Chapter 5 Gas Exchange
The primary function of the lungs is to exchange gases between the blood and the external air. Mostly, of course, it is only O2 and CO2 that undergo exchange, but during gaseous anesthesia, the anesthetic gas is taken up by the lungs during induction or eliminated by the lungs during recovery. In addition, when a person is exposed to foreign gases in the air, these gases can be inhaled and may undergo exchange as well. Furthermore, gases with selected physical and chemical properties are sometimes used in cardiorespiratory research or even clinical care. For example, acetylene as a moderately soluble gas can be used to measure pulmonary blood flow; carbon monoxide (in very low concentrations) is routinely used to measure the lung diffusing capacity or transfer factor.
Fortunately, all such gases behave in accordance with the same basic physical principles underlying gas transport and exchange—mass conservation—explained in some detail further on. Although different gases appear to behave differently, this reflects their different physicochemical properties related to how they are transported in blood, and not differences in conforming to the mass conservation principles of exchange. Moreover, gas uptake from air into blood obeys the same rules as for gas elimination from the blood to the air. Thus, the topic of gas exchange can be treated as a general process applicable to all gases, whether taken up or eliminated. Subsequent applications can be made for individual gases in accord with their blood transport properties. In this chapter, the focus is primarily on the respiratory gases O2 and, to a lesser extent, CO2.
The lungs conduct gas exchange through three interacting processes: ventilation, diffusion, and perfusion (or blood flow). Ventilation brings O2 from the air to the alveoli (and simultaneously eliminates CO2, transferred from the blood, to the air). Diffusion is the process by which O2 in the alveoli passes across the alveolar wall into the pulmonary capillary. Perfusion moves the blood through the pulmonary circulation and allows continuously flowing red cells to take on O2. Ventilation and perfusion are mostly convective processes that require energy expenditure by the organism. Ventilation is an alternating, bidirectional process of inspiration and expiration, while perfusion is unidirectional from right ventricle to left atrium. Inspiration is accomplished by the respiratory muscles (diaphragm and external intercostal muscles mostly), which on contraction expand the thoracic cage, thus reducing the intrapleural pressure around the lungs, resulting in passive lung expansion. Expiration generally is passive and occurs as the respiratory muscles relax and allow the elastic recoil of the lung to expel air. Diffusion is passive and does not require the organism to expend energy. It simply reflects random molecular motion that over time tends to equalize molecular concentrations in space.
The evolutionary “decision” to conduct gas exchange by passive diffusion (rather than by energy-requiring active transport) was a profound one that dictated the basic structure of the lungs. The laws of diffusion show that diffusive mass transfer rates are directly proportional to the surface area available for diffusion and are inversely proportional to the distance the molecule must diffuse. The fundamental unit of structure in the lung is the alveolus, small and roughly spherical in shape, with an average radius of 150 micrometers (µm). There are about 300 million alveoli in the human lung. Each is supplied with air that must pass through the branching bronchial tree (conducting airways). The wall of each alveolus, shared by adjacent alveoli, is packed with capillaries. The tissue separating alveolar gas from the blood in the capillaries consists of the capillary endothelium, interstitial matrix, alveolar epithelium, and a thin layer of fluid. The entire wall is less than 0.5 µm in thickness.
These dimensions imply a total alveolar surface area of about 80 m2, yet a gas volume of only 4 L (small enough to fit within the chest cavity). Thus, the actual lung can conduct diffusive exchange efficiently because of the large surface area and small diffusion distance. By contrast, if the lungs consisted of just a single large sphere of the same 4-L volume, its surface area would be only m2 (640-fold less). Moreover, if the same mass of 0.5-µm-thick alveolar wall tissue covering all 300 million alveoli were spread around this one sphere, its thickness would be over 300 µm, also about 600 times greater than in the actual lung. Because diffusion rates depend on the ratio of area to thickness, the real lung is about 640 × 600, or 400,000 times better at diffusive transport than would be a single sphere of the same volume and mass. The message is that by dividing up the lung into a very large number of very small structures, diffusion becomes a feasible and energy-efficient method of gas exchange, circumventing the need for active transport.
