Effects of hyperventilation on gas exchange Acute hypoxia compared with acclimatization Physiology of diffusion in the lung Reaction rates with hemoglobin Rate of oxygen uptake along the pulmonary capillary Diffusion and perfusion limitation of oxygen transfer Pulmonary diffusing capacity at high altitude Diffusion limitation of oxygen transfer at high altitude Ventilation/Perfusion inequality Shunt and gas exchange at high altitude Diffusion in the placenta at high altitude Important changes in pulmonary gas exchange occur at high altitude. It is known that pulmonary gas exchange efficiency gets worse with acute ascent to high altitude, especially during exercise, but improves with acclimatization. Contributors to pulmonary gas exchange efficiency, as measured by the alveolar-to-arterial oxygen difference ([A-a]ΔO2) include diffusion limitation, ventilation/perfusion (V/Q) heterogeneity, and shunt. Diffusion limitation of oxygen transfer across the blood-gas barrier occurs during exercise at even moderate altitudes and at rest at extreme altitude. This is one of the few situations when diffusion limitation for oxygen is seen in the normal lung. Lowlanders who go to high altitude have a small increase in diffusing capacity caused partly by polycythemia. Despite the presence of patent foramen ovale (PFO) in 25% to 35% of the population, a potential source of right-to-left shunt, the significance of this in altitude illness or pulmonary gas exchange at altitude is unclear. The improvement in gas exchange with acclimatization is typically attributed to improvement in lung diffusing capacity. Highlanders may have higher diffusing capacities than lowlanders possibly because of the accelerated growth of the lung in a hypoxic environment. A review of these topics is provided in this chapter. Some aspects of the effects of high altitude on pulmonary gas exchange, particularly the hyperventilation and the cyanosis, have been recognized ever since the early days of the balloonists. For example, in 1804, the eminent French scientist Louis Joseph Gay-Lussac ascended to an altitude of what was thought to be 7020 m in a balloon and reported that his breathing was difficult, and his pulse and respiration were high. There were also reports of discoloration of the hands and face presumably the result of cyanosis. In fact, during the ill-fated flight of the Zénith referred to in Chapter 1, Tissandier reported that Sivel’s face was black (Tissandier 1875). On the other hand, the early balloonists did not complain as much about difficulties with breathing, including breathlessness, as did high altitude climbers, and this is consistent with the fact that acute hypoxia does not result in as large a ventilatory response as prolonged hypoxia, as we shall see later in this chapter. Early mountain climbers were well aware of the shortness of breath at high altitudes. During an early ascent of Mont Blanc by the Swiss physicist Horace-Bénédict de Saussure in 1787, he complained that “the rarity of the air gave me more trouble than I could have believed. At last I was obliged to stop for breath every 15 or 16 steps….” In fact, on the summit he complained that he was “constantly forced to interrupt my work and devote myself entirely to breathing” (Saussure 1787). The eminent climber Edward Whymper, during the first ascent of Chimborazo (6420 m) in 1880, gave a colorful description of shortness of breath, stating that: Some of the most striking accounts of breathlessness at high altitude came from the early expeditions to Mount Everest (8848 m). For example, in 1924, at an altitude of about 8380 m, E.F. Norton stated that: His companion T. Howard Somervell was even more breathless, stating, “From taking three or four breaths to a step we were reduced to having to take ten or more.” Finally, Reinhold Messner, who along with Peter Habeler made the first ascent of Everest without supplementary oxygen in 1978, stated when he was on the summit, “I have nothing more to do than breathe…. I am nothing more than a single, narrow, gasping lung” (Habeler 1979). It is remarkable that in spite of so many anecdotal accounts of hyperventilation at high altitude, some of the most eminent physiologists claimed that it did not occur. For example, Paul Bert stated that hyperventilation does not occur at high altitude and wrote: Possibly this error can be traced to the fact that Bert worked exclusively with low pressure chambers that only allowed short-term