Classical Greece and Rome

It is perhaps surprising that there are so few references to the ill effects of high altitude in the extensive writings of classical Greece and Rome. The Greek epics and myths, in particular, are so rich in the accounts of travelers and the foibles of human nature that one might expect there to be a reference to the deleterious effects of high altitude, but this is generally not the case. However, 17th-century writers believed that the ancient Greeks were aware of the thinness of the air at high altitude. For example, Robert Boyle (1627–91) claimed that Aristotle (384–322 BC) held this view when he wrote:

However, modern historians have not been able to find this statement in Aristotle’s extensive writings. Similar attributions to Aristotle can be found in the writings of Francis Bacon (1561–1626) and St. Augustine of Hippo (AD 354–430). See West (1998) for additional information.

Chinese Headache Mountains

There is a tantalizing reference to what may have been acute mountain sickness (AMS) in the classical Chinese history, the Ch’ien Han Shu, which dates from about 30 BC. One of the Chinese officials warned about the dangers of traveling to the Western regions, probably part of present day Afghanistan, when he stated that travelers would not only be exposed to attacks from robbers but they would also become ill. One of the translations reads:

Several people have tried to identify the site of the Headache Mountains, suggesting for instance that it is the Kilik Pass (4827 m) in the Karakoram Range on the route from Kashgar to Gilgit (Gilbert 1983). However, there is not universal agreement on this.

Possible early reference to high altitude pulmonary edema

Fâ-Hien was a Chinese Buddhist monk who made a remarkable journey through China and adjoining countries in about AD 400. He related that when crossing the “Little Snowy Mountains” (probably in Afghanistan) his companion became ill, “a white froth came from his mouth,” and he died. It is tempting to identify this as the first description of high altitude pulmonary edema.

Joseph de Acosta’s description of mountain sickness

Joseph de Acosta (1540–1600) was a Jesuit priest who traveled to Peru in about 1570. While he was there, he ascended the Andes and gave a very colorful account of illness associated with high altitude. This was first published in 1590 in Spanish (Acosta 1590) (Figure 1.1), and a new English translation entitled Natural and Moral History of the Indies appeared in 2002 (Acosta 2002). The following is from his account when the party crossed the Pariacaca mountain range:

Acosta’s book was widely read such that, for example, Robert Boyle was familiar with his description of mountain sickness. Various people including Gilbert (1991) have attempted to identify the site of Pariacaca but there is some disagreement over this.

Invention of the barometer

A key advance in high altitude science was the recognition that barometric pressure falls with increasing altitude. In 1644, Evangelista Torricelli (1608–47) wrote a letter to his friend Michelangelo Ricci in which he described how he had filled a glass tube with mercury and inverted it so that one end was immersed in a dish of the same liquid (Torricelli et al. 1644) (Figure 1.2). The mercury descended to form a column about 76-cm high, and Torricelli argued that the mercury was supported by the weight of the atmosphere acting on the dish. His letter included the striking sentence: “We live submerged at the bottom of an ocean of the element air, which by unquestioned experiments is known to have weight….” This was a conceptual breakthrough. Torricelli also speculated that on the tops of high mountains the pressure might be less because the air is “distinctly rare.”

However, it was left to Blaise Pascal (1623–62) to prove that barometric pressure falls with increasing altitude. In 1648, he persuaded his brother-in-law, Florin Perier, to carry a mercury barometer up the Puy-de-Dôme in central France. This was an elaborate experiment with careful controls and he was successful in showing that on the summit the pressure had fallen by approximately 12% of its value in the village of Clermont.

Invention of the air pump

The first effective air pump was constructed by Otto von Guericke (1602–86), who was mayor of the city of Magdeburg in central Germany. In a famous experiment, he constructed two metal hemispheres which fitted together accurately when the air within them was pumped out. Two teams of horses were then unable to separate the two hemispheres, graphically demonstrating the enormous force that could be developed by the air pressure.

