Walter F. Boron
Although diffusion is at the very heart of the gas exchange, as we discussed in Chapter 30, two other parameters are also extremely important. Ventilation and perfusion—both of which require energy—are critical because they set up the partial pressure gradients along which O2 and CO2 diffuse. Ventilation is the convective movement of air that exchanges gases between the atmosphere and the alveoli. In Chapter 27, we discussed the mechanics of ventilation. In the first part of this chapter, we consider the importance of ventilation for determination of alveolar PO2 and PCO2 and also see that ventilation varies from one group of alveoli to the next. Perfusion is the convective movement of blood that carries the dissolved gases to and from the lung. In Chapters 17 to 25 Chapter 18 Chapter 19 Chapter 20 Chapter 21 Chapter 22Chapter 23 Chapter 24, we discussed the cardiovascular system. In the second part of this chapter, we examine the special properties of the pulmonary circulation and see that, like ventilation, perfusion varies in different regions of the lung. Finally, in the third part of this chapter, we see that the ratio of ventilation to perfusion—and the distribution of ventilation-perfusion ratio among alveolar units—is critically important for gas exchange and thus for the composition of the arterial blood gases: PO2, PCO2, and pH.
About 30% of total ventilation in a respiratory cycle is wasted ventilating anatomical dead space (i.e., conducting airways)
Total ventilation (VT) is the volume of air moved out of the lungs per unit of time:
Here, V is the volume of air exiting the lungs during a series of breaths. Note that we are using differently than in Chapter 27, where represented flow through an airway at a particular instant in time. A practical definition is that T is the product of tidal volume (TV or VT) and the respiratory frequency (f). Thus, for someone with a tidal volume of 0.5 L, breathing 12 breaths/min:
Because total ventilation is usually reported as liters per minute, it is sometimes called minute ventilation.
Before an inspiration, the conducting airways are filled with “stale” air having the same composition as alveolar air (Fig. 31-1, step 1); we will see why shortly. During inspiration, ~500 mL of “fresh” atmospheric air (high PO2/low PCO2) enters the body (step 2). However, only the first 350 mL reaches the alveoli; the final 150 mL remains in the conducting airways (nose, pharynx, larynx, trachea, and other airways without alveoli)—that is, the anatomical dead space. These figures are typical for a 70-kg person; VT and Vd are roughly proportional to body size. During inspiration, ~500 mL of air also enters the alveoli. However, the first 150 mL is stale air previously in the conducting airways; only the final 350 mL is fresh air. By the end of inspiration, the 500 mL of air that entered the alveoli (150 mL of stale air plus 350 mL of fresh air) has mixed by diffusion with the preexisting alveolar air (step 3). During expiration (step 4), the first 150 mL of air emerging from the body is the fresh air left in the conducting airways from the previous inspiration. As the expiration continues, 350 mL of stale alveolar air sequentially moves into the conducting airways and then exits the body—for a total of 500 mL of air leaving the body. Simultaneously, 500 mL of air leaves the alveoli. The first 350 mL is the same 350 mL that exited the body. The final 150 mL of stale air to exit the alveoli remains in the conducting airways, as we are ready to begin the next inspiration.
Figure 31-1 Ventilation of dead space and alveolar space during a respiratory cycle.
Thus, with each 500-mL inspiration, only the initial 350 mL of fresh air entering the body reaches the alveoli. With each 500-mL expiration, only the final 350 mL of air exiting the body comes from the alveoli. One 150-mL bolus of fresh air shuttles back and forth between the atmosphere and conducting airways. Another 150-mL bolus of stale air shuttles back and forth between the conducting airways and alveoli. Dead-space ventilation (D) is the volume of the stale air so shuttled per minute. Alveolar ventilation (A) is the volume of fresh air per minute that actually reaches the alveoli, or the volume of stale alveolar air that reaches the atmosphere. Thus, total ventilation—a reflection of the work invested in breathing—is the sum of the wasted dead-space ventilation and the useful alveolar ventilation. In our example, (See Note: Inhaled vs. Exhaled Volume)
so that the dead-space ventilation is 30% of the total ventilation.
The inset of Figure 31-1 illustrates how inspiration and expiration lead to small fluctuations in the alveolar partial pressures for O2 and CO2, noted earlier in Figure 30-3B. Throughout the respiratory cycle, blood flowing through the pulmonary capillaries continuously draws O2 out of the alveolar air and adds CO2. Just before an inspiration, alveolar PO2 has fallen to its lowest point, and alveolar PCO2 has risen to its highest. During inspiration, a new bolus of inspired fresh air mixes with preexisting alveolar air, causing alveolar PO2 to rise and alveolar PCO2 to fall. During expiration and until the next inspiration, alveolar PO2 and PCO2 gradually drift to the values that we saw at the start of the respiratory cycle. Assuming that functional residual capacity (FRC) is 3 L and that each breath adds 350 mL of fresh air, one can calculate that alveolar PO2 oscillates with an amplitude of ~6 mm Hg, whereas alveolar PCO2oscillates with an amplitude of ~4 mm Hg. (See Note: Oscillations in PO2 and PCO2 during Breathing)
Fowler’s single-breath N2 washout estimates anatomical dead space
In 1948, Ward Fowler introduced an approach for estimation of the anatomical dead space based on the washout from the lungs of N2. The key concept is that N2 is physiologically inert. After the subject has been breathing room air, the alveolar air is ~75% N2. After a quiet expiration, when lung volume is FRC (Fig. 31-2A, step 1), the subject takes a single, normal-sized breath (~500 mL). The inspired air is 100% O2, although in principle we could use any nontoxic gas mixture lacking N2. The first portion of inspired O2 enters the alveolar spaces (step 2), where it rapidly mixes by diffusion and dilutes the N2 and other gases remaining after the previous breaths of room air (step 3). The last portion of the inspired O2 (~150 mL) remains in the conducting airways, which have a PN2 of zero.
Figure 31-2 Fowler’s technique for measurement of anatomical dead space.
The subject now exhales ~500 mL of air (step 4). If no mixing occurred between the N2-free air in the most distal conducting airways and the N2-containing air in the most proximal alveolar spaces, then the first ~150 mL of air emerging from the body would have an [N2] of zero (Fig. 31-2B, red lines). After this would come a sharp transition to a much higher [N2] for the final ~350 mL of expired air. Thus, the expired volume with an [N2] of zero would represent air from the conducting airways (anatomical dead space), whereas the remainder would represent air from the alveoli.
In reality, some mixing occurs between the air in the conducting airways and alveoli, so that the transition is S shaped (Fig. 31-2C, red curve). A vertical line drawn through the S-shaped curve, so that area ais the same as area b,marks the idealized transition between air from conducting and alveolar airways—as in Figure 31-2B. The expired lung volume at the point of this vertical line is thus the anatomical dead space. In Figure 31-2C, the part of the S-shaped curve with an expired [N2] of zero represents pure dead-space air, the part where [N2] gradually rises represents a mixture of dead-space and alveolar air, and the part where [N2] is high and flat represents pure alveolar air. This plateau is important because it is during this plateau that one obtains an alveolar gas sample. (See Note: The Shape of the Single-Breath Nitrogen Washout Curve; Obtaining a Sample of Alveolar Air)
Bohr’s expired [CO2] approach estimates physiological dead space
In principle, we could compute the dead space using any gas whose expiration profile looks like that of N2. Nitrogen is useful because we can easily create an artificial situation in which the subject makes a single inhalation of N2-free air (e.g., a single breath of 100% O2). Another possibility is CO2. Its profile during expiration is similar to that of N2. Moreover, we do not need to use any special tricks to get it to work because room air has practically no CO2. Yet plenty of CO2 is in the alveoli, where it evolves from the incoming mixed-venous blood. After a quiet expiration (Fig. 31-3A, step 1), the PCO2 of the alveolar air is virtually the same as the PCO2 of the arterial blood (see Chapter 30), ~40 mm Hg. The subject now inhales a normal tidal volume (~500 mL) of room air, although any CO2-free gas mixture would do. The first portion enters the alveoli (step 2), where it rapidly dilutes the CO2 and other gases remaining after the previous breath (step 3). The rest (~150 mL) remains in the conducting airways, which now have a PCO2 of ~0. When the subject now expires (step 4), the first air that exits the body is the CO2-free gas that had filled the conducting airways, followed by the CO2-containing alveolar air. Thus, the idealized profile of expired [CO2] (Fig. 31-3B, red lines) is similar to the idealized [N2] profile (Fig. 31-2B). In particular, the volume of expired air at the vertical line in Figure 31-3B is the estimated anatomical dead space.
Figure 31-3 Bohr’s method for measurement of physiological dead space.
One could use a CO2 probe to record the expired [CO2] profile during a single-breath CO2 washout rather than the [N2] profile that Fowler used to measure anatomical dead space. However, because CO2probes did not exist in his day, Christian Bohr used a single-breath CO2 washout but analyzed the average PCO2 in the mixed-expired air (i.e., averaged over the dead space plus expired alveolar air). (See Note: Christian Bohr (1855-1911))
The principle of Bohr’s approach is that the amount of CO2 present in the volume of mixed-expired air (VE) is the sum of the CO2 contributed by the volume of air from the dead space (VD) plus the CO2contributed by the volume of air coming from the alveoli (VE − VD). As summarized in Figure 31-3B:
1. The amount of CO2 coming from the dead space is the product of VD and [CO2] in this dead-space air. Because [CO2]d is zero, the area beneath VD is also zero.
2. The amount of CO2 coming from alveolar air is the product of (VE − VD) and alveolar [CO2] and is represented by the rose area in Figure 31-3B.
3. The total amount of CO2 in the mixed-expired air is the product of VE and the average [CO2] in this air and is represented by the hatched area in Figure 31-3B.
Because the rose and hatched areas in Figure 31-3B must be equal, and because the alveolar and expired [CO2] values are proportional to their respective PCO2 values, it is possible to show that (See Note: The Bohr Equation)
This is the Bohr equation. Typically, VD/VE ranges between 0.20 and 0.35. For a VD of 150 mL and a VE of 500 mL, VD/VE would be 0.30. For example, if the alveolar PCO2 is 40 mm Hg and the mixed-expired PCO2 is 28 mm Hg, then
Equation 31-4 makes good intuitive sense. In an imaginary case in which we reduced VD to zero, the expired air would be entirely from the alveoli, so that
On the other hand, if we reduced the tidal volume to a value at or below the dead-space volume, then all of the expired air would be dead-space air. In this case, PECO2 would be zero and
Two examples of this principle are of practical importance. During panting, the respiratory frequency is very high, but the tidal volume is only slightly greater than the anatomical dead space. Thus, most of the total ventilation is wasted as dead-space ventilation. If we reduced tidal volume below VD, then in principle there would be no alveolar ventilation at all! During snorkeling, a swimmer breathes through a tube that increases VD. If the snorkeling tube had a volume of 350 mL and the dead space within the body of the swimmer were 150 mL, then a tidal volume of 500 mL would in principle produce no alveolar ventilation. Consequently, the swimmer would suffocate, even though total ventilation was normal! Thus, the fractional dead space (VD/VE) depends critically on tidal volume.
Although Fowler’s and Bohr’s methods yield about the same estimate for VD in healthy individuals, the two techniques actually measure somewhat different things. Fowler’s approach measures anatomical dead space—the volume of the conducting airways from the mouth and nose up to the point where N2 in the alveolar gas rapidly dilutes inspired 100% O2. Bohr’s approach, on the other hand, measures the physiological dead space—the volume of airways not receiving CO2 from the pulmonary circulation and therefore not engaging in gas exchange. In a healthy person, the anatomical and physiological dead spaces are identical—the volume of the conducting airways. However, if some alveoli are ventilated but not perfused by pulmonary capillary blood, these unperfused alveoli, like conducting airways, do not contain CO2. The air in such unperfused alveoli, known as alveolar dead space, contributes to the physiological dead space:
Fowler’s and Bohr’s methods could yield very different results in a patient with a pulmonary embolism, a condition in which a mass such as a blood clot wedges into and obstructs part or all of the pulmonary circulation. Alveoli downstream from the embolus are ventilated but not perfused; that is, they are alveolar dead space (Fig. 31-3C). Thus, Bohr’s method—but not Fowler’s method—could detect an increase in the physiological dead space caused by a pulmonary embolism.
Alveolar ventilation is the ratio of CO2 production rate to CO2 mole fraction in alveolar air
One way of computing alveolar ventilation is to subtract the dead space from the tidal volume and multiply the difference by the respiratory frequency (see Equation 31-3). We can also calculate A from alveolar PCO2. The body produces CO2 by oxidative metabolism at a rate of ~200 mL/min. In the steady state, this rate of CO2 production (CO2) must equal the rate at which the CO2 enters the alveoli and the rate at which we exhale the CO2. Of course, this 200 mL/min of exhaled CO2 is part of the ~4200 mL of total alveolar air that we exhale each minute. Therefore, the exhaled 200 mL of CO2 is ~5% of the exhaled 4200 mL of alveolar air:
Rearrangement of this equation and solving for A yields
The equation above the brace is true only when we measure all parameters under the same conditions. This obvious point would hardly be worth noting if respiratory physiologists had not managed, by historical accident, to measure the two volume terms under different conditions:
1. Body temperature and pressure, saturated with water vapor (BTPS; see Chapter 26) for A.
2. Standard temperature and pressure, dry (STPD; see Chapter 26) for CO2.
Thus, in Equation 31-10, we introduce a constant k that not only indicates that PACO2 (alveolar PCO2—measured at 37°C) is proportional to the mole fraction of CO2 in alveolar air but also accounts for the different conditions for measuring the parameters. (See Note: The Conversion Factor 0.863)
This is the alveolar ventilation equation, which we can use to compute A. We determine CO2 by collecting a known volume of expired air during a fixed time period and analyzing its CO2. For a 70-kg human, CO2 is ~200 mL/min. We can determine PACO2 by sampling the expired air at the end of an expiration—an alveolar gas sample. This end-tidal PCO2 (Fig. 31-2C) is ~40 mm Hg. In practice, clinicians generally measure arterial PCO2 (PaCO2) and assume that alveolar and arterial PCO2 are identical (see Chapter 30). Inserting these values into the alveolar ventilation equation, we have (See Note: Obtaining a Sample of Alveolar Air)
For the sake of simplicity—and consistency with our example in Equation 31-3—we round this figure to 4.2 L/min.
Although it is usually safe to regard CO2 as being constant for a person at rest, a clinical example in which CO2 can increase markedly is malignant hyperthermia (see Chapter 9 for the box on this topic), which is associated with increased oxidative metabolism. One hallmark of this clinical catastrophe is that the increase in CO2 leads to an increase in PACO2 even though CO2 is normal.
Alveolar and arterial PCO2 are inversely proportional to alveolar ventilation
Viewed from a different perspective, Equation 31-11 illustrates one of the most important concepts in respiratory physiology: other things being equal, alveolar PCO2 is inversely proportional to alveolar ventilation. This conclusion makes intuitive sense because the greater the A, the more that the fresh, inspired air dilutes the alveolar CO2. Rearrangement of Equation 31-11 yields
In other words, if CO2 production is fixed, then doubling of A causes PACO2 to fall to half of its initial value. Conversely, halving of A causes PACO2 to double. Because arterial PCO2 is virtually the same as alveolar PCO2 (see Chapter 30), changes in A affect PACO2 and PaCO2.
The blue curve in Figure 31-4 helps illustrate the principle. Imagine that your tissues are producing 200 mL/min of CO2. In a steady state, your lungs must blow off 200 mL of CO2 each minute. Also, imagine that your lungs are exhaling 4200 mL/min of alveolar air. Because the 200 mL of expired CO2 must dissolve in the 4200 mL of exhaled alveolar air (center point in Fig. 31-4), Equation 31-13 tells us that your alveolar PCO2 (and thus PACO2) must be ~40 mm Hg.
Figure 31-4 Dependence of alveolar CO2 and O2 on alveolar ventilation. As alveolar ventilation increases, alveolar PO2 and PCO2 approach their values in inspired air. At extremely low or high A, where O2 consumption and CO2 production do not remain constant, these idealized curves are no longer valid.
What would happen if the excitement of reading about respiratory physiology caused your alveolar ventilation to double, to 8400 mL/min? This is an example of hyperventilation. You could double A either by doubling respiratory frequency or by doubling the difference between tidal volume and dead space, or a combination of the two (see Equation 31-3). Immediately on doubling of A, you would be blowing off at twice the previous rate not only alveolar air (i.e., 8400 mL/min) but also CO2 (i.e., 400 mL/min). Because your body would continue to produce only 200 mL/min of CO2—assuming that doubling of Adoes not increase CO2—you would initially blow off CO2 faster than you made it, causing CO2 levels throughout your body to fall. However, the falling PCO2 of mixed-venous blood would cause alveolar PCO2to fall as well, and thus the rate at which you blow off CO2 would gradually fall. Eventually, you would reach a new steady state in which the rate at which you blow off CO2 would exactly match the rate at which you produce CO2 (i.e., 200 mL/min).
On reaching a new steady state, the PCO2 values in your mixed-venous blood, arterial blood, and alveolar air would be stable. But what would be the PACO2? Because each minute you now are blowing off 8400 mL of alveolar air (i.e., twice normal) but still only 200 mL of CO2 (right point in Fig. 31-4), your alveolar PCO2 must be half normal, or ~20 mm Hg. Not only does the hyperventilation cause alveolar PCO2 to fall by half, it also causes arterial PCO2 to fall by half. Thus, hyperventilation leads to respiratory alkalosis (see Chapter 28). This respiratory alkalosis causes the arterioles in the brain to constrict (see Chapter 24), reducing blood flow to the brain, which causes dizziness.
What would happen if instead of doubling alveolar ventilation, you halved it from 4200 to 2100 mL/min? This is an example of hypoventilation. At the instant you began hypoventilating, the volume of CO2expired per unit time would fall by half, to 100 mL/min, even though CO2 production by the tissues would remain at 200 mL/min. Thus, CO2 would build up throughout the body, causing PACO2 to rise. To what value would PACO2 have to increase before you would reach a new steady state? Because each minute you must exhale 200 mL of CO2, but this can be diluted in only 2100 mL or half the usual amount of alveolar air (left point in Fig. 31-4), the alveolar [CO2] must double from ~40 to 80 mm Hg. Of course, this doubling of alveolar PCO2 is paralleled by a doubling of arterial PCO2, leading to a respiratory acidosis(see Chapter 28).
Therefore, the steady-state alveolar PCO2 is inversely proportional to alveolar ventilation. The higher the A, the lower the PACO2. If A were infinitely high, then PACO2 would theoretically fall to zero, the PCO2of inspired air.
Alveolar and arterial PO2 rise with increased alveolar ventilation
As illustrated by the orange curve in Figure 31-4, increases in alveolar ventilation cause alveolar PO2 to rise and—at an infinite A—to approach the inspired PO2 of ~149 mm Hg.
Although alveolar PO2 obviously depends critically on A, it is also influenced to a lesser extent by alveolar gases other than O2—namely, H2O, N2, and CO2. The partial pressure of H2O at 37°C is 47 mm Hg, and PH2O will not change unless body temperature changes. The partial pressures of all of the other gases “fit” into what remains of barometric pressure (PB) after PH2O has claimed its mandatory 47 mm Hg. We can think of N2 as a “spectator molecule” because it is not metabolized; PN2 is whatever it has to be to keep the total pressure of the dry alveolar air at 760 − 47 = 713 mm Hg. That leaves us to deal with CO2.
Because inspired air contains virtually no CO2, we can think of the alveolar CO2 as coming exclusively from metabolism. However, CO2 depends not only on how fast the tissues burn O2 but also on the kind of fuel they burn. If the fuel is carbohydrate, then the tissues produce one molecule of CO2 for each O2 consumed (see Chapter 58). This ratio is termed the respiratory quotient (RQ):
In this example, the RQ is 1, which is a good place to start when considering how alveolar PCO2 affects alveolar PO2. If we consider only the dry part of the inspired air that enters the alveoli (see Table 26-1), then PIN2 is 713 × 0.78 = 557, PIO2 is 713 × 0.2095 = 149 mm Hg, and PICO2 is ~0. As pulmonary capillary blood takes up incoming O2, it replaces the O2 with an equal number of CO2 molecules in the steady state (RQ = 1). Because the exchange of O2 for CO2 is precisely 1 for 1, alveolar PO2 is what is left of the inspired PO2 after metabolism replaces some alveolar O2 with CO2 (PACO2= 40 mm Hg):
A typical fat-containing diet in industrialized nations produces an RQ of ~0.8 (see Chapter 58), so that 8 molecules of CO2 replace 10 molecules of O2 in the alveolar air. This 8-for-10 replacement has two consequences. First, the volume of alveolar air falls slightly during gas exchange. Because the non-H2O pressure remains at 713 mm Hg, this volume contraction concentrates the N2 and dilutes the O2. Second, the volume of expired alveolar air is slightly less than the volume of inspired air. (See Note: The Alveolar Gas Equation)
The alveolar gas equation describes how alveolar PO2 depends on RQ:
FIO2 is the fraction of inspired dry air that is O2, which is 0.21 for room air (see Table 26-1). Note that when RQ is 1, the term in parentheses becomes unity, and Equation 31-17 reduces to Equation 31-16. The term in parentheses also becomes unity, regardless of RQ, if FIO2 is 100% (i.e., the subject breathes pure O2)—in this case, no N2 is present to dilute the O2.
A simplified version of Equation 31-17 is nearly as accurate:
The concepts developed in the last two sections allow us to compute both alveolar PCO2 and PO2. The approach is to first use Equation 31-13 to calculate PaCO2 from CO2 and A and then use Equation 31-17 to calculate PAO2 from PaCO2 and RQ Imagine that we first found that PaCO2 is 40 mm Hg, and that we know that RQ is 0.8. What is PAO2?
By default, the partial pressure of N2 and other gases (e.g., argon) is PB − PACO2 − PAO2 or 713 − 40 − 101 = 572 mm Hg. For simplicity, we round down this PAO2 to 100 mm Hg in our examples.
Because of the action of gravity on the lung, regional ventilation in an upright subject is normally greater at the base than at the apex
Until now, we have assumed that all alveoli are ventilated to the same extent. We could test this hypothesis by use of an imaging technique to assess the uniformity of ventilation. Imagine that a subject who is standing up breathes air containing 133Xe. Because Xe has very low water solubility, it (like He and N2) has a very low diffusing capacity (see Chapter 30); during a short period, it remains almost entirely within the alveoli.
Imaging of the 133Xe radioactivity immediately after a single breath of [133Xe] provides an index of absolute regional ventilation (Fig. 31-5A). However, [133Xe] might be low in a particular region either because the alveoli truly receive little ventilation or because the region has relatively little tissue. Therefore, we normalize the absolute data to the maximal regional alveolar volume. The subject continues to breathe the 133Xe until [133Xe] values stabilize throughout the lungs. When the subject now makes a maximal inspiratory effort (VL = total lung capacity [TLC]), the level of radioactivity detected over any region reflects that region’s maximal volume. Dividing the single-breath image by the steady-state image at TLC yields a ratio that describes regional ventilation per unit volume.
Figure 31-5 Distribution of ventilation. (Data from West JB: Respiratory Physiology—The Essentials, 4th ed. Baltimore, Williams & Wilkins, 1990.)
This sort of analysis shows that alveolar ventilation in a standing person gradually falls from the base to the apex of the lung (Fig. 31-5B). Why? The answers are posture and gravity. In Chapter 27 we saw that because of the lung’s weight, intrapleural pressure (PIP) is more negative at the apex than at the base when the subject is upright (Fig. 31-5C). The practical consequences of this PIP gradient become clear when we examine a static pressure-volume diagram not for the lungs as a whole (as we did in Fig. 27-5) but rather for a small piece of lung (Fig. 31-5D). We assume that the intrinsic mechanical properties of the airways are the same, regardless of whether the tissue is at the base or at the apex. At the base, where PIP might be only −2.5 cm H2O at FRC, the alveoli are relatively underinflated compared with tissues at the apex, where PIP might be −10 cm H2O and the alveoli are relatively overinflated. However, because the base of the lung is underinflated at FRC, it is on a steeper part of the pressure-volume curve (i.e., it has a greater static compliance) than the overinflated apex. Thus, during an inspiration, the same ΔPIP (e.g., 2.5 cm H2O) produces a larger ΔVL near the base than near the apex. Keep in mind that it is the change in volume per unit time, not the initial volume, that defines ventilation.
The relationship between ventilation and basal versus apical location in the lung would be reversed if the subject hung by the knees from a trapeze. A person reclining on the right side would ventilate the dependent lung tissue on the right side better than the elevated lung tissue on the left. Of course, the right-to-left PIP gradient in the reclining subject would be smaller than the apex-to-base PIP gradient in the standing subject, reflecting the smaller distance (i.e., smaller hydrostatic pressure difference). Subjects under microgravity conditions (see Chapter 58), such as astronauts aboard the International Space Station, experience no PIP gradients and thus no gravity-dependent regional differences in ventilation.
Restrictive and obstructive pulmonary diseases can exacerbate the nonuniformity of ventilation
Even in microgravity, where we would expect no regional differences in ventilation, ventilation would still be nonuniform at the microscopic or local level because of seemingly random differences in local static compliance (C) and airway resistance (R). In fact, such local differences in the ventilation of alveolar units are probably more impressive than gravity-dependent regional differences. Moreover, pathological changes in compliance and resistance can substantially increase the local differences and thus the nonuniformity of ventilation. (See Note: Detecting Nonuniformity of Ventilation)
Restrictive Pulmonary Disease As discussed in the box on diseases affecting ventilation in Chapter 27, restrictive pulmonary diseases include disorders that decrease the static compliance of alveoli (e.g., fibrosis) as well as disorders that limit the expansion of the lung (e.g., pulmonary effusion). Figure 31-6A shows a hypothetical example in which R is normal and disease has halved the static compliance of one lung but left the other unaffected. Thus, for the usual change in PIP, the final volume change (ΔV) of the diseased lung is only half normal, so that its ventilation is also halved. Because the ventilation of the other unit is normal, decreased local compliance has increased the nonuniformity of ventilation. (See Note: Effect of Changes in Compliance on the Time Constant Governing Changes in Lung Volume)
Figure 31-6 Pathologic nonuniformity of ventilation.
Obstructive Pulmonary Disease As discussed in the box on asthma in Chapter 27, obstructive pulmonary diseases include disorders (e.g., asthma, COPD) that increase the resistance of conducting airways. Scar tissue or a local mass, such as a neoplasm, can also occlude a conducting airway or compress it from the outside. Even if the effect is not sufficiently severe to increase overall airway resistance, a local increase in R causes an increase in the time constant τ for filling or emptying of the affected alveoli (Fig. 31-6B, lower curve). An isolated increase in R would not affect ΔV if sufficient time were available for the inspiration. However, if sufficient time is not available, then alveoli with an elevated τ will not completely fill or empty, and their ventilation will decrease. Of course, the mismatching of ventilation between the two units worsens as respiratory frequency increases, as we saw in our discussion of dynamic compliance (see Chapter 27). (See Note: Effect of Changes in Compliance on the Time Constant Governing Changes in Lung Volume)
PERFUSION OF THE LUNG
The pulmonary circulation has low pressure and resistance but high compliance
The pulmonary circulatory system handles the same cardiac output as the systemic circulation but in a very different way. The systemic circulation is a high-pressure system. This high pressure is necessary to pump blood to the top of the brain while standing or even to a maximally elevated fingertip. The systemic circulation also needs to be a high-pressure system because it is a high-resistance system. It uses this high resistance to control the distribution of blood flow. Thus, at rest, a substantial fraction of the systemic capillaries are closed, giving the system the flexibility to redistribute large amounts of blood (e.g., to muscle during exercise). The mean pressure of the aorta is ~95 mm Hg (Table 31-1). At the opposite end of the circuit is the right atrium, which has a mean pressure of ~2 mm Hg. Thus, the driving pressure for blood flow through the systemic circulation is ~93 mm Hg. Given a cardiac output () of 5 L/min or 83 mL/s, we can compute the resistance of the systemic system by use of an equation like Ohm’s law (see Equation 17-10):
Table 31-1 Comparison of Pressures in the Pulmonary and Systemic Circulatory System*
PRU is a peripheral resistance unit (see Chapter 17), which has the dimensions mm Hg/(mL/s).
In contrast, the pulmonary circulation is a low-pressure system. It can afford to be a low-pressure system because it needs to pump blood only to the top of the lung. Moreover, it must be a low-pressure system to avoid the consequences of Starling forces (see Chapter 20), which would otherwise flood the lung with edema fluid. The mean pressure in the pulmonary artery is only ~15 mm Hg. Because the mean pressure of the left atrium, at the other end of the circuit, is ~8 mm Hg, and because the cardiac output of the right side of the heart is the same as for the left side, we have
Thus, the total resistance of the pulmonary circulation is less than one tenth that of the systemic system, which explains how the pulmonary circulation accomplishes its mission at such low pressures. Unlike in the systemic circulation, where most of the pressure drop occurs in the arterioles (i.e., between the terminal arteries and beginning of the capillaries), in the pulmonary circulation almost the entire pressure drop occurs rather uniformly between the pulmonary artery and the end of the capillaries. In particular, the arterioles make a much smaller contribution to resistance in the pulmonary circulation than in the systemic circulation.
What are the properties of the pulmonary vasculature that give it such a low resistance? First, let us examine the complete circuit. The pulmonary artery arises from the right ventricle, bifurcates, and carries relatively deoxygenated blood to each lung. The two main branches of the pulmonary artery follow the two mainstem bronchi into the lungs and bifurcate along with the bronchi and bronchioles. A single pulmonary arteriole supplies all of the capillaries of a terminal respiratory unit (see Chapter 26). Together, the two lungs have ~300 million alveoli. However, they may have as many as 280 billion highly anastomosing capillary segments (each looking like the edge of a hexagon in a piece of chicken wire), or nearly 1000 such capillary segments per alveolus—creating a surface for gas exchange of ~100 m2. It is easy to imagine why some have described the pulmonary capillary bed as a nearly continuous flowing sheet of blood surrounding the alveoli. At rest, the erythrocytes spend ~0.75 second navigating this capillary bed, which contains ~75 mL of blood. During exercise, capillary blood volume may increase to ~200 mL. Pulmonary venules collect the oxygenated blood from the capillary network, converge, course between the lobules, converge some more, and eventually enter the left atrium through the pulmonary veins. The total circulation time through the pulmonary system is 4 to 5 seconds.
Pulmonary blood vessels are generally shorter and wider than their counterparts on the systemic side. Arterioles are also present in much higher numbers in the pulmonary circulation. Although the pulmonary arterioles contain smooth muscle and can constrict, these vessels are far less muscular than their systemic counterparts, and their resting tone is low. These properties combine to produce a system with an unusually low resistance.
The walls of pulmonary vessels have another key property: thinness, like the walls of veins elsewhere in the body. The thin walls and paucity of smooth muscle give the pulmonary vessels a high compliance, which has three consequences. First, pulmonary vessels can accept relatively large amounts of blood that shift from the legs to the lungs when a person changes from a standing to a recumbent position. Second, as we discuss later, the high compliance also allows the vessels to dilate in response to modest increases in pulmonary arterial pressure. Third, the pulse pressure in the pulmonary system is rather low (on an absolute scale). The systolic and diastolic pressures in the pulmonary artery are typically 25 and 8 mm Hg, yielding a pulse pressure of ~17 mm Hg. In contrast, the systolic and diastolic pressures in the aorta are ~120 and 80 mm Hg, for a pulse pressure of ~40 mm Hg. Nonetheless, relative to the mean pulmonary artery pressure of 15 mm Hg, the pulmonary pulse pressure of 17 mm Hg is quite high.
Overall pulmonary vascular resistance is minimal at functional residual capacity
Because pulmonary blood vessels are so compliant, they are especially susceptible to deformation by external forces. These forces are very different for vessels that are surrounded by alveoli (i.e., alveolar vessels) compared with those that are not (i.e., extra-alveolar vessels). In both types, the key consideration is whether these external forces pull vessels open or crush them.
Alveolar Vessels Alveolar vessels include the capillaries as well as slightly larger vessels that are also surrounded on all sides by alveoli (Fig. 31-7A). The resistance of these alveolar vessels depends on both the transmural pressure gradient and lung volume.
Figure 31-7 A and B, Pulmonary vascular resistance. FRC, functional residual capacity; RV, respiratory volume; TLC, total lung capacity. (B, Data from Murray JF: The Normal Lung, 2nd ed. Philadelphia, WB Saunders, 1986.)
We have already introduced the transmural pressure gradient (PTM) in our discussions of systemic blood vessels (see Chapter 17) and conducting airways (see Chapter 27). For alveolar vessels, PTM is the difference between the pressures in the vessel lumen and in the surrounding alveoli (PA). For simplicity, we consider the factors affecting PTM at a fixed lung volume.
The pressure inside these vessels varies with the cardiac cycle; indeed, the pulmonary capillary bed is one of the few in which flow is pulsatile (see Chapter 22). The pressure inside the alveolar vessels also depends greatly on their vertical position relative to the left atrium: the higher the vessel, the lower the pressure.
The pressure in the alveoli varies with the respiratory cycle. With no airflow and the glottis open, PA is the same as PB (i.e., 0 cm H2O). On the other hand, PB is negative during inspiration and positive during expiration. A combination of a high intravascular pressure and a negative PA tends to dilate the compliant alveolar vessels, lowering their resistance. But a combination of a low intravascular pressure and a positive PA crushes these vessels, raising their resistance.
Changes in lung volume (VL) have characteristic effects on alveolar vessels. For simplicity, here we assume that each time we examine a new VL, airflow has stopped, so that PA is zero. As VL increases, the alveolar walls become more stretched out. Consequently, the alveolar vessels become stretched along their longitudinal axis but crushed when viewed in cross section. Both of these effects tend to raise vessel resistance. Thus, as VL increases, the resistance of the alveolar vessels also increases (Fig. 31-7B, red curve).
Extra-alveolar Vessels Because they are not surrounded by alveoli, the extra-alveolar vessels are sensitive to intrapleural pressure (Fig. 31-7A). Again for simplicity, we examine the effect of changing VL after airflow has already stopped. The increasingly negative values of PIP needed to achieve increasingly higher lung volumes also increase the PTM of the extra-alveolar vessels and tend to dilate them. Thus, as VLincreases, the resistance of the extra-alveolar vessels decreases (Fig. 31-7B, blue curve).
In summary, increases in VL tend to crush alveolar vessels and thus increase their resistance but to expand extra-alveolar vessels and thus decrease their resistance. The net effect on overall pulmonary vascular resistance of increasing VL from residual volume (RV) to TLC is biphasic (Fig. 31-7B, violet curve). Starting at RV, an increase in VL first causes pulmonary vascular resistance to fall, as the dilation of extra-alveolar vessels dominates. Pulmonary vascular resistance reaches its minimum value at about FRC. Further increases in VL (as during a normal inspiration) increase overall resistance, as the crushing of alveolar vessels dominates. (See Note: Additional Factors Affecting the Resistance of Pulmonary Vessels)
Increases in pulmonary arterial pressure reduce pulmonary vascular resistance by recruiting and distending pulmonary capillaries
Although the pulmonary circulation is normally a low-resistance system under resting conditions, it has a remarkable ability to lower its resistance even further. During exercise, 2-fold to 3-fold increases in cardiac output may elicit only a minor increase in mean pulmonary arterial pressure. In other words, a slight increase in pulmonary arterial pressure is somehow able to markedly decrease resistance (Fig. 31-8A) and thus markedly increase flow (Fig. 31-8B). This behavior is a general property of a passive/elastic vascular bed (see Fig. 19-7A, red curve). Two “passive” mechanisms—that is, mechanisms not related to “active” changes in the tone of vascular smooth muscle—are at work here: the recruitment and distention of pulmonary capillaries. However, before we can understand either change, we must more completely describe the pulmonary capillaries at “rest.”
Figure 31-8 Effects of perfusion pressure on pulmonary hemodynamics.
Under “resting” conditions (i.e., at relatively low values of pulmonary arterial pressure), some pulmonary capillaries are open and conducting blood, others are open but not conducting substantial amounts of blood, and still others are closed (Fig. 31-8C). Why should some capillaries be open but have no flow? In a highly anastomosing capillary network, tiny differences in driving pressure might exist. In addition, seemingly random differences in the dimensions of parallel capillaries may lead to differences in resistance. In low-pressure systems, such slight differences in absolute resistance allow pathways with relatively low resistances to steal flow from neighbors with slightly higher resistances, leaving some “open” pathways heavily underused. A familiar example is a type of garden hose used to drizzle water on a flower bed; this hose is closed at its distal end but perforated with hundreds of tiny holes. If water pressure is low, only some of the holes conduct water.
Why should some parallel vessels be closed? Popping open a previously closed vessel requires that the perfusion pressure overcome the tone of the vascular smooth muscle and reach that vessel’s critical closing pressure (see Chapter 19), which varies from vessel to vessel. As we discuss later, alveolar vessels also may be closed because the alveolar pressure exceeds intravascular pressure, thereby crushing the vessel.
Recruitment Imagine that the pressure inside a pulmonary arteriole starts out at a fairly low level. As pressure increases, some vessels that were completely closed may now open (Fig. 31-8C). Similarly, capillaries that previously had been open but not conducting now begin to conduct blood. The greater the increase in perfusion pressure, the greater the number of open and conducting vessels. This recruitment of additional parallel capillary pathways reduces overall vascular resistance.
Distention Once a vessel is open and conducting, further pressure increases will increase PTM and thus cause the vessel to dilate (Fig. 31-8C). The net effect is a reduction in overall pulmonary resistance. Although a pressure increase can simultaneously recruit and distend various vessels, distention probably tends to occur later; that is, distention is the primary mechanism for lowering resistance under conditions in which the initial pressure was already relatively high.
Hypoxia is a strong vasoconstrictor, opposite to its effect in the systemic circulation
In addition to lung volume and perfusion pressure, several other factors can modulate pulmonary vascular resistance.
Oxygen The effects of changes in PO2, PCO2, and pH on pulmonary vascular resistance are opposite to those observed in the systemic circulation. Thus, hypoxia causes pulmonary vasoconstriction. What appears to be critical is not so much the PO2 in the lumen of the arterioles and venules but rather the PO2 in the alveolar air adjacent to the vessel. Indeed, perfusion of the pulmonary vasculature with a hypoxic solution is far less effective than ventilation of the airways with a low-PO2 air mixture.
Hypoxic vasoconstriction occurs in isolated lung tissue and thus does not rely on either the nervous system or systemic hormones. Rather, the low PO2 is generally believed to act directly on the pulmonary vascular smooth muscle cells. How this occurs is unknown, but hypothesized mechanisms include all those proposed for the sensing of hypoxia by the peripheral chemoreceptor, which we discuss in Chapter 32. Somehow, the hypoxia inhibits one or more K+ channels, causing the membrane potential of vascular smooth muscle cells to move away from EK. This depolarization opens voltage-gated Ca2+ channels, leading to an influx of Ca2+ and smooth muscle contraction (see Chapter 9).
CO2 and Low pH High PCO2 and low interstitial pH promote vasoconstriction, although with far less potency than hypoxia. Elevated PCO2 may produce its effect by decreasing the pH of either the extracellular or intracellular fluid. Following a general pattern that is repeated in the control of Ventilation, hypoxia makes the vascular smooth muscle cells more sensitive to respiratory acidosis.
Autonomic Nervous System The sympathetic and parasympathetic innervation of the pulmonary vasculature is far less impressive than that of the systemic circulation. Increased sympathetic tone seems to reduce the compliance of (i.e., stiffen) the pulmonary artery walls without increasing resistance per se. Increased parasympathetic tone causes a mild vasodilation, the relevance of which is unknown.
Hormones and Other Humoral Agents The pulmonary blood vessels are relatively unresponsive to hormones and other signaling molecules. Table 31-2 summarizes the actions of some factors that modify pulmonary vascular resistance.
Table 31-2 Changes or Agents That Affect Pulmonary Vascular Resistance
Histamine H2 agonists
Histamine H1 agonists
PGI2 (prostacyclin), PGE1
Thromboxane A2, PGF2α, PGE2
β-Adrenergic agonists (e.g., isoproterenol)
Because of gravity, regional perfusion in an upright subject is far greater near the base than the apex of the lung
When it comes to perfusion—like ventilation—not all alveoli are created equal. First of all, microscopic or local differences in pulmonary vascular resistance lead to corresponding local differences in perfusion. Of course, disease can exacerbate these differences. In addition, gravity causes large regional differences in perfusion that we can assess by use of a 133Xe imaging technique. In Figure 31-5A, we used the inhalation of 133Xe gas to measure the uniformity of ventilation. In Figure 31-9A, we equilibrate a saline solution with 133Xe and then inject the solution intravenously as the patient holds his or her breath. When the 133Xe reaches the lungs, it rapidly enters the alveolar air, inasmuch as Xe is poorly soluble in water. A lung scan reveals the distribution of radioactivity, which now reflects the regional uniformity of perfusion. If we normalize the 133Xe to account for differences in regional lung volume—as we did for the ventilation scan—then we can obtain a graph showing how blood flow varies from the bottom to the top of the lung of an upright subject.
Figure 31-9 Physiological nonuniformity of pulmonary perfusion.
The results of such a 133Xe perfusion study show that when the patient is upright, perfusion () is greatest near the base of the lungs and falls toward low levels near the apex (Fig. 31-9B). Note that although regional is highest near the base of the lung, falls off somewhat from this peak as we approach the extreme base. With exercise, perfusion increases in all regions of the lung but more so near the apex, so that the nonuniformity of perfusion is less.
Why should have this peculiar height dependence? The basic answers are the same as those for the similar question we raised about the regional nonuniformity of ventilation:posture and gravity. Thus, standing on your head will reverse the flow-height relationship, and we would expect height-related differences in flow to be minimal in microgravity conditions.
Figure 31-9C shows how we can divide the upright lung into four zones based on the relationships among various pressures. We define the first three zones on the basis of how alveolar blood vessels are affected by the relative values of three different pressures: alveolar pressure (PA), the pressure inside pulmonary arterioles (PPA), and the pressure inside pulmonary venules (PPV). In the fourth zone, we instead focus on how extra-alveolar vessels are affected by intrapleural pressure (PIP).
Zone 1: PA > PPA > PPV These conditions prevail at the apex of the lung under certain conditions. The defining characteristic of a zone 1 alveolar vessel is that PPA and PPV are so low that they have fallen below PA.
At the level of the left atrium (the reference point for the pressure measurements), the mean PPA is ~15 mm Hg (Table 31-1), which—because mercury is 13.6-fold more dense than water—corresponds to ~20 cm H2O (Fig. 31-9C, lower panel of zone 3). Similarly, mean PPV is ~8 mm Hg, or ~10 cm H2O. As we move upward closer to the apex of an upright lung, the actual pressures in the lumens of pulmonary arterioles and venules fall by 1 cm H2O for each 1 cm of vertical ascent. In the hypothetical case in which alveoli at the lung apex are 20 cm above the level of the left atrium, the mean PPA of these alveoli would be 0 cm H2O (Fig. 31-9C, zone 1). The corresponding PPV would be about −10 cm H2O. The pressure inside the pulmonary capillary (Pc) would be intermediate, perhaps −5 cm H2O. In principle, blood would still flow through this capillary—the driving pressure would be ~10 cm H2O—were it not for the pressure inside the alveoli, which is 0 cm H2O between breaths. Therefore, because PA is much higher than Pc, the negative PTM would crush the capillary and greatly reduce blood flow.
Fortunately, zone 1 conditions do not exist for normal people at rest. However, they can arise if there is either a sufficient decrease in PPA (e.g., in hemorrhage) or a sufficient increase in PA (e.g., in positive-pressure ventilation).
Zone 2: PPA > PA > PPV These conditions normally prevail from the apex to the midlung. The defining characteristic of zone 2 is that mean PPA and PPV are high enough so that they sandwich PA (Fig. 31-9C, zone 2). Thus, at the arteriolar end, the positive PTM causes the alveolar vessel to dilate. Farther down the capillary, though, luminal pressure gradually falls below PA, so that the negative PTM squeezes the vessel, raising resistance and thus reducing flow. As we move downward in zone 2, the crushing force decreases because the hydrostatic pressures in the arteriole, capillary, and venule all rise in parallel by 1 cm H2O for each 1 cm of descent (Fig. 31-9C, upper → lower panels of zone 2). Simultaneously, resistance decreases. The conversion of a closed vessel (or one that is open but not conducting) to a conducting one by increased PPA and PPV is an example of recruitment.
Zone 3: PPA > PPV > PA These conditions prevail in the middle to lower lung. The defining characteristic of zone 3 is that mean PPA and PPV are so high that they both exceed PA (Fig. 31-9C, zone 3). Thus, PTMis positive along the entire length of the alveolar vessel, tending to dilate it. As we move downward in zone 3, the hydrostatic pressures in the arteriole, capillary, and venule all continue to rise by 1 cm H2O for each 1 cm of descent. Because PA between breaths does not vary with height in the lung, the gradually increasing pressure of the alveolar vessel produces a greater and greater PTM, causing the vessel to dilate more and more—an example of distention (Fig. 31-9C, upper →lower panels of zone 3). This distention causes a gradual decrease in resistance of the capillaries as we move downward in zone 3. Hence, although the driving force (PPA − PPV) remains constant, perfusion increases toward the base of the lung.
The arrangement in which a variable PTM controls flow is known as a Starling resistor. Keep in mind that the driving force (PPA − PPV) is constant in all of the zones.
Zone 4: PPA > PPV > PA These conditions prevail at the extreme base of the lungs. In zone 4, the alveolar vessels behave as in zone 3; they dilate more as we descend toward the base of the lung. However, the extra-alveolar vesselsbehave differently. At the base of the lung, PIP is least negative (Fig. 31-5C). Thus, as we approach the extreme base of the lung, the distending forces acting on the extra-alveolar blood vessels fade, and the resistance of these extra-alveolar vessels increases (Fig. 31-9C, zone 4). Recall that we saw a similar effect—at the level of the whole lung (Fig. 31-7B, blue curve)—where resistance of the extra-alveolar vessels increased as lung volume fell (i.e., as PIPbecame less negative). Because these extra-alveolar vessels feed or drain the alveolar vessels, begins to fall from its peak as we approach the extreme base of the lungs (Fig. 31-9B).
These lung zones are physiological, not anatomical. The boundaries between the zones are neither fixed nor sharp. For example, the boundaries can move downward with positive-pressure ventilation (which increases PA) and upward with exercise (which increases PPA). In our discussion of lung zones, we have tacitly assumed that PA is always zero and that the values of PPA and PPV are stable and depend only on height in the lung. In real life, of course, things are more complicated. During the respiratory cycle, PA becomes negative during inspiration (promoting dilation of alveolar vessels) but positive during expiration. During the cardiac cycle, the pressure inside the arterioles and pulmonary capillaries is greatest during systole (promoting dilation of the vessel) and lowest during diastole. Thus, we would expect blood flow through an alveolar vessel to be greatest when inspiration coincides with systole.
MATCHING VENTILATION AND PERFUSION
The greater the ventilation-perfusion ratio, the higher the PO2 and the lower the PCO2 in the alveolar air
In Figure 31-4, we saw that all other factors being equal, alveolar ventilation determines alveolar PO2 and PCO2. The greater the ventilation, the more closely PAO2 and PACO2 approach their respective values in inspired air. However, in Figure 31-4, we were really focusing on total alveolar ventilation and how this influences the average, or idealized, alveolar PO2 and PCO2. In fact, we have already learned that both ventilation and perfusion vary among alveoli. In any group of alveoli, the greater the local ventilation, the more closely the composition of local alveolar air approaches that of the inspired air. Similarly, because blood flow removes O2 from the alveolar air and adds CO2, the greater the perfusion, the more closely the composition of local alveolar air approaches that of mixed-venous blood. Thus, the local ventilation-perfusion ratio (A/) determines the local PAO2 and PACO2.
You might view the alveoli as a sports venue where ventilation and perfusion are engaged in a continuous struggle over control of the composition of alveolar air. To the extent that ventilation gains the upper hand, PAO2 rises and PACO2 falls. To the extent that perfusion holds sway, these parameters change in the opposite direction.
As a physical analogue of this struggle over control of alveolar PO2, consider water flowing (analogous to A) from a faucet into a sink (alveoli); the water exits () through a drain with an adjustable opening. If the drain opening is in midposition and we begin flowing water moderately fast, then the water level (PAO2) will gradually increase and reach a steady state. Increasing the inflow of water (A) will cause the water level (PAO2) to rise until the product of pressure head and drain conductance is high enough to drive water down the drain as fast as the water flows in. If we increase the drain opening and thus the outflow of water (), then the water level (PAO2) will fall until the decrease in the pressure head matches the increase in drain conductance, so that once again water inflow and outflow are balanced. Just as a high faucet/drain ratio will raise the water level, a high A/ ratio will increase alveolar PO2.
Because of the action of gravity, the regional ventilation-perfusion ratio () in an upright subject is greater at the apex of the lung than at the base
We have already seen that when a subject is upright in a gravitational field, ventilation falls from the base to the apex of the lung (Fig. 31-5B), and perfusion also falls, but more steeply (Fig. 31-9B). Thus, it is not surprising that the ratio A/ itself varies with height in the lung (Fig. 31-10A). A/ is lowest near the base, where exceeds A. The ratio gradually increases to 1 at about the level of the third rib and further increases toward the apex, where falls more precipitously than A.
Figure 31-10 Regional differences in A/ ratio and alveolar gas composition. (Data from West JB: Ventilation/Blood Flow and Gas Exchange. Oxford, UK, Blackwell, 1985.)
Table 31-3 shows how differences in A/ at the apex and base of the lungs influence the regional composition of alveolar air. At the apex (the most rostral 7% of lung volume in this example), where A/ is highest, alveolar PO2and PCO2 most closely approach their values in inspired air. Because both O2 and CO2 transport across the blood-gas barrier are perfusion limited (see Chapter 30), O2 and CO2 have completely equilibrated between the alveolar air and the blood by the end of the pulmonary capillaries. Thus, blood leaving the apex has the same high PO2 and low PCO2 as the alveolar air. Of course, the relatively low PCO2 produces a respiratory alkalosis (see Chapter 28) in the blood leaving the apex.
Table 31-3 Effect of Regional Differences in / on the Composition of Alveolar Air and Pulmonary Capillary Blood
The situation is just the opposite near the base of the lung (the most caudal 13% of lung volume in this example). Because A/ here is lowest, alveolar PO2 and PCO2 tend more toward their values in mixed-venous blood. What impact do these different regions of the lung, each with its own A/ ratio, have on the composition of systemic arterial blood? Each region makes a contribution that is proportional to its blood flow (see the rightmost column in Table 31-3). Because the apex is poorly perfused, it makes only a small contribution to the overall composition of arterial blood. On the other hand, pulmonary tissue at the base of the lungs, which receives ~26% of total cardiac output, makes a major contribution. As a result, the average composition of blood exiting the lung more closely reflects the composition of the blood that had equilibrated with the air in the base of the lung.
The O2-CO2 diagram introduced as Figure 29-11 is a helpful tool to depict how different A/ ratios throughout the lung produce different blood gas compositions. The curve in Figure 31-10B represents all possible combinations of PO2 and PCO2 in the alveolar air or end–pulmonary capillary blood. The H2O-saturated inspired air (PO2 = 149 mm Hg, PCO2 = ~0 mm Hg) represents the rightmost extreme of the diagram. By definition, the A/ ratio of inspired air is ∞ because it does not come into contact with pulmonary capillary blood. The mixed-venous blood (PO2 = 40 mm Hg, PCO2= 46 mm Hg) represents the other extreme. By definition, the A/ ratio of mixed-venous blood is 0 because it has not yet come into contact with alveolar air. With the endpoints of the diagram established, we can now predict—with the help of the alveolar gas equation (Equation 31-17) and the Bohr effect and the Haldane effect (see Chapter 29)—all possible combinations of PO2 and PCO2 throughout the lung. As shown in Figure 31-10B, the base, midportion, and apex of the lungs correspond to points along the O2-CO2 diagram between mixed-venous blood at one extreme and inspired air at the other.
The ventilation of unperfused alveoli (local = ∞) triggers compensatory bronchoconstriction and a fall in surfactant production
The effects of gravity on ventilation and perfusion cause regional A/ to vary widely, even in idealized lungs (Fig. 31-10A). However, microscopic or local physiological and pathological variations in ventilation and perfusion can cause even greater mismatches of A/, the extremes of which are alveolar dead-space ventilation (this section) and shunt (next section).
Alveolar Dead-Space Ventilation At one end of the spectrum of A/ mismatches is the elimination of blood flow to a group of alveoli. For example, if we ligated the pulmonary artery feeding one lung, the affected alveoli would receive no perfusion even though ventilation would initially continue normally (Fig. 31-11A). Earlier, we saw that such alveolar dead space together with the anatomical dead space constitutes the physiological dead space (Equation 31-8). The ventilation of the unperfused alveoli is called alveolar dead-space ventilation because it does not contribute to gas exchange. Thus, these alveoli behave like conducting airways. (See Note: Notes on the Differences between Anatomic and Physiological Dead Space)
Figure 31-11 Extreme A/ mismatch and compensatory response—alveolar dead-space ventilation.
A natural cause of alveolar dead-space ventilation is a pulmonary embolism, which obstructs blood flow to a group of alveoli. Because one task of the lung is to filter small emboli from the blood (see Chapter 26), the lung must deal with small regions of alveolar dead-space ventilation on a recurring basis. At the instant the blood flow ceases, the alveoli supplied by the affected vessels contain normal alveolar air. However, each cycle of inspiration and expiration replaces some stale alveolar air with fresh, inspired air. Because no exchange of O2 and CO2 occurs between these unperfused alveoli and pulmonary capillary blood, the alveolar gas gradually achieves the composition of moist inspired air, with alveolar PO2 rising to ~149 mm Hg and PCO2 falling to ~0 mm Hg (Fig. 31-11A, step 2). By definition, alveolar dead space has a A/ ratio of ∞, as described by the “inspired air” point on the x-axis of an O2-CO2 diagram (Fig. 31-10B).
Redirection of Blood Flow Blocking of blood flow to one group of alveoli diverts blood to other “normal” alveoli, which then become somewhat hyperperfused. Thus, the blockage not only increases A/ in alveoli downstream from the blockage but also decreases A/ in other regions. Redirection of blood flow thus accentuates the nonuniformity of ventilation.
Regulation of Local Ventilation Because alveolar dead-space ventilation causes alveolar PCO2 to fall to ~0 mm Hg in downstream alveoli, it leads to a respiratory alkalosis (see Chapter 28) in the surrounding interstitial fluid. These local changes trigger a compensatory bronchiolar constriction in the adjacent tissues (Fig. 31-11B), so that during a period of seconds to minutes, airflow partially diverts away from the unperfused alveoli and toward normal alveoli, to which blood flow is also being diverted. This compensation makes teleological sense because it tends to correct the A/ shift in both the unperfused and normal alveoli. The precise mechanism of bronchiolar constriction is unknown, although bronchiolar smooth muscle may contract—at least in part—in response to a high extracellular pH. (See Note: Bronchiolar Constriction during Alveolar Dead-Space Ventilation)
In addition to a local respiratory alkalosis, the elimination of perfusion has a second consequence. Downstream from the blockage, alveolar type II pneumocytes become starved for various nutrients, including the lipids they need to make surfactant. (These cells never become starved for O2!) As a result of the decreased blood flow, surfactant production falls during a period of hours to days. The result is a local decrease in compliance, further reducing local ventilation.
These compensatory responses—bronchiolar constriction (i.e., increased resistance, a property of conducting airways) and reduced surfactant production (i.e., decreased compliance, a property of alveoli)—work well only if the alveolar dead space is relatively small, so that an ample volume of healthy tissue remains into which the airflow can be diverted.
The perfusion of unventilated alveoli (local = 0) triggers a compensatory hypoxic vasoconstriction
Shunt Alveolar dead-space ventilation is at one end of the spectrum of A/ mismatches. At the opposite end is shunt—the flow of blood past unventilated alveoli. For example, if we ligate a mainstem bronchus, then inspired air cannot refresh alveoli distal to the obstruction (Fig. 31-12A). As a result, mixed-venous blood perfusing the unventilated alveoli “shunts” from the right side to the left side of the heart, without benefit of ventilation. When the low-O2shunted blood mixes with high-O2 unshunted blood (which is ventilated), the result is that the mixture has a lower than normal PO2, causing hypoxia in the systemic arteries. It is possible to calculate the extent of the shunt from the degree of hypoxia. (See Note: The Shunt Equation)
Figure 31-12 Extreme A/ mismatch and compensatory response—shunt.
Natural causes of airway obstruction include the aspiration of a foreign body or the presence of a tumor in the lumen of a conducting airway. The collapse of alveoli (atelectasis) also produces a right-to-left shunt, a pathological example of which is pneumothorax (see Chapter 27). Atelectasis also occurs naturally in dependent regions of the lungs, where PIP is not so negative (Fig. 31-5C) and surfactant levels gradually decline. Sighing or yawning stimulates surfactant release (see Chapter 27) and can reverse physiological atelectasis.
Imagine that an infant aspirates a peanut. Initially, the air trapped distal to the obstruction has the composition of normal alveolar air. However, pulmonary capillary blood gradually extracts O2 from the trapped air and adds CO2. Eventually, the PO2 and PCO2 of the trapped air drift to their values in mixed-venous blood. If the shunt is small, so that it does not materially affect the PO2 or PCO2 of the systemic arterial blood, then the alveoli will have a PO2 of 40 mm Hg and a PCO2 of 46 mm Hg. By definition, shunted alveoli have a A/ of 0 and are represented by the “mixed-venous blood” point on an O2-CO2diagram (Fig. 31-10B).
Redirection of Airflow Blocking of airflow to one group of alveoli simultaneously diverts air to normal parts of the lung, which then become somewhat hyperventilated. Thus, shunt not only decreases A/ in unventilated alveoli but also increases A/ in other regions. The net effect is a widening of the nonuniformity of A/ ratios.
Asthma Although it is less dramatic than complete airway obstruction, an incomplete occlusion also decreases A/. An example is asthma, in which hyperreactivity of airway smooth muscle increases local airway resistance and decreases ventilation of alveoli distal to the pathological process.
Normal Anatomical Shunts The thebesian veins drain some of the venous blood from the heart muscle, particularly the left ventricle, directly into the corresponding cardiac chamber. Thus, delivery of deoxygenated blood from thebesian veins into the left ventricle (<1% of cardiac output) represents a right-to-left shunt. The bronchial arteries, branches of the aorta that carry ~2% of the cardiac output, supply the conducting airways (see Chapter 26). After passing through capillaries, about half of the bronchial blood drains into a systemic vein—the azygos vein—and then to the right side of the heart. The other half (~1% of cardiac output) anastomoses with oxygenated blood in pulmonary venules and thus represents part of the anatomical right-to-left shunt (see Chapter 17).
Pathological Shunts In Chapter 57, we discuss examples of right-to-left shunts. Respiratory distress syndrome of the newborn (see Chapter 57 for the box on this topic) can cause airway collapse. Generalized hypoxemia in the newborn can constrict the pulmonary vasculature, as we will see in the next paragraph, leading to pulmonary hypertension and the shunting of blood through the foramen ovale or a patent ductus arteriosus (see Chapter 57). (See Note: Right-to-Left Shunts)
Regulation of Local Perfusion The alveoli that derive from a single terminal bronchiole surround the pulmonary arteriole that supplies these alveoli. Thus, the vascular smooth muscle cells (VSMCs) of this pulmonary arteriole are bathed in an interstitial fluid whose composition reflects that of the local alveolar gas. In the case of shunt, VSMCs sense a decrease in PO2, an increase in PCO2, and a fall in pH. The decrease in local alveolar PO2 triggers a compensatory hypoxic pulmonary vasoconstriction, which the accompanying respiratory acidosis augments (Fig. 31-12B). Note that this response is just the opposite of that of systemic arterioles, which dilate in response to hypoxia (see Chapter 20). Hypoxic pulmonary vasoconstriction makes teleological sense because it diverts blood flow away from unventilated alveoli toward normal alveoli, to which airflow is also being diverted. This compensation tends to correct the A/ shift in both the unventilated and normal alveoli.
If the amount of pulmonary tissue involved is sufficiently small (<20%), then hypoxic vasoconstriction has a minimal effect on overall pulmonary vascular resistance. The vasoconstriction causes a slight increase in pulmonary arterial pressure, which recruits and distends pulmonary vessels outside of the shunt zone. In contrast, global alveolar hypoxia—caused, for example, by ascending to high altitude—produces a generalized hypoxic vasoconstriction that may cause the resistance of the pulmonary vasculature to more than double. In susceptible individuals, the result can be acute mountain sickness (see Chapter 61).
Even if whole-lung and are normal, exaggerated local mismatches produce hypoxia and respiratory acidosis
As we saw in Table 31-3, even a normal person has lung regions with A/ values ranging from ~0.6 to 3.3. In addition, even a normal person has local variations in A/ due to alveolar dead-space ventilation as well as physiological and anatomical shunts. These physiological A/ mismatches produce an arterial PCO2 (i.e., ~40 mm Hg) that we regard as normal and an arterial PO2 (i.e., ~100 mm Hg) that we also regard as normal. If pathological processes exaggerate this A/ mismatch, the result is respiratory acidosis and hypoxia. The sophisticated compensatory responses—discussed before—to alveolar dead-space ventilation and shunt help minimize these mismatches. Thus, uncompensated A/ abnormalities lead to respiratory acidosis and hypoxia. To illustrate how A/ mismatches produce these consequences, here we examine CO2 and O2 handling in a normal individual and then in two extreme, idealized examples: alveolar dead-space ventilation and shunt—each in the absence of any local or system-wide compensation.
Normal Lungs Figure 31-13 shows how an individual with a normal A/ distribution in each lung handles CO2 and O2. We assume that total A (4.2 L/min) and (5 L/min) are normal and divided equally between the two lungs. Each lung eliminates half of the 200 mL/min of CO2 produced by metabolism (Fig. 31-13A), and each takes up half of the 250 mL/min of O2 consumed by metabolism (Fig. 31-13B). The physiological A/ distribution, as discussed in the preceding paragraph, yields a mean alveolar PCO2 of ~40 mm Hg in each lung and a mean alveolar PO2 of ~100 mm Hg. Because the fluxes of CO2 and O2 across the alveolar blood-gas barrier are each perfusion limited (see Chapter 30), the CO2 and O2 partial pressures in the systemic arterial blood are the same as in the alveoli, and arterial pH is normal.
Figure 31-13 Normal distribution of A and . This is an idealized example. In the upper panels of A and B, the light beige boxes give the alveolar ventilation to each lung as well as the total alveolar ventilation (A). The pink boxes give the blood flow to each lung as well as the total cardiac output (). The white boxes give the rates of CO2 or O2 transport (mL/min) at either the pulmonary or systemic capillaries. The blue boxes give the CO2 and O2 partial pressures (mm Hg) in alveolar air. The lavender boxes give the CO2 partial pressure (mm Hg) and CO2 content (mL/dL) in the mixed-venous blood, in the blood leaving each of the lungs, and in the mixed-arterial blood. The dark beige boxes give the same information for O2. The lower panel of A shows hypothetical plots of how total CO2 content varies with PCO2 at the Hb-O2 saturations typical of arterial blood (red line) and mixed-venous blood (violet line). The vertical arrow indicates the decrease in total CO2 content between the mixed-venous and arterial blood (4 mL/dL). The lower panel of B shows comparable plots for how total O2 content varies with PO2 at the pH and PCO2 values typical of mixed-venous blood (violet curve) and arterial blood (red curve). The vertical arrow indicates the increase in total O2 content between the mixed-venous and arterial blood (5 mL/dL). (See Note: Analysis of V/Q Patterns in Figure 31-13)
Alveolar Dead-Space Ventilation Affecting One Lung To simulate alveolar dead-space ventilation (Fig. 31-14) in the laboratory, we can surgically ligate the left pulmonary artery, thereby eliminating all perfusion to the left lung. Total remains at its normal 5 L/min, but all blood goes to the right lung. A remains at its normal 4.2 L/min and is evenly distributed between the two lungs. Thus, the A/ to the left lung is 2.1/0 or ∞, whereas the A/ to the right lung is 2.1/5 or 0.42. The overall A/ is normal, 0.84. The key question is whether a combination of a high A/ in the abnormal lung and a low A/ in the normal lung can yield normal blood gases.
Figure 31-14 Alveolar dead-space ventilation. The numbers in this idealized example refer to a time after the individual has achieved a new steady state. In the upper panels of A and B, the light beige boxes give the alveolar ventilation to each lung as well as the total alveolar ventilation (A). The green boxes give the blood flow to each lung as well as the total cardiac output (). The white boxes give the rates of CO2 or O2 transport (mL/min) at either the pulmonary or systemic capillaries. The blue boxes give the CO2 and O2 partial pressures (mm Hg) in alveolar air. The lavender boxes give the CO2 partial pressure (mm Hg) and CO2 content (mL/dL) in the mixed-venous blood, in the blood leaving each of the lungs, and in the mixed-arterial blood. The dark beige boxes give the same information for O2. The lower panel of A shows plots of how total CO2 content in this example varies with PCO2 at the Hb-O2saturations of arterial blood (red line) and mixed-venous blood (violet line). Despite the severe respiratory acidosis, the decrease in total CO2 content between the mixed-venous and arterial blood is normal (4 mL/dL). The lower panel of B shows comparable plots for how total O2 content varies with PO2 at the pH and PCO2 values of mixed-venous blood (violet curve) and arterial blood (red curve). Despite the severe hypoxia, the increase in total O2 content between the mixed-venous and arterial blood is normal (5 mL/dL). (See Note: Analysis of V-Q Patterns in Figure 31-14)
The normal right lung must now eliminate all of the CO2 that the body produces—that is, the right lung must eliminate CO2 at twice the rate that it normally does. However, the right lung has its usual A of 2.1 L/min. Because a normal amount of alveolar air must carry away twice as much CO2 in the new steady state, the right lung’s alveolar PCO2 doubles to ~80 mm Hg (Fig. 31-14A). Because the entire cardiac output perfuses the normal right lung, arterial PCO2 is also ~80 mm Hg. Thus, even with the severe A/ abnormality produced by alveolar dead-space ventilation, the lung is able to expel the usual 200 mL/min of CO2, but at a tremendous price: a very high arterial PCO2 and thus respiratory acidosis.
The normal right lung must also supply all of the body’s O2—delivering O2 to the blood at twice its normal rate. However, because the right lung still has its normal A of 2.1 L/min, its alveolar PO2 falls to ~51 mm Hg in the new steady state. The blood leaving the right lung, which is identical to systemic arterial blood, also has a PO2 of ~51 mm Hg. Thus, even with a severe A/ abnormality, the lung is able to import the usual 250 mL/min of O2, but at a tremendous price: a very low arterial PO2 (hypoxia).
We can now answer the question that we posed earlier: the hyperperfused “good” lung cannot make up for the deficit incurred by the hypoperfused “bad” lung. In our example, the fundamental problem was that the ventilation of unperfused alveoli in the left lung effectively reduced the alveolar ventilation by half. In real life, the body would have compensated both locally and systemically. Locally, bronchiolar constriction and decreased surfactant production in the abnormal left lung (Fig. 31-11B) would diminish alveolar dead-space ventilation and increase the effective alveolar ventilation to the normal right lung. Systemically, as we discuss in the next chapter, the respiratory acidosis and hypoxia would stimulate chemoreceptors to increase ventilation. If the body could double A to the right lung—and if this right lung has a normal diffusing capacity—then it would be matching the doubled perfusion of the right lung with a doubled ventilation, and all resting blood gas parameters would return to normal. (See Note: Surgical Removal of One Lung)
A massive pulmonary embolism that obstructs the left pulmonary artery is superficially similar to the example that we have just discussed. However, other associated problems (e.g., right-sided heart failure secondary to an increase in pulmonary vascular resistance, release of vasoactive agents) make the pulmonary embolism potentially fatal.
Shunt Affecting One Lung Imagine that an object occludes the left mainstem bronchus, eliminating all ventilation to the left lung. Total A remains at 4.2 L/min, but all ventilation goes to the right lung. Thus, the A/ to the left lung is 0/2.5, or 0, whereas the A/ to the right lung is 4.2/2.5, or 1.68. The overall A/ is normal, 0.84. Again, the key question is whether a combination of a low A/ in the abnormal lung and a high A/ in the normal lung can yield normal blood gases.
The normal right lung must now eliminate CO2 at twice its normal rate. However, the right lung also has twice its normal A. Because twice the normal amount of alveolar air carries away twice the normal amount of CO2, the right lung’s new steady-state alveolar PCO2 is normal, ~40 mm Hg (Fig. 31-15A). The blood leaving the normal lung also has a PCO2 of ~40 mm Hg. However, the unventilated lung has the PCO2 of mixed-venous blood, ~51 mm Hg in this example. After the two streams of blood mix—known as venous admixture, because venous blood combines with blood from ventilated alveoli—arterial blood in the left ventricle has a CO2 content that is midway between the CO2 contents of the two streams of blood, corresponding to an arterial PCO2 of ~46 mm Hg. Thus, even with the severe A/ abnormality produced by shunt, the lung is once again able to expel the usual 200 mL/min of CO2, but once again at a price: a high arterial PCO2 (respiratory acidosis).
Figure 31-15 Shunt. The numbers in this idealized example refer to a time after the individual has achieved a new steady state. In the upper panels of A and B, the light beige boxes give the alveolar ventilation to each lung as well as the total alveolar ventilation (A). The green boxes give the blood flow to each lung as well as the total cardiac output (). The white boxes give the rates of CO2 or O2 transport (mL/min) at either the pulmonary or systemic capillaries. The blue boxes give the CO2 and O2 partial pressures (mm Hg) in alveolar air. The lavender boxes give the CO2 partial pressure (mm Hg) and CO2content (mL/dL) in the mixed-venous blood, in the blood leaving each of the lungs, and in the mixed-arterial blood. The dark beige boxes give the same information for O2. The lower panel of A shows plots of how total CO2 content in this example varies with PCO2 at the Hb-O2 saturations for unshunted blood at the end of the pulmonary capillary (red line), for shunted/mixed-venous blood (violet line), and for mixed-arterial blood (green line). Because of the 50% shunt, the decrease in total CO2 content between mixed-venous blood (point ) and unshunted blood (point c) must be twice normal (8 mL/dL) to produce a normal decrease (4 mL/dL) between mixed-venous blood (point ) and mixed-arterial blood (point a). The lower panel of B shows comparable plots for how total O2 content varies with PO2 at the pH and PCO2 values of mixed-venous blood (violet curve) and arterial blood (red curve). Because of the 50% shunt, the increase in total O2 content between mixed-venous blood (point ) and unshunted blood (point c) must be twice normal (10 mL/dL) to produce a normal increase (5 mL/dL) between mixed-venous blood (point ) and mixed-arterial blood (point a). (See Note: Analysis of V-Q Patterns in Figure 31-15)
The normal right lung must also deliver O2 to the blood at twice the normal rate. However, because the right lung’s A is also twice its usual value, its new steady-state alveolar PO2 is normal, ~100 mm Hg. The blood leaving the right lung also has a PO2 of ~100 mm Hg, a hemoglobin (Hb) saturation (SO2) of ~97.5%, and an O2 content of ~20 mL/dL. However, the unventilated lung has a PO2 of mixed-venous blood, ~29 mm Hg in this example. Thus, the blood leaving the shunted lung has an SO2 of ~49% and an O2 content of ~10 mL/dL. After venous admixture, arterial O2 content is (20 + 10)/2 or 15 mL/dL, which corresponds to an arterial SO2 (SaO2) of 73 and a PO2 of ~40 mm Hg. Thus, even with the severe A/ abnormality caused by shunt, the lung is able to import the usual 250 mL/min of O2, but at the price of an extremely low arterial PO2 (hypoxia).
Why did the A/ mismatch caused by shunt lead to only a mild respiratory acidosis but a severe hypoxia? The fundamental problem is that the Hb-O2 dissociation curve (see Fig. 29-3) is nearly saturated at the normal arterial PO2. If O2 content were proportional to PO2, then mixing of unshunted blood (PO2 = 100 mm Hg) with shunted blood (PO2 = 29 mm Hg) would have yielded arterial blood with a PO2 of (100 + 29)/2 = ~65 mm Hg, which is far higher than the arterial PO2 of ~40 mm Hg in our example.
In our example, shunt would trigger compensation at two levels. Locally, hypoxic vasoconstriction would divert blood to well-ventilated alveoli. Systemically, an increase in A would lower PCO2 and raise PO2in the normal right lung. In fact, even a modest increase in A would be sufficient to lower arterial PCO2 to 40 mm Hg. However, even if A approached infinity (raising the right lung’s alveolar PO2 to the inspired PO2 of ~149 mm Hg), arterial PO2 would still be well under 100 mm Hg. In fact, even if the inspired air were 100% O2, the arterial PO2 would still fail to reach 100 mm Hg; because of the shape of the Hb-O2 dissociation curve, an increased alveolar PO2 can increase the O2content of arterial blood only marginally (see the box titled Clinical Approaches for Diagnosis of a A/ Mismatch).
Mixed Mismatches Pathological A/ mismatches cause the range of A/ ratios to broaden beyond the physiological range. Some alveoli may be true alveolar dead space (i.e., perfusion absent, A/= ∞), but others are more modestly underperfused. Some alveoli may be totally shunted (i.e., ventilation absent, A/ = 0), but others are more modestly underventilated. Thus, the left ventricle receives a mixture of blood from alveoli with A/ ratios from ∞ to 0, corresponding to all of the points along the O2-CO2 diagram in Figure 31-10B. What is the composition of this mixed blood? The principles that we developed in our simplified examples of alveolar dead-space ventilation and shunt still hold. Even if total A and total remain normal, pathologically high A/ ratios in some alveoli cannot make up for pathologically low ratios in others, and vice versa. The result of uncompensated pathological A/ mismatching is always respiratory acidosis and hypoxia.
Clinical Approaches for Diagnosis of a Mismatch
Simple diagnostic methods are available to detect the presence of a A/ mismatch, to assess its severity, and to identify a shunt.
Diagnosis of Exclusion
The physician can often diagnose a pathological nonuniformity of A/ by excluding other possibilities. In general, low arterial PO2—under basal metabolic conditions—could be due to reduced inspired PO2 (e.g., high altitude), reduced alveolar ventilation, decreased diffusing capacity (DL), or A/mismatch. Let us assume that arterial PO2 is appropriate for the altitude (see Equations 31-16 and 31-17) and that simple spirometry test results indicate that respiratory mechanics are normal. Because DL is normally about 3-fold greater than necessary for achieving diffusion equilibrium for O2 and CO2, a problem with DL is unlikely in the absence of a positive history. By default, the most likely cause is a A/ defect.
Alveolar-Arterial Gradient for O2
The difference between the mean alveolar PO2 and the systemic arterial PO2 is known as the alveolar-arterial (A-a) gradient for PO2. In our “normal” example in Figure 31-13B, both mean alveolar PO2 and arterial PO2 were 100 mm Hg. In real life, however, physiological A/mismatches cause arterial PO2 to be 5 to 15 mm Hg below the mean alveolar value.
A defining characteristic of A/ mismatches is that they widen the A-a PO2 gradient. In our example of alveolar dead space in Figure 31-14B, the mean alveolar PO2 was (51 + 149)/2 = 100 mm Hg, whereas the systemic arterial PO2 was 51 mm Hg, for an A-a gradient of 49 mm Hg. In our example of shunt in Figure 31-15B, the mean alveolar PO2 was 100 mm Hg, whereas the arterial PO2 was only 40 mm Hg—an A-a gradient of 60 mm Hg.
Because the A-a gradient for PO2 is an index of the severity of the A/ mismatch, physicians routinely estimate the A-a gradient in the intensive care unit. The approach is (1) to obtain the arterial blood gas values, which include PaO2 and PaCO2; (2) to assume that the mean PACO2 is the same as the measured PaCO2; (3) to use the alveolar gas equation (see Equation 31-17) to compute the mean PAO2 from mean PACO2; and (4) to compute the difference PAO2 − PaO2. However, the assumption in point 2 is not entirely true because A/ mismatches cause an A-a gradient for CO2 just as they do for O2. (See Note: A-a Differences for CO2 (Robin Test))
Effect of Breathing 100% O2
Once a A/ mismatch has been identified, it is important to distinguish between a shunt, which might be corrected surgically, and other causes. Imagine two patients with similar degrees of hypoxia. In the first patient, one lung is relatively hypoventilated (low A/) and the other lung is relatively hyperventilated (high A/). However, no alveoli are shunted. In the second patient, a complete shunting of blood makes one lung totally unventilated (a A/ of 0, as in Fig 31-15). The normal lung has a high A/. We can distinguish between the two cases by having both subjects inspire 100% O2.
When the patient without predominant shunt breathes 100% O2, the PO2 of the blood leaving both lungs will be far higher than normal (Fig. 31-16A). Blood leaving the hypoventilated lung has a PO2 somewhat lower than that of the blood leaving the hyperventilated lung. However, because the PO2 is on the flat part of the Hb-O2 dissociation curve in both cases, the SO2 values are virtually identical. The miniscule difference in O2 contents between the two streams of blood is due to a difference in dissolved O2. Thus, the mixed systemic arterial blood will have slightly elevated O2 content, SaO2 of ~100%, and markedly elevated PO2.
Figure 31-16 Analysis of A/ mismatch by administration of 100% O2.
The situation is very different in the patient with a severe shunt (Fig. 31-16B). Because blood leaving the shunted lung does not equilibrate with the alveoli ventilated with 100% O2, it has the low PO2, SO2, and O2 content characteristic of mixed-venous blood. Although blood leaving the normal lung will have an extremely high PO2, both the SO2 and O2 content will be only slightly above normal—like the hyperventilated lung in Figure 31-16. Thus, when one stream of blood with a slightly increased O2 content (“normal” lung) mixes with another stream with a markedly decreased O2 content (“shunted” lung), the mixed systemic arterial blood has a lower than normal O2 content. This low O2 content translates to a low SaO2 and thus to a low systemic arterial PO2. Thus, unlike subjects with other kinds of A/ mismatches that do not include substantial shunt (e.g., alveolar dead-space ventilation in Fig. 31-14), those with substantial shunt have low arterial PO2 values, even while breathing 100% O2. Because breathing of 100% O2 greatly increases mean alveolar PO2 without substantially increasing arterial PO2, this maneuver greatly exaggerates the A-a difference for PO2.
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