This picture of the lungs is similar in some ways to a bunch of grapes in which each grape is an alveolus, the skin is the alveolar wall (containing the capillaries) and the pulp inside is the alveolar air space. The stalks connecting each grape to its cluster depict the conducting airways and blood vessels. A major shortcoming to the grape analogy, however, is that each grape in a bunch is physically detached from all others in the bunch. However, all alveoli are connected, sharing common alveolar walls, much like the cells of a honeycomb. This connectivity means that the alveoli are mechanically interdependent—they pull on each other, forming a self-stabilizing three-dimensional network.
Inequality of ventilation and blood flow: Because the lungs are ventilated through a single main airway (trachea), yet air must reach all 300 million alveoli, there must be a substantial branching airway system. Indeed, some 23 orders of largely dichotomous branching are recognized, resulting in a very large number of very small airways arranged in parallel with each other—much like tree branches emanating and serially dividing from a single trunk. It is impossible to imagine that inhaled air can be distributed homogeneously to all 300 million alveoli, and nonuniform ventilation distribution is well known to occur. Similarly, blood flow reaches the lungs from the main pulmonary artery by a corresponding branching system, and it also is known that perfusion is nonuniform. Nonuniform distribution of ventilation and blood flow are important for gas exchange efficiency as will be shown later.
Wasted ventilation (dead space): The first 17 or so generations of the airways are conducting airways—plumbing whose walls are unable to perform any gas exchange. Their total volume is about 150 mL. This means that with every single breath, 150 mL of inhaled air never reaches the alveoli yet must be moved by muscle contraction. Normally, each breath is about 500 mL in total volume, so about 30% of each breath represents wasted effort. This is not important in health, but in some lung diseases, the effort of breathing is so high that this wasted ventilation, called dead space, leads to insufficient ventilation of fresh gas to the alveoli.
Alveolar collapse: A very large number of very small collapsible structures is potentially physically unstable, due to surface tension forces. The laws of physics show that the pressure inside a soap bubble caused by surface tension is inversely proportional to the bubble radius. To the extent that the soap bubble analogy applies to the alveoli, which simply are not all exactly equal in size, surface tension forces will therefore tend to empty small alveoli into larger alveoli. Unchecked, this progression would lead to massive alveolar collapse with loss of gas exchange surface area and could prove fatal. In fact, the neonatal respiratory distress syndrome is considered to represent an example of just this phenomenon. The body has solved this problem by generating, in normal full-term newborns, a surfactant that lines each alveolus. It reduces surface tension by about an order of magnitude, greatly mitigating the risk of alveolar collapse. What also helps prevent collapse is the aforementioned interdependence whereby adjacent alveoli share common alveolar walls, creating a mesh or network that is inherently self-stabilizing.
Particle deposition: An array of about 20 orders of dichotomous branching leads to a very large (220 in this case) number of small peripheral airways. Although individually each is very small, there are so many of them that their total cross-sectional area becomes very large. With this arrangement, the forward velocity of the air in each small airway is reduced as air is inhaled, which in turn increases the chance that an inhaled dust (or other) particle will settle out and deposit on the small airway wall (compared with larger, more proximal airways, in which the velocity of air flow is much greater). If such a particle is physically, chemically, or biologically dangerous, disease may result, often starting in those small peripheral airways—as is the case for emphysema caused by inhalation of tobacco smoke.
Airway obstruction by mucus: Although the airways have developed a sophisticated particle clearance mechanism using mucociliary transport, the mucus that traps the particles may itself occlude small airways, impairing distal ventilation of the alveoli.
Capillary stress failure: The pulmonary microcirculation is at risk from the inherent structure of the lungs. With capillaries poorly supported in very thin alveolar walls (good for diffusion), they risk rupture into the alveolar space when intravascular pressures rise even modestly. Such alveolar hemorrhage occurs in several conditions, and especially in racehorses, whose lungs are relatively small, leading to high vascular pressures, which in this setting can be fatal.
Pulmonary hypertension: Because all of the cardiac output has to pass through the lungs (compare the systemic circulation, for which flow is divided among all of the body’s other tissues and organs), the potential for high vascular pressures is considerable. The twin processes of capillary distention and recruitment mitigate increases in pressure when perfusion is increased, as in exercise.
In sum, many life-threatening challenges may be associated with a lung built for diffusion, affecting the airways, alveoli, and blood vessels. In the normal lung, defenses against them are satisfactory, but in lung disease, they often are inadequate, with sometimes fatal outcomes.
