Guyton and Hall Textbook of Medical Physiology, 12th Ed


Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Through the Respiratory Membrane

image After the alveoli are ventilated with fresh air, the next step in the respiratory process is diffusion of oxygen from the alveoli into the pulmonary blood and diffusion of carbon dioxide in the opposite direction, out of the blood. The process of diffusion is simply the random motion of molecules in all directions through the respiratory membrane and adjacent fluids. However, in respiratory physiology, one is concerned not only with the basic mechanism by which diffusion occurs but also with the rate at which it occurs; this is a much more complex problem, requiring a deeper understanding of the physics of diffusion and gas exchange.

Physics of Gas Diffusion and Gas Partial Pressures

Molecular Basis of Gas Diffusion

All the gases of concern in respiratory physiology are simple molecules that are free to move among one another, a process called “diffusion.” This is also true of gases dissolved in the fluids and tissues of the body.

For diffusion to occur there must be a source of energy. This is provided by the kinetic motion of the molecules themselves. Except at absolute zero temperature, all molecules of all matter are continually undergoing motion. For free molecules that are not physically attached to others, this means linear movement at high velocity until they strike other molecules. Then they bounce away in new directions and continue until striking other molecules again. In this way, the molecules move rapidly and randomly among one another.

Net Diffusion of a Gas in One Direction—Effect of a Concentration Gradient

If a gas chamber or a solution has a high concentration of a particular gas at one end of the chamber and a low concentration at the other end, as shown in Figure 39-1, net diffusion of the gas will occur from the high-concentration area toward the low-concentration area. The reason is obvious: There are far more molecules at end A of the chamber to diffuse toward end B than there are molecules to diffuse in the opposite direction. Therefore, the rates of diffusion in each of the two directions are proportionately different, as demonstrated by the lengths of the arrows in the figure.


Figure 39-1 Diffusion of oxygen from one end of a chamber (A) to the other (B). The difference between the lengths of the arrows represents net diffusion.

Gas Pressures in a Mixture of Gases—“Partial Pressures” of Individual Gases

Pressure is caused by multiple impacts of moving molecules against a surface. Therefore, the pressure of a gas acting on the surfaces of the respiratory passages and alveoli is proportional to the summated force of impact of all the molecules of that gas striking the surface at any given instant. This means that the pressure is directly proportional to the concentration of the gas molecules.

In respiratory physiology, one deals with mixtures of gases, mainly of oxygen, nitrogen, and carbon dioxide. The rate of diffusion of each of these gases is directly proportional to the pressure caused by that gas alone, which is called the partial pressure of that gas. The concept of partial pressure can be explained as follows.

Consider air, which has an approximate composition of 79 percent nitrogen and 21 percent oxygen. The total pressure of this mixture at sea level averages 760 mm Hg. It is clear from the preceding description of the molecular basis of pressure that each gas contributes to the total pressure in direct proportion to its concentration. Therefore, 79 percent of the 760 mm Hg is caused by nitrogen (600 mm Hg) and 21 percent by oxygen (160 mm Hg). Thus, the “partial pressure” of nitrogen in the mixture is 600 mm Hg, and the “partial pressure” of oxygen is 160 mm Hg; the total pressure is 760 mm Hg, the sum of the individual partial pressures. The partial pressures of individual gases in a mixture are designated by the symbols PO2, PCO2, PN2, PHe, and so forth.

Pressures of Gases Dissolved in Water and Tissues

Gases dissolved in water or in body tissues also exert pressure because the dissolved gas molecules are moving randomly and have kinetic energy. Further, when the gas dissolved in fluid encounters a surface, such as the membrane of a cell, it exerts its own partial pressure in the same way that a gas in the gas phase does. The partial pressures of the separate dissolved gases are designated the same as the partial pressures in the gas state, that is, PO2, PCO2, PN2, PHe, and so forth.

Factors That Determine the Partial Pressure of a Gas Dissolved in a Fluid

The partial pressure of a gas in a solution is determined not only by its concentration but also by the solubility coefficient of the gas. That is, some types of molecules, especially carbon dioxide, are physically or chemically attracted to water molecules, whereas others are repelled. When molecules are attracted, far more of them can be dissolved without building up excess partial pressure within the solution. Conversely, in the case of those that are repelled, high partial pressure will develop with fewer dissolved molecules. These relations are expressed by the following formula, which is Henry’s law:


When partial pressure is expressed in atmospheres (1 atmosphere pressure equals 760 mm Hg) and concentration is expressed in volume of gas dissolved in each volume of water, the solubility coefficients for important respiratory gases at body temperature are the following:



Carbon dioxide


Carbon monoxide






From this table, one can see that carbon dioxide is more than 20 times as soluble as oxygen. Therefore, the partial pressure of carbon dioxide (for a given concentration) is less than one-twentieth that exerted by oxygen.

