Sixteenth to nineteenth centuries

It has been known for many centuries that very high altitude has a deleterious effect on the human body and that the amount of work that a person can do becomes more and more limited as the altitude increases. Until the end of the 19th century, however, most of the climbing and exploration was limited to what would today be considered more moderate altitudes (<6000 m).

One of the first descriptions of the disabling effects of high altitude was given by the Jesuit missionary Joseph de Acosta, who accompanied the early Spanish conquistadores to Peru in the 16th century. He described how, as he traveled over a high mountain, he “was suddenly surprised with so mortal and strange a pang, that I was ready to fall from the top to the ground.” His dramatic description was first published in 1590 (Acosta 1590).

In the 18th century, climbers in the European Alps reported a variety of disagreeable sensations which now seem to us greatly exaggerated. For example, the physicist de Saussure, who was the third person to reach the summit of Mont Blanc, reported during the climb:

When he was near the summit, he complained of extreme exhaustion:

On the summit itself, he reported:

These dramatic complaints at an altitude of only 4807 m or less reflect a combination of almost no acclimatization and the fear of the unknown.

In the 19th century, numerous ascents were made of higher mountains, including those in the Andes, and there were abundant accounts of the disabling effects of extreme altitude. In 1879, Whymper made the first ascent of Chimborazo and described how, at an altitude of 5079 m (16,664 ft), he was incapacitated by the thin air:

However, Whymper and his two guides gradually recovered their strength and in fact his lively account shows that he was aware of the beneficial effects of high altitude acclimatization.

In the latter part of the 19th century, there was considerable interest in the highest altitude that could be tolerated by climbers. Thomas W. Hinchliff, President of the (British) Alpine Club (1875–77), wrote an account of his travels around the world and described his feelings as he looked at the view from Santiago in Chile.

Twentieth century

With the onset of the 20th century, mountaineers began exploring the extremes of elevation. In 1909, the Duke of Abruzzi attempted an ascent of K2 (8611 m) in the Karakoram Range on the China-Pakistan border, and although his party was unsuccessful in reaching the summit, they attained the remarkable altitude of 7500 m without supplemental oxygen. According to the Duke’s biographer, one of the reasons given for this expedition was “to see how high man can go” (de Filippi 1912), and certainly the climb had a dramatic effect on both the mountaineering and the medical communities interested in high altitude tolerance. In contrast to the florid accounts of paralyzing fatigue and breathlessness given by de Saussure, Whymper and others at much lower altitudes, the Duke made light of the physiological problems associated with this great altitude. However, as discussed in Chapter 8, his feat prompted heated arguments among physiologists about whether the lungs actively secreted oxygen at this previously unheard-of altitude.

Ten years later, a milestone in the history of the physiology of extreme altitude was provided by the British physiologist, Alexander M. Kellas, whose contributions were largely overlooked for many years. Kellas was a lecturer in chemistry at the Middlesex Hospital Medical School in London during the first two decades of the 20th century, but, despite this full-time faculty position, managed to make eight expeditions to the Himalayas, and probably spent more time above 6100 m than anyone else. In 1919, he wrote an extensive paper entitled, “A consideration of the possibility of ascending Mount Everest,” which was not published until 2001 (Kellas 2001). In this, he analyzed the physiology of a climber near the Everest summit, including a discussion of the summit altitude, barometric pressure, alveolar PO₂, arterial oxygen saturation, maximal oxygen consumption, and maximal ascent rate. On the basis of his study, he concluded that:

The importance of this study was not that he reached the correct conclusion. Kellas had so little data that many of his calculations were erroneous. However, Kellas asked all the right questions and can claim the distinction of being the first physiologist to seriously analyze the limiting factors at the highest point on earth (West 1987). It was not until almost 60 years later that all of his predictions were fulfilled. For a biography of Kellas, see Mitchell and Rodway (2011).

Kellas was a member of the first official reconnaissance expedition to Everest in 1921, but tragically died during the approach march just as the expedition had its first view of the mountain they came to climb. Three years later, EF Norton, who was a member of the third Everest expedition, reached a height of about 8589 m on the north side of Everest without supplemental oxygen. He was accompanied to just below that altitude by Dr. TH Somervell, who collected alveolar gas samples at an altitude of 7010 m, though unfortunately these were stored in rubber bladders through which the carbon dioxide rapidly diffused (Somervell 1925). Somervell also referred to the extreme breathlessness at that altitude, stating that “for every step forward and upward, 7 to 10 complete respirations were required.”