observations of the effects of acute hypoxia. However, even Angelo Mosso, who had the advantage of studying long-term residents at the Capanna Margherita, reported that although respiratory frequency was increased at high altitude, total ventilation was decreased (Mosso 1898). He reached this erroneous conclusion because he converted the volumes to standard conditions (0°C and 1000 mmHg in his case) rather than to body temperature and pressure, saturated with water vapor (BTPS). Turning now to the role of diffusion in pulmonary gas exchange, the controversy over oxygen secretion constitutes one of the most colorful episodes in the history of high altitude medicine. The debate was briefly alluded to in Chapter 1. An early proponent of the secretion hypothesis was the Danish physiologist Christian Bohr. In a paper published in 1891 he compared the PO2 and PCO2 of alveolar gas with that of gas in a tonometer equilibrated with arterial blood taken at the same time (Bohr 1891). In some instances the alveolar PO2 was found to be as much as 30 mmHg below, and the PCO2 as much as 20 mmHg above, the arterial blood values. Bohr’s conclusion was: “In general, my experiments have shown definitely that the lung tissue plays an active part in gas exchange; therefore, the function of the lung can be regarded as analogous to that of the glands.” Bohr referred to the secretion ability of the lung as its “specific function,” and claimed that the active secretion of oxygen and carbon dioxide by the lung could use large amounts of oxygen, up to 60% of the total requirements of the body. August Krogh was one of Bohr’s students and assisted him in his experiments on gas secretion from 1899 to 1908. However, Krogh gradually became persuaded that passive diffusion rather than active secretion could account for the experimental data and, in 1910, published a landmark paper on this topic (Krogh 1910). Since Bohr was his major professor and very jealous of the secretion theory, the introductory section of Krogh’s paper required an unusually delicate touch. Part of it reads: The British physiologist J.S. Haldane visited Bohr in Copenhagen and also became convinced of the secretion theory, at least as far as oxygen was concerned. For example, in 1897, Haldane and Lorraine Smith (Haldane and Smith 1897) wrote: “The absorption of oxygen by the lungs thus cannot be explained by diffusion alone.” Haldane argued that oxygen secretion would be particularly beneficial at high altitudes, and in order to test the hypothesis, the Anglo-American expedition to Pikes Peak was organized in 1911. Arterial PO2 was calculated by an indirect method following the inhalation of carbon monoxide, and the results appeared to strongly support the secretion hypothesis. However, the theory was also attacked by Marie Krogh (wife of August) when she developed a method for measuring the diffusing capacity of the lung using small concentrations of carbon monoxide. Her results indicated that the normal lung was capable of transferring very large amounts of oxygen by passive diffusion even when the inspired PO2 was greatly reduced. Another physiologist who did not accept the secretion story was Joseph Barcroft. He conducted a heroic experiment on himself by living in a sealed glass chamber filled with hypoxic gas for 6 days (Barcroft et al. 1920). His left radial artery was exposed “for an inch-and-a-half” and blood was taken for measurements of oxygen saturation. There was a “somewhat dramatic moment” when the first blood sample was drawn because it “looked dark.” Measurements on the blood then showed that diffusion was the only mechanism necessary for oxygen transfer across the blood-gas barrier during hypoxia. Barcroft and his colleagues subsequently tested the secretion hypothesis further on the International High Altitude Expedition to Cerro de Pasco (4330 m) in the Peruvian Andes in 1921–22. The diffusing capacity of the lung for carbon monoxide was measured on five members of the expedition both at sea level and at Cerro de Pasco, and only a small increase was found. Barcroft therefore argued that the tendency for the arterial oxygen saturation to fall during exercise at high altitude could be explained by the failure of equilibration of PO2 between alveolar gas and pulmonary capillary blood (Barcroft et al. 1923). This was one of the first direct demonstrations of diffusion limitation of oxygen at high altitude, a finding that has been confirmed many