Editorials

Acetazolamide for the prophylaxis of acute mountain sickness

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7077 (Published 31 October 2012) Cite this as: BMJ 2012;345:e7077
  1. Chris Imray, professor and consultant vascular and renal transplant surgeon
  1. 1Warwick Medical School, University Hospital Coventry and Warwickshire, Coventry, CV2 2DX, UK
  1. christopher.imray{at}uhcw.nhs.uk

Time for a more personalised approach to dosage?

In 2000, a systematic review concluded that when ascending rapidly to above 4000 m, prophylactic dexamethasone 8-16 mg daily or acetazolamide 750 mg daily both reduced acute mountain sickness.1 However, acetazolamide 500 mg daily was not found be effective. At the time, many doctors who specialise in high altitude sickness thought that this did not reflect their clinical experience, and there were concerns about incomplete inclusion criteria, inadequate control of ascent rates, and unduly strict endpoints.2 3

In a linked systematic review and meta-analysis (doi:10.1136/bmj.e6779), Low and colleagues look at the important question of the efficacy of acetazolamide at lower doses to prevent acute mountain sickness above 3000 m.4 They found that acetazolamide 250 mg and 500 mg daily were both effective in reducing the severity of acute mountain sickness. The different altitudes studied (3000 v 4000 m) could have led to differences in the incidence and severity of acute mountain sickness and may partly account for the studies’ different conclusions.1 4

More people are travelling to high altitude for work (soldiers, miners, construction workers, and astronomers) or recreation (skiing, trekking, mountain biking, and mountaineering). On ascent to altitude, several adaptive physiological processes occur (including hyperventilation, erythropoiesis, and increased cardiac output), all of which tend to increase convective oxygen transport to the tissues, a process termed “acclimatisation.”5

Failure to acclimatise results in acute mountain sickness—a symptom complex consisting of headache and nausea, fatigue, dizziness, or difficulty sleeping. Symptoms appear six to 12 hours after arrival at altitude (usually >2500 m) and normally resolve within one to three days.5 The risk of acute mountain sickness depends on the person’s susceptibility, the rate of ascent, and the absolute altitude achieved (box). Surprisingly, physical fitness does not protect against its development, and ascending slowly and allowing time to acclimatise remains the best approach.5 People who travel above 3000 m should ascend at less than 300 m a day, with a rest day for every 1000 m climbed.6

Risk categorisation of acute mountain sickness and suggested prophylactic approaches6

Low risk
  • People with no history of altitude illness who are ascending to below 2800 m

  • Those taking more than two days to arrive at 2500-3000 m with subsequent increases in sleeping height of less than 500 m/day

  • Suggested approach: Gradual ascent should be adequate and prophylactic drugs are not usually necessary

Moderate risk
  • People with a history of altitude illness who are ascending to above 2500-2800 m in one day

  • Those with no history of acute mountain sickness but who are ascending to above 2800 m in one day

  • All people ascending more than 500 m/day (increase in sleeping height) at altitudes above 3000 m

  • Suggested approach: Gradual ascent, prophylactic acetazolamide (250-750 mg daily) should be considered. Lower doses are likely to be sufficient.

High risk
  • People with a history of acute mountain sickness who are ascending to above 2800 m in one day

  • All those with a history of high altitude pulmonary oedema or high altitude cerebral oedema

  • All those ascending to above 3500 m in one day

  • All those ascending by more than 500 m/day (increase in sleeping height) above 3500 m

  • Very rapid ascents (such as Mount Kilimanjaro)

  • Suggested approach: Prophylactic acetazolamide (250-750 mg daily) should be seriously considered. Consider higher doses

  • Altitudes are the height at which the person sleeps. Ideally the drug is started a day before exposure to high altitude.

  • Dexamethasone 8-16 mg daily remains an option in those in whom acetazolamide is not appropriate. Dexamethasone can be combined with acetazolamide if extreme ascent profiles are essential.

Improving oxygenation with the carbonic anhydrase inhibitor, acetazolamide, or attenuating the cytokine and inflammatory responses with the glucocorticoid, dexamethasone, are both effective prevention strategies.5 However, the potential side effects of glucocorticoids are generally thought to outweigh the benefits and these drugs are not normally used for prophylaxis. Exceptions are if acetazolamide is contraindicated or when a very rapid ascent rate is essential—for example, for unacclimatised rescue workers. The evidence supporting alternative approaches—such as ginkgo biloba, antioxidants,5 6 and hypoxic preconditioning—is less clear.7

Acetazolamide is a synthetic non-bacteriostatic sulfonamide, which causes a bicarbonate diuresis through the inhibition of renal carbonic anhydrase. The resulting metabolic acidosis stimulates ventilation. The drug is excreted unmetabolised in the urine. Although early studies showed that acetazolamide is efficacious in preventing acute mountain sickness,8 9 the optimal dosage is unclear.

Even though the efficacy of acetazolamide for the prevention of acute mountain sickness is more limited when the baseline risk is low, Low and colleagues’ study provides clinicians with evidence to support the use of a lower dose of acetazolamide in prevention.4 This is important because higher doses of acetazolamide may increase the risk of drug side effects. Various drug interactions have been described, but the most common ones are with high dose aspirin, cardiac glycosides, antihypertensive drugs, and lithium. The drug should be avoided in pregnancy, particularly during the first trimester, and should not be prescribed in the presence of hepatic or renal impairment.

Recognised dose dependent side effects of acetazolamide include paraesthesia, diuresis, and altered taste,10 and less commonly, headache and nausea.11 A recent meta-analysis assessed efficacy, harm, and dose responsiveness.12 The study found that the faster the ascent rate (14 m/h (when climbing) v 133 m/h (mechanised transport) v 4438 m/h (hypobaric chambers)), the greater the risk of acute mountain sickness, but also the greater the efficacy of acetazolamide. The risk of paraesthesia was the same for all doses, whereas the risk of polyuria and taste disturbance increased with 500 mg and 750 mg daily. Caution is needed in people with a known cross sensitivity to sulfonamides, and acetazolamide is contraindicated in those with a history of anaphylaxis with sulfonamides.

In conclusion, the risk of acute mountain sickness depends on the ascent rate, the absolute altitude attained, and the individual’s susceptibility. No single preventive strategy will work in every situation, so a personalised approach, which takes into account the cumulative risk factors, is recommended.6 People who have not had serious problems on previous ascent to moderate altitude (~2800 m) should ascend gradually. In higher risk people or more rapid ascent to higher altitudes (>2800 m) prophylactic acetazolamide should be considered. Importantly, doses as low as 250 mg a day can be effective when ascending to a height of above 3000 m.4 The exact dose prescribed should take into account individual risk and the acceptability of side effects.

Questions remain about the exact causes of acute mountain sickness, the mechanisms by which acetazolamide reduces symptoms, and whether even lower doses (125 mg daily) might be effective.

The final decision to use drugs to assist the acclimatisation process is one for the individual. Low and colleagues’ study gives doctors the evidence to prescribe at lower doses than previously suggested and provides preliminary evidence of dose responsiveness.

Notes

Cite this as: BMJ 2012;345:e7077

Footnotes

  • Research, doi:10.1136/bmj.e6779
  • Competing interests: The author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Commissioned; not externally peer reviewed.

References