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Altitude sickness

Altitude sickness

In the first of two articles, Jeremy Windsor explains how and why altitude sickness can undermine even the fittest of high-altitude athletes

Trekkers, skiers, mountaineers and anyone else heading for high-altitude always have three questions uppermost in their minds:

* Will I get altitude sickness?

* What causes it?

* What can I do to reduce my risk of it?

In this, the first of two articles, I’ll attempt to answer these questions. In part 2, I will focus upon the current management of high-altitude sickness and the new treatment options beginning to appear on the horizon. Altitude sickness or ‘high-altitude illness’ as it is sometimes known, affects newcomers to altitude in three different ways:

* acute mountain sickness (AMS)

* high-altitude pulmonary oedema (HAPE)

* high-altitude cerebral oedema (HACE).


While AMS is usually a self-limiting condition often seen in large numbers of climbers, trekkers and winter sports enthusiasts who ascend to altitude, HAPE and HACE are rare conditions that can prove fatal if not diagnosed and treated urgently. The clinical signs and symptoms of each condition often overlap and tend to occur soon after arrival at a new altitude (see tables 1, 2 and 3).

High-altitude illness presents unpredictably, with youth, mountain knowledge and physical fitness offering little or no protection. In the spring of 2006, eight mountaineers aged between 30 and 54 died in separate incidents on the uppermost slopes of Mt Everest (8,850m). All were experienced: the Russian Igor Plyushkin (54) had earned the prestigious ‘Silver Leopard’ award for climbing the highest peaks in the former Soviet Union, while Thomas Weber (32) had previously climbed four of the seven highest peaks in the world. Nevertheless, the accounts of their final days showed that most had suffered from symptoms of AMS, HAPE or HACE before they died.

Although high-altitude illnesses are most likely at the extremes, they can also occur at much lower altitudes. This is well illustrated by a recent study undertaken in the Himalayas, showing that AMS first occurs at an altitude of around 3,000m and increases rapidly with gains in height (see table 4 overleaf). Although HAPE and HACE also increase with altitude, the incidence of these conditions is much smaller. In a landmark study undertaken at the Himalayan Rescue Association’s clinic in Pheriche, a village along the popular Everest Base Camp trek, Peter Hackett and his colleagues diagnosed AMS in 53%, HAPE in 1.5% and HACE in 1% of those ascending to heights of between 4,200 and 5,500m(3).

The cause of high-altitude illness has been known for more than a century. In 1878 the French physiologist Paul Bert published, La Pression Bariometrique, which provided the first evidence to link high-altitude illness with a fall in atmospheric pressure. On the summit of Mt Everest the atmospheric pressure is one-third of that found at sea level. As the concentration of oxygen is the same at both altitudes, the amount of oxygen present is also one third of its sea-level value. This, as Bert correctly identified, results in low concentrations of oxygen reaching the body’s tissues and provides the trigger for a chain of minute events that eventually result in AMS, HAPE and HACE.



Despite knowing what is behind all three conditions, scientists have had difficulty explaining individual differences. Why, for instance, do some suffer from high-altitude illness on a gentle hike to moderate altitude, while others, such as the mountaineer Ed Viesters, can climb Everest six times without supplemental oxygen? Over the last two decades, important epidemiological studies have allowed researchers to begin to predict, to some extent, those who are likely to suffer from high-altitude conditions, with the major risk factors being:

* rapid ascent

* long-term residence at an altitude below 900m

* exertion

* less than 60 years old

* history of high-altitude illness

*poor awareness of high-altitude illness.



Rapid ascent

As we have already seen, the final altitude reached by a climber clearly influences their chances of high-altitude illness. However the rate at which this altitude is reached is also important. The late high-altitude expert Herb Hultgren described, in his lectures, the experience of visitors to Merida in Venezuela. From the town centre (1,680m), a teleférico carries tourists to a lookout (4,760m) in 45 minutes. On arrival, most are so stricken with AMS that they ignore the curio shops and restaurants and descend immediately.

Although the trek from Lukla (2,900m) to Everest Base Camp (5,400m) takes considerably longer, the incidence of AMS remains high. However. those who choose to take six days rather than four to reach Base Camp are 26% less likely to develop AMS(2). This fits well with current advice that recommends an ascent of no more than 400m a day above 3,000m and a rest day every fourth day in order to improve acclimatisation and thereby minimise the risk of illness.

Living at low altitude

People normally resident at low altitude are at least three times more likely than those who live permanently above 900m to suffer from AMS following a rapid ascent to 3,000m (27% vs 8%). This difference can be reduced by a one-week stay at 1,600m and eliminated completely by spending more than two months at 1,800m before ascending to 3,000m(5). Clearly, by allowing the body time to adapt to any changes, it is possible to reduce the risk of high-altitude illnesses.