times since. It is remarkable that J.S. Haldane remained a staunch supporter of oxygen secretion all his life. In the second edition of his book Respiration, written with J.G. Priestley and published in 1935, a year before Haldane’s death, a whole chapter was devoted to evidence for oxygen secretion (Haldane and Priestley 1935). Haldane gradually shifted his position as evidence mounted against the secretion hypothesis. He initially thought that oxygen secretion occurred under all conditions, but later argued that it only became significant at high altitude, and later still that it only occurred after a period of acclimatization. His obsession with this theory seems strange to us now, but Haldane was something of a vitalist, believing that not all the phenomena of living creatures could be fully explained by classical chemistry and physics (Sturdy 1988). The most important feature of pulmonary gas exchange at high altitude is the increase in minute and, as a result, alveolar ventilation and its consequences. The importance of hyperventilation is emphasized if we look at its role at extreme altitude, for example on the summit of Mount Everest. First, we need to refer to two simple equations governing pulmonary gas exchange. The first is the alveolar ventilation equation: where V⋅A is alveolar ventilation, V⋅CO2 is the CO2 production, and PACO2 is the alveolar partial pressure of carbon dioxide. This equation states that if the rate of CO2 production is constant, the alveolar ventilation and alveolar PCO2 are inversely related. For example, if the alveolar ventilation is doubled, the PCO2 is halved. The second equation is the alveolar gas equation: where PAO2 and PACO2 are the alveolar partial pressures of oxygen and carbon dioxide, respectively; PIO2 is the inspired partial pressure of oxygen; R is the respiratory exchange ratio; and F is a correction factor that is generally small while breathing ambient air. At sea level the normal alveolar ventilation equation results in an alveolar PCO2 of about 40 mmHg. If we insert this value into the alveolar gas equation, assuming an inspired PO2 of 150 and a normal respiratory exchange ratio at rest of 0.8, the alveolar PO2 is given by Now suppose we apply this equation to a climber on the summit of Mount Everest where the barometric pressure is, say, 250 mmHg (Chapter 2). The PO2 of moist inspired gas is given by where 0.2094 is the fractional concentration of oxygen, PB is the barometric pressure, and 47 mmHg is the water vapor partial pressure. This gives an inspired PO2 of about 43 mmHg. If we now assume that both the alveolar ventilation and the CO2 production of the climber at rest are unchanged compared with sea level, his alveolar PCO2 is 40 mmHg. The alveolar gas equation then gives an alveolar PO2 of which, of course, is not physiologically possible. However, if the climber now increases his alveolar ventilation fivefold, thus reducing his alveolar PCO2 to 8 mmHg, the alveolar gas equation gives While this value is very low, it is just sufficient to maintain life. This simple calculation shows the crucial importance of hyperventilation at high altitude. The mechanism of the hyperventilation is predominantly mediated via hypoxic stimulation of the peripheral chemoreceptors as discussed in Chapter 9. There is a striking difference between the degree of hyperventilation that occurs when subjects are exposed acutely to hypoxia on the one hand, and when they are acclimatized to high altitude on the other. One of the classical studies was performed by Rahn and Otis (1949) and their original results are shown in Figure 8.1. The data on subjects exposed acutely to high altitude (upper line) were obtained using low pressure chambers. The data for the acclimatized line come from a number of sources including lowlanders who spent various periods at a given altitude, and in some cases permanent residents at high altitudes. Figure 8.1Oxygen–carbon dioxide diagram showing the alveolar gas composition in subjects acutely exposed to high altitude (upper line) and after acclimatization (lower line). The two diagonal lines are for a respiratory exchange ratio (RQ) of 0.85 for altitudes of 12,000 ft (3660 m) and 18,000 ft (5490 m). The numbers in the circles show the sources of the data (see original article). (Source: Rahn and Otis 1949) It can be seen that with acute exposure to high altitude there is typically no change in alveolar PCO2, which implies no change in alveolar ventilation, up to an altitude of about 12,000 ft or about 3600 m. By contrast, acclimatized subjects show a fall in alveolar PCO2 indicating an increase in alveolar ventilation for any increase in altitude. Note that altitude itself is not shown explicitly on the graph but the intersection of the diagonal RQ lines with the lower horizontal axis indicates the inspired PO2, which falls as altitude increases. Looking back at Figure 7.1 in Chapter 7, the PO2 data are redrawn so that they are now plotted against altitude. This plot shows more clearly the relentless fall in alveolar PO2 with increasing altitude for both acute exposure and full acclimatization. However, acclimatization results in an increase in ventilation, which lowers the alveolar PCO2 and thus increases the alveolar PO2 at any given altitude according to the alveolar gas equation shown earlier. The altitudes can be read off the horizontal axis and some important high altitude sites are identified, including several locations where high altitude telescopes are located, the summit of Mauna Kea in Hawaii at an altitude of 4208 m and the Chajnantor plateau in north Chile at an altitude of 5050 m. Figure 7.1 emphasizes that, in spite of the hyperventilation that occurs at high altitude, severe alveolar hypoxia and therefore arterial hypoxemia may occur. As an example, astronomers on Mauna Kea, even if they are fully acclimatized, have an alveolar PO2 on average less than 55 mmHg. Their arterial PO2 will therefore be a little lower. Forster (1986) reported that the mean arterial PO2 on the first day at 4200 m was 42 mmHg rising to 44 mmHg on day 5. Comparably, following gradual ascent to 5050 m in 17 healthy volunteers, the mean arterial PO2 increased significantly from 44 mmHg to 48 mmHg after a two-week stay at this altitude (Lucas et al. 2011). The severity of the hypoxemia is further indicated by the fact that an arterial PO2 of 55 or less is the accepted criterion for long-term supplemental oxygen therapy in patients with chronic obstructive pulmonary disease. This emphasizes the severe hypoxemia that occurs even in fully acclimatized subjects at these altitudes. In fact, astronomers at Mauna Kea never become fully acclimatized because of the limited time they spend there. Figures 7.1 and 8.1 emphasize the advantages of acclimatization in raising the alveolar PO2 at high altitude. However, it is interesting that permanent residents of high altitude often have lower alveolar PO2 values and higher alveolar PCO2 values than fully acclimatized lowlanders. This is discussed in Chapter 4. Fick’s law of diffusion states that the rate of transfer of a gas through a sheet of tissue is proportional to the area of the tissue and to the difference in gas partial pressure between the two sides, and inversely proportional to the tissue thickness. The area of the blood-gas barrier in the human lung is approximately 50–100 m2, and the thickness is less than 0.3 µm in many places, so the dimensions of the barrier are well suited to diffusion. In addition, the rate of gas transfer is proportional to a diffusion constant, which depends on the properties of the tissue and the particular gas. The constant is proportional to the solubility of the gas and inversely proportional to the square root of its molecular weight. This means that carbon dioxide diffuses about 20 times more rapidly than oxygen through tissue sheets since its solubility is about 24 times greater at 37°C and the molecular weights of carbon dioxide and oxygen are in the ratio of 1.375 to 1. Fick’s law can be written as where V⋅ is volume of gas per unit time, A is area, T is thickness, D is the diffusion constant, and P1 and P2 denote the two partial pressures. For a complex structure such as the blood-gas barrier of the human lung, it is not possible to measure the area and thickness during life. Instead, we combine A, T, and D and rewrite the equation as where DL is the diffusing capacity of the lung. The gas of choice for measuring the diffusing capacity of the lung is carbon monoxide (at very low concentrations) because the affinity of this gas for hemoglobin is so great that the partial pressure in the capillary blood is extremely small (except in smokers) and thus the uptake of the gas is solely limited by the diffusion properties of the blood-gas barrier. (The complication caused by finite reaction rates is considered below.) Thus, if we rewrite the above equation as where P1 and