Diffusion of Gases Between the Gas Phase in the Alveoli and the Dissolved Phase in the Pulmonary Blood

The partial pressure of each gas in the alveolar respiratory gas mixture tends to force molecules of that gas into solution in the blood of the alveolar capillaries. Conversely, the molecules of the same gas that are already dissolved in the blood are bouncing randomly in the fluid of the blood, and some of these bouncing molecules escape back into the alveoli. The rate at which they escape is directly proportional to their partial pressure in the blood.

But in which direction will net diffusion of the gas occur? The answer is that net diffusion is determined by the difference between the two partial pressures. If the partial pressure is greater in the gas phase in the alveoli, as is normally true for oxygen, then more molecules will diffuse into the blood than in the other direction. Alternatively, if the partial pressure of the gas is greater in the dissolved state in the blood, which is normally true for carbon dioxide, then net diffusion will occur toward the gas phase in the alveoli.

Vapor Pressure of Water

When nonhumidified air is breathed into the respiratory passageways, water immediately evaporates from the surfaces of these passages and humidifies the air. This results from the fact that water molecules, like the different dissolved gas molecules, are continually escaping from the water surface into the gas phase. The partial pressure that the water molecules exert to escape through the surface is called the vapor pressure of the water. At normal body temperature, 37°C, this vapor pressure is 47 mm Hg. Therefore, once the gas mixture has become fully humidified—that is, once it is in “equilibrium” with the water—the partial pressure of the water vapor in the gas mixture is 47 mm Hg. This partial pressure, like the other partial pressures, is designated PH2O.

The vapor pressure of water depends entirely on the temperature of the water. The greater the temperature, the greater the kinetic activity of the molecules and, therefore, the greater the likelihood that the water molecules will escape from the surface of the water into the gas phase. For instance, the water vapor pressure at 0°C is 5 mm Hg, and at 100°C it is 760 mm Hg. But the most important value to remember is the vapor pressure at body temperature, 47 mm Hg; this value appears in many of our subsequent discussions.

Diffusion of Gases Through Fluids—Pressure Difference Causes Net Diffusion

From the preceding discussion, it is clear that when the partial pressure of a gas is greater in one area than in another area, there will be net diffusion from the high-pressure area toward the low-pressure area. For instance, returning to Figure 39-1, one can readily see that the molecules in the area of high pressure, because of their greater number, have a greater chance of moving randomly into the area of low pressure than do molecules attempting to go in the other direction. However, some molecules do bounce randomly from the area of low pressure toward the area of high pressure. Therefore, the net diffusion of gas from the area of high pressure to the area of low pressure is equal to the number of molecules bouncing in this forward direction minus the number bouncing in the opposite direction; this is proportional to the gas partial pressure difference between the two areas, called simply the pressure difference for causing diffusion.

Quantifying the Net Rate of Diffusion in Fluids

In addition to the pressure difference, several other factors affect the rate of gas diffusion in a fluid. They are (1) the solubility of the gas in the fluid, (2) the cross-sectional area of the fluid, (3) the distance through which the gas must diffuse, (4) the molecular weight of the gas, and (5) the temperature of the fluid. In the body, the last of these factors, the temperature, remains reasonably constant and usually need not be considered.

The greater the solubility of the gas, the greater the number of molecules available to diffuse for any given partial pressure difference. The greater the cross-sectional area of the diffusion pathway, the greater the total number of molecules that diffuse. Conversely, the greater the distance the molecules must diffuse, the longer it will take the molecules to diffuse the entire distance. Finally, the greater the velocity of kinetic movement of the molecules, which is inversely proportional to the square root of the molecular weight, the greater the rate of diffusion of the gas. All these factors can be expressed in a single formula, as follows:


in which D is the diffusion rate, ΔP is the partial pressure difference between the two ends of the diffusion pathway, A is the cross-sectional area of the pathway, S is the solubility of the gas, d is the distance of diffusion, and MW is the molecular weight of the gas.

