Gas Diffusion

The high-speed random impacts of atmospheric air molecules on solid surfaces create the atmosphere’s pressure. Air is a gas mixture; the contribution each gas makes to the atmospheric pressure is proportional to the number of its molecules present (i.e., each gas exerts its own partial pressure, as explained in Chapter 4). A gas diffuses from one point to another in a gas mixture when there are differences in its partial pressures within the mixture; the direction of diffusion is always from high to low partial pressure. When no partial pressure difference exists for any gas throughout the mixture, equilibrium is present. Individual gas partial pressure differences are called diffusion gradients. During diffusion, each gas in a mixture moves down its own diffusion gradient, from high pressure to low pressure. This means two different gases may simultaneously diffuse in opposite directions because of oppositely oriented partial pressure gradients. This occurs for oxygen (O₂) and carbon dioxide (CO₂) across the alveolar-capillary membrane (Fig. 7.1).

Fig. 7.1 Alveolar capillary gas-exchange membrane. From Hall JE. *Guyton and Hall textbook of medical physiology*. 13th ed. Philadelphia: Elsevier; 2016.

Diffusion is not the same as bulk gas flow, in which a large pressure gradient causes all molecules of all gases to move together in one direction. An example of bulk gas flow is ventilation, in which mouth and alveolar pressure differences cause all gas molecules in the mixture that is air to move together, in and out of the lungs. In terminal airways and alveoli, random molecular diffusion is the main mechanism by which gas molecules reach the alveolar membrane surface.

Concept Question 7.1

Which of the following problems—both of which cause hypoxemia—is called a diffusion defect: partially obstructed airways that reduce ventilation in certain lung regions or the destruction of alveolar tissues and their associated capillaries?

Diffusion Gradients of Respiratory Gases

Fig. 7.2 illustrates diffusion gradients between alveolar gases and blood and between blood and body tissues. Inspired air contains about 21% O₂ and almost 0% CO₂. Inspired oxygen partial pressure (P_IO₂) is almost 160 mm Hg, as the following calculation shows:

PI O2 = 0.2095 × 760 mm Hg = 159 mm Hg 1

Fig. 7.2 Partial pressure diffusion gradients for oxygen and carbon dioxide (CO₂) at the alveolar and systemic tissue levels.

PO₂ in the conducting airway gas is lower than PO₂ in the atmosphere because gas in the lung is 100% saturated with water vapor. At body temperature, the partial pressure of water vapor in the lung (P_H2O) is 47 mm Hg. Therefore PO₂ in conducting airways is about 150 mm Hg, as the following calculation shows:

PIO2 (humidified) = 0.2093 × (760 − 47)= 149 mm Hg 2

Alveolar PO₂ (P_AO₂) is lower still because O₂ diffuses out of the alveoli, lowering P_AO₂ to about 100 mm Hg. (Calculation of P_AO₂ is discussed in the next section.)

The diffusion gradient between alveolar gas and mixed venous blood is much larger for O₂ than it is for CO₂ (60 mm Hg vs. 6 mm Hg, respectively), as shown in Fig. 7.2. At rest, these diffusion gradients transfer about 250 mL of O₂ into the blood and 200 mL of CO₂ into the alveoli each minute. By the time blood leaves the alveolar capillary, the PO₂ and PCO₂ of the blood have reached equilibrium with alveolar gases, even during exercise when blood flows very rapidly through the capillary. PO₂ of blood entering the left atrium is never as high as PO₂ of blood leaving the pulmonary capillaries (see Fig. 7.2) because a small amount of deoxygenated bronchial venous blood mixes with capillary blood; this constitutes a normal anatomical shunt. Anatomical shunt is mostly responsible for the normal P(A-a)O₂ (alveolar-to-arterial oxygen pressure difference). Left atrial blood then normally flows unaltered into the systemic arteries.

Alveolar Gas Equation

The sum of all gas pressures at any point in the lung is equal to 760 mm Hg at sea level. When air—which is CO₂-free—is inspired and enters the alveoli, its PCO₂ immediately increases to about 40 mm Hg as it mixes with the CO₂ that diffuses into the alveoli from capillary blood; because the sum of all alveolar gas pressures is constant (760 mm Hg), the P_AO₂ must decrease by a similar amount. If the amount of O₂ molecules diffusing out of alveoli into the blood each minute were exactly equal to the amount of CO₂ molecules diffusing from the blood into alveoli each minute, P_AO₂ would be calculated by simply subtracting P_ACO₂ (normally 40 mm Hg) from the result of eq. 2. However, O₂ diffuses out of the alveolus at a greater rate than CO₂ diffuses into the alveolus. At rest, pulmonary capillary blood removes about 250 mL of O₂ per minute from the alveoli, but only 200 mL/min of CO₂ diffuses from the blood into the alveoli. The ratio of CO₂ diffusion into the alveoli (V˙CO2) to oxygen diffusion out of the alveoli (V˙O2) is called the respiratory exchange ratio (R), and its value is normally about 0.8 (R = V˙CO2/V˙O2 = 200 mL/250 mL = 0.8). In other words, the amount of CO₂ entering the alveoli is equal to 0.8 or 80% of the amount of O₂ leaving the alveoli.