P2 are the partial pressures of alveolar gas and capillary blood, respectively, we can set P2 to zero. This leads to the equation for measuring the diffusing capacity of the lung for carbon monoxide: In other words, the diffusing capacity of the lung for carbon monoxide is the volume of carbon monoxide transferred in mL min−1 mmHg−1 of alveolar partial pressure. Early investigators assumed that all of the resistance to the transfer of oxygen from the alveolar gas into the capillary blood could be attributed to the diffusion process within the blood-gas barrier. However, when the rates of reaction of oxygen with hemoglobin were measured using a rapid reaction apparatus, it became clear that the rate of combination with hemoglobin might also be a limiting factor. If oxygen is added to deoxygenated blood, the formation of oxyhemoglobin is quite fast, being well on the way to completion in 0.2 seconds. However, oxygenation occurs so rapidly in the pulmonary capillary that even this rapid reaction significantly delays the loading of oxygen by the red cells and can be regarded as a resistance. Thus, the uptake of oxygen can be regarded as occurring in two stages: Diffusion of oxygen through the blood-gas barrier (including the plasma and red cell interior) Reaction of the oxygen with hemoglobin (Figure 8.2) Figure 8.2The measured diffusing capacity of the lung (DL) is made up of two components, one due to the diffusion process itself (DM), and one attributable to the time taken for oxygen to react with hemoglobin (θVc). In fact, it is possible to sum the two resulting resistances to produce an overall resistance (Roughton and Forster 1957). We saw earlier that the diffusing capacity of the lung is defined as that is, the flow of gas divided by the pressure difference. It follows that the inverse of DL is pressure difference divided by flow and is, therefore, analogous to electrical resistance. Consequently, the resistance of the blood-gas barrier in Figure 8.2 is shown as 1/DM where M denotes membrane. The rate of reaction of oxygen with hemoglobin can be described by θ, which gives the rate in mL min−1 of oxygen, which combines with 1 mL blood mmHg−1 PO2. This is analogous to the “diffusing capacity” of 1 mL of blood and, when multiplied by the volume of capillary blood (Vc), gives the effective “diffusing capacity” of the rate of reaction of oxygen with hemoglobin. Again, its inverse, 1/(θVc), describes the resistance of this reaction. It is possible to add the resistances offered by the membrane and the blood to obtain the total resistance. Thus, the complete equation is In practice, the resistances offered by the membrane and blood components are approximately equal in the normal lung. By using Fick’s law of diffusion and data on reaction rates of oxygen with hemoglobin, it is possible to calculate the time course of PO2 along the pulmonary capillary as the oxygen is loaded by the blood. The application of Fick’s law to this situation is not trivial because of the chemical bond which forms between oxygen and hemoglobin. This means that the relationship between PO2 and oxygen concentration in the blood is nonlinear, as shown by the hemoglobin-oxygen dissociation curve. This problem was first solved by Bohr (1909) and the numerical integration procedure which he developed is known as the Bohr integration. A further complication occurs because, as oxygen is being taken up, carbon dioxide is given off, and this alters hemoglobin’s affinity for oxygen and, as a result, the position of the oxygen dissociation curve. A full treatment of this latter process should take into account not only the rate of diffusion of carbon dioxide through the blood-gas barrier, but also the rates of reaction of carbon dioxide in blood. Since not all the rate constants are known under all the required conditions, some assumptions and simplifications are necessary. Figure 8.3 shows a typical time course calculated for the lung of a resting subject breathing air at sea level (Wagner and West 1972; West and Wagner 1980). The diffusing capacity of the blood-gas barrier itself (DM) was assumed to be 40 mL min−1 mmHg−1, and the time spent by the blood in the pulmonary capillary was taken as 0.75 seconds (Roughton 1945). Other assumptions include a resting cardiac output of 6 L min−1 and oxygen uptake of 300 mL min−1. Figure 8.3Calculated time course for PO2 in the resting human pulmonary capillary at sea level. Note that there is ample time