Traditionally new arrivals at high-altitude have been encouraged to rest. Herb Hultgren, on his regular visits to Chulec General Hospital in the Peruvian Andes (3,370m), would be shown to a room with a comfortable bed and told to avoid any physical activity for 24 hours. This advice has a scientific basis. In 2000, Robert Roach from the New Mexico Highlands University persuaded seven participants to undertake two hours of moderate exercise in a hypobaric chamber pressurised to an equivalent altitude of 4,572m(6). The next week the participants returned to the chamber and rested at the same altitude. The increase in the incidence and severity of AMS after exercise was considerably higher than after rest, suggesting that even moderate exercise can have a marked effect on high-altitude illness.

Less than 60 years old

Several studies have consistently shown that those aged over 60 suffer from less AMS than their younger colleagues. In a trip to moderate altitude by a group of elderly visitors (aged between 59 and 83, and a mean of 69.8 years), 16% suffered from AMS compared to 27% in a group with a mean age of 44(7). The reasons for this difference are unclear – older climbers may be ascending more slowly, avoiding exercise on arrival or simply refusing to acknowledge their symptoms. As more people head to altitude in the coming decades it may be possible to explain this phenomenon, but until then older adventurers should follow the same advice as everyone else.

History of high-altitude illness

An episode of high-altitude illness is a good predictor of further episodes. A study of 18 men working at the Mauna Kea infra red telescope in Hawaii, found that the same 13 suffered from AMS at the start of each five-day shift at the site(8). Although the risk of a further episode of AMS may be acceptable to most of us, those prone to HAPE and HACE should only ascend to altitude if medical treatment is available.

Poor awareness of AMS

A follow-up study published in 2004 demonstrated that trekkers travelling to Nepal had a much greater awareness of high-altitude illness compared to 12 years previously (95% vs 80%). This had resulted in slower ascents to altitude, better use of medications and a fall in the incidence of AMS from 45% to 29% above 4,000m(9).

How AMS works

To understand how low concentrations of oxygen damage the body, we have to start at the molecular level. Let’s assume that the accumulation of fluid (oedema) is the root of high-altitude illness. Although this remains somewhat controversial in the case of AMS, it certainly holds true for cases of HAPE and HACE. Normally fluids pass across through the lining of the blood vessels and into the tissues without causing any difficulties, because the balance between those fluids moving in and out is carefully regulated. However, at altitude this balance can be upset and lead to the accumulation of fluid in three different ways:

* excessive amounts of fluid being present in the blood vessels

* inadequate drainage of accumulated fluid through the veins and lymphatic tissue

* an increase in the permeability of the membranes separating the blood vessels from tissues.

Unfortunately for those trying to make some sense of how this process occurs at high-altitude, there are an enormous number of molecules that could be responsible. Described below are just five molecules which have been implicated in the formation of oedema at altitude: these represent some of the first steps taken in unravelling the process of high-altitude illness.

Nitric oxide (NO)

In recent years there has been a lot of focus on the role NO plays in the development of high-altitude illness. Despite its simplicity – NO contains just single atoms of nitrogen and oxygen – the molecule is crucial to an enormous number of physiological reactions, implicating it ‘in the pathogenesis of diseases ranging from hypertension to septic shock and dementia’(10). NO is released continuously from the endothelial lining of arteries and veins in order to alter the calibre of the vessel and provide tissues with the blood supply they require. When NO production is reduced, blood pressure rises and the cells lining the blood vessels risk damage. At high-altitude those susceptible to HAPE not only exhale lower concentrations of NO but also improve when NO is inhaled from pressurised cylinders(11). The production of NO in vessel walls is largely controlled by NO synthase 3. Recent studies have identified subtle variations (genetic polymorphisms) in the genetic material that is responsible for low levels of NO synthase 3 production in some individuals. Two of these genetic polymorphisms (4a and T894) have been found to occur repeatedly in those who suffer from HAPE(12). As further genetic polymorphisms are identified and their impact on HAPE becomes clearer, genetic testing may prove to be a useful screening tool that will allow those at risk of high-altitude illness to be identified prior to exposure. Similarly, modifying these genetic polymorphisms by gene therapy may, in the future, treat or prevent these cases.

Hypoxia inducible factor (HIF-1α)

As the concentration of oxygen received by the tissues falls, the cells in the body try to adapt. Within an hour of exposure, concentrations of the molecule HIF-1αpeak and trigger the release of an enormous number of different molecules. Some of these molecules are unhelpful, and two in particular have been implicated in high-altitude illness:

Vascular endothelium growth factor (VEGF):

On ascending to altitude, concentrations of VEGF increase. This results in widespread destruction of the endothelial lining of blood vessels and leakage of fluid. Although high concentrations of VEGF have not been associated with AMS or other high-altitude conditions, there is recent evidence to suggest that VEGF does have a role in the development of AMS. Work from the University of Colorado has focused upon the effect of a soluble VEGF receptor (sF/t-1) that is capable of inhibiting the effects of VEGF(13). After a rapid ascent to Pike’s Peak (4,300m), the team found that lower concentrations of the soluble VEGF receptor were present in those suffering from AMS. As concentrations of VEGF were similar in all those who were studied, these results suggest that those suffering from AMS had a greater proportion of ‘active’ VEGF.