The summit of Everest was finally attained in 1953 by Hillary and Tenzing (Hunt 1953). Naturally, this was a landmark event in the physiology of extreme altitude, but the fact that the two climbers used supplemental oxygen still did not answer the question of whether it was possible to reach the summit breathing air. Hillary did remove his oxygen mask on the summit for about 10 minutes and at the end of the time reported:

Nevertheless, the fact that he could survive for a few minutes without additional oxygen came as a surprise to some physicians who had predicted that he would lose consciousness during that brief time. However, there was a precedent for surviving for this period of time on the summit in the experiment Operation Everest I, carried out by Houston and Riley in 1945. As briefly described in Chapter 1, four volunteers spent 34 days in a low-pressure chamber of whom two were able to tolerate 20 minutes without supplemental oxygen at the equivalent of the summit altitude. In fact, the equivalent altitude was even higher than the true summit of Mount Everest because the standard atmosphere pressure was inadvertently used.

Additional information on whether there was enough oxygen in the air to allow a climber to reach the Everest summit while breathing air was obtained by Pugh and his colleagues during the 1960–61 Silver Hut Expedition (Pugh et al. 1964). Measurements of maximal oxygen consumption were made using a bicycle ergometer on a group of physiologists who wintered at an altitude of 5800 m and who were therefore extremely well acclimatized to this altitude. Figure 18.3 (lower curve) shows the results of measurements made up to an altitude of 7440 m. Note that extrapolation of the line to a barometric pressure of 250 mmHg on the Everest summit suggested that almost all the oxygen available would be required for the basal oxygen uptake. (For details of the extrapolation procedure, refer to West and Wagner 1980.) Thus, these results strongly suggested that a climber who could reach the Everest summit without supplemental oxygen would be very near the limit of human tolerance.

This ultimate climbing achievement occurred when Reinhold Messner and Peter Habeler reached the summit of Everest without supplemental oxygen in May 1978. Messner’s account (Messner 1979) makes it clear that he had very little in reserve:

And when he eventually reaches the summit:

The long period of 25 years between the first ascent of Everest in 1953 and this first “oxygen-less” ascent also suggests that humans are near the limit of tolerance at this extreme elevation. Again, as indicated earlier, Norton ascended to within 300 m of the Everest summit as early as 1924 without oxygen, but it was not until 1978 that climbers reached the top without supplemental oxygen. Thus, the last 300 m took 54 years!

Since that historic climb, Messner has further confirmed his outstanding tolerance to the extreme hypoxia of great altitudes. In 1980, he became the first person to ascend Everest alone without supplemental oxygen (Messner 1981), and in 1986, he became the first man to climb all 14 of the 8000 m peaks without supplemental oxygen. These accomplishments assure him a place not only in the history of mountaineering but also in the history of the physiology of extreme altitude. Nowadays, technical climbing to altitudes >8000 m without breathing supplemental oxygen is conducted successfully by elite mountaineers in both summer and winter.

Barometric pressure

Barometric pressure is a critical variable in physiological performance at extreme altitude because it determines the inspired PO₂, the first step in the oxygen cascade from the atmosphere to the mitochondria. As pointed out in Chapter 2, there has been considerable confusion in the past about the relationships between barometric pressure and altitude on high mountains such as the Himalayan chain. The resulting errors are particularly important at extreme altitude where maximal oxygen consumption is exquisitely sensitive to barometric pressure. It is remarkable that Paul Bert gave nearly the correct value of barometric pressure for the Everest summit in Appendix I of his classic book La Pression Barométrique (Bert 1878). His figure of 248 mmHg was based on an extrapolation of measurements made by Jourdanet and others at various locations including the Andes (Jourdanet 1875).

However, when the standard atmosphere was introduced and used extensively by aviation physiologists in the 1930s and 1940s, it was erroneously applied to Mount Everest, giving a value of 236 mmHg, which is much too low. Nevertheless, this figure was used by several high altitude physiologists. For example, during Operation Everest I, they were exposed to a pressure of 236 mmHg and their alveolar PO₂ fell to as low as 21 mmHg (Riley and Houston 1951)! As the next section shows, this is about 14 mmHg less than that of a well-acclimatized climber on the summit of Mount Everest.

As described in Chapter 2, Dr. Christopher Pizzo measured a barometric pressure of 253 mmHg on the Everest summit on October 24, 1981. This was about 2 mmHg higher than that expected from the mean barometric pressure for that month based on extensive weather balloon data (see Chapter 2). The discrepancy can be accounted for by normal variation and the high pressure system that made the weather ideal for climbing that day. The reading of 253 mmHg was within 1 mmHg of the pressure predicted for an altitude of 8848 m from radiosonde balloons released in New Delhi, India, on the same day (West et al. 1983a). Several direct measurements on the summit since 1981 have given similar values (see Chapter 2).