Why Alveolar Volume Shrinkage Increases Alveolar Nitrogen Partial Pressure but Decreases Alveolar Oxygen Partial Pressure

If CO₂ entering the alveoli does not replace all the volume vacated by O₂ that diffused out of the alveoli, alveolar volume must decrease. Why does this not concentrate all alveolar gases, making all partial pressures increase?

Discussion

O₂ (but not nitrogen [N₂]) concentration decreases because (1) alveolar CO₂ and alveolar partial pressure of water vapor (P_AH₂O) are predetermined constants, (2) nitrogen is metabolically inert, and (3) the sum of all alveolar gas partial pressures must equal 760 mm Hg at sea level (P_AO₂ + P_AN₂ + P_ACO₂ + P_AH₂O = 760 mm Hg). (P_AO₂ is alveolar oxygen partial pressure, P_AN₂ is alveolar nitrogen partial pressure, and P_ACO₂ is alveolar partial pressure of CO₂.) Temperature and relative humidity determine P_AH₂O and are constant in the lung. The rate of CO₂ entry into alveoli (V˙CO2) and its removal by alveolar ventilation (V˙A) determine the P_ACO₂; for a given V˙CO2 and V˙A, P_ACO₂ remains constant. Because N₂ is a metabolically inactive gas, the number of N₂ molecules in inspired gas is the same as in expired gas. When the inspired gas volume shrinks in the alveoli, the concentration and partial pressure of N₂ (P_AN₂) increase. The amount of the P_AO₂ reduction is exactly equal to the P_AN₂ increase.

Simply stated, when inspired gas enters the alveoli, its PO₂ falls because O₂ immediately diffuses into capillary blood; we need to know how much the PO₂ falls, and then subtract this amount from the inspired PO₂ calculated in eq. 2. Knowledge of R’s value helps us compute this amount. For example, if R is equal to its normal value of 0.8, then the milliliters of CO₂ entering the alveolus is equal to 80% of the milliliters of O₂ that left the alveolus. Similarly, if P_ACO₂ is 40 mm Hg, then 40 mm Hg is equal to 80% of fall in inspired PO₂ that occurred when gas entered the alveoli. In this example, if x equals the fall in inspired PO₂, then 40 mm Hg = 0.8(x), which means x = 40 mm Hg/0.8, or 50 mm Hg. P_AO₂ would then be calculated by subtracting 50 mm Hg from inspired PO₂ computed in eq. 2. In the clinical setting, PaCO₂ is substituted for P_ACO₂ because these values are generally almost equal and because PaCO₂ is a traditionally measured arterial blood gas value.

A more complex version of the alveolar gas equation increases accuracy but is clinically insignificant. For the sake of completeness, a brief explanation follows: The fact that more O₂ diffuses out of the alveoli than is replaced by CO₂ diffusing into the alveoli causes the alveolar gas volume to shrink slightly, but since alveolar gas ultimately communicates with the atmosphere through the trachea, alveolar gas pressure must equal atmospheric gas pressure, which is 760 mm Hg at sea level. The shrinkage in alveolar volume concentrates the alveolar nitrogen molecules, which the more complex alveolar gas equation takes into account. This equation is known as the ideal alveolar gas equation because it assumes the ventilation-to-blood flow ratios of each alveolus in the lung are identical:

PAO2 = PIO2 − PACO2[FIO2 + 1 − FIO2R] 3

In this equation PIO2 equals F_iO₂ (760 − 47). The bracketed part of eq. 3 is a correcting factor that takes into account the effect of R on P_AO₂. When R equals 1, the correction factor equals 1 and does not need to be applied.

Concept Question 7.2

What percentage of the O₂ diffusing out of the alveoli is replaced by incoming CO₂ when R equals 1.0?

The term 1 − F_iO₂ is actually equal to the inspired nitrogen concentration. When R is less than 1, the effect is to increase nitrogen concentration, causing the bracketed term of Eq. 3 to increase to values greater than 1. In eq. 3, if R = 0.8 and F_iO₂ = 0.21 (room air), the bracketed factor is equal to 1.1975, or 1.2.

Examination of eq. 3 shows that higher F_iO₂ values require progressively smaller correction factors; at 100% inspired oxygen (F_iO₂ = 1.0), no correction is needed. A sufficiently accurate equation for clinical use is a simplified form of eq. 3 for patients breathing an F_iO₂ of 0.60 or less. This is shown as follows:

PA O2 = PI O2 − (Pa CO2) 1.2 4

For F_iO₂ values greater than 0.60, a sufficiently accurate clinical equation is as follows:

PA O2 = PI O2 − Pa CO2 5

In Eqs. 4 and 5, arterial PCO₂ (PaCO₂) is substituted for alveolar PCO₂ (P_ACO₂₎ because these two values are generally almost equal, unless the lungs have a high degree of alveolar dead space. PaO₂ cannot be used as an estimate of P_AO₂ because shunting always creates an alveolar-arterial PO₂ difference.