It is obvious from this formula that the characteristics of the gas itself determine two factors of the formula: solubility and molecular weight. Together, these two factors determine the diffusion coefficient of the gas, which is proportional to S/image that is, the relative rates at which different gases at the same partial pressure levels will diffuse are proportional to their diffusion coefficients. Assuming that the diffusion coefficient for oxygen is 1, the relative diffusion coefficients for different gases of respiratory importance in the body fluids are as follows:



Carbon dioxide


Carbon monoxide






Diffusion of Gases Through Tissues

The gases that are of respiratory importance are all highly soluble in lipids and, consequently, are highly soluble in cell membranes. Because of this, the major limitation to the movement of gases in tissues is the rate at which the gases can diffuse through the tissue water instead of through the cell membranes. Therefore, diffusion of gases through the tissues, including through the respiratory membrane, is almost equal to the diffusion of gases in water, as given in the preceding list.

Compositions of Alveolar Air and Atmospheric Air Are Different

Alveolar air does not have the same concentrations of gases as atmospheric air by any means, which can readily be seen by comparing the alveolar air composition in Table 39-1 with that of atmospheric air. There are several reasons for the differences. First, the alveolar air is only partially replaced by atmospheric air with each breath. Second, oxygen is constantly being absorbed into the pulmonary blood from the alveolar air. Third, carbon dioxide is constantly diffusing from the pulmonary blood into the alveoli. And fourth, dry atmospheric air that enters the respiratory passages is humidified even before it reaches the alveoli.

Table 39-1 Partial Pressures of Respiratory Gases as They Enter and Leave the Lungs (at Sea Level)


Humidification of the Air in the Respiratory Passages

Table 39-1 shows that atmospheric air is composed almost entirely of nitrogen and oxygen; it normally contains almost no carbon dioxide and little water vapor. However, as soon as the atmospheric air enters the respiratory passages, it is exposed to the fluids that cover the respiratory surfaces. Even before the air enters the alveoli, it becomes (for all practical purposes) totally humidified.

The partial pressure of water vapor at a normal body temperature of 37°C is 47 mm Hg, which is therefore the partial pressure of water vapor in the alveolar air. Because the total pressure in the alveoli cannot rise to more than the atmospheric pressure (760 mm Hg at sea level), this water vapor simply dilutes all the other gases in the inspired air. Table 39-1 also shows that humidification of the air dilutes the oxygen partial pressure at sea level from an average of 159 mm Hg in atmospheric air to 149 mm Hg in the humidified air, and it dilutes the nitrogen partial pressure from 597 to 563 mm Hg.

Rate at Which Alveolar Air Is Renewed by Atmospheric Air

In Chapter 37, it was pointed out that the average male functional residual capacity of the lungs (the volume of air remaining in the lungs at the end of normal expiration) measures about 2300 milliliters. Yet only 350 milliliters of new air is brought into the alveoli with each normal inspiration, and this same amount of old alveolar air is expired. Therefore, the volume of alveolar air replaced by new atmospheric air with each breath is only one seventh of the total, so multiple breaths are required to exchange most of the alveolar air. Figure 39-2 shows this slow rate of renewal of the alveolar air. In the first alveolus of the figure, excess gas is present in the alveoli, but note that even at the end of 16 breaths, the excess gas still has not been completely removed from the alveoli.


Figure 39-2 Expiration of a gas from an alveolus with successive breaths.

Figure 39-3 demonstrates graphically the rate at which excess gas in the alveoli is normally removed, showing that with normal alveolar ventilation, about one-half the gas is removed in 17 seconds. When a person’s rate of alveolar ventilation is only one-half normal, one-half the gas is removed in 34 seconds, and when the rate of ventilation is twice normal, one half is removed in about 8 seconds.


Figure 39-3 Rate of removal of excess gas from alveoli.

Importance of the Slow Replacement of Alveolar Air

The slow replacement of alveolar air is of particular importance in preventing sudden changes in gas concentrations in the blood. This makes the respiratory control mechanism much more stable than it would be otherwise, and it helps prevent excessive increases and decreases in tissue oxygenation, tissue carbon dioxide concentration, and tissue pH when respiration is temporarily interrupted.

Oxygen Concentration and Partial Pressure in the Alveoli

Oxygen is continually being absorbed from the alveoli into the blood of the lungs, and new oxygen is continually being breathed into the alveoli from the atmosphere. The more rapidly oxygen is absorbed, the lower its concentration in the alveoli becomes; conversely, the more rapidly new oxygen is breathed into the alveoli from the atmosphere, the higher its concentration becomes. Therefore, oxygen concentration in the alveoli, as well as its partial pressure, is controlled by (1) the rate of absorption of oxygen into the blood and (2) the rate of entry of new oxygen into the lungs by the ventilatory process.

