Because your parents have designated you as the family doctor, your Uncle Joe calls to ask you if he should take this medication called Diamox before going trekking in the Himalayas. You work at Bellevue in New York City: who climbs mountains here? What do you say?

Why do illnesses develop from changes in altitude?

The essential culprit is the fall in atmospheric pressure with an increase in altitude. While at sea level, barometric pressure (Pb) is ~760mm Hg (1atm), whereas at the summit of Mount Everest (~8800 meters high), this pressure drops to ~250mm Hg. The fraction of inspired oxygen remains constant (21% of air is made of oxygen molecules), so the net result is a decrease in the pressure of inspired oxygen. Remember that the pressure of oxygen in our alveoli is determined by the alveolar gas equation: PAO2 = ( FiO2 * (Pb – 47)) – (PaCO2 / 0.8). For example, the pressure of oxygen at sea level is roughly 100mm Hg, whereas at Mount Everest, this pressure would be <50 mm Hg.

How do our bodies respond to this lack of oxygen?

Normal responses to hypoxemia acutely include hypoxic pulmonary vasoconstriction to shunt blood away from poorly oxygenated areas, and vasodilation in other organs, namely in the brain, to improve delivery of oxygen. The body compensates with an increase in minute ventilation. In cases of altitude related illness it is not well understood what goes wrong but, essentially, these normal adaptations are inadequate or maladaptive.

The term mountain sickness includes a spectrum of illnesses, namely the following entities: acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high altitude pulmonary edema (HAPE). AMS is a clinical syndrome that occurs in someone who has ascended >2500 meters. Clinical features are the presence of a headache AND at least one of the following: GI symptoms, insomnia, fatigue, or dizziness. HACE is considered an end-stage form of AMS; ataxia and change in mental status are the key features of this syndrome. HAPE is a type of noncardiogenic pulmonary edema that results from acute pulmonary hypertension and manifests with typical symptoms of pulmonary edema-dyspnea, cough, decreased exercise tolerance, etc.

Treatment of all forms of mountain sickness includes immediate descent and oxygen supplementation. Vasodilators (calcium channel blockers, phosphodiesterase 5 inhibitors) and long acting beta agonists have been studied in the prevention of HAPE. In addition, steroids, diuretics, and vasodilators have also been studied for the treatment of HACE and HAPE. Treatment and prevention of AMS includes primarily the use of acetazolamide (diamox).

Slow ascent to allow acclimatization is the key to preventing AMS; avoiding a direct ascent of 2750 meters is considered a standard recommendation. Acetazolamide is a carbonic anhydrase inhibitor and works by stimulating renal bicarbonate excretion. The increased blood acidity serves as a central stimulus to increase ventilation, thus facilitating adaptation to hypoxic conditions.

Show me the data! Here are a few trials:

Basnyat et al, looked at the efficacy of low-dose acetazolamide for the prophylaxis of AMS.1 In this prospective, double-blind, randomized, placebo-controlled trial, acetazolamide at 125mg bid or placebo was given to approximately 200 healthy trekkers to Mount Everest. In the treatment group, only 9 out of 74 (12.2%) developed AMS versus 20 out of 81 (24.7%) in the placebo group; the number needed to treat (NNT) in this trial was 8. Another randomized, double-blind, placebo-controlled trial, compared ginkgo biloba and acetazolamide for the prevention of acute mountain sickness among Himalayan trekkers.2 In this trial, acetazolamide 250 mg bid, gingko biloba, both, or placebo were given to more than 600 western trekkers to Mount Everest. In the acetazolamide group, 12% developed AMS versus 14%, 34%, and 35% for combined group, placebo, and gingko groups, respectively. The NNT in this trial was only about 4.

So regarding our family member, unless Uncle Joe is allergic to sulfonamides, I would recommend acetazolamide at the 250 mg twice-daily dose. Other contraindications to taking acetazolamide include hepatic disease, hyponatremia or hypokalemia; adrenocortical insufficiency, hyperchloremic acidosis, severe renal dysfunction, and severe pulmonary obstruction. Addressing any underlying cardiac, pulmonary function prior to climbing to such a great height would be of utmost importance. In addition, if Uncle Joe is diabetic, acetazolamide should be used with caution as it can cause a change in glucose control. Assuming Uncle Joe has none of the above medical conditions to cause concern in recommending acetazolamide, he should begin taking it 24-48 hours before ascending and continue it for at least 48 hours after arrival at his high altitude.

Dr. Pursnani is a third year resident in internal medicine at NYU Medical Center.

References
1. Basnyat B et al. 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(1): 45-52.

2. Gertsch JH 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(7443):797. Epub 2004 Mar 11.

Faculty peer reviewed and commentary by Nishay Chitkara MD, Instructor of Clinical Medicine, Division of Pulmonary and Critical Care Medicine:

The hypoxic ventilatory response (HVR) is an increase in alveolar ventilation initiated by the carotid body upon ascent. When one remains at the same altitude, this peripheral chemosensor increases its sensitivity to hypoxemia, and an even greater increase in ventilation ensues. The result is a rise in arterial oxygen content and a respiratory alkalosis which is only partially compensated by kidneys. Acetazolamide effectively mimics this normal acclimatization response, by inducing a respiratory acidosis (impaired cellular delivery of CO2 to the lungs) and a metabolic acidosis (enhanced renal bicarbonate excretion), thus stimulating alveolar ventilation. It also prevents two commonly encountered phenomena in acclimatizing individuals: periodic breathing and accentuated hypoxemia during sleep.

The mechanisms of disease for both HACE and HAPE have undergone much investigation. The HVR protects against hypoxia-induced stresses which lie at the root of their development. Much evidence supports the formation of HACE as a consequence of vasogenic edema and hypoxia-induced increased permeability of the endothelium. In HAPE, exaggerated pulmonary vascular responses to hypoxia can lead to high intravascular pressures and stress injury of the pulmonary microvasculature. Acetazolamide can be effective in the prevention of HAPE, by reducing pulmonary vascular resistance. It does not however substitute for more established HAPE treatments such as calcium channel blockers, PDE-5 inhibitors, glucocorticoids, or beta-agonists.

You may want to warn your Uncle Joe about carbonated beverages during his trek to the Himalayas – acetazolamide tends to make them distasteful!

References
1. Schoene, Robert B. Illness at High Altitude. Chest. 2008; 134:402-416.

One Response to From The Archives: Does Acetazolamide Prevent Altitude Sickness?

  1. Warwick Selby on September 30, 2011 at 4:33 pm

    This is very helpful information. I am a physician going trekking and it helps me understand the physiology of what is going to happen when I trek in a couple of weeks. And has definitely swung me towards taking acetazolamide. And I certainly agree about the carbonated drinks. I have taken a test dose and beer is terrible. Why does that happen? I presume it is related to the CO2 in the drinks. But it is a good way to avoid alcohol on the trek.

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