A normal P_AO₂ for a person breathing room air at sea level, with a PaCO₂ equal to 40 mm Hg and an R equal to 0.8, is about 100 mm Hg (using eq. 4). This is shown as follows:

PAO2 = 0.2093 (760 − 47) − (40 × 1.2)PAO2 = 149.2 − 48PAO2 = 101.2 5

Table 7.1 summarizes respiratory gas partial pressures at sea level in dry inspired air, humidified (tracheal) air, alveolar air, and mixed-expired air. Expired gas PO₂, PCO₂, and PN₂ differ from alveolar values because expired air contains dead space gas mixed with alveolar gas.

Concept Question 7.3

Calculate the P_AO₂ when the F_iO₂ equals 0.40 and the PaCO₂ equals 35 mm Hg.

Table 7.1

Partial Pressures of Gases at Sea Level
	Dry Air		Humidified Air		Alveolar Air		Expired Air
Gases	mm Hg	%	mm Hg	%	mm Hg	%	mm Hg	%
Nitrogen	600.2	78.98	563.4	74.09	569.0	74.9	566.0	74.5
Oxygen	159.5	20.98	149.3	19.67	104.0	13.6	120.0	15.7
Carbon dioxide	0.3	0.04	0.3	0.04	40.0	5.3	27.0	3.6
Water vapor	0.0	0.0	47.0	6.20	47.0	6.2	47.0	6.2

Laws Governing Diffusion

Fick’s law summarizes the factors that determine the rate of gas diffusion through the alveolar-capillary membrane. This is shown as follows:

V˙gas = A × D × (P1 − P2)T

In this equation, V˙gas represents the volume of gas diffusing through the membrane per minute (milliliters per minute), and A represents the surface area of the membrane available for diffusion (cm²).

Using the Alveolar Air Equation: The Effect of Hypoventilation on Alveolar Partial Pressure of Oxygen When Room Air Is Breathed

A healthy 60-year-old woman was brought to the emergency department in a comatose state, breathing very shallowly. Her family stated that she had taken an overdose of sleeping pills. Arterial blood gases, obtained while she was breathing room air (fractional concentration of oxygen in inspired gas [F_iO₂] = 0.21), revealed a PaO₂ of 55 mm Hg, a PaCO₂ of 70 mm Hg, and pH of 7.15. Normal PaCO₂ is equal to 40 mm Hg. Her elevated PaCO₂ is explained by her hypoventilation; she cannot remove CO₂ from her lungs as rapidly as it diffuses in from the capillary blood. But why is her PaO₂ reduced?

Discussion

The high partial pressure of carbon dioxide in alveolar gas (P_ACO₂) of hypoventilation reduces the alveolar oxygen partial pressure (P_AO₂) and thus the PaO₂. This can be shown by calculating the P_AO₂ during hypoventilation (PaCO₂ = 70 mm Hg) and comparing it with P_AO₂ when ventilation is normal (PaCO₂ = 40 mm Hg), using the following alveolar air equation:

PA O2 = FI O2 (PB − 47) − (PaCO2 × 1.2)

P_B represents barometric pressure.

Situation 1: Hypoventilation on Room Air, PaCO₂ = 70 mm Hg

0.21 (760 − 47) − (70 × 1.2)= 0.21 (713) − 84= 149.73 − 84PA O2 = 65.73 mm Hg

Situation 2: Normal Ventilation on Room Air, PaCO₂ = 40 mm Hg

0.21 (760 − 47) − (40 × 1.2)= 0.21 (713) − 48= 149.73 − 48PA O2 = 101.73 mm Hg

In situation 1, hypoventilation caused high PaCO₂, and low PaO₂ is a secondary consequence. Hypoventilation is the major abnormality present, not O₂ transfer across the lung. Correction of oxygenation in this situation involves improving the patient’s ventilation, not administering O₂. Although administering O₂ might eliminate hypoxemia, it would not address the underlying defect (hypoventilation) that causes the hypoxemia.

D represents the diffusion coefficient, or diffusivity, of a particular gas. It is directly proportional to the gas solubility (sol) but inversely proportional to the square root of the gas molecular weight (mw):

D ∝ solmw

P₁ − P₂ represents the partial pressure difference across the membrane (i.e., diffusion pressure gradient [mm Hg]). T represents the membrane thickness, or diffusion path distance (cm).

This equation states that V˙gas increases if there are increases in the membrane surface area, gas diffusivity, or diffusion pressure gradient. The diffusion rate decreases if membrane thickness increases. Doubling the membrane surface area or diffusion pressure gradient doubles the overall diffusion rate; doubling the membrane thickness reduces the diffusion rate by half. Fig. 7.3 illustrates the factors involved in Fick’s law.

Concept Question 7.4

Why does exercise increase the diffusion rate of O₂?

Fig. 7.3 Fick’s law of diffusion states that oxygen and carbon dioxide diffuse from high (P₁) to low (P₂) pressures across the alveolar-capillary membrane.

Physical Gas Characteristics and Diffusion

O₂ and CO₂ diffuse through gaseous and liquid phases in the lung; the alveolar-capillary membrane (see Fig. 7.1) is a liquid barrier. Light gases diffuse more rapidly than heavier gases, and highly soluble gases diffuse through liquids more rapidly than less soluble gases. The rate of gas diffusion in the lung is inversely proportional to its molecular weight and directly proportional to its solubility; the diffusion coefficient in Fick’s law is derived from these two factors. Specifically, the gas diffusion rate is inversely proportional to the square root of its gram molecular weight (gmw) (Graham’s law). Relative rates of diffusion for O₂ (molecular weight = 32) and CO₂ (molecular weight = 44) in a gaseous medium are as follows:

O2 rateCO2 rate = gmwCO2gmwO2 = 4432 = 6.635.66 = 1.171.0

Because O₂ is a lighter molecule, it diffuses through a gas medium 1.17 times faster than CO₂.

However, CO₂ is much more soluble in water than O₂. Henry’s law states that the amount of gas dissolving in a liquid is directly proportional to the gas partial pressure. At body temperature (37°C) and 760 mm Hg pressure, 0.592 mL of CO₂ and 0.0244 mL of O₂ dissolve in 1 mL of water. CO₂ is about 24 times more soluble than O₂, as the following equation shows:

CO2 solO2 sol = 0.5920.0244 = 24.31.0

Combining Graham’s law and Henry’s law, CO₂ diffuses across the alveolar-capillary membrane about 20 times faster than O₂. This is shown as follows:

CO2 rateO2 rate = 3244 = 0.5920.16 = 3.350.16 = 20.7

For this reason, alveolar-capillary membrane defects limit O₂ diffusion long before they limit CO₂ diffusion. In a practical, clinical sense, the alveolar-capillary membrane never limits outward diffusion of CO₂ from blood to alveoli. Discussion of diffusion in this chapter is therefore primarily focused on O₂ diffusion.

Factors Affecting Oxygen Diffusion

Factors influencing the rate of O₂ transfer across the alveolar-capillary membrane include (1) the partial pressure gradient across the membrane, (2) the diffusion path length, and (3) the membrane surface area. (All factors are included in Fick’s law of diffusion.)

Effects of the Partial Pressure Gradient and Capillary Blood Transit Time on Gas Equilibrium

At a resting cardiac output, a red blood cell (RBC) spends about 0.75 second traveling through the pulmonary capillary. Normally, the equilibrium between alveolar gas and capillary blood PO₂ occurs within the first 0.25 second, or about one-third of the distance through the capillary (Fig. 7.4, dark curved line). The time to reach equilibrium may be prolonged if alveolar-capillary membranes are thickened (light curved line in Fig. 7.4). Even so, equilibrium is practically always achieved at rest. The rate of diffusion is rapid at first, when the partial pressure gradient across the alveolar-capillary membrane is greatest. The diffusion rate then continuously slows as the partial pressure gradient diminishes (notice the shape of the PO₂ curve [dark line] in Fig. 7.4) until diffusion completely ceases at equilibrium. Thus during the last two-thirds of travel through the pulmonary capillary, no net diffusion occurs.

Fig. 7.4 Resting capillary transit time and gas pressure equilibrium time for pulmonary blood flow. Oxygen diffusion normally ceases after blood traverses one-third of the capillary distance (within 0.25 second) because alveolar and capillary partial pressures of oxygen (PO₂) equilibrate. PO₂ equilibrium usually occurs even across alveolar-capillary membranes thickened by disease. Oxygen diffusion is normally perfusion limited.

Even when capillary transit time is shortened to 0.25 second by a high blood flow rate during exercise, complete O₂ equilibrium normally still occurs between alveolar gas and end-capillary blood; it simply occurs at the end of the capillary path. In such a situation, the number of O₂ molecules transferred into the blood each minute increases greatly, because the greater rate of blood flow takes up more O₂ molecules from the alveoli each minute. Another reason exercise increases the number of O₂ molecules transferred each minute is that previously nonperfused capillaries are recruited, which increases the surface area for diffusion.

If a healthy person exercises vigorously at a high altitude, where atmospheric PO₂ is very low, the O₂ diffusion gradient may be so low that O₂ cannot diffuse across the alveolar-capillary membrane fast enough to establish equilibrium during the shortened capillary transit time. Alternatively, if disease thickens the alveolar-capillary membrane, the diffusion rate across the membrane may be slowed enough to prevent complete O₂ equilibrium by the time blood leaves the capillary during exercise. In the clinical setting, this situation rarely occurs at rest, even in severe lung disease.1 However, exercise immediately exposes the diffusion abnormality problem because it shortens the blood’s transit time through the capillary, making it likely that alveolar and capillary O₂ equilibrium never occur (Fig. 7.5). Patients with thickened alveolar-capillary membranes, as seen in pulmonary fibrosis, are most likely to show evidence of O₂ diffusion impairment during exercise.²

Fig. 7.5 Exercise increases blood flow velocity, shortening capillary transit time. In this situation, diseased, thickened alveolar-capillary membranes slow the diffusion rate enough to prevent oxygen equilibrium by the time blood leaves the capillary. Exercise unmasks diffusion defects not apparent at rest (compare with Fig. 7.4).

Perfusion and Diffusion Limitations to Oxygen Transfer

Fig. 7.4 shows that diffusion normally stops when O₂ equilibrium is reached between the alveolus and capillary, which occurs long before the blood travels the length of the capillary. If blood flow rate (perfusion) increases, more O₂ leaves the lung each minute because the O₂-saturated blood moves out of the capillary more quickly, which means deoxygenated blood enters more quickly to take up more O₂. Therefore the O₂ diffusion rate through the alveolar-capillary membrane is normally perfusion limited (see Fig. 7.4); that is, a change in blood flow rate alters the number of O₂ molecules that cross the alveolar-capillary membrane each minute. If O₂ equilibrium between the alveolus and capillary never occurs because of thickened membranes, O₂ transfer is truly diffusion limited. In such an instance, it is the alveolar-capillary membrane, not blood flow rate, that influences the O₂ transfer rate (see Fig. 7.5).

Concept Question 7.5

In what way would changes in pulmonary blood flow interfere with the measurement of diffusion capacity of the lung for O₂ (as opposed to carbon monoxide)?

If one wishes to evaluate the extent to which the alveolar-capillary membrane itself impedes the diffusion rate (milliliters per minute of O₂ transfer per millimeters of mercury pressure gradient), one should not measure the O₂ diffusion rate because it is affected by blood flow rate. Instead, one should measure the diffusion rate of a gas that never reaches equilibrium between alveolar gas and capillary blood, even in resting conditions. In other words, the blood’s capacity for this gas should be so great that the gas cannot diffuse across the membrane fast enough to saturate the blood to capacity before it leaves the capillary, regardless of blood flow rate. For such a gas, the only factor that limits diffusion is the resistance of the alveolar-capillary membrane itself. Carbon monoxide (CO) is the ideal gas for this kind of measurement because blood can absorb it at a much greater rate than CO can diffuse across the alveolar-capillary membrane, even under resting conditions. For this reason, CO is always diffusion limited. Fig. 7.6 illustrates the diffusion-limited characteristics of CO. All events that are illustrated in Fig. 7.6 occur at rest; an increased blood flow would not result in greater CO uptake because CO equilibrium never occurs between alveolar gas and capillary blood, which means CO is already diffusing through the alveolar-capillary membrane at its maximum rate under resting conditions. For this reason, CO is commonly used in pulmonary function laboratories to evaluate the lung’s true diffusion capacity.

Concept Question 7.6

What is the main reason CO₂ diffuses across the alveolar-capillary membrane so much more rapidly than O₂?

Fig. 7.6 Hemoglobin removes carbon monoxide (CO) so rapidly from the plasma that it maintains the diffusion gradient of CO all along the length of the capillary. This makes CO the ideal test gas for evaluating diffusion defects. Hemoglobin removes CO from the plasma faster than it can diffuse across the alveolar-capillary membrane. The only factor limiting CO diffusion is the membrane itself.

Hemoglobin in the RBC chemically binds with and takes up O₂ and CO, in effect making these gases much more soluble in whole blood than they are in the alveolar-capillary membrane interstitial fluid or the blood plasma. In contrast, a gas such as nitrous oxide (N₂O), which is highly soluble in the alveolar-capillary membrane and plasma, does not chemically bind with hemoglobin; therefore its solubility in whole blood is much less than that of CO or O₂. If N₂O is inhaled, the pulmonary capillary blood reaches its maximum capacity for N₂O almost instantly (Fig. 7.7). N₂O partial pressures across the alveolar-capillary membrane reach equilibrium in the first one-twentieth of the distance along the capillary. An increased blood flow in this situation would cause the N₂O-saturated blood to exit the capillary sooner, allowing more mixed venous blood to enter the capillary and take up N₂O from the alveolus. Thus diffusion of N₂O in the lung is strictly perfusion limited because equilibrium between capillary blood and alveolar gas occurs almost instantly. This characteristic makes N₂O an ideal test gas to measure pulmonary blood flow.