Figure 39-4 shows the effect of both alveolar ventilation and rate of oxygen absorption into the blood on the alveolar partial pressure of oxygen (PO2). One curve represents oxygen absorption at a rate of 250 ml/min, and the other curve represents a rate of 1000 ml/min. At a normal ventilatory rate of 4.2 L/min and an oxygen consumption of 250 ml/min, the normal operating point in Figure 39-4 is point A. The figure also shows that when 1000 milliliters of oxygen is being absorbed each minute, as occurs during moderate exercise, the rate of alveolar ventilation must increase fourfold to maintain the alveolar Po2 at the normal value of 104 mm Hg.


Figure 39-4 Effect of alveolar ventilation on the alveolar PO2 at two rates of oxygen absorption from the alveoli—250 ml/min and 1000 ml/min. Point A is the normal operating point.

Another effect shown in Figure 39-4 is that an extremely marked increase in alveolar ventilation can never increase the alveolar PO2 above 149 mm Hg as long as the person is breathing normal atmospheric air at sea level pressure, because this is the maximum PO2 in humidified air at this pressure. If the person breathes gases that contain partial pressures of oxygen higher than 149 mm Hg, the alveolar PO2 can approach these higher pressures at high rates of ventilation.

CO2 Concentration and Partial Pressure in the Alveoli

Carbon dioxide is continually being formed in the body and then carried in the blood to the alveoli; it is continually being removed from the alveoli by ventilation. Figure 39-5 shows the effects on the alveolar partial pressure of carbon dioxide (PCO2) of both alveolar ventilation and two rates of carbon dioxide excretion, 200 and 800 ml/min. One curve represents a normal rate of carbon dioxide excretion of 200 ml/min. At the normal rate of alveolar ventilation of 4.2 L/min, the operating point for alveolar PCO2 is at point A in Figure 39-5 (i.e., 40 mm Hg).


Figure 39-5 Effect of alveolar ventilation on the alveolar PCO2 at two rates of carbon dioxide excretion from the blood—800 ml/min and 200 ml/min. Point A is the normal operating point.

Two other facts are also evident from Figure 39-5: First, the alveolar PCO2 increases directly in proportion to the rate of carbon dioxide excretion, as represented by the fourfold elevation of the curve (when 800 milliliters of CO2are excreted per minute). Second, the alveolar PCO2 decreases in inverse proportion to alveolar ventilation. Therefore, the concentrations and partial pressures of both oxygen and carbon dioxide in the alveoli are determined by the rates of absorption or excretion of the two gases and by the amount of alveolar ventilation.

Expired Air Is a Combination of Dead Space Air and Alveolar Air

The overall composition of expired air is determined by (1) the amount of the expired air that is dead space air and (2) the amount that is alveolar air. Figure 39-6 shows the progressive changes in oxygen and carbon dioxide partial pressures in the expired air during the course of expiration. The first portion of this air, the dead space air from the respiratory passageways, is typical humidified air, as shown in Table 39-1. Then, progressively more and more alveolar air becomes mixed with the dead space air until all the dead space air has finally been washed out and nothing but alveolar air is expired at the end of expiration. Therefore, the method of collecting alveolar air for study is simply to collect a sample of the last portion of the expired air after forceful expiration has removed all the dead space air.


Figure 39-6 Oxygen and carbon dioxide partial pressures in the various portions of normal expired air.

Normal expired air, containing both dead space air and alveolar air, has gas concentrations and partial pressures approximately as shown in Table 39-1 (i.e., concentrations between those of alveolar air and humidified atmospheric air).

Diffusion of Gases Through the Respiratory Membrane

Respiratory Unit

Figure 39-7 shows the respiratory unit (also called “respiratory lobule”), which is composed of a respiratory bronchiole, alveolar ducts, atria, and alveoli. There are about 300 million alveoli in the two lungs, and each alveolus has an average diameter of about 0.2 millimeter. The alveolar walls are extremely thin, and between the alveoli is an almost solid network of interconnecting capillaries, shown in Figure 39-8. Indeed, because of the extensiveness of the capillary plexus, the flow of blood in the alveolar wall has been described as a “sheet” of flowing blood. Thus, it is obvious that the alveolar gases are in very close proximity to the blood of the pulmonary capillaries. Further, gas exchange between the alveolar air and the pulmonary blood occurs through the membranes of all the terminal portions of the lungs, not merely in the alveoli themselves. All these membranes are collectively known as the respiratory membrane, also called the pulmonary membrane.


Figure 39-7 Respiratory unit.


Figure 39-8 A, Surface view of capillaries in an alveolar wall. B, Cross-sectional view of alveolar walls and their vascular supply.

