Diffusion of O2 from alveoli to pulmonary capillary blood is the next step in the O2 cascade after alveolar ventilation. However, it is important to note that blood leaving the pulmonary capillaries is in equilibrium with alveolar gas in healthy lungs under normal resting conditions. Hence, the small decrease between Pao2 and PaO2 shown in Fig. 1 is not caused by diffusion, but by ventilation-perfusion mismatching in healthy lungs under normal conditions (see Ventilation-Perfusion Mismatching section).

O2 moves from the alveoli into pulmonary capillary blood barrier according to Fick's first law of diffusion (Chapter 18):

VO2 = APO2 • DO2, where APo2 is the average Po2 gradient across the blood-gas barrier and Do2 is a "diffusing capacity'' for

O2 across the barrier. Some readers may find it helpful to note the analogy between Fick's law for O2 flux and Ohm's law for the flow of electrons (current = voltage/ resistance). Vo2 is analogous to current and APo2 is analogous to the potential energy difference of voltage. However, Do2 is analogous to a conductance, which is the inverse of resistance (current = voltage • conductance). O2 flux can be increased either by increasing the PO2 gradient or increasing the O2 conductance (Do2).

DO2 depends on both the molecular properties of O2 and the geometric properties of that membrane:

Do2 = (solubility/MW)o2 •(area/thickness)membrane.

Solubility is important because gas molecules have to ''dissolve'' in a membrane before they can diffuse across it and, once dissolved, low-molecular-weight (MW) molecules move more quickly by the random motions of diffusion. Large surface areas increase the probability that an O2 molecule will come into contact with the membrane through random motion, but membrane thickness increases the distance over which O2 molecules must travel.

Pathway for Oxygen

Figure 3 shows the pathway for an O2 molecule diffusing from alveolar gas to hemoglobin inside an erythrocyte (red blood cell). This is the anatomic basis for D02. The total area of the blood-gas barrier is nearly

100 m2 in the human lung (Chapter 18). The barrier is also extremely thin but variable in thickness, and it consists of several different layers. The ''thin'' side of a pulmonary capillary (0.3 mm) separates gas from plasma with (1) thin cytoplasmic extensions from type I alveolar epithelial cells, (2) a thin basement membrane, and (3) thin cytoplasmic extensions from capillary endothelial cells. The thicker side of a capillary has collagen in the interstitial space to provide mechanical strength in the alveoli. Epithelial and endothelial cell bodies are in alveolar corners between capillaries, to minimize further the thickness of the gas exchange barrier. Finally, 02 has to diffuse through plasma and across the red blood cell membrane before it can combine with hemoglobin. The diffusing capacity for O2 between the alveolar gas and hemoglobin is called the membrane diffusing capacity for O2, or DmO2.

After O2 diffuses into red blood cells, the finite rate of reaction between O2 and hemoglobin (abbreviated with the symbol 6) offers an additional ''resistance'' to 02 uptake. The magnitude of this chemical resistance depends on 6 and the total amount of hemoglobin, which is a physiologic function of pulmonary capillary volume (Vc). This chemical resistance is in series with the membrane resistance, so the total resistance to O2

FIGURE 3 Electron micrograph of a pulmonary capillary showing the pathway for O2 diffusion in the lung. O2 diffuses from the alveolar space (open areas above and below capillary, C) through epithelial cell (EP1), interstitial space and endothelial cell (EN), and plasma before combining with hemoglobin in the erythrocyte (EC). Collagen fibers (F) and fibroblasts (Fb) thicken the interstitial space on one side of the capillary. N, nucleus; J, endothelial cell junctions. Scale marker = 2 mm. (From Weibel, Chap. 82 in Crystal et al, eds., The lung: Scientific foundations. Philadelphia: Lippincott-Raven, 1997.)

diffusion in the lung can be defined as follows:

1/Dlo2 = 1/Dmo2 + 1/(0 Vc), where Dlo2 is the lung diffusing capacity for O2. (Dlo2 is a conductance; recall that conductance is the inverse of resistance and resistors in series are additive.)

It is estimated that membrane and chemical reaction resistances to O2 diffusion are about equal in normal lungs. Both Dmo2 and Vc are under physiologic control through pulmonary capillary recruitment and distension. Therefore, Dlo2 increases with exercise by recruitment of Dmo2 and 0 Vc. Methods for measuring Dlo2 are described in a later section.

Po2 Changes along the Pulmonary Capillary

The APo2 value used in Fick's law is an average value, corresponding to the mean partial pressure gradient operating over the entire length of the pulmonary capillary. Alveolar Po2 is constant everywhere outside the capillary because diffusion is rapid in the gas phase and effectively mixes O2 in the small alveolar spaces. However, PO2 in the capillary blood must increase from mixed-venous levels at the beginning to arterial levels at the end of the capillary. Figure 4 shows the normal time course of PO2 changes along the capillary in a healthy lung at normal PO2 levels.