Fig. 7.7 Nitrous oxide (N₂O) is extremely soluble in the alveolar-capillary membrane and plasma but does not combine with hemoglobin (no red blood cells are shown). Plasma N₂O pressure reaches equilibrium with alveolar N₂O almost instantly. The rate of N₂O uptake by the blood depends strictly on the blood flow rate.

In the healthy lung, O₂ diffusion is normally perfusion limited because its pressure equilibrates across the alveolar-capillary membrane long before blood leaves the capillary, even under exercise conditions; increased blood flow increases the amount of O₂ taken up from the alveolus. However, in the unhealthy lung with thickened alveolar-capillary membranes, exercise may increase blood flow enough that O₂ becomes diffusion limited—that is, the thickened membrane may prevent alveolar-capillary PO₂ equilibrium from ever occurring.

Diffusion Path Length

The distance for diffusion includes the entire path length from alveolar gas to the hemoglobin in the RBC. It was originally thought that the alveolar-capillary membrane was the only important rate-limiting barrier to diffusion; it is now known that the RBC membrane and the rate at which O₂ combines with hemoglobin limit the lung’s O₂ uptake to the same extent as the alveolar-capillary membrane itself.3 The total diffusion path distance is normally less than 0.1 μ and includes the following elements (see Fig. 7.1): (1) the surfactant layer that lines the alveolar surface, (2) the alveolar epithelium, (3) the basement membrane of the alveolar epithelium, (4) the extremely thin interstitial space, (5) the basement membrane of the capillary endothelium, (6) the capillary endothelium, (7) the plasma, (8) the RBC membrane, and (9) the intracellular fluid bathing the hemoglobin molecule.

Various abnormal conditions can increase the diffusion path length, including the following: (1) fibrotic thickening of alveolar and capillary walls; (2) interstitial edema fluid, separating alveolar and capillary membranes; (3) fluid in the alveoli; (4) interstitial fibrotic processes that thicken the interstitial space; and (5) dilated, engorged capillaries, which allow RBCs to flow side by side. However, abnormalities that increase the distance for diffusion are rarely the cause of decreased arterial PO₂ at rest. The major cause of resting hypoxemia in these patients is a mismatch between ventilation and blood flow.¹ That is, the processes that increase diffusion distance generally also decrease lung compliance, which decreases ventilation in these areas. Blood perfusing these underventilated areas tends to be inadequately oxygenated, which ultimately lowers the PaO₂.

Diffusion Surface Area

Diffusion surface area is the total area of contact between ventilated alveoli and perfused capillaries. A decrease in the number of open, perfused capillaries or in the number of open, ventilated alveoli decreases the diffusion surface area and the lung’s diffusion capacity. In such instances, diffusion capacity is decreased, although the diffusion path length may be normal at all points. For example, emphysema destroys alveolar walls and their associated capillaries, which decreases the diffusion surface area. Although the diffusion path length is not thickened at any point, overall diffusion rate is decreased because much of the functional gas-exchange surface area is lost.

Concept Question 7.7

Pulmonary embolism blocks blood flow to alveolar capillaries; completely obstructed airways block ventilation to alveoli. What category of diffusion limitation do these two defects represent?

Measuring Diffusion Capacity

General Principles

A strictly diffusion-limited test gas such as CO is used to measure the diffusion capacity of the lung. As clinically performed, the single-breath CO diffusion test measures the amount (in milliliters) of CO that diffuses across the alveolar-capillary membranes during a 10-second breath holding period after first inhaling a known concentration of CO. The average diffusion pressure gradient also must be calculated during the breath-holding period, that is, the mean P_ACO − mean capillary PCO. (Partial pressure of CO in the capillary blood is denoted by the symbol PćCO). The theoretical formula for the diffusion capacity of the lung for CO (DLCO) is as follows:

DLCO = milliliters of CO transferred to the blood per minutemean PACO − mean capillary pc′ CO

Normal Values

Normal D_LCO values in healthy individuals vary considerably, depending on age, body size, body position, and other factors, as explained in subsequent sections. The average D_LCO in a healthy young man under resting conditions is 21 mL/min/mm Hg.4 The diffusion capacity of the lung for oxygen (D_LO₂) is obtained by multiplying D_LCO by 1.23. A mean D_LCO of 21 mL/min/mm Hg yields a normal D_LO₂ of about 26 mL/min/mm Hg. It may seem odd that D_LO₂ is greater than D_LCO, considering the much greater affinity of hemoglobin for CO than O₂. This peculiarity is explained by the fact that O₂ is more soluble than CO in the alveolar-capillary membrane and the plasma, and therefore it diffuses more rapidly. The fact that hemoglobin has 210 times greater affinity for CO than for O₂ simply means that at a given partial pressure (PCO or PO₂), the hemoglobin carries more CO than O₂. This fact is unrelated to the O₂ and CO diffusion rate across the alveolar-capillary membrane, which is determined by molecular weight and solubility coefficients.