Endothelin: Sitting alongside nitric oxide in the lining of blood vessels are large reservoirs of endothelin. Endothelin and a family of related compounds oppose and inhibit the actions of nitric oxide within minutes of high-altitude exposure. This is seen most dramatically in the pulmonary arteries that supply blood from the right side of the heart to the lungs. In 22 volunteers taken to an altitude of 4,559m in a pressure chamber, blood concentrations of endothelin were found to double and correlated closely with a rise in blood pressure in the pulmonary arteries(14). This, together with increases in fluid retention and blood-vessel permeability, makes endothelin an important factor in the formation of oedema. Recent work with the endothelin inhibitor bosentan has shown reductions in pulmonary artery pressure and increases in arterial oxygen saturation in those taking the drug before rapidly ascending to 4,559m(15). Despite these promising results, formal clinical trials are needed before this agent can be used in practice.

Angiotensin converting enzyme (ACE)

Angiotensin converting enzyme (ACE) is largely responsible for the production of angiotensin II. Like endothelin, angiotensin II is a potent constrictor of blood vessels, capable of elevating blood pressure and exerting considerable force on blood vessels. As healthy mountaineers climb to high-altitudes, levels of ACE and angiotensin II fall. But in those who fail to adapt at altitude the concentration of both molecules remains unchanged. In keeping with NO and other molecules, ACE production can be affected by a range of genetic polymorphisms. The most commonly studied ACE polymorphism in the high-altitude setting are ACE-1and ACE-D. The presence of ACE-1is associated with lower concentrations of circulating ACE and, in early studies, was found to be present in successful high-altitude mountaineers(16). This was supported in subsequent studies that demonstrated the presence of ACE-D and high concentrations of ACE in those susceptible to HAPE. Recent studies, though, have been unable to substantiate these earlier claims and the role of ACE genetic polymorphisms remains unclear(17).


While much is known about the incidence and risk factors of high-altitude illness, the process that leads to conditions such as AMS, HAPE and HACE has yet to be worked out. Until this progress is made, these conditions will continue to represent a significant danger to the growing numbers who head to the mountains for work and recreation. Next issue: the management of AMS and latest treatment options.


1. Bartsch, P, Roach, RC ‘Acute mountain sickness and high-altitude cerebral oedema’. In: high-altitude – An Exploration of Human Adaptation. Eds: Hornbein TF and Schoene RB. 2001 Marcel Decker, New York. pp731-76.

2. Hultgren, H, high-altitude Medicine. 2001 Hultgren Publications, Stamford, USA. p263 and p327.

3. Hackett, PH, et al. ‘The incidence, importance and prophylaxis of acute mountain sickness’. 1976 Lancet Nov 27;2(7996):1149-55.

4.Vardy, J, et al. ‘Acute mountain sickness and ascent rates in trekkers above 2500m in the Nepali Himalaya’. 2006 Aviat. Space Environ. Med. Jul;77(7):742-4.

5.Purkayastha, SS, et al. ‘Acclimatization at high-altitude in gradual and acute induction’. 1995 J. Appl. Physiol. 79:487-92.

6.Roach, RC, et al. ‘Exercise exacerbates acute mountain sickness at simulated high-altitude’. 2000 J Appl Physiol.Feb;88(2):581-5.

7.Roach, RC, et al. ‘How well do older persons tolerate moderate altitudes?’ 1995 West. J Med. 162:32-6.

8.Forster, P ‘Reproducibility of individual response to exposure to high-altitude’. 1984 BMJ Nov 10;289:1269.

9.Gaillard, S, et al. ‘Awareness, prevalence, medication use, and risk factors of acute mountain sickness in tourists trekking around the Annapurna in Nepal: A 12 year follow-up’. 2004 High Alt. Med. Biol. Winter;5(4):410-9.

10.Vallance, P, Collier, J ’Fortnightly review: biology and clinical relevance of nitric oxide’. 1994 BMJ Aug 13;309:453-7.

11. Busch, T, et al. ‘Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary oedema’. 2001 Am J Respir. Crit. Care Med. 163:368-73.

12.Rupert, JL, Koehle, MS ‘Evidence for a genetic basis for altitude related illness’. 2006 High Alt. Med. Biol. 7:150-67.

13.Tissot van Patot, MC, et al. ‘Greater free plasma VEGF and lower soluble VEGF receptor- 1 in acute mountain sickness’. 2005 J Appl Physiol. May;98(5):1626-9.

14.Goerre, S, et al. ‘Endothelin-1 in pulmonary hypertension associated with high-altitude exposure’. 1995 Circulation91:359-64.

15.Modesti, PA et al. ‘Role of endothelin-1 in exposure to high-altitude’. 2006 Circulation 114:1410-6.

16. Montgomery, HE et al. ‘Human gene for physical performance’. 1997Nature393:221-2.

17. Woods, DR, et al. ‘The ACE I/D polymorphism and human physical performance’. 2000 Trends Endocrinol. Metab.11:416-20.

Altitude sickness