(A, From Maloney JE, Castle BL: Pressure-diameter relations of capillaries and small blood vessels in frog lung. Respir Physiol 7:150, 1969. Reproduced by permission of ASP Biological and Medical Press, North-Holland Division.)

Respiratory Membrane

Figure 39-9 shows the ultrastructure of the respiratory membrane drawn in cross section on the left and a red blood cell on the right. It also shows the diffusion of oxygen from the alveolus into the red blood cell and diffusion of carbon dioxide in the opposite direction. Note the following different layers of the respiratory membrane:

1. A layer of fluid lining the alveolus and containing surfactant that reduces the surface tension of the alveolar fluid

2. The alveolar epithelium composed of thin epithelial cells

3. An epithelial basement membrane

4. A thin interstitial space between the alveolar epithelium and the capillary membrane

5. A capillary basement membrane that in many places fuses with the alveolar epithelial basement membrane

6. The capillary endothelial membrane


Figure 39-9 Ultrastructure of the alveolar respiratory membrane, shown in cross section.

Despite the large number of layers, the overall thickness of the respiratory membrane in some areas is as little as 0.2 micrometer, and it averages about 0.6 micrometer, except where there are cell nuclei. From histological studies, it has been estimated that the total surface area of the respiratory membrane is about 70 square meters in the normal adult human male. This is equivalent to the floor area of a 25-by-30-foot room. The total quantity of blood in the capillaries of the lungs at any given instant is 60 to 140 milliliters. Now imagine this small amount of blood spread over the entire surface of a 25-by-30-foot floor, and it is easy to understand the rapidity of the respiratory exchange of oxygen and carbon dioxide.

The average diameter of the pulmonary capillaries is only about 5 micrometers, which means that red blood cells must squeeze through them. The red blood cell membrane usually touches the capillary wall, so oxygen and carbon dioxide need not pass through significant amounts of plasma as they diffuse between the alveolus and the red cell. This, too, increases the rapidity of diffusion.

Factors That Affect the Rate of Gas Diffusion Through the Respiratory Membrane

Referring to the earlier discussion of diffusion of gases in water, one can apply the same principles and mathematical formulas to diffusion of gases through the respiratory membrane. Thus, the factors that determine how rapidly a gas will pass through the membrane are (1) the thickness of the membrane, (2) the surface area of the membrane, (3) the diffusion coefficient of the gas in the substance of the membrane, and (4) the partial pressure difference of the gas between the two sides of the membrane.

The thickness of the respiratory membrane occasionally increases—for instance, as a result of edema fluid in the interstitial space of the membrane and in the alveoli—so the respiratory gases must then diffuse not only through the membrane but also through this fluid. Also, some pulmonary diseases cause fibrosis of the lungs, which can increase the thickness of some portions of the respiratory membrane. Because the rate of diffusion through the membrane is inversely proportional to the thickness of the membrane, any factor that increases the thickness to more than two to three times normal can interfere significantly with normal respiratory exchange of gases.

The surface area of the respiratory membrane can be greatly decreased by many conditions. For instance, removal of an entire lung decreases the total surface area to one half normal. Also, in emphysema, many of the alveoli coalesce, with dissolution of many alveolar walls. Therefore, the new alveolar chambers are much larger than the original alveoli, but the total surface area of the respiratory membrane is often decreased as much as fivefold because of loss of the alveolar walls. When the total surface area is decreased to about one-third to one-fourth normal, exchange of gases through the membrane is impeded to a significant degree, even under resting conditions, and during competitive sports and other strenuous exercise even the slightest decrease in surface area of the lungs can be a serious detriment to respiratory exchange of gases.

The diffusion coefficient for transfer of each gas through the respiratory membrane depends on the gas’s solubility in the membrane and, inversely, on the square root of the gas’s molecular weight. The rate of diffusion in the respiratory membrane is almost exactly the same as that in water, for reasons explained earlier. Therefore, for a given pressure difference, carbon dioxide diffuses about 20 times as rapidly as oxygen. Oxygen diffuses about twice as rapidly as nitrogen.

The pressure difference across the respiratory membrane is the difference between the partial pressure of the gas in the alveoli and the partial pressure of the gas in the pulmonary capillary blood. The partial pressure represents a measure of the total number of molecules of a particular gas striking a unit area of the alveolar surface of the membrane in unit time, and the pressure of the gas in the blood represents the number of molecules that attempt to escape from the blood in the opposite direction. Therefore, the difference between these two pressures is a measure of the net tendency for the gas molecules to move through the membrane.