Factors Affecting Measured Carbon Monoxide Diffusion in the Lung

Body Size

D_LCO increases with body size. Larger lungs have a greater absolute D_LCO than smaller lungs because they have a greater gas-exchange surface area.

Age

D_LCO increases as the lungs develop from infancy to adulthood. In people older than 20 years, D_LCO decreases gradually as the lung ages and structural changes reduce the functional gas-exchange surface area. A ten-year age increase is associated with a decline of about 1.32 mL/min/mm Hg in D_LCO.

Lung Volume

D_LCO is significantly greater at high lung volumes than low volumes. This may reflect increased pulmonary blood volume at high lung volumes (the greater subatmospheric intrapleural pressure near total lung capacity [TLC] draws more blood into the pulmonary circulation) or an increased functional surface area for diffusion. Dividing D_LCO by the lung volume at which it was measured (D_LCO per unit of lung volume [D_L/V_L]) eliminates the effect of volume on D_LCO. For example, the abnormally large lung volume of a patient with emphysema may have a total D_LCO in the normal range, obscuring the true decrease in surface area per unit of lung volume. The calculated D_L/V_L in this instance yields an abnormally low value, revealing the loss of diffusion capacity.

Exercise

D_LCO increases markedly with exercise as higher blood pressure recruits previously collapsed capillaries; this greatly increases the surface area for diffusion. Increased cardiac output means capillary transit time decreases, and more O₂ can be transferred into the blood each minute. During exercise (in contrast to rest), blood stays in the capillary only long enough to reach equilibrium with alveolar gas. Increased cardiac output dilates capillaries, exposing more hemoglobin to alveolar gas and allowing greater O₂ uptake per minute.

Body Position

D_LCO is 15% to 20% greater in supine than in standing positions.1 This increase probably occurs because gravity decreases pulmonary blood volume in the standing position—especially in the lung apices.

Clinical Focus 7.3

Technique for Measuring Carbon Monoxide Diffusion in the Lung

When measuring the D_LCO, a volume of gas equal to vital capacity containing about 0.3% CO is inhaled through a tube attached to a spirometer. This means the patient first exhales forcefully to the residual volume (RV), then inhales the CO gas mixture maximally to TLC. This breath is held at TLC for ten seconds, after which the vital capacity is forcefully exhaled back to the RV level. As the exhalation approaches RV, a gas sample from the exhaled stream is collected in a small balloon by opening a valve in the apparatus. This gas represents the composition of alveolar gas. The amount of CO that diffused into the blood is calculated by analyzing the alveolar gas sample for CO and comparing it with the calculated initial alveolar CO concentration. (The amount diffusing in ten seconds is multiplied by six to obtain the amount diffusing in one minute.) The spirometer’s microprocessor performs a complicated calculation of the average CO diffusion gradient over the ten-second breath-holding interval. The calculation is complicated because it is not simply the average of beginning and final PCO diffusion gradients but the average of an infinite number of continuously changing pressure gradients occurring over ten seconds. The pressure gradient driving CO diffusion changes continuously as pressures between alveolus and capillary approach equilibrium. This means the CO diffusion rate changes continuously over the ten-second breath-hold period as well. (Note the changing pressure gradient examples in Fig. 7.6.) The microprocessor calculates the average diffusion rate in units of milliliters per minute per millimeter of mercury (mL/min/mm Hg).

Alveolar Partial Pressure of Oxygen and Partial Pressure of Carbon Dioxide

Increased P_AO₂ is associated with decreased D_LCO because in the blood O₂ competes with CO for binding sites on the hemoglobin molecule. In other words, the rate of CO uptake by hemoglobin is hindered by increased arterial PO₂ values but is enhanced by decreased arterial PO₂ values. People with severe hypoxia have higher D_LCO values because of this phenomenon and because hypoxia increases cardiac output, pulmonary blood flow, and capillary recruitment and distention. This phenomenon also explains why an abnormally elevated P_ACO₂ increases D_LCO; an elevated P_ACO₂ means hypoventilation is present, which means P_AO₂ must be low.

Alveolar Partial Pressure of Carbon Monoxide

Heavy smokers already have CO in their mixed venous blood. The presence of CO in mixed venous blood lowers the diffusion pressure gradient across the alveolar-capillary membrane and slows the diffusion rate.

Clinical Focus 7.4

Abnormally High and Abnormally Low Lung Volumes: Mechanisms of Reduced Carbon Monoxide Diffusion in the Lung

A person with advanced pulmonary emphysema and a TLC 150% of the predicted value has an abnormally low D_LCO. Another person with advanced pulmonary fibrosis and a TLC 60% of the predicted value also has a low D_LCO. What are the mechanisms producing the low D_LCO in these two people?

Discussion

Emphysema, an obstructive lung disease, destroys alveolar walls and their capillaries, reducing elastic recoil and functional tissue for gas exchange. D_LCO is decreased because less gas can diffuse into the blood per unit of lung tissue. A loss of elastic lung tissue increases lung compliance, which eventually leads to an increased TLC.