However, Guericke’s pump was cumbersome to operate and it was impossible to place objects in the hemispheres to study the effects of the reduced air pressure. This was first done by Robert Boyle (1627–91) and his colleague Robert Hooke (1635–1703). Hooke was a mechanical genius who designed an air pump consisting of a piston inside a brass cylinder. Above this was a large glass receiver into which various objects and small animals could be placed (Figure 1.3). In his groundbreaking book, New Experiments Physico-Mechanicall, Touching the Spring of the Air, and Its Effects (Boyle 1660), he demonstrated the effects of a reduced atmospheric pressure in a variety of experiments. In one of these a lark was placed in the receiver and Boyle wrote:

Following these experiments Hooke made a chamber large enough for a man to sit in it while it was partially evacuated and he reported to the young Royal Society:

Discovery of oxygen

Progress in the remainder of the 17th century and most of the 18th century was largely stymied until the nature of the respiratory gases was characterized. There is not space here to follow the interesting story of the work of Boyle, Hooke, Lower, and Mayow in the 17th century and the discovery of oxygen by Joseph Priestley (1733–1804), Carl Scheele (1742–86), and Antoine Lavoisier (1743–94). For more information see the excellent review by Severinghaus (2016). John Mayow (1641–79) was aware in 1674 of what he called “nitro-aerial spirit,” which we now recognize as oxygen, but his work was largely ignored for almost a century. Both Priestley and Scheele independently isolated oxygen but Priestley was confused about its nature, believing that it was “unphlogisticated air,” and Scheele’s report was delayed because of publication problems. It was left to the brilliant French chemist Lavoisier (Figure 1.4) to clearly describe the three respiratory gases. In 1777, he stated:

Carbon dioxide had been discovered earlier by Joseph Black (1728–99) while he was a medical student, although he used the term “fixed air.”

First balloon ascents and the recognition of severe acute hypoxia

The Montgolfier brothers, Joseph (1740–1810) and Jacques (1745–99), invented the man-carrying balloon, first using heated air, and later hydrogen. The first free ascent of a manned balloon took place in Paris in 1783. It was not long before these adventurous balloonists became aware of the deleterious effects of high altitude on the body. For example, Alexandre Charles (1746–1823) (of Charles’ law) ascended in a hydrogen-filled balloon in December 1783 and reported, “In the midst of the inexpressible rapture of this contemplative ecstasy, I was recalled to myself by a very extraordinary pain in the interior of my right ear….” He correctly attributed this to the effects of air pressure.

However, more ominous effects were soon noted. Jean Blanchard (1753–1809) claimed to have ascended to an altitude of over 10,000 m in 1785 (although the altitude was contested) and reported that “Nature grew languid, I felt a numbness, prelude of a dangerous sleep….” However, much more dramatic were the events in 1862 when James Glaisher (1809–1903) and Henry Coxwell (1819–1900) rose to an altitude which was estimated to exceed 10,000 m. Glaisher became partly paralyzed and then unconscious, and Coxwell lost the use of his hands, and could only open the valve of the balloon by seizing the cord with his teeth. Glaisher also reported losing his sight before his partial paralysis.

The most famous and tragic balloon ascent was by three French aeronauts, Gaston Tissandier (1843–99), Joseph Crocé-Spinelli (1843–75), and Theodore Sivel (1834–75), in their balloon Zénith in 1875. Paul Bert recommended that they take oxygen but they had too little and there were difficulties in inhaling it. Tissandier’s report (1875) is dramatic (De Oliveira 2019).

When the balloon ultimately reached the ground, Sivel and Crocé-Spinelli were dead, having perished as a result of the severe hypoxia. The disaster caused a sensation in France.