When the partial pressure of a gas in the alveoli is greater than the pressure of the gas in the blood, as is true for oxygen, net diffusion from the alveoli into the blood occurs; when the pressure of the gas in the blood is greater than the partial pressure in the alveoli, as is true for carbon dioxide, net diffusion from the blood into the alveoli occurs.

Diffusing Capacity of the Respiratory Membrane

The ability of the respiratory membrane to exchange a gas between the alveoli and the pulmonary blood is expressed in quantitative terms by the respiratory membrane’s diffusing capacity, which is defined as the volume of a gas that will diffuse through the membrane each minute for a partial pressure difference of 1 mm Hg. All the factors discussed earlier that affect diffusion through the respiratory membrane can affect this diffusing capacity.

Diffusing Capacity for Oxygen

In the average young man, the diffusing capacity for oxygen under resting conditions averages 21 ml/min/mm Hg. In functional terms, what does this mean? The mean oxygen pressure difference across the respiratory membrane during normal, quiet breathing is about 11 mm Hg. Multiplication of this pressure by the diffusing capacity (11 × 21) gives a total of about 230 milliliters of oxygen diffusing through the respiratory membrane each minute; this is equal to the rate at which the resting body uses oxygen.

Increased Oxygen Diffusing Capacity During Exercise

During strenuous exercise or other conditions that greatly increase pulmonary blood flow and alveolar ventilation, the diffusing capacity for oxygen increases in young men to a maximum of about 65 ml/min/mm Hg, which is three times the diffusing capacity under resting conditions. This increase is caused by several factors, among which are (1) opening up of many previously dormant pulmonary capillaries or extra dilation of already open capillaries, thereby increasing the surface area of the blood into which the oxygen can diffuse; and (2) a better match between the ventilation of the alveoli and the perfusion of the alveolar capillaries with blood, called the ventilation-perfusion ratio, which is explained in detail later in this chapter. Therefore, during exercise, oxygenation of the blood is increased not only by increased alveolar ventilation but also by greater diffusing capacity of the respiratory membrane for transporting oxygen into the blood.

Diffusing Capacity for Carbon Dioxide

The diffusing capacity for carbon dioxide has never been measured because of the following technical difficulty: Carbon dioxide diffuses through the respiratory membrane so rapidly that the average PCO2 in the pulmonary blood is not far different from the PCO2 in the alveoli—the average difference is less than 1 mm Hg—and with the available techniques, this difference is too small to be measured.

Nevertheless, measurements of diffusion of other gases have shown that the diffusing capacity varies directly with the diffusion coefficient of the particular gas. Because the diffusion coefficient of carbon dioxide is slightly more than 20 times that of oxygen, one would expect a diffusing capacity for carbon dioxide under resting conditions of about 400 to 450 ml/min/mm Hg and during exercise of about 1200 to 1300 ml/min/mm Hg. Figure 39-10 compares the measured or calculated diffusing capacities of carbon monoxide, oxygen, and carbon dioxide at rest and during exercise, showing the extreme diffusing capacity of carbon dioxide and the effect of exercise on the diffusing capacity of each of these gases.


Figure 39-10 Diffusing capacities for carbon monoxide, oxygen, and carbon dioxide in the normal lungs under resting conditions and during exercise.

Measurement of Diffusing Capacity—the Carbon Monoxide Method

The oxygen diffusing capacity can be calculated from measurements of (1) alveolar PO2, (2) PO2 in the pulmonary capillary blood, and (3) the rate of oxygen uptake by the blood. However, measuring the PO2in the pulmonary capillary blood is so difficult and so imprecise that it is not practical to measure oxygen diffusing capacity by such a direct procedure, except on an experimental basis.

To obviate the difficulties encountered in measuring oxygen diffusing capacity directly, physiologists usually measure carbon monoxide diffusing capacity instead and then calculate the oxygen diffusing capacity from this. The principle of the carbon monoxide method is the following: A small amount of carbon monoxide is breathed into the alveoli, and the partial pressure of the carbon monoxide in the alveoli is measured from appropriate alveolar air samples. The carbon monoxide pressure in the blood is essentially zero because hemoglobin combines with this gas so rapidly that its pressure never has time to build up. Therefore, the pressure difference of carbon monoxide across the respiratory membrane is equal to its partial pressure in the alveolar air sample. Then, by measuring the volume of carbon monoxide absorbed in a short period and dividing this by the alveolar carbon monoxide partial pressure, one can determine accurately the carbon monoxide diffusing capacity.

