The Gas Exchanger: Matching Ventilation and Perfusion

Oxygenation and the Gas Exchanger

Having examined the factors that affect carbon dioxide elimination from the blood, we now turn our attention to oxygen. The binding of oxygen to hemoglobin is quite different than for carbon dioxide. These differences have a profound effect on the physiologic causes of hypoxemia and the response of the body to breathing supplemental oxygen in various disease states.

Oxygen Binding to Hemoglobin ↑

In contrast to the carbon dioxide–hemoglobin dissociation curve, which is linear, the oxygen–hemoglobin dissociation curve is sigmoid or S shaped (Fig. 5-8). The Y axis denotes the percentage of hemoglobin that is in the oxy-hemoglobin state, that is, the oxygen-binding sites on hemoglobin are filled with oxygen atoms. This is expressed as a function of the partial pressure of oxygen in the plasma.

The shape of the curve facilitates the release of oxygen in hypoxic tissues and the uptake of oxygen by the blood in the alveolus. The PO₂ of the tissues is typically about 40 mm Hg. At this partial pressure, oxygen leaves hemoglobin (note the steep slope of the curve as the P_aO₂ decreases below 60 mm Hg), as reflected by the lower saturation on the vertical axis. Thus, as arterial blood travels through the capillaries in the tissues, the oxygen is released to support aerobic metabolism.

When the venous blood returns to the alveoli, it is exposed to a PO₂ of approximately 100 mm Hg in the alveolus (more on this in a moment). Oxygen diffuses from the alveoli into the plasma, displaces carbon dioxide from the hemoglobin (remember the Haldane effect), and binds to the hemoglobin until the saturation reaches the value that corresponds to the PO₂ in the plasma.

The relatively flat portion of the curve between a P_aO₂ of 60 and 100 mm Hg has another evolutionary advantage: it ensures that the hemoglobin will remain nearly fully saturated with oxygen even when the alveolar—and hence, arterial, PO₂—decreases to levels as low as 60 mm Hg. Because most of the oxygen carried in the blood is bound to hemoglobin, this ensures that the oxygen content of the blood (the sum of the oxygen bound to hemoglobin and dissolved in the blood) will remain high. Thus, tissues receive adequate amounts of oxygen when a person is at moderate altitudes or when there is a problem with the gas exchanger, such as pneumonia, that causes the P_aO₂ to decrease below 100 mm Hg.

When we examined the carbon dioxide–hemoglobin dissociation curve, we saw that the relationship could be altered by the addition of oxygen; the curve shifted to the right. The oxygen–hemoglobin relationship may also be altered by a number of factors that increase the affinity of hemoglobin for oxygen (shift in the curve to the left) or decrease the affinity for oxygen (shift in the curve to the right). When the pH of the blood decreases (i.e., the hydrogen ion concentration increases), the curve is shifted to the right, a phenomenon termed the Bohr effect (and conversely, an increase in pH shifts the curve to the left). Hydrogen ion binds to hemoglobin and alters the conformation of the oxygen-binding sites, much as carbon dioxide does, to reduce the affinity of hemoglobin for oxygen. Because a decrease in pH in the tissues often reflects anaerobic metabolism, the product of which is lactic acid, the shift of the curve to the right may be seen as a compensation that results in greater release of oxygen to the tissues (for a given PO₂, less oxygen is bound to hemoglobin and more is available to the tissue) and an attempt by the system to restore aerobic metabolism. Temperature affects the relationship (increases in body temperature shift the curve to the right), as do carbon dioxide (increases in P_aCO₂ shift the curve to the right) and 2,3 diphosphoglycerate, an organic phosphate that is a byproduct of red blood cell (RBC) metabolism (a decrease in 2,3 DPG shifts the curve to the left).

Use Animated Figure 5-8A to observe the effects of shifts in the oxygen dissociation curve. The horizontal axis shows PO₂, including values corresponding to the alveoli and the tissues. The vertical axes show oxygen saturation of hemoglobin and the oxygen concentration of the blood. The shaded portions of the vertical axes show the differences in oxygen saturation and content between the alveoli and the tissues (in other words, how much oxygen is offloaded). Note how shifting the curve to the right facilitates oxygen offloading at the tissues (shown by the increase in the saturation and content differences for oxygen between alveoli and tissues). In particular, as you shift the curve to the right, notice how the alveolar PO₂ still corresponds to the flat portion of the dissociation curve (and thus a high oxygen saturation), but the saturation corresponding to the tissues' PO₂ (located on the steep portion of the curve) decreases quite a bit as the curve shifts.

Use Animated Figure 5-8A, Part 2 to see what happens if other factors such as pH and P_aCO₂ are held constant while the alveolar or tissues PO₂ values change. The shaded portion shows the difference in oxygen saturation between the alveoli and the tissues (in other words, the degree of oxygen offloading). Note how, with other factors held constant, changes in the tissues' PO₂ cause dramatic changes in the oxygen saturation difference between alveoli and tissues. In contrast, observe that when you lower the alveolar PO₂, the oxygen saturation of the corresponding arterial blood doesn't fall below 95% until the PO₂ drops considerably. These differences reflect the S-shape of the oxygen-hemoglobin dissociation curve, with the steeper portion toward the left.

Carbon monoxide (CO), a byproduct of combustion, is a toxic gas that exerts its effects by binding to hemoglobin. When present in the environment, CO competes with oxygen for the heme-binding sites on hemoglobin (hemoglobin's affinity for CO is 200 times greater than for oxygen), thereby reducing the amount of oxygen carried by the blood to the tissues. In addition, CO alters the relationship between PO₂ and oxygen saturation. The oxygen-hemoglobin saturation curve loses its sigmoid shape and is shifted to the left (Fig. 5-9).

This change in the curve reflects the greater affinity of oxygen to hemoglobin in the presence of CO and greatly accentuates the clinical consequences of CO poisoning. The consequence is that less oxygen is released to the tissues than would be predicted based solely on the reduced oxygen content of the blood. The effect of the combination of these two factors is to deprive metabolically active tissues of oxygen. Carbon monoxide poisoning is characterized by alterations in cognitive function, seizures, coma (in severe cases), chest pain, and the accumulation of metabolic acid in the blood caused by the body's necessity to use anaerobic metabolism to generate energy.

Oxygenation ↑

In this section we investigate the physiological causes of low oxygen levels in the blood. Hypoxia is a generic term that refers to a low PO₂. Hypoxemia refers to a low PO₂ in the blood.

The Alveolar Gas Equation

The alveolar gas equation is used to calculate the partial pressure of oxygen within the ideal alveolus in the lung (P_AO₂; recall that a lower case a signifies arterial gas and a capital A denotes alveolar gas). ("Ideal" is used here to mean that this would be the value seen in an alveoli if there were no mismatch). The equation describes the relationship between the concentration of inspired oxygen, the ventilation of the alveolus (as represented by the alveolar carbon dioxide, or P_ACO₂), and the P_AO₂:

= the fraction of oxygen in the inspired gas (for atmospheric gas, this number is 0.21)

= barometric pressure (remember, this changes depending on altitude), which is 760 mm Hg at sea level

= water vapor pressure when the gas is fully saturated (because the air we breathe is humidified by the upper airway on its way to the alveolus), which is equal to 47 mm Hg

= the respiratory quotient which represents the ratio between oxygen consumed and carbon dioxide produced by the body (as oxygen is absorbed from the alveolus, carbon dioxide is eliminated proportional to this ratio). The respiratory quotient varies with the nature of the individuals diet. In a typical American diet, R = 0.8. If an individual eats primarily carbohydrates, R becomes closer to 1.0. If an individual eats a diet rich in fat, R becomes closer to 0.7.

At sea level, for an individual with a normal P_aCO₂ of 40 mm Hg (because carbon dioxide diffuses readily between the blood and the alveolus, one can assume that alveolar and arterial carbon dioxide have come into equilibrium by the time the blood leaves the pulmonary capillary), the P_AO₂ is approximately 100 mm Hg (0.21(760 − 47) × 40/0.8 = 100).

To determine the P_AO₂, you must obtain a sample of arterial blood, measure the P_aO₂ and P_aCO₂ (the sample is called an arterial blood gas [ABG], which provides you with the P_aO₂, P_aCO₂, and pH of the blood), and compute the P_AO₂ from the alveolar gas equation. With this value in hand, you can now compare the alveolar and arterial PO₂. Because ventilation and perfusion are not perfectly matched, even in normal individuals (remember that there is relatively more ventilation toward the apex of the lungs and relatively more perfusion toward the bases), there is always a difference between P_AO₂ and P_aO₂. In addition, the normal gradient may reflect the mixture of a small amount of deoxygenated blood from the bronchial veins, with oxygenated blood returning from the lungs to the left heart. The difference between P_AO₂ and P_aO₂ is called the alveolar to arterial oxygen difference (A-aDO₂) and defines whether there is a problem with the gas exchange. The A-aDO₂ increases in normal people as they age because of changes in ventilation that relate to loss of elastic recoil in the lung. Until 30 years, a normal A-aDO₂ is less than or equal to 10 mm Hg. At ages older than 30 years, the normal A-aDO₂ can be approximated as age 0.3 (e.g., a 70-year-old person can have an A-aDO₂ of 20 mm Hg and still have a normal gas exchange). With supplemental oxygen, the A-aDO₂ increases because of mild worsening of mismatch and an increased effect on P_aO₂ of the small amount of shunted blood (deoxygenated blood returning to the left side of the heart) under these conditions (a full discussion on the effect of shunt on P_aO₂ will follow shortly). Because it is difficult to know what constitutes a normal A-aDO₂ when a patient is breathing supplemental oxygen, we primarily perform this calculation based on the patient breathing room air.

If a person has a low P_aO₂, it is important to calculate the A-aDO₂ to determine if the hypoxemia is caused by a problem with the gas exchanger. If the A-aDO₂ is abnormally high, then there must be a pathological problem with either the lung tissue or the pulmonary circulation. If the A-aDO₂ is normal, the gas exchange (the alveoli and pulmonary capillaries) is normal and an alternative explanation must be sought to explain the hypoxemia.

Causes of Hypoxemia

Alveolar Hypoventilation. If alveolar ventilation is reduced due to a reduction in total ventilation or a change in the pattern of breathing (e.g., more rapid, shallow breaths), the P_ACO₂ increases because the gas in the alveolus is not being exchanged at the normal rate. Thus, carbon dioxide delivered from the blood perfusing the alveolus will begin to accumulate. As you look back at the alveolar gas equation, you will see that an increase in the P_ACO₂ causes the P_AO₂ to decrease. Physiologically, the decrease in alveolar ventilation leads to a decrease in alveolar oxygen because the oxygen present in the alveolus is diffusing into the blood but is not being replaced at a normal rate. The alveolar and arterial partial pressure of oxygen will decrease by the same amount. The A-aDO₂ will remain within the normal range. Thus, one can conclude that the hypoxemia is not caused by a gas exchanger problem. In this case, the hypoxemia would be caused by an abnormality of the controller (see Chapter 6) or a neuromuscular problem, such as myasthenia gravis (a disease that interferes with the transmission of neural impulses to skeletal muscles), that affects the ventilatory pump.

Reduced P_IO₂. When you go to a high altitude, the P_aO₂ decreases. Looking at the alveolar gas equation, the P_AO₂ is affected at higher altitudes because barometric pressure, P_atm, is reduced. The F_IO₂ remains the same, but with a reduction in barometric pressure, the partial pressure of the inspired gas decreases. As with decreases in alveolar ventilation, the decrease of the alveolar and arterial partial pressure of oxygen will be the same, and the A-aDO₂, will remain within the normal range. The hypoxemia associated with altitude, therefore, is not caused by a problem with the gas exchanger. A similar decrease in inspired P_IO₂ might be seen when the F_IO₂ is reduced. A person who was caught in an enclosed space in which a fire is burning will be exposed to a low F_IO₂, because of the consumption of oxygen by the fire.

Ventilation–Perfusion Mismatch. As noted previously, even normal individuals have a small amount of mismatch that leads to a discrepancy between alveolar and arterial oxygenation. Many disease states, including pneumonia, heart failure, asthma, and emphysema, can cause a worsening of mismatch. The hypoxemia seen in these conditions, if caused by mismatch, is associated with an abnormally large A-aDO₂. mismatch is the most common pathologic explanation for hypoxemia.

Earlier in the chapter, we observed how well-ventilated alveoli can compensate for poorly ventilated alveoli in terms of the CO₂ content of the outgoing mixed blood (see Animated Figure 5-6). At this point, we examine how the nonlinear shape of the oxygen dissociation curve creates a different situation for oxygen content when we mix blood from well-ventilated and poorly ventilated alveoli, as occurs in mismatch.

First, use Animated Figure 5-8B to vary the ratio for a single alveolus, and observe how the PO₂ and oxygen content of the outgoing capillary blood change. In particular, note that a low ratio produces a PO₂ value that corresponds to the steep portion of the oxygen dissociation curve and thus significantly lowers the oxygen content of the outgoing capillary blood. In contrast, a high ratio produces a PO₂ value that corresponds to the relatively flat portion of the oxygen dissociation curve and thus does not significantly elevate the oxygen content of the outgoing blood compared with a normal ratio.

Animated Figure 5-8B (Work in progress)

Keeping this in mind, now use Animated Figure 5-8C to vary the ratios for a three alveolus model, and observe the changes in the oxygen content of the outgoing mixed blood. Try increasing the ratio in one alveolus while decreasing the ratio in another, and note how the small elevation in oxygen content caused by the high ratio alveolus does not compensate for the significant decrease in oxygen content caused by the low ratio alveolus. This observation is one of the keys to understanding how worsening mismatch may lead to hypoxemia.

Animated Figure 5-8C (Work in progress)

An extreme form of mismatch occurs when some of the alveoli of the lung completely collapse or are filled with fluid. In these cases, alveolar ventilation in the affected regions of the lung is 0. We term this condition shunt. (Note that even though shunt is an extreme form of mismatch, we distinguish these terms when referring to causes of hypoxemia and typically use mismatch to refer to the less extreme non-shunt case.) Although you would normally expect the blood vessel serving a collapsed or fluid-filled alveolus to constrict because of local hypoxia, the disease process causing the alveolar process may also affect the pulmonary circulation such that perfusion of the nonventilated alveolus continues. Thus, the shunt is established. Hypoxemia caused by a shunt, similar to hypoxemia caused by other causes of mismatch, is characterized by an abnormally large A-aDO₂, indicating a problem with the gas exchanger.

Diffusion Abnormality. The movement of gas between the alveolus and the blood occurs by diffusion. Both oxygen and carbon dioxide diffuse quickly so that under normal conditions in a patient at rest, equilibration is reached well before an RBC completes its travel through the alveolar capillary (carbon dioxide diffuses approximately 20 times more rapidly than does oxygen and is able to establish an equilibrium between the blood and the alveolus despite a relatively low diffusion pressure). For oxygen, equilibration occurs when the RBC is approximately one third of the way through the capillary.

As a result of this rapid equilibration, significant “reserve capacity” is available for diffusion. In other words, even if a disease process interferes with diffusion and equilibration takes twice as long, the blood will have picked up all of its oxygen before the RBC exits the capillary. Thus, diffusion abnormalities are not usually a cause of hypoxemia at rest.

During exercise, cardiac output may increase by fivefold. This increase in blood flow leads to more rapid transit of the RBCs through the alveolar capillary. With exercise, if there is a problem with diffusion, the reserve that was present at rest no longer exists, and hypoxemia may develop.

In Animated Figure 5-10, equilibration of oxygen is shown along the pulmonary capillary. Observe how equilibration takes place farther along the capillary with increasing flow, as occurs during exercise. As mentioned, equilibration may not occur if conditions exist in which flow is sufficiently increased and a concurrent problem with diffusion is present.

Oxygen Content

Oxygen exists in the blood in two forms: bound to hemoglobin and dissolved in the liquid portion of the blood. The oxygen content of the blood reflects the amount of oxygen that is bound to hemoglobin and the amount dissolved in the liquid portion, or plasma component, of the blood (i.e., the total amount of oxygen in the blood). The equation for calculation of oxygen content is:

Each gram of hemoglobin can combine with approximately 1.35 mL of oxygen (you may see values of 1.34 to 1.39 mL of oxygen per gram of hemoglobin in different references). A normal hemoglobin value is approximately 14 g/100 mL of blood. The constant 0.003 transforms the P_aO₂ into mL of oxygen per 100 mL of blood.

Assuming a P_aO₂ of 100 mm Hg and a corresponding oxygen saturation of approximately 97.5% as well as a normal hemoglobin level, the amount of oxygen bound to hemoglobin is 18.4 mL/100 mL of blood. The amount of oxygen dissolved in the blood is 0.3 mL/100 mL of blood. As you can see, the amount of oxygen bound to hemoglobin overshadows the amount of oxygen dissolved in the blood. Furthermore, as soon as the hemoglobin is fully saturated or nearly fully saturated, further increases in P_aO₂ make relatively little difference in the oxygen content of the blood (recall Animated Figure 5-8B). For example, in the illustration cited above, if we give the person supplemental oxygen and increase the F_IO₂ (fraction of inspired oxygen) from 0.21 to 0.35, the P_AO₂ will be 200 mm Hg. Assuming an A-aDO₂ of 25 mm Hg (note that this value is increased from the patient is on room air), the P_aO₂ will be 175 mm Hg. With this increase in the P_aO₂ (and a new corresponding oxygen saturation of 99%), the new oxygen content is only 18.7 + 0.5 = 19.2 mL/100 mL of blood, barely above the 18.4 + 0.3 = 18.7 mL/100 mL of blood when the person was breathing room air.

A low hemoglobin level, or anemia, reduces oxygen content significantly. It does not change the P_aO₂, however. Thus, a person with anemia may have symptoms secondary to reduced delivery of oxygen to metabolically active tissues even though no hypoxemia (which refers specifically to a low PO₂ in the blood) is present. Use Animated Figure 5-8D to vary the hemoglobin level and observe the effect on the oxygen–hemoglobin dissociation curve. Notice that the saturation level stays the same for any given PO₂ (as shown by the saturation axis that scales with the amount of hemoglobin), but the total content (or concentration) of oxygen delivered varies with changes in the amount of hemoglobin (as shown by the changing O₂ concentration difference on the vertical axis).

Response to Supplemental Oxygen: Distinguishing Shunt from Less Extreme Ventilation–Perfusion Mismatch

In a patient who has hypoxemia due to mismatch, some areas of the lung have relatively poor ventilation compared with the amount of blood perfusing the alveolus. Oxygen diffuses from the alveolus to the blood but is not quickly replaced because ventilation of the lung unit is reduced. The P_AO₂ decreases. Subsequent blood that enters the alveolar capillary is exposed to a low P_AO₂ and exits the capillary with a low P_aO₂. If one now places the patient on supplemental oxygen and increases the F_IO₂, the alveolar oxygen will increase (even though ventilation of the alveolus has not changed, P_AO₂ will increase because the gradient for diffusion of oxygen between the airway and the alveolus has increased). Although there is an increase in A-aDO₂ when on supplemental oxygen (as mentioned in our discussion of the alveolar gas equation), it is relatively small, and the P_aO₂ increases almost as much as the P_AO₂. Thus, with administration of supplemental oxygen to a patient who is hypoxemic because of mismatch, the P_aO₂ will increase, as will oxygen content.

Now consider the extreme of mismatch that we call shunt, when the ventilation of an alveolus is 0. The blood perfusing the alveolus sees no gas and exits the alveolar capillary with the same PO₂ as it entered the alveolus. If one administers supplemental oxygen, although F_IO₂ is increased, the blood perfusing the nonventilated alveolus will still not see any gas and will exit the alveolar capillary without picking up any oxygen. What about the alveoli that are being ventilated? The P_AO₂ of these alveoli increases as F_IO₂ is increased, but the oxygen content of the blood perfusing these alveoli does not change significantly. The hemoglobin exiting these normal alveoli was nearly fully saturated when the patient was breathing room air. Based on what you have learned about the calculation of oxygen content, the increase of P_AO₂ under these circumstances will have relatively little effect on the oxygen content (Fig. 5-11).

When one mixes the blood from the well-ventilated alveoli with blood from the areas of shunt, the final oxygen content of the blood is changed minimally after the addition of supplemental oxygen. Animated Figure 5-11 illustrates this effect. Vary the degree of shunt and compare the final oxygen content of the mixed outgoing blood for the patient breathing room air versus 100% oxygen. Note in particular where the PO₂ values of the shunted, nonshunted, and mixed outgoing blood fall on the oxygen–hemoglobin dissociation curve. The PO₂ of the nonshunted blood corresponds to the relatively flat portion of the dissociation curve, whether breathing room air or 100% O₂. Thus, the incremental gains in O₂ content in the nonshunted blood from breathing 100% O₂ make little difference to the O₂ content of the mixed outgoing blood (as shown on the vertical axis of graph).

The response of the P_aO₂ to supplemental oxygen allows one to distinguish clinically, at the bedside, hypoxemia caused by mismatch (significant increase in P_aO₂) from hypoxemia caused by shunt (no significant increase in P_aO₂).

Distinguishing the Physiological Causes of Hypoxemia

We have now outlined the five physiological causes of hypoxemia: reduced P_IO₂, hypoventilation (decreased alveolar ventilation), mismatch, shunt, and diffusion abnormalities (note: we are not talking about specific disease states but rather the physiology that underlies conditions, both normal [e.g., high altitude] and pathological [e.g., pneumonia, emphysema]). Although shunt is actually an extreme form of mismatch, we list it separately for two reasons. First, the diseases that lead to significant shunt are relatively few in number and very distinct, for example, the adult respiratory distress syndrome and septal defects in the heart. Second, shunt can be distinguished very easily in the clinical setting from all other conditions that lead to less severe forms of mismatch. In a patient you suspect has mismatch or shunt, you should check the initial P_aO₂, administer supplemental oxygen, and recheck the P_aO₂. If a significant increase in the P_aO₂ has occurred with supplemental oxygen, one is dealing with typical mismatch; if the P_aO₂ does not change significantly, the patient has a shunt that accounts for the hypoxia (the appropriate magnitude of change in P_aO₂ for administration of 100% O₂ with different degrees of shunt can be appreciated by using Animated Figure 5-11).

In considering the physiology of a patient with hypoxemia, you should adopt a systematic approach to your analysis. First, calculate the A-aDO₂. This must be done with the patient breathing room air (i.e., off supplemental oxygen). With most techniques we use to administer supplemental oxygen, with the exception of the patient in respiratory failure who has an endotracheal tube in place and is attached to a ventilator, it is difficult to know the exact F_IO₂. Without a well-defined F_IO₂, it is impossible to calculate accurately the A-aDO₂ in a patient receiving oxygen via a mask or nasal tubing. Calculation of the A-aDO₂ in some patients receiving supplemental oxygen is complicated by one other factor. In patients with obstructive lung disease who have been receiving supplemental oxygen, it is important to remove the oxygen and wait at least 15 to 20 minutes before checking the P_aO₂. These patients have regions of the lung with long time constants (see Chapter 4 for a refresher on time constants), and it may take many minutes before the alveolar gas reflects the gas in the room as opposed to the gas that had been inspired with added oxygen.

Having calculated the A-aDO₂ on room air, determine if it is normal or abnormal, while taking into consideration that the normal range varies with age (the upper limit of normal is approximately 0.3 times the age of the person) (Quick Check 5-3). If the A-aDO₂ is normal, the hypoxemia must be attributable to a reduced P_IO₂ or hypoventilation. All the other physiological causes of hypoxemia are characterized by an abnormally large A-aDO₂.

If the A-aDO₂ is abnormally large, place the patient on supplemental oxygen and recheck the P_aO₂. If there is a significant increase in the P_aO₂ (generally more than 20 mm Hg), you are likely dealing primarily with mismatch or a diffusion problem. If the P_aO₂ does not increase significantly, the patient probably has a shunt. (For very high levels of supplemental oxygen, the increase may be more than 20 mm Hg even with a fair degree of shunt. See Animated Figure 5-11 to appreciate the magnitude of change in P_aO₂ when giving 100% O₂ for different degrees of shunt.) Note that patients may have a combination of mismatch and shunt present at the same time; recall that shunt is actually the extreme form of mismatch when = 0. The absence of a change in the P_aO₂ with supplemental oxygen indicates that shunt is the primary cause of the hypoxemia. A large change in P_aO₂ with increased F_IO₂ indicates that shunt is not the primary cause of the hypoxemia (Table 5-2).

If the patient has a normal P_aO₂ at rest but develops hypoxemia with exercise, one is likely dealing with a diffusion abnormality. One must remember, however, that more than one physiological derangement may be present in a given patient. For example, an individual with emphysema may have both mismatch and a diffusion abnormality.