for equilibration of the PO2 between alveolar gas and end-capillary blood. V⋅O2 300 mL min−1; DM,o2 40 mL min−1 mmHg−1. (Source: West and Wagner 1980) Note that the blood comes into the lung with a PO2 of 40 mmHg and the PO2 rapidly rises to almost the alveolar PO2 level by the time the blood has spent only about one-third of its available time in the capillary. The rate of rise of PO2 in the latter two-thirds of the capillary is extremely slow, and there is a negligible PO2 difference between alveolar gas and end-capillary blood. This time course can be contrasted with that calculated for a resting climber breathing air on the summit of Mount Everest (Figure 8.4). Again, the membrane diffusing capacity of the blood-gas barrier was assumed to be 40 mL min−1 mmHg−1 based on measurements made on acclimatized lowlanders at an altitude of 5800 m (West 1962). The oxygen uptake was taken to be 350 mL min−1, and other blood and alveolar gas variables were taken from measurements made on the American Medical Research Expedition to Everest (West et al. 1983b). The time spent by the blood in the pulmonary capillary was assumed to be unchanged at 0.75 seconds because this is determined by the ratio of capillary blood volume to cardiac output (Roughton 1945). The capillary blood volume was shown to be unchanged at 5800 m (West 1962), and the cardiac output is also the same as at sea level according to the measurements of Pugh (1964) (Chapter 11). Figure 8.4Calculated time course of the PO2 along the pulmonary capillary for a climber at rest on the summit of Mount Everest. Note that there is considerable diffusion limitation of oxygen uptake with a large alveolar end-capillary PO2 difference. PB 253 mmHg; V⋅O2 350 mL min−1 (Source: West et al. 1983b) It can be seen that the oxygen profile is very different at this extreme altitude. The blood comes into the lung with a PO2 of only about 21 mmHg, and the PO2 rises very slowly along the pulmonary capillary, reaching a value of only about 28 mmHg at the end. Thus, there is a large PO2 difference of some 7 mmHg between alveolar gas and capillary blood. This indicates a marked diffusion limitation of oxygen transfer. It can be shown that this diffusion limitation becomes more striking as the oxygen consumption is increased by exercise. Diffusion limitation at extreme altitude is discussed later in this chapter. The very different time courses for PO2 shown in Figures 8.3 and 8.4 represent the extremes between sea level and the highest point on earth for resting humans. At intermediate altitudes, the difference between alveolar and end-capillary PO2 will be considerably reduced at rest and may be negligibly small. However, exercise at high altitude will always tend to cause diffusion limitation of oxygen transfer as originally demonstrated by Barcroft et al. (1923). Whether carbon dioxide elimination is ever limited by diffusion is still unknown. This is partly because some of the reaction rates of carbon dioxide in blood remain uncertain. It is clear from Figure 8.3 that a resting subject at sea level has no diffusion limitation of oxygen transfer because there is no PO2 difference between alveolar gas and end-capillary blood. Under these conditions, the amount of oxygen taken up by the blood is determined by the pulmonary blood flow and, as a result, that oxygen uptake is perfusion limited. By contrast, Figure 8.4 shows a situation where oxygen uptake is, in part, diffusion limited. This is indicated by the large PO2 difference between alveolar gas and end-capillary blood. However, under these conditions, oxygen uptake is also partly perfusion limited because increasing pulmonary blood flow increases oxygen uptake, other things being equal. At first sight, the substantial diffusion limitation of oxygen transfer shown in Figure 8.4 might be attributed to the low alveolar PO2, and therefore the smaller driving gradient for oxygen diffusion. However, this is not correct. The conditions under which diffusion and perfusion limitation occur have been clarified by Piiper and Scheid (1980). They used a simplified model with several assumptions including linearity of the oxygen dissociation curve in the working range. This situation is approached during conditions of severe hypoxia when the lung is operating very low on the oxygen dissociation curve. Using this simplified model, Piiper and Scheid showed that the total transfer rate M of a gas is given by the expression where PA