To convert carbon monoxide diffusing capacity to oxygen diffusing capacity, the value is multiplied by a factor of 1.23 because the diffusion coefficient for oxygen is 1.23 times that for carbon monoxide. Thus, the average diffusing capacity for carbon monoxide in young men at rest is 17 ml/min/mm Hg, and the diffusing capacity for oxygen is 1.23 times this, or 21 ml/min/mm Hg.

Effect of the Ventilation-Perfusion Ratio on Alveolar Gas Concentration

In the early part of this chapter, we learned that two factors determine the PO2 and the PCO2 in the alveoli: (1) the rate of alveolar ventilation and (2) the rate of transfer of oxygen and carbon dioxide through the respiratory membrane. These earlier discussions made the assumption that all the alveoli are ventilated equally and that blood flow through the alveolar capillaries is the same for each alveolus. However, even normally to some extent, and especially in many lung diseases, some areas of the lungs are well ventilated but have almost no blood flow, whereas other areas may have excellent blood flow but little or no ventilation. In either of these conditions, gas exchange through the respiratory membrane is seriously impaired, and the person may suffer severe respiratory distress despite both normal total ventilation and normal total pulmonary blood flow, but with the ventilation and blood flow going to different parts of the lungs. Therefore, a highly quantitative concept has been developed to help us understand respiratory exchange when there is imbalance between alveolar ventilation and alveolar blood flow. This concept is called the ventilation-perfusion ratio.

In quantitative terms, the ventilation-perfusion ratio is expressed as image. When image (alveolar ventilation) is normal for a given alveolus and image (blood flow) is also normal for the same alveolus, the ventilation-perfusion ratio (image) is also said to be normal. When the ventilation (image) is zero, yet there is still perfusion (image) of the alveolus, the image is zero. Or, at the other extreme, when there is adequate ventilation (image) but zero perfusion (image), the ratio image is infinity. At a ratio of either zero or infinity, there is no exchange of gases through the respiratory membrane of the affected alveoli, which explains the importance of this concept. Therefore, let us explain the respiratory consequences of these two extremes.

Alveolar Oxygen and Carbon Dioxide Partial Pressures When image Equals Zero

When image is equal to zero—that is, without any alveolar ventilation—the air in the alveolus comes to equilibrium with the blood oxygen and carbon dioxide because these gases diffuse between the blood and the alveolar air. Because the blood that perfuses the capillaries is venous blood returning to the lungs from the systemic circulation, it is the gases in this blood with which the alveolar gases equilibrate. In Chapter 40, we describe how the normal venous blood (image) has a PO2 of 40 mm Hg and a PCO2 of 45 mm Hg. Therefore, these are also the normal partial pressures of these two gases in alveoli that have blood flow but no ventilation.

Alveolar Oxygen and Carbon Dioxide Partial Pressures When image Equals Infinity

The effect on the alveolar gas partial pressures when image equals infinity is entirely different from the effect when image equals zero because now there is no capillary blood flow to carry oxygen away or to bring carbon dioxide to the alveoli. Therefore, instead of the alveolar gases coming to equilibrium with the venous blood, the alveolar air becomes equal to the humidified inspired air. That is, the air that is inspired loses no oxygen to the blood and gains no carbon dioxide from the blood. And because normal inspired and humidified air has a PO2 of 149 mm Hg and a PCO2 of 0 mm Hg, these will be the partial pressures of these two gases in the alveoli.

Gas Exchange and Alveolar Partial Pressures When image Is Normal

When there is both normal alveolar ventilation and normal alveolar capillary blood flow (normal alveolar perfusion), exchange of oxygen and carbon dioxide through the respiratory membrane is nearly optimal, and alveolar PO2 is normally at a level of 104 mm Hg, which lies between that of the inspired air (149 mm Hg) and that of venous blood (40 mm Hg). Likewise, alveolar PCO2 lies between two extremes; it is normally 40 mm Hg, in contrast to 45 mm Hg in venous blood and 0 mm Hg in inspired air. Thus, under normal conditions, the alveolar air PO2 averages 104 mm Hg and the PCO2 averages 40 mm Hg.

PO2-PCO2image Diagram

The concepts presented in the preceding sections can be shown in graphical form, as demonstrated in Figure 39-11, called the Po2-Pco2image diagram. The curve in the diagram represents all possible PO2 and PCO2 combinations between the limits of image equals zero and image equals infinity when the gas pressures in the venous blood are normal and the person is breathing air at sea-level pressure. Thus, point image is the plot of PO2 and PCO2 when image equals zero. At this point, the PO2 is 40 mm Hg and the PCO2 is 45 mm Hg, which are the values in normal venous blood.