Mountain sickness in mountaineers

During the 19th century, mountaineering became popular particularly in the European Alps. The result was many descriptions of AMS, some of which seem to us today to be greatly exaggerated. One of the first was from the great German naturalist Alexander von Humboldt (1769–1859) when he reached very high altitudes on two volcanoes in South America in 1799. On Chimborazo, at an altitude of about 5540 m, he stated that the whole party felt “a discomfort, a weakness, a desire to vomit, which certainly arises as much from the lack of oxygen in these regions as from the rarity of the air.” Another early account was by Horace-Bénédict de Saussure (1740–99) on Mont Blanc (4807 m) in 1787. When he was near the summit he stated:

Numerous other reports of the deleterious effects of high altitude while climbing mountains are given in the first chapter of Paul Bert’s book, La Pression Barométrique (Bert 1878), which is discussed in the following section.

Paul Bert and the publication of La Pression Barométrique

The French environmental physiologist Paul Bert (1833–86) is often cited as the father of modern high altitude physiology and medicine. The publication of his great book, La Pression Barométrique, in 1878 was certainly an important landmark. One of his principal findings was that the deleterious effects of exposure to low pressure could be attributed to the low PO₂. He did this by exposing experimental animals to a low pressure of air on the one hand (hypobaric hypoxia), and to gas mixtures at normal pressure but with a low oxygen concentration (normobaric hypoxia) on the other. In this way, he showed that the critical variable was the PO₂. La Pression Barométrique is essential reading for anybody with a serious interest in the history of high altitude medicine and physiology. For one thing, there is a long introductory section on the history as Bert saw it, and this makes fascinating reading today. Bert wrote with a charming style and urbane wit. The book not only deals with the medical and physiological effects of low pressure but high pressure as well.

Many of Bert’s studies were carried out at the Sorbonne in Paris, which was equipped with both low-pressure and high-pressure chambers (Figure 1.5). At one stage, he tested the three French balloonists Tissandier, Crocé-Spinelli, and Sivel who were referred to above and he actually warned them that they had insufficient oxygen but the warning letter arrived too late.

La Pression Barométrique includes many interesting passages. For example, it contains the first graphs of the oxygen and carbon dioxide dissociation curves in blood. Bert also speculated that polycythemia might occur at high altitude and this was shown a short time later by compatriots, including Viault (Viault 1890). Bert speculated on the possible reduction of metabolism in frequent visitors to high altitude and people who live permanently there. This short section will be cited partly because it gives a good feel for the style of Bert.

Two new, permanent high altitude laboratories

Observatoire Vallot

Toward the end of the 19th century, the pace of discoveries in high altitude medicine and physiology accelerated rapidly, partly as the result of the publication of La Pression Barométrique and partly due to the establishment of two high altitude laboratories. The first was the Observatoire Vallot on Mont Blanc, which was installed in 1890. Joseph Vallot (1854–1925) conceived the idea of placing a small building at an altitude of about 4350 m, which is about 460 m below the summit of Mont Blanc. With typical French panache, he was not satisfied with a simple hut, but in addition there were a comprehensive laboratory, a well-appointed kitchen, and attractive interior decorations including a French tapestry of courtly ladies in the 18th-century style. The laboratory was used for research in several of the physical sciences, including astronomy and glaciology, but physiological studies were also carried out including some of the first observations of periodic breathing at high altitude (Egli 1893). In 1891, a young physician, Dr. Jacottet, died in the Observatoire Vallot from what was almost certainly high altitude pulmonary edema (Simons and Oelz 2000). A description of the illness, including the postmortem findings, is in Mosso’s book, Life of Man on the High Alps (Mosso 1898), which is referred to in the next section. A description of more recent work at the Observatoire Vallot is provided later in this chapter, while an image of the modernized hut is shown in Figure 1.6.

Capanna Margherita

Shortly after the construction of the Observatoire Vallot, an even higher structure was placed on the Punta Gnifetti of the Monte Rosa massif on the Swiss-Italian border at an altitude of 4559 m. The original hut was completed in 1893 and 10 years later it was enlarged by the influential Italian scientist Angelo Mosso (1846–1910) to include a laboratory for physiological and medical studies. The structure owes its name to Queen Margherita of Savoy who was a lover of alpinism and a generous patron of science. In fact, she visited the Capanna in 1893 and spent the night there.