Measurements of V.O_2max on AMREE (West et al. 1983b) and Operation Everest II (Sutton et al. 1988), as well as the analysis described below show that exercise performance at these extreme altitudes is exquisitely sensitive to barometric pressure. For example, on AMREE, a decrease in inspired PO₂ of only 1 mmHg resulted in a fall of V.O_2max by about 63 mL min⁻¹ (West 1999). This is partly because the lung is working very low on the hemoglobin-oxygen dissociation curve where the slope is steep. As a consequence, a fall of barometric pressure of as little as 3 mmHg (less than twice the daily standard deviation) will apparently cause a reduction of maximal oxygen uptake of about 4%. This means that even the daily variations of barometric pressure caused by weather may affect physical performance.

Seasonal variations of barometric pressure can be expected to have a marked effect on maximal oxygen uptake. As already noted, mean barometric pressure falls from nearly 255 mmHg in the summer months to only 243 mmHg in midwinter, a decrease predicted to reduce maximal oxygen uptake by about 15%. This might explain why it took until 1987 before Mount Everest was climbed in winter without supplemental oxygen and until 2016 until a similar style ascent was made of Nanga Parbat (8126 m). Although the very cold temperatures and high winds significantly limit climbing efforts at this time of year, the reduced barometric pressure must certainly contribute. As pointed out in Chapter 2, the location of Mount Everest at 28°N latitude is fortunate because the barometric pressure at its summit is considerably higher than would be the case if it were at a higher latitude. As an example, if Denali (6190 m, 63°N latitude) were actually 8848 m, its barometric pressure for May and October (preferred climbing months for Everest) would be only 223 mmHg, which would make it impossible to reach the summit without supplemental oxygen.

A similar argument would apply if the barometric pressure on the Everest summit were only 236 mmHg, as predicted from the standard atmosphere model. The reduction of pressure by 17 mmHg below that measured by Pizzo would reduce the maximal oxygen consumption by over 20%, according to the analysis presented in this chapter. It seems very probable that climbing Everest without supplemental oxygen under these conditions would be impossible. Thus, the higher barometric pressure that Everest enjoys because of its near equatorial latitude makes it just possible for humans to reach the highest point on earth. Of the 14 mountains >8000 m, K2 remains the only unclimbed peak in the winter, with the most recent failed attempt taking place in the winter of 2019.

Alveolar gas composition

On ascent to high altitude, the alveolar PO₂ falls because of the reduction in the inspired PO₂. At the same time, alveolar PCO₂ falls because of increasing hyperventilation. As described in Chapter 8, Rahn and Otis (1949) clarified the differences between unacclimatized and fully acclimatized subjects at high altitude by plotting their alveolar PO₂ and PCO₂ values on an oxygen-carbon dioxide diagram (Chapter 9). There are apparently differences between the results obtained in the field, that is, on expeditions to high altitude, and those obtained from simulated ascents in a hypobaric chamber. The field studies will be discussed first followed by those using simulated ascents.

Figure 19.3 shows alveolar PCO₂ plotted against barometric pressure at extreme altitude from field studies. The closed circles show data reported by Greene (1934), Warren (1939), Pugh (1957), and Gill et al. (1962). The triangles show data obtained on the AMREE (West et al. 1983c). It can be seen that alveolar PCO₂ declines approximately linearly as barometric pressure falls and that the partial pressure on the summit of Mount Everest is about 7–8 mmHg. The measurements made on the summit itself had high respiratory exchange ratio (R) values, for reasons that are not clear. However, the data obtained at the slightly lower altitude of 8400 m (P_B 267 mmHg) had a mean R value of 0.82 with a PCO₂ of 8.0 mmHg, which means we can be confident of the very low values at this great altitude.

Figure 19.4 shows the line drawn by Rahn and Otis (1949) for fully acclimatized subjects together with additional data obtained at barometric pressures below 350 mmHg (Table 19.1). Note that the AMREE data (triangles) fit well with the extrapolation of the line. This method of plotting the data shows that as well-acclimatized humans go to higher and higher altitudes, the PO₂ falls because of the decreasing inspired PO₂, and the PCO₂ falls because of the increasing hyperventilation. However, above an altitude of about 7000 m (P_B 325 mmHg), the alveolar PO₂ becomes essentially constant at a value of about 35–37 mmHg. Measurements of alveolar PO₂ up to an altitude of 8000 m by Peacock and Jones (1997) are in good agreement with these data. This means that successful climbers are able to defend their alveolar PO₂ by the process of extreme hyperventilation. In other words, they insulate the PO₂ of their alveolar gas from the falling value in the atmosphere around them. This appears to be the most important feature of acclimatization at extreme altitude.

Not everyone can generate the enormous increase in ventilation required for the very low PCO₂ values shown in Figures 19.3 and 19.4. The pattern of alveolar gas values shown in Figure 19.4 is only obtained if sufficient time is allowed for full respiratory acclimatization. Figure 19.5 compares the results found in unacclimatized and fully acclimatized subjects at high altitude with alveolar gas data reported from two hypobaric chamber experiments in which the simulated rate of ascent was much faster. It can be seen that in Operation Everest I (Riley and Houston 1951), the subjects reached the simulated summit after only 31 days, and at the extreme altitudes, the data fell close to the region predicted by the line for unacclimatized humans. In Operation Everest II (Malconian et al. 1993), the ascent was a little slower, with the first simulated summit excursion occurring after 36 days. However, the alveolar gas values at extreme altitudes still deviated considerably from those found in fully acclimatized subjects. Little information is available about the time required for full respiratory acclimatization at extreme altitudes (>8000 m), but Figure 19.5 suggests that 36 days is inadequate, whereas 77 days clearly is much better. However, it may be that other factors, such as the level of physical activity and extent of periodic breathing during sleep, are also important.

Arterial blood composition

Until recently, no one had attempted to sample arterial blood at extreme altitude because of the obvious technical difficulties, although a possible procedure had been suggested (Catron et al. 2006). A landmark advance was made during the Caudwell Xtreme Everest Expedition when four arterial samples were collected at an altitude of 8400 m and barometric pressure of 272 mmHg (Grocott et al. 2009). The original intent was to sample blood on the summit, but this was infeasible due to a variety of logistical factors. A small tent was erected on the “balcony” about 450 m below the Everest summit during the descent, and samples were taken from the right femoral artery of four climbers. They used supplemental oxygen for climbing, but breathed ambient air for 20 minutes before the samples were taken. The blood samples were placed in an ice-water slurry and rapidly transported down to 6400 m, where the analyses were made using a Siemens blood gas analyzer that was modified for use at high altitude.

Table 19.2 shows the results for the PO₂, PCO₂, and pH and some other variables. Figure 19.6 shows the PO₂ and PCO₂ values plotted on an O₂–CO₂ diagram together with the mean results from Operation Everest II and Operation Everest III. More information on these is given later in the chapter. The chamber data were obtained at a barometric pressure of 253 mmHg corresponding to the Everest summit so that slightly lower values for PO₂ and PCO₂ might be expected. In addition to the absolute PO₂ values, it is also useful to note the measured alveolar-arterial oxygen difference in the subjects from the Xtreme Everest expedition. At first glance, the mean difference of 5.4 mmHg would seem normal. However, the normal range for this parameter decreases as the P_IO₂ falls with ascent and, in fact, at the altitude at which these samples were drawn, the alveolar-arterial oxygen difference should be <2 mmHg. As a result, the observed mean difference of 5.4 mmHg indicates the presence of abnormal gas exchange, which, as discussed further below, likely reflects the effects of diffusion limitation as well as increased ventilation-­perfusion mismatch.

Table 19.2 Arterial blood values at an altitude 8400 m, P_B 272 mmHg from the Caudwell Xtreme Everest Expedition

Figure 19.6 shows that two of the subjects on the Xtreme Everest expedition had PO₂ and PCO₂ values that fit well with those from Operation Everest II and Operation Everest III. However, the results from the other two subjects were far different for reasons that remain unclear (West 2009). Possibly these two subjects had low hypoxic ventilatory responses. Not shown in the figure are the calculated values from one subject from AMREE on the summit. His PO₂ was 28 mmHg, which fits well with the other data, but his PCO₂ was 7–8 mmHg, which is substantially lower. This might be related to his exceptionally high ventilatory response to hypoxia.

Incidentally, the altitude of 8400 m and barometric pressure of 272 mmHg do not match previous measurements on Everest discussed in Chapter 2. They give an altitude of 8309 m for that pressure. Perhaps the altitude was incorrectly estimated or the barometer was reading low. A barometer reading on the summit would have clarified this, but unfortunately, that was not recorded.

Acid–base status

The Lactate Paradox

In humans acutely exposed to high altitude during the International High Altitude Expedition to Chile in 1935, it was reported that blood lactate remained very low in acclimatized subjects at high altitude even during maximal work (Edwards 1936). Figure 19.7 shows data on resting and maximal blood lactate obtained by Cerretelli (1980). Also shown are measurements made at 6300 m after maximal exercise at the rate of 900 kg min⁻¹, corresponding to an oxygen uptake of 1.75 L min⁻¹ (West 1986). The mean value after exercise at 6300 m was only 3.0 mmol L⁻¹ despite an arterial PO₂ of less than 35 mmHg and therefore extreme tissue hypoxia. Note that extrapolation of the line relating maximal blood lactate concentration to altitude suggests that after maximal exercise at altitudes exceeding 7500 m, there is no increase in blood lactate concentration despite the extreme oxygen deprivation. This is indeed a paradox since it has often been observed that lactate release occurs during tissue hypoxia and the tissue PO₂ must be extremely low under these conditions.