Because gas exchange obeys mass conservation rules and occurs by passive diffusion, the exchange of gases can be understood and predicted quite accurately in a quantitative sense. In fact, quantitative discussion is essential to understanding of not just the principles but also the clinically very important differences in behavior of O2, CO2, and other gases. It is best to start with a perfectly homogeneous lung—one in which every alveolus is assumed to be identical and to receive an equal share of both ventilation and blood flow. Although an obvious oversimplification, this assumption allows the establishment of the basic principles, which can then be readily applied to lungs in which differences in ventilation and blood flow exist among alveoli.
For ventilation, mass conservation means that the amount of O2 diffusing into the pulmonary capillary blood from the alveolar gas in a given period (say, 1 minute—i.e., ) can be expressed as the difference between how much O2 was inhaled and how much was exhaled (over that minute). This relation holds because inhaled O2 has only two fates—diffusing into the blood or being exhaled. The amount inhaled is the product of minute ventilation and the concentration of O2 in inhaled air; the amount exhaled is the product of minute ventilation and the concentration of O2 in the exhaled gas. Because O2 concentration is constantly changing during the course of an exhalation, it is appropriate to use the mean concentration over exhalation. Minute ventilation is the product of the volume of each breath (L/breath) and the frequency of breathing (breaths/minute). Although the volumes inhaled and exhaled might be expected to be the same (or the lungs would either blow up or collapse), exhaled volume usually is 1% less than that inhaled because the amount of O2 absorbed into the blood is a little more than the amount of CO2 eliminated from the blood. This small difference can be neglected in most circumstances, as is the case in the following discussion. The mass conservation equation that then describes O2 uptake as a function of ventilation is
where is the volume of O2 taken up into the blood per minute, and is the minute ventilation, both expressed in L/minute. FIO2 and FEO2 are, respectively, the inhaled and exhaled mean O2 fractional concentrations. commonly is about 7 L/minute. Because about 21 of every 100 molecules in air are O2 molecules (the rest being mostly nitrogen), FIO2 is 0.21. FEO2 at rest is about 0.17; this difference shows that is about 0.3 L/minute. Because the conducting airways that feed the alveoli do not exchange O2 or CO2, it has become conventional to subtract the volume of gas left in the conducting airways each breath—the so-called anatomic dead space—from the total breath volume before multiplying by respiratory frequency to calculate ventilation, resulting in a variable known as alveolar ventilation (). Equation 1 then becomes
where FAO2 is now the mean alveolar O2 concentration. FAO2 is higher than FEO2 because the latter combines the inhaled air from the dead space with the alveolar gas, which is lower because of O2 transfer into the blood.
The tendency is to use partial pressure (PIO2, inhaled; PAO2, alveolar) rather than fractional concentration (FIO2, FAO2) in describing these relationships: From Dalton’s law of partial pressure, PO2 = FO2 × (barometric pressure − water vapor pressure). Allowing for proper units, Equation 2 can then be rewritten as
is the whole-body metabolic rate and as such is dictated by the body tissues, not the lungs. Because PIO2 is a constant, Equation 2 can be used to demonstrate the dependence of alveolar PO2 on alveolar ventilation for a given value of (Figure 5-1). The same concepts apply to CO2, for which it is simpler, because CO2 is essentially absent from inhaled air. The corresponding equation is
Figure 5-1 Relationship between alveolar PO2/PCO2 and alveolar ventilation when metabolic rate is held constant. Dashed lines indicate normal ventilation, PO2 and PCO2. Note that as ventilation is reduced, even moderately, PO2 falls sharply and PCO2 rises similarly.