Mosso was a physiologist with very broad interests, particularly in the area of exercise and environmental physiology. Some of the early studies in the Capanna Margherita were reported in his book, Fisiologia dell’uomo sulle Alpi: Studii fatti sul Monte Rosa (Mosso 1897), and this was translated into English as Life of Man on the High Alps (Mosso 1898). Among the projects carried out at the Capanna were some on periodic breathing, and also total ventilation at high altitude. In fact, Mosso believed that the deleterious effects of high altitude were related to the low PCO₂ in the blood rather than the reduced PO₂ as previously proposed by Paul Bert. Mosso coined the term “acapnia” to describe this condition, which he thought was important in the development of AMS. An interesting event at the Capanna was the illness of an Italian soldier, Pietro Ramella, who developed what was thought to be a respiratory infection and from which he recovered. In retrospect, this may have been high altitude pulmonary edema, as was the case with Dr. Jacottet at the Observatoire Vallot. Work continues today at Capanna Margherita (Figure 1.7) and is described further below.

Tenerife expedition

One of the first research expeditions was organized by Nathan Zuntz (1847–1920), who was the first author of an influential book on high altitude physiology published in 1906 (Zuntz et al. 1906). The expedition was to Tenerife in the Canary Islands and experiments were carried out at the Alta Vista hut at an altitude of 3350 m. Among the members of the expedition were Joseph Barcroft (1872–1947) and C.G. Douglas (1882–1963) and they made an interesting observation on the alveolar gases and acclimatization. Barcroft was the only member of the party who showed no significant fall in alveolar PCO₂ at the Alta Vista hut; that is, he was the only person who did not exhibit an increase in ventilation, and he was also the only person who was incapacitated by AMS. By contrast, the alveolar PCO₂ of Douglas fell from 41 to 32 mmHg, and that of Zuntz fell from 35 to 27 mmHg and both of these members had no mountain sickness. This was corroborative evidence that mountain sickness was caused by the low PO₂ as suggested by Paul Bert, rather than the low PCO₂ as proposed by Angelo Mosso.

Anglo-American expedition to Pikes Peak

A very important expedition took place in 1911 when an Anglo-American group led by J.S. Haldane (1860–1936) went to Pikes Peak just outside Colorado Springs, where there was a hotel on the summit at an altitude of 4300 m (Figure 1.8). One of the advantages of Pikes Peak was a cog railway and road all the way to the summit. The 1911 expedition was carefully planned so that there were measurements at a lower altitude prior to the ascent. Then, a rapid ascent was made and the party stayed on the summit where extensive data were collected. Finally, measurements were made again when the participants returned to low altitude. Many important observations were made. The hyperventilation that accompanies ascent to high altitude was documented with the alveolar PCO₂ falling to about two-thirds of its sea level value over two weeks on the summit. Periodic breathing was confirmed. Polycythemia was studied with the percentage of hemoglobin in the blood increasing over several weeks on the summit to values between 115% and 154% of normal as measured by color changes in the blood. All the measurements were reported in a long paper by Douglas et al. (1913).

The members of the expedition also believed that they had obtained evidence for oxygen secretion at high altitude. In fact, the report stated that the arterial PO₂ at rest was as much as 35 mmHg above the alveolar value on the summit, whereas at or near sea level the two values were the same. The investigators proposed that oxygen secretion was the most important factor in acclimatization. To this day, it is not clear where this large error was made in the measurements.

Oxygen secretion was an important controversy around this time and Haldane actually believed in it until his death in 1936. In fact, the second edition of his book on respiration has a whole chapter devoted to the evidence for oxygen secretion (Haldane 1935). Haldane had originally developed the notion after visiting Christian Bohr (1855–1911) in Copenhagen who was a great champion of oxygen secretion. However, the error was exposed in the view of most physiologists by August Krogh (1874–1949) and his wife Marie (1874–1943) in a series of papers published in 1910 (Krogh 1910a; 1910b; 1910c; 1910d; 1910e; Krogh and Krogh 1910a; 1910b).

Mabel FitzGerald’s field work in Colorado

Mabel FitzGerald (1872–1973) was invited to join the Pikes Peak expedition, but did not spend any time in the laboratory for reasons that are not entirely clear. Instead, she visited various mining camps in Colorado at altitudes between 1500 and 4300 m, where she measured the alveolar PCO₂ in acclimatized miners and produced data on acclimatization to moderate altitudes that are still cited (Fitzgerald and Haldane 1905; Fitzgerald and Haldane 1913). Although she studied at Oxford University for a number of years, it was not the custom then to give degrees to women. However, the university relented in 1972 when she was 100 years old and awarded her an honorary MA degree.

International high altitude expedition to Cerro de Pasco, Peru

Another classical expedition to high altitude was the International High Altitude Expedition to Cerro de Pasco, Peru, which took place in 1921–22, led by Joseph Barcroft (1872–1947). An attractive feature of this location at an altitude of about 4330 m was that it could be reached by railway from Lima, and the expedition fitted out a railway baggage van as an efficient laboratory (Figure 1.9). Again, there was a very extensive scientific program (Barcroft et al. 1923). The topic of oxygen secretion was investigated but no support for it was found. In fact, the PO₂ in arterial blood measured by a bubble equilibration method was about 3 mmHg lower than that in alveolar gas. There was an increase in red blood cell concentration by about 20–30% over the sea-level value. The arterial oxygen saturation fell during exercise at high altitude and this fall was correctly attributed to the failure of the PO₂ to equilibrate between alveolar gas and pulmonary capillary blood because of diffusion limitation. Extensive measurements of neuropsychological function showed that this was impaired at high altitude. In fact, Barcroft made the infamous statement “All dwellers at high altitude are persons of impaired physical and mental powers.”

One of the novel features of this expedition was its studies of permanent residents of high altitude. Cerro de Pasco was a substantial mining town with a large permanent population. It was shown that the red cell concentrations in the permanent residents had values of 40–50% above what would be expected at sea level, that is substantially higher than the newcomers to high altitude. It was also found that the permanent residents of Cerro de Pasco tended to have lower arterial oxygen saturations of 80–85%, one of the first intimations that highlanders have lower ventilation than newcomers to high altitude.

International high altitude expedition to Chile

In 1935, the International High Altitude Expedition to Chile took place, led by D.B. Dill (1891–1986). Many measurements were made at a mining camp, altitude 5334 m, and these resulted in a classical paper entitled “Blood as a physicochemical system. XII. Man at high altitudes” (Dill et al. 1937). Extensive measurements of exercise were carried out showing, for example, that in one of the members the maximal oxygen consumption fell from 3.72 to 1.80 L min⁻¹ at the altitude of the high camp (compared with sea level), while the maximal heart rate fell from 190 to 132 beats min⁻¹. A particularly interesting finding was that in well-acclimatized subjects the maximal levels of blood lactate were remarkably low, certainly much lower than in acute hypoxia or in subjects without acclimatization (Edwards 1936). This so-called “lactate paradox” has been observed on many occasions since and is still not fully understood. Indeed, some scientists disagree that the “lactate paradox” even exists and, as described in the section “Copenhagen Muscle Research Center High Altitude Expeditions,” research continues on this issue to this day.

Operation Everest I

After decades of important field studies, by the 1940s it was time to bring the mountain to the laboratory. In 1944, renowned mountaineer and physician Charles Houston (1913–2009) and his Navy colleague Richard Riley (1911–2001) carried out a remarkable study known as Operation Everest I at the US Naval School of Aviation Medicine in Pensacola, Florida. Four volunteers lived continuously in a low-pressure chamber for 35 days and were gradually decompressed to the equivalent of the altitude of Mount Everest. The project was justified to the Navy on the grounds that it was relevant to improving the tolerance of aviators to high altitudes. Alveolar gas and arterial blood studies were carried out and the most striking finding was that it was possible for resting, partly acclimatized subjects to survive without supplemental oxygen for 20 minutes or so at a simulated altitude that actually exceeded the summit of Mount Everest (Houston et al. 1987). This came about because they were using the Standard Atmosphere, which predicts a substantially lower pressure on the summit than actually exists.