The blood lactate concentrations after maximal exercise were appreciably higher on Operation Everest II (Sutton et al. 1988). For example, at an inspired PO₂ of 63 mmHg, the mean lactate concentration following maximal exercise was 4.7 mmol L⁻¹, which is about 56% higher than on the AMREE for the same inspired PO₂. Moreover, the “summit” measurements on Operation Everest II gave a blood lactate concentration of 3.4 mmol L⁻¹, a higher value than that found at only 6300 m on the AMREE (Figure 19.7). It was initially believed that the low lactate concentrations following maximal exercise at high altitude come about only as a result of high altitude acclimatization because acute hypoxia causes very high lactate levels. Presumably, therefore, the higher values seen on Operation Everest II compared with the AMREE and other field studies can be explained by the lesser degree of acclimatization.

The topic of the lactate paradox was extensively discussed in a Point–Counterpoint feature in Journal of Applied Physiology following initial statements on whether the paradox exists (van Hall 2007; West 2007). The discussion includes a large number of references, which the interested reader should consult. One hypothesis is that on acute exposure to hypoxia, sympathetic stimulation leads to augmented muscle lactate production and blood lactate concentration through beta-adrenergic-mediated increases in glycolytic flux. By contrast, chronic hypoxia causes beta-adrenergic adaptation, and it was originally believed that there was a reduced lactate response to exercise after acclimatization (Kayser 1996). However, studies on unacclimatized and acclimatized subjects at 4300 m altitude have not supported this hypothesis (Brooks et al. 1998). Consistent with this interpretation, based on the observations by Danish researchers (Lundby et al. 2000), it was revealed that the net lactate release from the active leg was higher after six weeks at 5260 m compared with acute hypoxia at sea level (van Hall et al. 2009). Therefore, it seems that sea-level residents in the course of acclimatization to high altitude do not exhibit a reduced capacity for the active muscle to produce lactate. These findings imply an enhanced lactate utilization with prolonged acclimatization to altitude, and supports the absence of a lactate paradox in lowlanders sufficiently acclimatized to altitude. However, although the underlying mechanisms that regulate blood lactate at rest and during exercise at high altitude remain unresolved, differences in magnitude of altitude exposure, degree of acclimatization, and experimental methodologies (absolute versus relative exercise testing) (Cerretelli 1980; Swenson 2016) likely explain some of these discrepancies. The latter point is important as testing at the same absolute workload (e.g., 200 watts) at both sea level and high altitude will result in a much greater relative workload because of the altitude-induced reductions in V.O_2max; as such, the relative comparisons of given blood concentrations will be confounded. See Chapter 18 for further details.

Cardiac output

Intuitively, it would be reasonable to expect increased cardiac output for a given work rate at extreme altitude compared with sea level, as it is known that cardiac output increases as a result of acute hypoxia (Chapter 11). Furthermore, the oxygen concentration of the arterial blood is extremely low at very high altitude, and an increase in cardiac output would be expected to help compensate for the reduced oxygen delivery. Paradoxically, however, the relationship between cardiac output and oxygen uptake in acclimatized subjects at an altitude of 5800 m is essentially the same as at sea level (Chapters 11 and 18), and this apparently holds true even at extreme altitudes, although data are sparse. However, because of the altitude-induced reductions in V.O_2max, maximal cardiac output is also reduced. Theoretical calculations indicate, however, that that increasing cardiac output for the conditions on the Everest summit did not improve calculated V.O_2max because of diffusion limitation (Wagner 1996).

Pulmonary diffusing capacity

As discussed in Chapter 8, oxygen transfer during exercise at high altitude is, in part, diffusion limited, and all calculations suggest that this limitation will be exaggerated at the extreme altitudes near the summit of Mount Everest. However, very few data on diffusing capacity at extreme altitude are available. Available measurements at an altitude of 5800 m (P_B 380 mmHg) indicate that the diffusing capacity for carbon monoxide during exercise is essentially unchanged from the sea-level value, except for the expected increase caused by the faster rate of combination of carbon monoxide with hemoglobin under the prevailing hypoxic conditions (West 1962). These data indicate that the diffusing capacity of the pulmonary membrane itself is unaltered by acclimatization. A recent study of lowlanders who trekked into the Everest base camp (5400 m) and spent two weeks there reported a substantial increase in diffusing capacity for carbon monoxide (Agostoni et al. 2011), but this seems to be at variance with most previous studies.

Measurements of the diffusing capacity for carbon monoxide at different alveolar PO₂ values allow calculation of the pulmonary capillary blood volume. Again, in measurements made at 5800 m, there appeared to be little change in capillary blood volume, although there was a suggestion that it was slightly lower, possibly as a result of hypoxic pulmonary vasoconstriction (West 1962). If we accept the conclusion that capillary blood volume is unchanged, and that the cardiac output/oxygen consumption relationship is the same as at sea level, this implies that capillary transit time in the lung is normal since this is given by capillary blood volume divided by cardiac output (Roughton 1945).

Using these data, it is possible to calculate the changes in PO₂ along the pulmonary capillary for a climber at rest on the summit of Mount Everest. This shows that the rate of oxygenation is extremely slow and that the end-capillary PO₂ is much lower than the alveolar value, indicating severe diffusion limitation of oxygen transfer. This topic is discussed further in Chapter 8.

PO₂ of venous blood

During maximal exercise at extreme altitude, peripheral tissue oxygen extraction results in a very low venous PO₂ in the exercising muscles, which in turn, reduces the PO₂ of mixed venous blood. In order to analyze the relationships between many variables and determine what limits exercise performance at extreme altitude, one possible assumption is that the body does not tolerate a mixed venous PO₂ below a certain threshold, for example 15 mmHg (West 1983; West and Wagner 1980). This assumption received strong support from Operation Everest II, where direct measurements of mixed venous PO₂ gave similar values (Sutton et al. 1988). For example, during 60 W of exercise on the “summit,” the mixed venous PO₂ had a mean value of 14.8 ± 1 mmHg, and at 120 W, which was the highest work level, the mean mixed venous PO₂ was 13.8 ± 0.6 mmHg.

Heat loss by hyperventilation

Matthews (1932) argued that tolerance to extreme altitude might be limited by the high rate of heat loss from the lungs as a result of the extreme hyperventilation. However, subsequent experience has not supported this early notion. Calculations of net heat loss are complex because the upper respiratory tract acts as a heat exchanger. During expiration, expired gas warms the respiratory tract, and this heat is then available to warm the cold inspired gas. Climbers who have reached the summit of Mount Everest without supplemental oxygen have not been affected by cold beyond the extent expected from the very low temperatures of the environment. When Pizzo reached the summit to take his alveolar gas samples during the course of the AMREE, he became overheated during the climb and photographs taken on the summit when he was breathing air show that he was not even wearing his down jacket, which he carried with him in his backpack (West 1985).

Oxygen cost of ventilation

A climber at extreme altitude has considerable hyperventilation at rest, and even more during moderate exercise, as evidenced by the measured alveolar PCO₂ of 7–8 mmHg at the Everest summit and an arterial value of 10.3 mmHg at 8400 m (Grocott et al. 2009). Since it is known that the carbon dioxide production both at rest and for a given work level is independent of altitude, we can conclude that the alveolar ventilation at these elevations was four to five times the resting value. Even small amounts of physical activity will greatly increase this. If we take the normal resting ventilation to be 7–8 L min⁻¹, this means that the resting ventilation on the summit is at least 40 L min⁻¹.

Assuming a mechanical efficiency of 5% (Cibella et al. 1999), the oxygen cost of breathing at high altitude and sea level amounts to 26 and 5.5% of V.O_2max, respectively. The authors concluded that, at high altitude, the mechanical power of breathing may substantially limit the ability to do external work. They also calculated what they called the “critical ventilation,” that is, the ventilation at which the mechanical power of breathing was so high that increasing ventilation above this level did not provide additional oxygen for external work. At the altitude of 5050 m, the maximal exercise ventilation exceeded the critical ventilation even when the efficiency was assumed to be as high as 20% (Cibella et al. 1999; Figure 19.8). It should be noted, of course, that the vast majority (>98%) of climbers at extreme altitude use supplemental oxygen and, as such, will negate much of the influence of the high altitude on gas exchange impairment and potential oxygen cost of breathing.

Metabolic changes

Substantial changes in the muscle may represent important metabolic responses to exposure to environmental hypoxia (O’Brien et al. 2019). At the cellular level, the transcriptional response to hypoxia is mediated by the hypoxia-inducible factor (HIF) pathway and results in promotion of glycolytic capacity and suppression of oxidative metabolism. In the Sherpa population, lower muscle peroxisome proliferator activated receptor alpha expression is associated with a decreased capacity for fatty acid oxidation, potentially improving the efficiency of oxygen utilization. In lowlanders on a gradual ascent to base camp on Mount Everest (5300 m), a similar suppression of fatty acid oxidation occurs, although the underlying molecular mechanism appears to differ along with the consequences. Moreover, although subacute exposure to high altitude (19 days after initiating ascent to Everest base camp) was not associated with mitochondrial loss, after 66 days at altitude and ascent beyond 6400 m, mitochondrial densities fell by 21%, with loss of 73% of subsarcolemmal mitochondria. Correspondingly, levels of the transcriptional coactivator PGC-1α fell by 35%, suggesting down regulation of mitochondrial biogenesis (Levett et al. 2012). Unlike lowlanders, however, Sherpas appear to be protected against oxidative stress and the accumulation of intramuscular lipid intermediates at high altitude (Horscroft et al. 2017). Moreover, Sherpas are able to defend muscle ATP and phosphocreatine levels in the face of decreased oxygen delivery, possibly due to suppression of ATP demand pathways (Murray et al. 2018). The molecular mechanisms allowing Sherpas to successfully live, work, and reproduce at altitude may hold key information about the cellular and genetic factors that limit performance at extreme altitude. Despite new insight into these molecular mechanisms, physiological testing (anthropometry, electrocardiography, pulmonary function, strength, echocardiography, and exercise capacity) at 1325 m and 2063 m in two world-record-holding Sherpa revealed they were in the normal ranges for the general population (McIntosh et al. 2011). It might be that the reported alterations in the molecular phenotype in Sherpa become of more functional importance for performance at extreme altitudes.

Operation Everest I

This was carried out in 1944 under the leadership of Charles Houston and Richard Riley at the US Naval School of Aviation Medicine in Pensacola, Florida (Riley and Houston 1951). Four Navy volunteers were placed in a small chamber for 35 days and the pressure was gradually reduced to that believed to occur on the summit of Mount Everest. However, as indicated earlier, the standard atmosphere was used and the chamber pressure was actually reduced to as low as 234 mmHg, which corresponds to an altitude of about 9400 m, some 550 m above the Everest summit. The small chamber measured only about 3.0 × 3.0 × 2.1 m and contained four bunks. After 29 days, the pressure was reduced to that at the “summit” and two of the subjects were able to tolerate the severe hypoxia at rest during air breathing, while the other two needed oxygen. During these studies, alveolar PO₂ values in the low 20s were measured (Riley and Houston 1951). These are presumably the lowest values of alveolar PO₂ ever recorded for periods of several minutes. As indicated earlier (Figure 19.3), the subjects of Operation Everest I showed almost no acclimatization at the extreme altitudes as judged from their alveolar gas values. The reason for this is unclear, but it is noted that only one out of the four subjects exercised regularly (albeit briefly) on a bicycle ergometer and this physical inactivity may have been a contributing factor. Nevertheless, the collective findings from Operation Everest I clearly demonstrated for the first time how acclimatization to high altitude consists of a series of integrated adaptations or responses, designed to restore tissue oxygenation in the face of hypoxic hypoxia. These collective changes are illustrated in Figure 19.9. This was the first comprehensive laboratory description that acclimatization requires changes in all body systems involved in the uptake of oxygen into the body, the transport of that oxygen to the tissues, and the unloading of that oxygen at the tissues.

Operation Everest II

This took place in 1985 and again was spearheaded by Charles Houston (Houston et al. 1987). A sophisticated hypobaric chamber at the US Army Research Institute of Environmental Medicine in Natick, Massachusetts, was used, and eight subjects aged 21–29 years spent 40 days and nights in the chamber. The subjects were gradually decompressed over a period of about 35 days followed by excursions to the “summit” where the inspired PO₂ was 43 mmHg, which this time was the correct value. Not all the subjects made it to the “summit,” but nevertheless very valuable physiological information was obtained, because the investigators were able to perform more invasive procedures, such as right heart catheterization, than can normally be performed in a field environment. Individuals who become ill during such invasive procedures can rapidly be removed from the chamber and taken to a hospital.

Some of the most important studies were on the pulmonary circulation, and these were referred to in Chapter 11. Right heart catheterization was carried out at barometric pressures of 760 mmHg, 347 mmHg, 282 mmHg, and 240 mmHg. For the last measurement, the oxygen concentration in the chamber was 22% giving an inspired PO₂ of 43 mmHg. The mean pulmonary arterial pressure at rest at sea level was 15 ± 0.9 mmHg, but this increased to 34 ± 3 mmHg at a barometric pressure of 282 mmHg (Groves et al. 1987). At the same time, the pulmonary vascular resistance increased from 1.2 to 4.3 mmHg L⁻¹ min⁻¹. When the subjects performed maximal exercise, the increases in mean pulmonary artery pressure were even more remarkable, rising from 33 ± 1 mmHg at sea level to 54 ± 2 mmHg at a barometric pressure of 282 mmHg. However, the pulmonary artery wedge pressure was unchanged with the increase in simulated altitude, indicating that the increase in pulmonary artery pressure was related to increased pulmonary vascular resistance rather than left heart dysfunction.

Cardiac output was measured and shown to have the same relationship with oxygen consumption as at sea level (Chapter 11), confirming earlier measurements made on the Silver Hut Expedition (Pugh 1964). However, heart rate as a function of work level was higher as altitude increased. A particularly interesting finding was that when the subjects breathed 100% oxygen at the high altitudes, pulmonary vascular resistance did not return to the sea level values. This finding, which is supported by more recent field data (Luks et al. 2017), indicated a substantial degree of irreversibility in pulmonary vascular resistance after two or three weeks of hypoxia that is highly suggestive of vascular remodeling.

Additional information was found regarding pulmonary gas exchange, as the investigators used the multiple inert gas elimination technique to separate the effect of ventilation-perfusion inequality from that of diffusion limitation. These studies were referred to in Chapter 8. Diffusion limitation of oxygen transfer across the blood-gas barrier occurred at oxygen uptakes greater than 3 L min⁻¹ at sea level, and at less than 1 L min⁻¹ on the “summit.” This is a graphic demonstration of diffusion limitation at extreme altitude. A new finding was the increasing ventilation-perfusion inequality from rest to exercise at all altitudes, which indirect evidence suggested may have been caused by interstitial pulmonary edema. Table 19.3 summarizes the arterial blood gases during rest and maximal exercise on Operation Everest II.

Table 19.3 Barometric pressures, equivalent altitudes, and arterial blood gases during rest and maximal exercise on Operation Everest II

During Operation Everest II, skeletal muscle volume was inferred from computed tomography scans of the arms and legs. Muscle area decreased by about 14% during the “ascent.” The biopsies showed that this could be accounted for by a significant decrease in the cross-sectional area of both type I and type II fibers. As a result, there was an apparent increase in capillary volume density although this was not significant. Muscle enzymes were also measured and showed that at the highest altitude of 282 mmHg where biopsies were taken, there were significant reductions in succinic dehydrogenase, citrate synthase and hexokinase compared with measurements made after returning to sea level. Finally, the biopsies showed significant reductions in muscle lactate concentrations at the higher altitudes consistent with the low blood lactate concentrations referred to earlier in this chapter. As noted earlier, an important consideration in the interpretation of prolonged chamber studies is the profound influence of physical inactivity. As outlined in Chapter 16, many of the endocrine changes (that can influence fuel metabolism, among other things) are markedly influenced by both exercise and hypoxia. Although the participants in Operation Everest II were, on the whole, more active than those in Operation Everest I, they were still not as well acclimatized as those on AMREE. The physical activity levels are clearly much less in the chamber than those in the field.

Operation Everest III

This hypobaric chamber experiment in 1997 was carried out at the COMEX facility in Toulouse, France, and had a number of similarities with Operation Everest II (Richalet 2010). However, an innovative feature was that the eight volunteers preacclimatized in the Vallot Observatory (4350 m) for several days before spending a total of 31 days in the hypobaric chamber, ultimately reaching the summit barometric pressure of 253 mmHg. The arterial blood-gas values were similar to those found on Operation Everest II (Table 19.3) with a “summit” arterial PO₂ of 31 mmHg, PCO₂ of 12 mmHg, and pH of 7.58. The fact that the PCO₂ was higher than on AMREE in both of the chamber studies is consistent with a lesser degree of acclimatization (compare Figure 19.5). Body weight fell by an average of 5.4 kg, again in line with findings from Operation Everest II and AMREE. Cardiovascular measurements largely confirmed those made on Operation Everest II (Boussuges et al. 2000). A noteworthy finding was transient neurological disorders, which were attributed to gas emboli, and the marked changes in mood of some of the subjects (Nicolas et al. 2000).

Concept of limitation

The oxygen cascade from the atmosphere to the mitochondria includes the processes of convective and diffusive ventilation of oxygen to the alveoli, diffusion of oxygen across the blood-gas barrier, uptake of oxygen by the hemoglobin in the pulmonary capillaries, convective flow of the blood to the peripheral capillaries, unloading of the oxygen from the hemoglobin, diffusion to the mitochondria, and utilization of oxygen by the electron transport system. How can we determine to what extent each of these factors is limiting exercise at extreme altitude?

One approach is to use the analogy of a turbine that is fed by water flowing through a pipe that has a series of constrictions in it. Clearly, all sections of the pipe limit the flow of water to some extent. However, a useful description of the extent to which flow is limited by any particular section of the pipe can be found by calculating the percentage change (say 5%) in total flow for a given change in diameter at that point. In carrying out this calculation, we assume that all other factors remain unchanged. Such an analysis can only be carried out if the whole system is modeled using a computer.

Limitations to oxygen uptake on the summit of Mount Everest

The model analysis described above has been carried out for a hypothetical subject exercising on the summit of Mount Everest (West 1983). Some assumptions and extrapolations are necessary because so few data have yet been obtained at these great altitudes. In general, the physiological variables have been noted above and are summarized in Table 19.4.

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