The laws of diffusion dictate that the rate at which a gas diffuses between two points is the product of the diffusion coefficient for the gas and the partial pressure difference between the two points. In the lungs, the diffusion coefficient, measured as the diffusing capacity, is determined by surface area and distance of the diffusion pathway (see earlier). When a red cell leaves the pulmonary arteries and enters the pulmonary capillary, it arrives with a reduced level of O2, because the tissues visited by that red cell took O2 from the red cell for the tissue’s metabolic needs. The PO2 in the red cell in this blood commonly is about 40 mm Hg. Alveolar PO2, on the other hand, usually is about 100 mm Hg. The large PO2 difference (“driving gradient”) of 60 mm Hg leads to rapid diffusion of O2 from the alveolar gas into the capillary blood. Consequently, however, the blood PO2 increases, reducing the driving gradient, and O2 diffusion slows down as the red cell progresses along the lung capillary network. With modeling of this process, again using mass conservation principles, PO2 is seen to rise approximately exponentially as the red cell moves along the lung capillary until PO2 in the red cell has reached the alveolar value, indicating that diffusion equilibration has occurred. This process is shown in Figure 5-2. Note that for O2, equilibration occurred in about 0.25 second. On average, each red cell takes about 0.75 second to move through the alveolar capillary system, so that diffusion equilibration is complete already a third of the way along the capillary, and thus well before its end. As might be expected, during exercise, time available for a red cell to pick up O2 in the lung is reduced, because blood flow rate is increased, and at very high exercise intensity, there may not be sufficient time for PO2 in the red cell to reach the alveolar value. Accordingly, PO2 in the systemic arterial blood will be lower than that in the alveolus—a situation referred to as hypoxemia caused by diffusion limitation. This effect is seen commonly in exceptional athletes exercising heavily at sea level, and in all subjects exercising at altitude.
Figure 5-2 A, Rate of rise in gas partial pressure along the capillary. Inert gases equilibrate very rapidly, and O2 more slowly, but CO fails to equilibrate. B, Rate of fall in CO2 partial pressure along the capillary. CO2 equilibrates about twice as rapidly as does O2.
While CO2 moves from blood to gas, the principle is the same as for O2. Here, the red cell enters the alveolar capillary with a high PCO2 (because of addition of waste CO2 from tissues visited by the red cell), whereas alveolar PCO2 is lower. Thus, diffusion will move CO2 from red cell to alveolar gas, and red cell PCO2 will fall toward the alveolar value in mirror image to the rise in PO2 described earlier (see Figure 5-2). The speed of equilibration for CO2 is about twice that for O2, so it takes about half the time to reach equilibration. In practice, CO2 is never diffusion-limited. Gases carried in blood only in physical solution (i.e., inert and anesthetic gases) equilibrate even faster—about 10 times as quickly as for O2 (see Figure 5-2). This rule holds true for gases of any solubility.
In the remainder of this chapter, diffusion equilibration is assumed to be complete for all gases discussed. What this means is that the alveolar (A) and end-of-the-capillary (ec) PO2 values are the same for any one gas. Thus, for O2, PAO2 = PecO2.
From the preceding, it is clear that O2 brought to the alveoli by ventilation then diffuses into the flowing blood in lung capillaries. O2 uptake into the blood can be described using mass conservation principles, just as for ventilation. Thus, the amount of O2 taken up into the flowing blood per minute () is the amount of O2 in the blood leaving the lungs each minute heading for the left atrium, minus the amount that had entered the lungs in the pulmonary arterial blood. These amounts are the product of the concentration of O2 in each site and the blood flow rate. If CecO2 is the concentration of O2 in the end-capillary blood, CvO2 is the concentration of O2 in the capillary blood as it enters the lung capillaries, and is the blood flow rate through the lungs, mass conservation gives
Because O2 concentration in end-capillary blood is virtually unchanged between the end of the capillary and the systemic arterial circulation, end-capillary O2 concentration can be replaced with arterial CaO2, giving
Focusing on O2, Equations 3 and 8 should now be considered together. They both embody mass conservation but express it differently, with Equation 3 reflecting alveolar loss of O2 into blood and Equation 8, red cell gain of O2 into blood. Figure 5-3 shows how, for given constant values of and , and for designated values of inspired PO2 (PIO2) and inflowing pulmonary arterial O2 concentration (CvO2), would have to vary with alveolar PO2 (to satisfy both these equations) when determined by each of the two equations independently. Because each molecule of O2 that leaves the alveolus by crossing the blood gas barrier appears in the capillary blood, the calculated from the two equations must be the same—again, conservation of mass. Thus, only a single value of PAO2 can exist—that at the point of intersection of the two relationships in Figure 5-3. If the calculations in Figure 5-3 were repeated for different values of , and thus (in this example, keeping the same), the lines and their point of intersection would change as in Figure 5-4. This figure shows that alveolar PO2 (x axis) and the amount of O2 that can be taken up (, y axis) both depend on and . Commonly, Equations 3 and 8 are combined, because must be the same when calculated from either equation. This yields the ventilation-perfusion equation: