Mechanical Aspects of the Lungs and Chest Wall

The discussion of pulmonary physiology begins with an introduction to a few concepts about the mechanical properties of the respiratory system, which have important implications for assessment of pulmonary function and its derangement in disease states.

The lungs and chest wall have elastic properties. They have a particular resting size (or volume) they would assume if no internal or external pressure were exerted on them, and any deviation from this volume requires some additional influencing force. If the lungs were removed from the chest and no longer had the external influences of the chest wall and pleural space acting on them, they would collapse to the point of being almost airless; they would have a much lower volume than they have within the thoracic cage. To expand these lungs, positive pressure would have to be exerted on the air spaces, as could be done by putting positive pressure through the airway. (Similarly, a balloon is essentially airless unless positive pressure is exerted on the opening to distend the elastic wall and fill it with air.)

Alternatively, instead of positive pressure exerted on alveoli through the airways, negative pressure could be applied outside the lungs to cause their expansion. Thus, what increases the volume of the isolated lungs from the resting, essentially airless, state is application of a positive transpulmonary pressure—the pressure inside the lungs relative to the pressure outside. Internal pressure can be made positive, or external pressure can be made negative; the net effect is the same. With the lungs inside the chest wall, the internal pressure is alveolar pressure, whereas external pressure is the pressure within the pleural space (Fig. 1-2). Therefore, transpulmonary pressure is defined as alveolar pressure (P_alv) minus pleural pressure (P_pl). For air to be present in the lungs, pleural pressure must be relatively negative compared with alveolar pressure.

The relationship between transpulmonary pressure and lung volume can be described for a range of transpulmonary pressures. The plot of this relationship is the compliance curve of the lung (Fig. 1-3, A). As transpulmonary pressure increases, lung volume naturally increases. However, the relationship is not linear but curvilinear. At relatively high volumes, the lungs reach their limit of distensibility, and even rather large increases in transpulmonary pressure do not result in significant increases in lung volume.

Switching from the lungs to the chest wall, if the lungs were removed from the chest, the chest wall would expand to a larger size when no external or internal pressures were exerted on it. Thus the chest wall has a springlike character. The resting volume is relatively high, and distortion to either a smaller or larger volume requires alteration of either the external or internal pressures acting on it. The pressure across the chest wall is akin to the transpulmonary pressure. Again, with the lungs back inside the chest wall, the pressure across the chest wall is the pleural pressure (internal pressure) minus the external pressure surrounding the chest wall (atmospheric pressure).

The compliance curve of the chest wall relates the volume enclosed by the chest wall to the pressure across the chest wall (Fig. 1-3, B). The curve becomes relatively flat at low lung volumes at which the chest wall becomes stiff. Further changes in pressure across the chest wall cause little further decrement in volume.

To examine how the lungs and chest wall behave in situ, remember that the elastic properties of each are acting in opposite directions. At the normal resting end-expiratory position of the respiratory system (functional residual capacity [FRC]), the lung is expanded to a volume greater than the resting volume it would have in isolation, whereas the chest wall is contracted to a volume smaller than it would have in isolation. However, at FRC the tendency of the lung to become smaller (the inward or elastic recoil of the lung) is exactly balanced by the tendency of the chest wall to expand (the outward recoil of the chest wall). The transpulmonary pressure at FRC is equal in magnitude to the pressure across the chest wall but acts in an opposite direction (Fig. 1-3, C). Therefore pleural pressure is negative, a consequence of the inward recoil of the lungs and the outward recoil of the chest wall.

The chest wall and the lungs can be considered as a unit, the respiratory system. The respiratory system has its own compliance curve, which is essentially a combination of the individual compliance curves of the lungs and chest wall (see Fig. 1-3, C). The transrespiratory system pressure, again defined as internal pressure minus external pressure, is airway pressure minus atmospheric pressure. At a transrespiratory system pressure of 0, the respiratory system is at its normal resting end-expiratory position, and the volume within the lungs is FRC.

Two additional lung volumes can be defined, as can the factors that determine each of them. Total lung capacity (TLC) is the volume of gas within the lungs at the end of a maximal inhalation. At this point the lungs are stretched well above their resting position, and even the chest wall is stretched beyond its resting position. We are able to distort both the lungs and chest wall so far from FRC by using our inspiratory muscles, which exert an outward force to counterbalance the inward elastic recoil of the lung and, at TLC, the chest wall. However, at TLC it is primarily the extreme stiffness of the lungs that prevents even further expansion by inspiratory muscle action. Therefore, the primary determinants of TLC are the expanding action of the inspiratory musculature balanced by the inward elastic recoil of the lung.

At the other extreme, when we exhale as much as possible, we reach residual volume (RV). At this point a significant amount of gas still is present within the lungs—that is, we can never exhale enough to empty the lungs entirely of gas. Again, the reason can be seen by looking at the compliance curves in Figure 1-3, C. The chest wall becomes so stiff at low volumes that additional effort by the expiratory muscles is unable to decrease the volume any further. Therefore, RV is determined primarily by the balance of the outward recoil of the chest wall and the contracting action of the expiratory musculature. However, this simple model for RV applies only to the young individual with normal lungs and airways. With age or airway disease, further expulsion of gas during expiration is limited not only by the outward recoil of the chest wall but also by the tendency for airways to close during expiration and for gas to be trapped behind the closed airways.

Ventilation

To maintain normal gas exchange to the tissues, an adequate volume of air must pass through the lungs for provision of O₂ to and removal of CO₂ from the blood. A normal person at rest typically breathes approximately 500 mL of air per breath at a frequency of 12 to 16 times per minute, resulting in a ventilation of 6 to 8 L/min (minute ventilation []).* The volume of each breath (tidal volume [VT]) is not used entirely for gas exchange; a portion stays in the conducting airways and does not reach the distal part of the lung capable of gas exchange. The portion of the tidal volume that is “wasted” (in the sense of gas exchange) is termed the volume of dead space (VD), and the volume that reaches the gas-exchanging portion of the lung is the alveolar volume (VA). The anatomic dead space, which includes the larynx, trachea, and bronchi down to the level of the terminal bronchioles, is approximately 150 mL in a normal person; thus, 30% of a tidal volume of 500 mL is wasted.

As for CO₂ elimination by the lung, alveolar ventilation (), which is equal to the breathing frequency (f) multiplied by VA, bears a direct relationship to the amount of CO₂ removed from the body. In fact, the partial pressure of CO₂ in arterial blood (PaCO₂) is inversely proportional to ; as increases, PaCO₂ decreases. Additionally, PaCO₂ is affected by the body’s rate of CO₂ production (); if increases without any change in , PaCO₂ shows a proportional increase. Thus, it is easy to understand the relationship given in Equation 1-1:

This defines the major factors determining PaCO₂. When a normal individual exercises, increases, but increases proportionately so that PaCO₂ remains relatively constant.

As mentioned earlier, the dead space comprises that amount of each breath going to parts of the tracheobronchial tree not involved in gas exchange. The anatomic dead space consists of the conducting airways. In disease states, however, areas of lung that normally participate in gas exchange (parts of the terminal respiratory unit) may not receive normal blood flow, even though they continue to be ventilated. In these areas, some of the ventilation is wasted; such regions contribute additional volume to the dead space.

Hence, a more useful clinical concept than anatomic dead space is physiologic dead space, which takes into account the volume of each breath not involved in gas exchange, whether at the level of the conducting airways or the terminal respiratory units. Primarily in certain disease states, in which there may be areas with normal ventilation but decreased or no perfusion, the physiologic dead space is larger than the anatomic dead space.

Quantitation of the physiologic dead space or, more precisely, the fraction of the tidal volume represented by the dead space (VD/VT), can be made by measuring PCO₂ in arterial blood (PaCO₂) and expired gas (PECO₂) and by using Equation 1-2, known as the Bohr equation for physiologic dead space:

For gas coming directly from alveoli that have participated in gas exchange, PCO₂ approximates that of arterial blood. For gas coming from the dead space, PCO₂ is 0 because the gas never came into contact with pulmonary capillary blood.

Consider the two extremes. If the expired gas came entirely from perfused alveoli, PECO₂ would equal PaCO₂, and according to the equation, VD/VT would equal 0. On the other hand, if expired gas came totally from the dead space, it would contain no CO₂, PECO₂ would equal 0, and VD/VT would equal 1. In practice, this equation is used in situations between these two extremes, and it quantifies the proportion of expired gas coming from alveolar gas (PCO₂ = PaCO₂) versus dead space gas (PCO₂ = 0).

In summary, each normal or tidal volume breath can be divided into alveolar volume and dead space, just as the total minute ventilation can be divided into alveolar ventilation and wasted (or dead space) ventilation. Elimination of CO₂ by the lungs is proportional to alveolar ventilation; therefore, PaCO₂ is inversely proportional to alveolar ventilation and not to minute ventilation. The wasted ventilation can be quantified by the Bohr equation, with use of the principle that increasing amounts of dead space ventilation augment the difference between PCO₂ in arterial blood and expired gas.

Circulation

Because the entire cardiac output flows from the right ventricle to the lungs and back to the left side of the heart, the pulmonary circulation handles a blood flow of approximately 5 L/min. If the pulmonary vasculature were similar in structure to the systemic vasculature, large pressures would have to be generated because of the thick walls and high resistance offered by systemic-type arteries. However, pulmonary arteries are quite different in structure from systemic arteries, with thin walls that provide much less resistance to flow. Thus, despite equal right and left ventricular outputs, the normal mean pulmonary artery pressure of 15 mm Hg is much lower than the normal mean aortic pressure of approximately 95 mm Hg.

One important feature of blood flow in the pulmonary capillary bed is the distribution of flow in different areas of the lung. The pattern of flow is explained to a large degree by the effect of gravity and the necessity for blood to be pumped “uphill” to reach the apices of the lungs. In the upright person, the apex of each lung is approximately 25 cm higher than the base, so the pressure in pulmonary vessels at the apex is 25 cm H₂O (19 mm Hg) lower than in pulmonary vessels at the bases. Because flow through these vessels depends on the perfusion pressure, the capillary network at the bases receives much more flow than the capillaries at the apices. In fact, flow at the lung apices falls to 0 during the part of the cardiac cycle when pulmonary artery pressure is insufficient to pump blood up to the apices.

West developed a model of pulmonary blood flow that divides the lung into zones, based on the relationships among pulmonary arterial, venous, and alveolar pressures (Fig. 1-4). As stated earlier, the vascular pressures—that is, pulmonary arterial and venous—depend in part on the vertical location of the vessels in the lung because of the hydrostatic effect. Apical vessels have much lower pressure than basilar vessels, the difference being the vertical distance between them (divided by a correction factor of 1.3 to convert from cm H₂O to mm Hg).

At the apex of the lung (zone 1 in Fig. 1-4), alveolar pressure exceeds arterial and venous pressures and no flow results. Normally, such a condition does not arise unless pulmonary arterial pressure is decreased or alveolar pressure is increased (by exogenous pressure applied to the airways and alveoli). In zone 2, arterial but not venous pressure exceeds alveolar pressure, and the driving force for flow is determined by the difference between arterial and alveolar pressures. In zone 3, arterial and venous pressures exceed alveolar pressure, and the driving force is the difference between arterial and venous pressures, as is the case in the systemic vasculature.

When cardiac output is increased (e.g., on exercise) the normal pulmonary vasculature is able to handle the increase in flow by recruiting previously unperfused vessels and distending previously perfused vessels. The ability to expand the pulmonary vascular bed and thus decrease vascular resistance allows major increases in cardiac output with exercise to be accompanied by only small increments in mean pulmonary artery pressure. In disease states that affect the pulmonary vascular bed, however, the ability to recruit additional vessels with increased flow may not exist, and significant increases in pulmonary artery pressure may result.

Diffusion

For O₂ and CO₂ to be transferred between the alveolar space and blood in the pulmonary capillary, diffusion must take place through several compartments: alveolar gas, alveolar and capillary walls, plasma, and membrane and cytoplasm of the red blood cell. In normal circumstances, the process of diffusion of both gases is relatively rapid, and full equilibration occurs during the transit time of blood flowing through the pulmonary capillary bed. In fact, the PO₂ in capillary blood rises from the mixed venous level of 40 mm Hg* to the end-capillary level of 100 mm Hg in approximately 0.25 second, or one third the total transit time (0.75 second) an erythrocyte normally spends within the pulmonary capillaries. Similarly, CO₂ transfer is complete within approximately the same amount of time.

Diffusion of O₂ is normally a rapid process, but it is not instantaneous. Resistance to diffusion is provided primarily by the alveolar-capillary membrane and by the reaction that forms oxygenated hemoglobin within the erythrocyte. Each factor provides approximately equal resistance to the transfer of O₂, and each can be disturbed in various disease states. However, as discussed later in this chapter, even when diffusion is measurably impaired, it rarely is a cause of impaired gas exchange. Sufficient time still exists for full equilibration of O₂ or CO₂ unless transit time is significantly shortened, as with exercise.

Even though diffusion limitation rarely contributes to hypoxemia, an abnormality in diffusion may be a useful marker for diseases of the pulmonary parenchyma that affect the alveolar-capillary membrane, the volume of blood in the pulmonary capillaries, or both. Rather than using O₂ to measure diffusion within the lung, clinicians generally use carbon monoxide, which also combines with hemoglobin and is a technically easier test to perform and interpret. The usefulness and meaning of the measurement of diffusing capacity are discussed in Chapter 3.

Oxygen Transport

Because the eventual goal of tissue oxygenation requires transport of O₂ from the lungs to the peripheral tissues and organs, any discussion of oxygenation is incomplete without consideration of transport mechanisms.

In preparation for this discussion, an understanding of the concepts of partial pressure, gas content, and percent saturation is essential. The partial pressure of any gas is the product of the ambient total gas pressure and the proportion of total gas composition made up by the specific gas of interest. For example, air is composed of approximately 21% O₂. Assuming a total pressure of 760 mm Hg at sea level and no water vapor pressure, the partial pressure of O₂ (PO₂) is 0.21 × 760, or 160 mm Hg. If the gas is saturated with water vapor at body temperature (37°C), the water vapor has a partial pressure of 47 mm Hg. The partial pressure of O₂ is then calculated on the basis of the remaining pressure: 760 − 47 = 713 mm Hg. Therefore, when room air is saturated at body temperature, PO₂ is 0.21 × 713 = 150 mm Hg. Because inspired gas is normally humidified by the upper airway, it becomes fully saturated by the time it reaches the trachea and bronchi, where inspired PO₂ is approximately 150 mm Hg.

In clinical situations, we also must consider the concept of partial pressure of a gas within a body fluid, primarily blood. When a gas mixture is in contact with a liquid, the partial pressure of a particular gas in the liquid is the same as its partial pressure in the gas mixture, assuming full equilibration has taken place. Some of the gas molecules will dissolve in the liquid, and the amount of dissolved gas reflects the partial pressure of gas in the liquid. Therefore, the partial pressure of the gas acts as the driving force for the gas to be taken up by the liquid phase.

However, the quantity of a gas carried by a liquid medium depends not only on the partial pressure of the gas in the liquid, but also on the “capacity” of the liquid for that particular gas. If a specific gas is quite soluble within a liquid, more of that gas is carried for a given partial pressure than is a less soluble gas. In addition, if a component of the liquid is also able to bind the gas, more of the gas is transported at a particular partial pressure. This is true, for example, of the interaction of hemoglobin and O₂. Hemoglobin in red blood cells vastly increases the capacity of blood to carry O₂, as more detailed discussion will show.

The content of a gas in a liquid, such as blood, is the actual amount of the gas contained within the liquid. For O₂ in blood, the content is expressed as milliliters of O₂ per 100 mL blood. The percent saturation of a gas is the ratio of the actual content of the gas to the maximal possible content if there is a limit or plateau in the amount that can be carried.

Oxygen is transported in blood in two ways, either dissolved in the blood or bound to the heme portion of hemoglobin. Oxygen is not very soluble in plasma, and only a small amount of O₂ is carried this way under normal conditions. The amount dissolved is proportional to the partial pressure of O₂, with 0.0031 mL dissolved for each millimeter of mercury of partial pressure. The amount bound to hemoglobin is a function of the oxyhemoglobin dissociation curve, which relates the driving pressure (PO₂) to the quantity of O₂ bound. This curve reaches a plateau, indicating that hemoglobin can hold only so much O₂ before it becomes fully saturated (Fig. 1-5). At PO₂ = 60 mm Hg, hemoglobin is approximately 90% saturated, so only relatively small amounts of additional O₂ are transported at a PO₂ above this level.

This curve can shift to the right or left, depending on a variety of conditions. Thus, the relationships between arterial PO₂ and saturation are not fixed. For instance, a decrease in pH or an increase in PCO₂ (largely by a pH effect), temperature, or 2,3-diphosphoglycerate (2,3-DPG) levels shifts the oxyhemoglobin dissociation curve to the right, making it easier to unload (or harder to bind) O₂ for any given PO₂ (see Fig. 1-5). The opposite changes in pH, PCO₂, temperature, or 2,3-DPG shift the curve to the left and make it harder to unload (or easier to bind) O₂ for any given PO₂. These properties help ensure that oxygen is released preferentially to tissues that are more metabolically active because intense anaerobic metabolism results in decreased pH and elevations in 2,3-DPG, whereas increased heat and CO₂ are generated by intense aerobic metabolism.

Perhaps the easiest way to understand O₂ transport is to follow O₂ and hemoglobin as they course through the circulation in a normal person. When blood leaves the pulmonary capillaries, it has already been oxygenated by equilibration with alveolar gas, and the PO₂ should be identical to that in the alveoli. Because of O₂ uptake and CO₂ excretion at the level of the alveolar-capillary interface, alveolar PO₂ is less than the 150 mm Hg that was calculated for inspired gas within the airways (see discussion on Hypoxemia and Equation 1-7). Alveolar PO₂ in a normal individual (breathing air at sea level) is approximately 100 mm Hg. However, the PO₂ measured in arterial blood is actually slightly lower than this value for alveolar PO₂, partly because of the presence of small amounts of “shunted” blood that do not participate in gas exchange at the alveolar level, such as (1) desaturated blood from the bronchial circulation draining into pulmonary veins and (2) venous blood from the coronary circulation draining into the left ventricle via thebesian veins.

Assuming PO₂ = 95 mm Hg in arterial blood, the total O₂ content is the sum of the quantity of O₂ bound to hemoglobin plus the amount dissolved. To calculate the quantity bound to hemoglobin, the patient’s hemoglobin level and the percent saturation of the hemoglobin with O₂ must be known. Because each gram of hemoglobin can carry 1.34 mL O₂ when fully saturated, the O₂ content is calculated by Equation 1-3:

Assume that hemoglobin is 97% saturated at PO₂ = 95 mm Hg and the individual has a hemoglobin level of 15 g/100 mL blood (Equation 1-4):

In contrast, the amount of dissolved O₂ is much smaller and is proportional to PO₂, with 0.0031 mL O₂ dissolved per 100 mL blood per mm Hg PO₂. Therefore, at an arterial PO₂ of 95 mm Hg (Equation 1-5):

The total O₂ content is the sum of the hemoglobin-bound O₂ plus the dissolved O₂, or 19.5 + 0.3 = 19.8 mL O₂/100 mL blood.

Arterial PO₂ is not the sole determinant of O₂ content; the hemoglobin level is also crucial. With anemia (reduced hemoglobin level), fewer binding sites are available for O₂, and the O₂ content falls even though PO₂ remains unchanged. In addition, the O₂ content of blood is a static measurement of the quantity of O₂ per 100 mL blood. The actual delivery of oxygen to tissues is dynamic and depends on blood flow (determined primarily by cardiac output but also influenced by regulation at the microvascular level) as well as O₂ content. Thus, three main factors determine tissue O₂ delivery: arterial PO₂, hemoglobin level, and cardiac output. Disturbances in any one of these factors can result in decreased or insufficient O₂ delivery.

When blood reaches the systemic capillaries, O₂ is unloaded to the tissues and PO₂ falls. The extent to which PO₂ falls depends on the balance of O₂ supply and demand: The local venous PO₂ of blood leaving a tissue falls to a greater degree if more O₂ is extracted per volume of blood because of increased tissue requirements or decreased supply (e.g., due to decreased cardiac output).

On average in a resting individual, PO₂ falls to approximately 40 mm Hg after O₂ extraction occurs at the tissue-capillary level. Because PO₂ = 40 mm Hg is associated with 75% saturation of hemoglobin, the total O₂ content in venous blood is calculated by Equation 1-6:

The quantity of O₂ consumed at the tissue level is the difference between the arterial and venous O₂ contents, or 19.8 − 15.2 = 4.6 mL O₂ per 100 mL blood. The total O₂ consumption () is the product of cardiac output and the difference noted previously in arterial-venous O₂ content. Because (1) normal resting cardiac output for a young individual is approximately 5 to 6 L/min and (2) 46 mL O₂ is extracted per liter of blood flow (note difference in units), the resting O₂ consumption is approximately 250 mL/min.

When venous blood returns to the lungs, oxygenation of this desaturated blood occurs at the level of the pulmonary capillaries, and the entire cycle can repeat.

Carbon Dioxide Transport

Carbon dioxide is transported through the circulation in three different forms: (1) as bicarbonate (HCO₃⁻), quantitatively the largest component; (2) as CO₂ dissolved in plasma; and (3) as carbaminohemoglobin bound to terminal amino groups on hemoglobin. The first form, bicarbonate, results from the combination of CO₂ with H₂O to form carbonic acid (H₂CO₃), catalyzed by the enzyme carbonic anhydrase, and subsequent dissociation to H⁺ and HCO₃⁻ (Equation 1-7). This reaction takes place primarily within the red blood cell, but HCO₃⁻ within the erythrocyte is then exchanged for Cl⁻ within plasma.

Although dissolved CO₂, the second transport mechanism, constitutes only a small portion of the total CO₂ transported, it is quantitatively more important for CO₂ transport than dissolved O₂ is for O₂ transport, because CO₂ is approximately 20 times more soluble than O₂ in plasma. Carbaminohemoglobin, formed by the combination of CO₂ with hemoglobin, is the third transport mechanism. The oxygenation status of hemoglobin is important in determining the quantity of CO₂ that can be bound, with deoxygenated hemoglobin having a greater affinity for CO₂ than oxygenated hemoglobin (known as the Haldane effect). Therefore, oxygenation of hemoglobin in the pulmonary capillaries decreases its ability to bind CO₂ and facilitates elimination of CO₂ by the lungs.

In the same way the oxyhemoglobin dissociation curve depicts the relationship between the PO₂ and O₂ content of blood, a curve can be constructed relating the total CO₂ content to the PCO₂ of blood. However, within the range of gas tensions encountered under physiologic circumstances, the PCO₂–CO₂ content relationship is almost linear compared with the curvilinear relationship of PO₂ and O₂ content (Fig. 1-6).

PCO₂ in mixed venous blood is approximately 46 mm Hg, whereas normal arterial PCO₂ is approximately 40 mm Hg. The 6 mm Hg decrease when going from mixed venous to arterial blood, combined with the effect of oxygenation of hemoglobin on release of CO₂, corresponds to a change in CO₂ content of approximately 3.6 mL per 100 mL blood. Assuming a cardiac output of 5 to 6 L/min, CO₂ production can be calculated as the product of the cardiac output and arteriovenous CO₂ content difference, or approximately 200 mL/min.

Ventilation-Perfusion Relationships

Ventilation, blood flow, diffusion, and their relationship to gas exchange (O₂ uptake and CO₂ elimination) are more complicated than initially presented because the distribution of ventilation and blood flow within the lung was not considered. Effective gas exchange critically depends upon the relationship between ventilation and perfusion in individual gas-exchanging units. A disturbance in this relationship, even if the total amounts of ventilation and blood flow are normal, is frequently responsible for markedly abnormal gas exchange in disease states.

The optimal efficiency for gas exchange would be provided by an even distribution of ventilation and perfusion throughout the lung so that a matching of ventilation and perfusion is always present. In reality, such a circumstance does not exist, even in normal lungs. Because blood flow is determined to a large extent by hydrostatic and gravitational forces, the dependent regions of the lung receive a disproportionately larger share of the total perfusion, whereas the uppermost regions are relatively underperfused. Similarly, there is a gradient of ventilation throughout the lung, with greater amounts also going to the dependent areas. However, even though ventilation and perfusion both are greater in the gravity-dependent regions of the lung, this gradient is more marked for perfusion than for ventilation. Consequently, the ratio of ventilation () to perfusion () is higher in apical regions of the lung than in basal regions. As a result, gas exchange throughout the lung is not uniform but varies depending on the ratio of each region.

To understand the effects on gas exchange of altering the ratio, first consider the individual alveolus and then the more complex model with multiple alveoli and variable ratios. In a single alveolus, a continuous spectrum exists for the possible relationships between and (Fig. 1-7). At one extreme, where is maintained and approaches 0, the ratio approaches ∞. When there is actually no perfusion ( = 0), ventilation is wasted insofar as gas exchange is concerned, and the alveolus is part of the dead space. At the other extreme, approaches 0 and is preserved, and the ratio approaches 0. When there is no ventilation ( = 0), a “shunt” exists, oxygenation does not occur during transit through the pulmonary circulation, and the hemoglobin still is desaturated when it leaves the pulmonary capillary.

Again dealing with the extremes, for an alveolar-capillary unit acting as dead space ( = ∞), PO₂ in the alveolus is equal to that in air (i.e., 150 mm Hg, taking into account the fact that air in the alveolus is saturated with water vapor), whereas PCO₂ is 0 because no blood and therefore no CO₂ is in contact with alveolar gas. With a region of true dead space, there is no blood flow, so no gas exchange has occurred between this alveolus and blood. If there were a minute amount of blood flow—that is, if the ratio approached but did not reach ∞—the blood also would have a PO₂ approaching (but slightly less than) 150 mm Hg and a PCO₂ approaching (but slightly more than) 0 mm Hg. At the other extreme, for an alveolar-capillary unit acting as a shunt ( = 0), blood leaving the capillary has gas tensions identical to those in mixed venous blood. Normally, mixed venous blood has a PO₂ = 40 mm Hg and PCO₂ = 46 mm Hg.

In reality, alveolar-capillary units fall anywhere along this continuum of ratios. The higher the ratio in an alveolar-capillary unit, the closer the unit comes to behaving like an area of dead space and the more PO₂ approaches 150 mm Hg and PCO₂ approaches 0 mm Hg. The lower the ratio, the closer the unit comes to behaving like a shunt, and the more the PO₂ and PCO₂ of blood leaving the capillary approach the gas tensions in mixed venous blood (40 and 46 mm Hg, respectively). This continuum is depicted in Figure 1-8, in which moving to the left signifies decreasing the ratio, and moving to the right means increasing the ratio. The ideal circumstance lies between these extremes, in which PO₂ = 100 mm Hg and PCO₂ = 40 mm Hg.

When multiple alveolar-capillary units are considered, the net PO₂ and PCO₂ of the resulting pulmonary venous blood returning to the left atrium depend on the total O₂ or CO₂ content and the total volume of blood collected from each of the contributing units. Considering PCO₂ first, areas with relatively high ratios contribute blood with a lower PCO₂ than do areas with low ratios. Recall that the relationship between CO₂ content and PCO₂ is nearly linear over the physiologic range (see Fig. 1-6.) Therefore, if blood having a higher PCO₂ and CO₂ content mixes with an equal volume of blood having a lower PCO₂ and CO₂ content, an intermediate PCO₂ and CO₂ content (approximately halfway between) results.

In marked contrast, a high PO₂ in blood coming from a region with a high ratio cannot compensate for blood with a low PO₂ from a region with a low ratio. The difference stems from the shape of the oxyhemoglobin dissociation curve, which is curvilinear (rather than linear) and becomes nearly flat at the top (see Fig. 1-5). After hemoglobin is nearly saturated with O₂ (on the relatively flat part of the oxyhemoglobin dissociation curve), increasing PO₂ only contributes to the very small amount of oxygen dissolved in blood and does not significantly boost the O₂ content. In other words, since most of the oxygen content in blood is due to O₂ bound to hemoglobin, once the hemoglobin is fully saturated, blood with a higher than normal PO₂ does not have a correspondingly higher O₂ content and cannot compensate for blood with a low PO₂ and low O₂ content.

In the normal lung, regional differences in the ratio affect gas tensions in blood coming from specific regions, as well as gas tensions in the resulting arterial blood. At the apices, where the ratio is approximately 3.3, PO₂ = 132 mm Hg and PCO₂ = 28 mm Hg. At the bases, where the ratio is approximately 0.63, PO₂ = 89 mm Hg and PCO₂ = 42 mm Hg. As discussed, the net PO₂ and PCO₂ of the combined blood coming from the apices, bases, and the areas between are a function of the relative amounts of blood from each of these areas and the gas contents of each.

In disease states, ventilation-perfusion mismatch frequently is much more extreme, resulting in clinically significant gas exchange abnormalities. When an area of lung behaves as a shunt or even as a region having a very low ratio, blood coming from this area has a low O₂ content and saturation, which cannot be compensated for by blood from relatively preserved regions of lung. mismatch that is severe, particularly with areas of a high ratio, can effectively produce dead space and therefore decrease the alveolar ventilation to other areas of the lung carrying a disproportionate share of the perfusion. Because CO₂ excretion depends on alveolar ventilation, PCO₂ may rise unless an overall increase in the minute ventilation restores the effective alveolar ventilation.

Hypoxemia

Blood that has traversed pulmonary capillaries leaves with a PO₂ that should be in equilibrium with and almost identical to the PO₂ in companion alveoli. Although it is difficult to measure the O₂ tension in alveolar gas, it can be conveniently calculated by a formula known as the alveolar gas equation. A simplified version of this formula is relatively easy to use and can be extremely useful in the clinical setting, particularly when trying to deduce why a patient is hypoxemic. The alveolar O₂ tension (PAO₂)* can be calculated by Equation 1-8:

where FIO₂ = fractional content of inspired O₂ (FIO₂ of air = 0.21), PB = barometric pressure (approximately 760 mm Hg at sea level), PH₂O = vapor pressure of water in the alveoli (at full saturation at 37°C, PH₂O = 47 mm Hg), PACO₂ = alveolar CO₂ tension (which can be assumed to be identical to arterial CO₂ tension, PaCO₂), and R = respiratory quotient (CO₂ production divided by O₂ consumption, usually approximately 0.8). In practice, for the patient breathing room air (FIO₂ = 0.21), the equation often is simplified. When numbers are substituted for FIO₂, PB, and PH₂O and when PaCO₂ is used instead of PACO₂, the resulting equation (at sea level) is Equation 1-9:

By calculating PAO₂, the expected PaO₂ can be determined. Even in a normal person, PAO₂ is greater than PaO₂ by an amount called the alveolar-arterial oxygen difference or gradient (AaDO₂). A gradient exists even in normal individuals for two main reasons: (1) A small amount of cardiac output behaves as a shunt, without ever going through the pulmonary capillary bed. This includes venous blood from the bronchial circulation, a portion of which drains into the pulmonary veins, and coronary venous blood draining via thebesian veins directly into the left ventricle. Desaturated blood from these sources lowers O₂ tension in the resulting arterial blood. (2) Ventilation-perfusion gradients from the top to the bottom of the lung result in somewhat less-oxygenated blood from the bases combining with better-oxygenated blood from the apices.

AaDO₂ normally is less than 15 mm Hg, but it increases with age. AaDO₂ may be elevated in disease for several reasons. First, a shunt may be present so that some desaturated blood combines with fully saturated blood and lowers PO₂ in the resulting arterial blood. Common causes of a shunt are:

Another cause of elevated AaDO₂ is ventilation-perfusion mismatch. Even when total ventilation and total perfusion to both lungs are normal, if some areas receive less ventilation and more perfusion (low ratio) while others receive more ventilation and less perfusion (high ratio), AaDO₂ increases and hypoxemia results. As just mentioned, the reason for this phenomenon is that areas having a low ratio provide relatively desaturated blood with a low O₂ content. Blood coming from regions with a high ratio cannot compensate for this problem because the hemoglobin is already fully saturated and cannot increase its O₂ content further by increased ventilation (Fig. 1-9).

In practice, the contribution to hypoxemia of true shunt ( = 0) and mismatch (with areas of that are low but not 0) can be distinguished by having the patient inhale 100% O₂. In the former case, increasing inspired PO₂ does not add more O₂ to the shunted blood, and O₂ content does not increase significantly. In the latter case, alveolar and capillary PO₂ rise considerably with additional O₂, fully saturating blood coming even from regions with a low ratio, and arterial PO₂ rises substantially.

A third cause of elevated AaDO₂ occurs primarily in specialized circumstances. This cause is a “diffusion block” in which PO₂ in pulmonary capillary blood does not reach equilibrium with alveolar gas. If the interface (i.e., the tissue within the alveolar wall) between the capillary and the alveolar lumen is thickened, one can hypothesize that O₂ does not diffuse as readily and that the PO₂ in pulmonary capillary blood never reaches the PO₂ of alveolar gas. Even with a thickened alveolar wall, however, there is still sufficient time for this equilibrium. Unless the transit time of erythrocytes through the lung is significantly shortened, failure to equilibrate does not appear to be a problem. A specialized circumstance in which a diffusion block plus more rapid transit of erythrocytes together contribute to hypoxemia occurs during exercise in a patient with interstitial lung disease, as will be discussed later. However, for most practical purposes in the nonexercising patient, a diffusion block should be considered only a hypothetical rather than a real mechanism for increasing AaDO₂ and causing hypoxemia.

Increasing the difference between alveolar and arterial PO₂ is not the only mechanism that results in hypoxemia. Alveolar PO₂ can be decreased, which must necessarily lower arterial PO₂ if AaDO₂ remains constant. Referring back to the alveolar gas equation, it is relatively easy to see that alveolar PO₂ drops if barometric pressure falls (e.g., with altitude) or if alveolar PCO₂ rises (e.g., with hypoventilation). In the latter circumstance, when total alveolar ventilation falls, PCO₂ in alveolar gas rises at the same time alveolar PO₂ falls. Hypoventilation is relatively common in lung disease and is defined by the presence of a high PCO₂ accompanying the hypoxemia. If PCO₂ is elevated and AaDO₂ is normal, then hypoventilation is the exclusive cause of low PO₂. If AaDO₂ is elevated, either mismatch or shunting also contributes to hypoxemia.

In summary, lung disease can result in hypoxemia for multiple reasons. Shunting and ventilation-perfusion mismatch are associated with elevated AaDO₂. They often can be distinguished, if necessary, by inhalation of 100% O₂, which markedly increases PaO₂ with mismatch but not with true shunting. In contrast, hypoventilation (identified by high PaCO₂) and low inspired PO₂ lower alveolar PO₂ and cause hypoxemia, although AaDO₂ remains normal. Because many of the disease processes examined in this text cause several pathophysiologic abnormalities, it is not at all uncommon to see more than one of the aforementioned mechanisms producing hypoxemia in a particular patient.

Hypercapnia

As discussed earlier in the section on ventilation, alveolar ventilation is the prime determinant of arterial PCO₂, assuming CO₂ production remains constant. It is clear that alveolar ventilation is compromised either by decreasing the total minute ventilation (without changing the relative proportion of dead space and alveolar ventilation) or by keeping the total minute ventilation constant and increasing the relative proportion of dead space to alveolar ventilation. A simple way to produce the latter circumstance is to change the pattern of breathing (i.e., decrease tidal volume and increase frequency of breathing). With a lower tidal volume, a larger proportion of each breath ventilates the anatomic dead space, and the proportion of alveolar ventilation to total ventilation must decrease.

In addition, if significant ventilation-perfusion mismatching is present, well-perfused areas may be underventilated, whereas underperfused areas receive a disproportionate amount of ventilation. The net effect of having a large proportion of ventilation go to poorly perfused areas is similar to that of increasing the dead space. By wasting this ventilation, the remainder of the lung with the large share of the perfusion is underventilated, and the net effect is to decrease the effective alveolar ventilation. In many disease conditions, when such significant mismatch exists, any increase in PCO₂ stimulates breathing, increases total minute ventilation, and compensates for the effectively wasted ventilation.

Therefore, several causes of hypercapnia can be defined, all of which have in common a decrease in effective alveolar ventilation. Causes include a decrease in minute ventilation, an increase in the proportion of wasted ventilation, and significant ventilation-perfusion mismatch. By increasing the total minute ventilation, however, a patient often is capable of compensating for the latter two situations so CO₂ retention does not result.

Increasing CO₂ production necessitates an increase in alveolar ventilation to avoid CO₂ retention. Thus, if alveolar ventilation does not rise to compensate for additional CO₂ production, hypercapnia also will result.

As is the case with hypoxemia, pathophysiologic explanations for hypercapnia do not necessarily follow such simple rules so that each case can be fully explained by one mechanism. In reality, several of these mechanisms may be operative, even in a single patient.

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