and PV are the partial pressures of oxygen in the alveolar gas and venous blood, respectively, Q⋅ is cardiac output, D is the diffusing capacity, and β is the slope of the oxygen dissociation curve (assumed to be linear). The total conductance, G, for gas exchange between alveolar gas and capillary blood may be defined as the transfer rate divided by the total effective partial pressure difference (PA − PV), or This expression clarifies the factors responsible for diffusion and perfusion limitation. The equation shows that if D is very much larger than Q⋅β, the expression inside the large brackets tends to 1, and gas transfer is limited by perfusion only. In this case, the (perfusive) conductance is given by G = Q⋅β. The relative difference between the conductance without diffusion limitation and the actual conductance is an index of diffusion limitation, Ldiff, as shown in Figure 8.5. Figure 8.5Conditions under which diffusion limitation of gas transfer in the lung occurs. Ldiff is a measure of diffusion limitation; when its value is 1.0, gas transfer is entirely diffusion limited. It can be seen that Ldiff is greatest for carbon monoxide, and least for oxygen under hyperoxic conditions. D, diffusing capacity; Q⋅, pulmonary blood flow; β, solubility of the gas in blood, or slope of its dissociation curve. See text for details. (Modified from Piiper and Scheid 1980.) By contrast, diffusion limitation occurs if Q⋅β is so large that it greatly exceeds D, or to put it in another way, D becomes relatively very small. In this case the (diffusive) conductance is given by G = D. The relative difference between the conductance without perfusion limitation and the actual conductance is an index of perfusion limitation. Zero on the vertical axis of Figure 8.5 indicates complete perfusion limitation. Figure 8.5 shows that oxygen uptake is entirely perfusion limited in hyperoxia (extreme right of diagram) and that this is also true for the uptake of inert gases (those that do not combine with hemoglobin) such as nitrogen and sulfur hexafluoride. However, oxygen transfer during hypoxia becomes diffusion limited to some extent (middle of diagram) and this is particularly the case during exercise when oxygen consumption is greatly increased. For carbon monoxide, gas transfer is essentially diffusion limited under all conditions (left of diagram). The above analysis emphasizes that an important factor leading to diffusion limitation is an increase in β; that is, the slope of the blood-gas dissociation curve. This is the reason why the uptake of carbon monoxide is entirely diffusion limited; the slope of its dissociation curve is extremely large. An increased slope of the oxygen dissociation curve tending to diffusion limitation occurs for three reasons at high altitude: The lung is working on a low part of the oxygen dissociation curve, which is very steep. The polycythemia of high altitude increases the change in blood oxygen concentration per unit change in PO2. The left shift of the curve caused by the respiratory alkalosis increases its slope. In fact, at extreme altitude, oxygen begins to resemble carbon monoxide to some extent. For readers who prefer an intuitive explanation to the more formal analysis given above, the essential conclusion can be stated as follows. Diffusion limitation is likely when the “effective solubility” of the gas in pulmonary capillary blood (that is, the slope of the dissociation curve) greatly exceeds the solubility of the gas in the tissues of the blood-gas barrier. This condition is met for carbon monoxide, which has an enormous affinity for hemoglobin, and is approached for oxygen at high altitude because of the steepness of its dissociation curve at low PO2 values and the increased blood hemoglobin concentration. An analogy is the rate at which sheep can enter a field through a gate. If the gate is narrow but the field is large, the number of sheep that can enter in a given time is limited by the size of the gate. This is the situation at high altitude because the steepness of the oxygen dissociation curve allows a lot of oxygen to be loaded for a small rise in arterial PO2. However, if both the gate and the field are small (or both are big) the number of sheep is limited by the size of the field. This is the case at sea level. It can be shown that increasing the affinity of hemoglobin for oxygen expedites the loading of oxygen in the pulmonary capillary under conditions of diffusion limitation at high altitude. The oxygen affinity of hemoglobin is conveniently expressed by the P50, which is the PO2 for 50% saturation of the hemoglobin. The normal value for adult human hemoglobin is about 27 mmHg. Numerical analysis shows that increasing the affinity (leftward shift of the oxygen dissociation curve) results in more rapid equilibration between the PO2 of alveolar gas and pulmonary capillary blood. A simplified way of looking at this is that the left-shifted curve keeps the blood PO2 low in the initial stages of oxygen loading and thus maintains a large PO2 difference between alveolar gas and capillary blood during much of the oxygenation time. This increased PO2 difference therefore maintains the driving pressure and accelerates loading. However, a left-shifted oxygen dissociation curve interferes with the unloading of oxygen in peripheral capillaries because, for a given PO2 in venous blood (required to maintain the diffusion head of pressure to the tissues), the blood unloads less oxygen. It is therefore not intuitively obvious whether the advantages of a left-shifted curve in assisting the loading of oxygen in the pulmonary capillaries outweigh the disadvantages of unloading the oxygen in the peripheral capillaries. Several pieces of evidence suggest that a high oxygen affinity of hemoglobin is beneficial under hypoxic conditions. For example, the llama and vicuna, animals native to the Peruvian highlands, have left-shifted oxygen dissociation curves (Figure 8.6), as do some burrowing animals whose environment becomes oxygen depleted (Hall et al. 1936). The human fetus, which is believed to have arterial PO2 in the descending aorta of less than 25 mmHg, has a greatly increased oxygen affinity by virtue of its fetal hemoglobin, which has a P50 at pH 7.4 of about 17 mmHg. Experimental studies have shown that rats with artificially left-shifted oxygen dissociation curves tolerate severe acute hypoxia better than rats with normal dissociation curves (Eaton et al. 1974). Again, Hebbel et al. (1978) described a family in which two of the four children had an abnormal hemoglobin (Andrew-Minneapolis) with a P50 of 17 mmHg. These two siblings had a higher V⋅O2max at an altitude of 3100 m than the two with normal hemoglobin. Consistent with these studies, a novel human in vivo study reported a pH-related reduction in the P50 in subjects at 4000 m, compared to sea-level subjects (Balaban et al. 2013). Although important experimental differences and assumptions between in vitro and in vivo should be noted (Böning and Pries 2013), it was concluded that a pH-mediated increase in hemoglobin oxygen affinity in vivo may be part of the acclimatization process in humans at altitude. Further details on changes in the oxygen dissociation curve at high altitude are provided in Chapter 10. Figure 8.6Hemoglobin-oxygen dissociation curves for blood of llama (circle) and vicuna (triangle) compared with other mammals. The left-shifted curve for these high altitude native animals indicates an increased affinity of the hemoglobin for oxygen, which assists in oxygen loading along the pulmonary capillaries. (Source: Hall, Dill, and Barron 1936.) Numerical modeling gives some basis for these findings by showing that the increased oxygen affinity of the hemoglobin improves oxygenation in the pulmonary capillaries under conditions of diffusion limitation more than it interferes with the release of oxygen by peripheral capillaries (Bencowitz et al. 1982). Table 8.1 lists some of the strategies used by animals (including humans) to increase the oxygen affinity of their hemoglobin under hypoxic conditions. Strategy Subject Different sequence in globin chain Human fetus, bar-headed goose, toadfish Decrease in red cell 2,3-DPG Fetus of dog, horse, pig Decrease in ATP Trout, eel Different hemoglobin, small Bohr effect Tadpole Mutant hemoglobin (Andrew-Minneapolis) Humans Respiratory alkalosis Climber at extreme altitude Note: 2,3-DPG, 2,3-diphosphoglycerate; ATP, adenosine triphosphate.
Pulmonary gas exchange
Introduction
Historical
Effects of Hyperventilation on Gas Exchange
Acute Hypoxia Compared with Acclimatization
Physiology of Diffusion in the Lung
Fick’s law of diffusion
Reaction rates with hemoglobin
Rate of oxygen uptake along the pulmonary capillary
Diffusion and perfusion limitation of oxygen transfer
Oxygen affinity of hemoglobin and diffusion limitation
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