Figure 39-11 Normal PO2-PCO2image diagram.

At the other end of the curve, when image equals infinity, point I represents inspired air, showing PO2 to be 149 mm Hg while PCO2 is zero. Also plotted on the curve is the point that represents normal alveolar air when image is normal. At this point, PO2 is 104 mm Hg and PCO2 is 40 mm Hg.

Concept of “Physiologic Shunt” (When image Is Below Normal)

Whenever image is below normal, there is inadequate ventilation to provide the oxygen needed to fully oxygenate the blood flowing through the alveolar capillaries. Therefore, a certain fraction of the venous blood passing through the pulmonary capillaries does not become oxygenated. This fraction is called shunted blood. Also, some additional blood flows through bronchial vessels rather than through alveolar capillaries, normally about 2 percent of the cardiac output; this, too, is unoxygenated, shunted blood.

The total quantitative amount of shunted blood per minute is called the physiologic shunt. This physiologic shunt is measured in clinical pulmonary function laboratories by analyzing the concentration of oxygen in both mixed venous blood and arterial blood, along with simultaneous measurement of cardiac output. From these values, the physiologic shunt can be calculated by the following equation:


in which image is the physiologic shunt blood flow per minute, image is cardiac output per minute, CiO2 is the concentration of oxygen in the arterial blood if there is an “ideal” ventilation-perfusion ratio, CaO2 is the measured concentration of oxygen in the arterial blood, and image is the measured concentration of oxygen in the mixed venous blood.

The greater the physiologic shunt, the greater the amount of blood that fails to be oxygenated as it passes through the lungs.

Concept of the “Physiologic Dead Space” (When image Is Greater Than Normal)

When ventilation of some of the alveoli is great but alveolar blood flow is low, there is far more available oxygen in the alveoli than can be transported away from the alveoli by the flowing blood. Thus, the ventilation of these alveoli is said to be wasted. The ventilation of the anatomical dead space areas of the respiratory passageways is also wasted. The sum of these two types of wasted ventilation is called the physiologic dead space. This is measured in the clinical pulmonary function laboratory by making appropriate blood and expiratory gas measurements and using the following equation, called the Bohr equation:


in which image is the physiologic dead space, image is the tidal volume, PaCO2 is the partial pressure of carbon dioxide in the arterial blood, and image is the average partial pressure of carbon dioxide in the entire expired air.

When the physiologic dead space is great, much of the work of ventilation is wasted effort because so much of the ventilating air never reaches the blood.

Abnormalities of Ventilation-Perfusion Ratio

Abnormal image in the Upper and Lower Normal Lung

In a normal person in the upright position, both pulmonary capillary blood flow and alveolar ventilation are considerably less in the upper part of the lung than in the lower part; however, blood flow is decreased considerably more than ventilation is. Therefore, at the top of the lung, image is as much as 2.5 times as great as the ideal value, which causes a moderate degree of physiologic dead space in this area of the lung.

At the other extreme, in the bottom of the lung, there is slightly too little ventilation in relation to blood flow, with image as low as 0.6 times the ideal value. In this area, a small fraction of the blood fails to become normally oxygenated, and this represents a physiologic shunt.

In both extremes, inequalities of ventilation and perfusion decrease slightly the lung’s effectiveness for exchanging oxygen and carbon dioxide. However, during exercise, blood flow to the upper part of the lung increases markedly, so far less physiologic dead space occurs, and the effectiveness of gas exchange now approaches optimum.

Abnormal image in Chronic Obstructive Lung Disease

Most people who smoke for many years develop various degrees of bronchial obstruction; in a large share of these persons, this condition eventually becomes so severe that they develop serious alveolar air trapping and resultant emphysema. The emphysema in turn causes many of the alveolar walls to be destroyed. Thus, two abnormalities occur in smokers to cause abnormal image. First, because many of the small bronchioles are obstructed, the alveoli beyond the obstructions are unventilated, causing a image that approaches zero. Second, in those areas of the lung where the alveolar walls have been mainly destroyed but there is still alveolar ventilation, most of the ventilation is wasted because of inadequate blood flow to transport the blood gases.

Thus, in chronic obstructive lung disease, some areas of the lung exhibit serious physiologic shunt, and other areas exhibit serious physiologic dead space. Both conditions tremendously decrease the effectiveness of the lungs as gas exchange organs, sometimes reducing their effectiveness to as little as one-tenth normal. In fact, this is the most prevalent cause of pulmonary disability today.


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