Human’s quest to climb Mount Everest: Scientific underpinnings

A major high-altitude physiologist at this time was L.C.G.E. Pugh (1909–94), who was a participant in the first expedition to make a successful ascent of Mount Everest in 1953. During 1952, Pugh and others conducted physiological studies on the nearby mountain Cho Oyu to clarify some of the logistics of tolerating extreme altitude, including ventilation rates, maximal oxygen consumptions, effects of oxygen breathing, hydration, food, and clothing. A recent biography of Pugh provides background and insight into many of these important studies (Tuckey 2013). Pugh’s contributions were a major factor in the ultimate success of the expedition when Edmund Hillary and Tenzing Norgay became the first people to reach the highest point in the world.

1960s

Silver Hut Expedition

The Himalayan Scientific and Mountaineering Expedition of 1960–61, led by Griffith Pugh, was the first party to winter high in the Himalayas, with the team spending eight and a half months at over at an altitude of >5800 m in a wooden structure painted silver (Figure 1.10). Even 60 years later, the physiological studies remain relevant and oft-quoted. The physiological program consisted mainly in a detailed investigation of the oxygen transport system (West et al. 1962), with studies of the blood (Gill and Pugh 1964) and respiratory gases (Gill et al. 1962), lung diffusion (West 1962), and cardiac output (Pugh 1964b), as well as oxygen intake and ventilation during bicycle ergometer exercise (Pugh et al. 1964). Blood-volume and respiratory regulation were also investigated (Michel and Milledge 1963; Pugh 1964a).

1970s

1980–90s

High altitude chambers

In the late 20th century, many laboratories installed “hypoxic rooms” allowing easy and relatively inexpensive study of subjects and patients with varying degrees of low inspired oxygen. After it became apparent that there are significant differences between the physiologic responses seen with normobaric hypoxic chambers and those seen with exposure to simulated or terrestrial hypobaric hypoxia, there has been a resurgence of interest in hypobaric exposure since the beginning of the 21st century. Large new facilities in Europe (TerraXcube in Bolzano, Italy, and Envihab near Cologne, Germany) and existing facilities in the United States (Colorado Altitude Research Center in Denver, Institute for Exercise and Environmental Medicine in Dallas, and the Natick Lab chambers near Boston) are sites of significant work.

Caudwell Xtreme Everest Expedition

In 2007, the Caudwell Xtreme Everest Expedition, led by Michael Grocott, conducted an extensive number of experiments on a cohort of 200 individuals who trekked into Everest base camp, as well as studies on climbers traveling to the summit of the mountain and other expedition support personnel who spent an extended period of time at base camp (Levett et al. 2010). Among the high impact reports from this expedition were the collection of arterial blood samples from four climbers at an altitude of 8400 m, which showed an arterial PO₂ as low as 19.1 mmHg (Grocott et al. 2010). Other important new findings were reported on skeletal muscle energetics (Edwards et al. 2010; Levett et al. 2012), cerebral blood flow changes (Wilson et al. 2011), cardiac function (Holloway et al. 2011), and acute pulmonary vascular responses (Luks et al. 2017). The Xtreme Everest group has completed additional projects including Xtreme Everest 2 (Gilbert-Kawai et al. 2015), Xtreme Alps (Martin et al. 2013), and the Young Everest Study (Gavlak et al. 2013), in which studies have focused on metabolic (Horscroft et al. 2017) and circulatory (Gilbert-Kawai et al. 2017) differences in Sherpas as well as shifts in metabolomic signatures (O’Brien et al. 2019) and cognitive function (Griva et al. 2017) in travelers to altitude.