Sir Edmund Hillary and Acute Mountain Sickness

Hillary and Tenzing

Editor - Sir Edmund Percival Hillary, the first human being to reach the summit of Mount Everest, died 3 years ago on January 11, 2008, at the age of 88.

At 11:30 am on May 29th, 1953, at the age of 33, Sir Hillary and Nepalese Sherpa mountaineer Tenzing Norgay reached Everest’s 29,028 ft (8,848 m) summit, the highest point on earth, carving their names into history.

Hillary and Tenzing were part of the ninth British expedition to Everest, led by John Hunt. Hillary was named by Time magazine as one of the 100 most influential people of the 20th century.

One of the most important challenges that Hillary and Tenzing faced 58 years ago and one that still poses a major challenge to climbers and hikers is that of altitude sickness. Acute mountain sickness (AMS) is a disorder of high altitude in humans caused by acute exposure to low partial pressure of oxygen at high altitude. It commonly occurs above 2,400 metres (8,000 feet).

Dr. David Leaf, a nephrology fellow in the combined Brigham and Women's/Massachusetts General Hospital Nephrology Program at Harvard Medical School published a fascinating article on acetazolamide and AMS that he discusses here. David trained at Columbia University Medical Center in New York City for his residency. His interests are in acute kidney injury and calcium phosphorus metablism.

Commentary - Dr. David Leaf

Probably one of the best research studies looking at the risk factors for acute mountain sickness was published this past October in the American Journal of respiratory and Critical Care Medicine (Richalet et al).

Richalet and colleagues from the University of Paris performed a prospective observational study of 1326 persons. Subjects went through a hypoxic exercise test before a sojourn above 4,000m. They were then followed up at high altitude and classified as suffering from severe high altitude illness (SHAI) or not. They report that severe acute mountain sickness occurred in 23.7%, high altitude pulmonary edema in 1.7% and high altitude cerebral edema in 0.98% patients. Among non acetazolamide users, main factors independently associated with SHAI were previous history of SHAI, ascent >400m/day, history of migraine, ventilatory response to hypoxia during exercise, and desaturation during exercise. Importantly, they report that acetazolamide reduced the relative risk of SHAI by 44%.

In our article in 2007 (Leaf and Goldfarb), we looked at the mechanism by which acetazolamide might prevent AMS. Acetazolamide, a potent carbonic anhydrase (CA) inhibitor, is the most commonly used  and best studied agent for the amelioration of acute mountain sickness (AMS). The actual mechanisms by which acetazolamide reduces symptoms of AMS, however, remain unclear. Traditionally, acetazolamide’s efficacy has been attributed to inhibition of CA in the kidneys, resulting in bicarbonaturia and metabolic acidosis. 

The result is offsetting hyperventilation-induced respiratory alkalosis and allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude.  Studies performed on both animals and humans, however, have shown that this explanation is unsatisfactory and that the efficacy of acetazolamide in the context of AMS is likely due to a multitude of effects.  The figure summarizes the effects of acetazolamide-induced CA inhibition in both renal and non-renal tissues and the mechanisms through which such inhibition ameliorates the symptoms of AMS.  

References

1. Richalet JP, Larmignat P, Poitrine E, Letournel M, Canouï-Poitrine F. Physiological Risk Factors of Severe High Altitude Illness: A Prospective Cohort Study. Am J Respir Crit Care Med. 2011 Oct 27.

2. Leaf DE and Goldfarb DS.  Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness.  J Appl Physiol 2007; 102: 1313-1322.