Pulmonary fibrosis is characterized by inflammation and scar tissue in the alveolar-capillary area. This scar tissue stiffens the lungs, creating high elastic recoil, low lung compliance, and a reduced TLC. Alveolar-capillary membranes are thickened, and some are destroyed. These defects slow the diffusion rate and reduce the gas-exchange surface area, decreasing D_LCO. Diffusing capacity is decreased when there is loss of functional alveolar-capillary membranes, regardless of the lung volume.

Hemoglobin Concentration

The blood of patients with anemia has abnormally low hemoglobin content and low CO-carrying capacity. Less CO can be taken up per minute during the D_LCO test. The opposite is true for polycythemia (increased RBCs and hemoglobin concentration).

Pulmonary Diseases

Box 7.1 lists conditions that decrease diffusion capacity. D_LCO is useful in differentiating emphysema from other obstructive diseases that are not associated with destroyed alveolar architecture, such as chronic bronchitis and asthma. Asthma is often associated with an increased D_LCO. An explanation may be that high inspiratory resistance created by narrowed airways increases negative intrathoracic pressure during maximal inspiration of the test gas, which increases the gas diffusion pressure gradient and the blood flow in lung apices.⁵

Clinical Use of Carbon Monoxide Diffusion Capacity Test Results

The D_LCO test assesses the extent to which the alveolar-capillary membrane is a barrier to gas diffusion. Because O₂ equilibrium normally occurs before blood traverses one-third of the pulmonary capillary distance, a 50% reduction in D_LCO can exist without affecting end-capillary and arterial PO₂. In this sense, the D_LCO test is more sensitive to potential O₂ transfer problems (i.e., as disease progresses, D_LCO becomes abnormal before PaO₂) than the PaO₂ obtained in arterial blood gas analysis. Impairment of diffusion across the alveolar-capillary membrane is only one mechanism that can cause arterial hypoxemia. Many factors decrease PaO₂ without affecting the diffusion path length or membrane surface area, such as ventilation–blood flow mismatches. The D_LCO test can help clarify the mechanism of arterial hypoxemia; if D_LCO is normal, diffusion impairment cannot be a contributing factor.

Clinical Focus 7.5

Using Carbon Monoxide Diffusion in the Lung to Differentiate Emphysema from Chronic Bronchitis

You are asked to perform a complete pulmonary function study on a 53-year-old woman who has chronic obstructive pulmonary disease (COPD). Results show markedly reduced expiratory flow rates, increased RV, and a normal D_LCO. Later that day, you perform a pulmonary function study on a 55-year-old woman who also has COPD. Her results show markedly reduced expiratory flow rates, increased RV, and an abnormally low D_LCO. Why is D_LCO reduced in only one of these women, even though they both have COPD?

Discussion

COPD is primarily composed of emphysema and chronic bronchitis; both disease processes cause chronic airflow obstruction but in different ways. Emphysema destroys alveolar structures, including the gas-exchange surface area. This destruction decreases the D_LCO. Chronic bronchitis refers to chronic airway inflammation and overproduction of abnormally thick mucus, which may partially obstruct the airways. The alveolar surface area for gas exchange remains intact, maintaining a normal D_LCO.

The first woman had a bronchitic component of COPD. The second woman had a predominantly emphysematous component of COPD.

Concept Question 7.8

As alveolar-capillary membranes gradually thicken over the course of disease, the O₂ diffusion rate gradually decreases. Which test reveals this problem first: the D_LCO test or the blood gas analysis that measures arterial blood PO₂? Explain.

Points to Remember

• Gas always diffuses from an area of high partial pressure to an area of low partial pressure.

• Diffusion ceases when partial pressure equilibrium across the alveolar-capillary membrane occurs; this normally occurs for O₂ long before blood flows through the length of the capillary but never occurs for CO diffusion.

• Gas transfer from alveolus to blood is diffusion limited if blood is able to take up the gas faster than the gas can diffuse through the alveolar-capillary membrane.

• Gas transfer from alveolus to blood is perfusion limited if its pressures in the alveolus and blood equalize so quickly that diffusion ceases before blood leaves the capillary.

• Diffusion impairments rarely cause hypoxemia at rest because gas equilibrium between alveolus and blood virtually always occurs; exercise unmasks the impairment because blood flows so fast that there is not enough time for equilibrium to occur.

• Diffusion rate is affected by membrane functional surface area, physical gas characteristics, partial pressure gradient for diffusion, and membrane thickness (diffusion path length).

• Light and soluble gases diffuse faster than heavy insoluble gases; because of its much greater solubility, CO₂ diffuses across the lung 20 times faster than O₂.

• Diseases affect diffusion capacity chiefly by increasing the membrane thickness or decreasing the functional surface area.

• D_LCO can be significantly reduced before any decrease in arterial PO₂ occurs.