An average capillary transit time of 0.75 sec (Fig. 4) is calculated from a cardiac output of 6 L/min and capillary

Time in capillary (sec)

FIGURE 4 The time course of the increase in partial pressure for different gases diffusing from alveolar gas into pulmonary capillary blood. N2O and O2 under normal conditions equilibrate very quickly, but CO or O2 under abnormal conditions does not equilibrate in the time it takes blood to flow through the capillary (0.75 sec).

Time in capillary (sec)

FIGURE 4 The time course of the increase in partial pressure for different gases diffusing from alveolar gas into pulmonary capillary blood. N2O and O2 under normal conditions equilibrate very quickly, but CO or O2 under abnormal conditions does not equilibrate in the time it takes blood to flow through the capillary (0.75 sec).

volume of 75 mL (time = volume/flow rate). Note that diffusion equilibrium normally occurs between blood and gas in only 0.25 sec, providing a threefold safety factor. However, if Dlo2 is decreased sufficiently with lung disease, then capillary PO2 may not equilibrate with PAO2 during the transit time (Fig. 4, abnormal O2 curve). In the abnormal case, Pc'o2 < Pao2, which is defined as a diffusion limitation for O2, where Pc0 is used to designate end-capillary partial pressure.

Only two conditions lead to diffusion limitation for 02 in healthy individuals: (1) Elite athletes at maximal exercise, with very high 02 consumption and cardiac outputs, can have transit times that are too short for 02 diffusion equilibrium. Capillary volume increases by recruitment and distension with elevated cardiac output (Chapter 18), but this is not sufficient to balance the huge increase in flow rate that occurs in elite athletes. (2) Normal individuals exercising at altitude may not achieve diffusion equilibrium because transit time and Pao2 decrease. Transit time will decrease with elevated cardiac output during exercise, but capillary volume recruitment and distension can preserve enough time for 02 diffusion equilibrium to occur if Pao2 is normal. However, Pao2 is decreased at altitude, and this slows 02 diffusion in two ways.

First, decreased Pao2 slows 02 diffusion by decreasing the Po2 gradient driving diffusion. For example, at an altitude of 3050 m (10,000 feet), the barometric pressure is only 523 mm Hg and Pio2 is 100 mm Hg [ = 0.21 (523 - 47) mm Hg]. In a normal individual doing mild exercise at this altitude, Pao2 is measured to be about 55 mm Hg. PVo2 decreases much less than this because of the shape of the 02-blood equilibrium curve (see below also, the Cardiovascular and Tissue Oxygen Transport section). Measurements show PVo2 is 24 mm Hg at altitude, compared with 30 mm Hg at sea level, with this amount of exercise. Therefore, the Po2 gradient at the beginning of the capillary decreases from 70 mm Hg with mild exercise at sea level (= 100 - 30 mm Hg) to 31 mm Hg (= 55 - 24 mm Hg) at altitude. The exact values in this example are not as important as the general concepts that the shape of the O2-blood equilibrium curve maintains PVo2 in exercise at altitude (see also Cardiovascular and Tissue Oxygen Transport section), and this decreases the Po2 gradient for diffusion in the lung.

Decreasing Pao2 also slows the rate of rise in Po2 because gas exchange is occurring on the steep portion of the 02-blood equilibrium curve. This means that a given increase in 02 concentration is not effective at increasing Po2 toward the alveolar equilibrium value. In contrast, the flat shape of the 02-blood equilibrium curve around normal Pao2 levels promotes diffusion equilibrium. Small amounts of 02 diffusing from alveolar gas into capillary blood cause large increases in PO2, so capillary PO2 rapidly approaches equilibrium with Pao2 in normoxia.

Diffusion- and Perfusion-Limited Gases

Figure 4 shows dramatic differences in the time course of diffusion equilibrium for different gases in the lung. The anesthetic gas nitrous oxide (N2O) achieves equilibrium rapidly, whereas carbon monoxide (CO) never comes close to diffusion equilibrium. Understanding the differences between these gases is not only important for anesthesiology and emergency medicine, but it also helps one understand the physiologic mechanisms for O2 diffusion limitations.

The uptake of a gas that achieves diffusion equilibrium depends on the magnitude of pulmonary blood flow. For example, N2O diffuses rapidly from the alveoli to capillary blood (Fig. 4), so the only way to increase its uptake is to increase the amount of blood flowing through the alveolar capillaries. N2O is an example of a perfusion-limited gas. Changes in the diffusing capacity have no effect on the uptake of a perfusion-limited gas or its partial pressure in the blood and body. All anesthetic and "inert" gases that do not react chemically with blood are perfusion limited. Notice that under normal resting conditions, O2 is a perfusion-limited gas also.

The uptake of a gas that does not achieve diffusion equilibrium could obviously increase if the diffusing capacity increased. CO is an example of such a diffusion-limited gas (Fig. 4). Hemoglobin has a very high affinity for CO, so the effective solubility of CO in blood is large. Therefore, increases in the CO concentration in blood are not effective at increasing PCO. This keeps blood Pco lower than alveolar Pco, and results in a large disequilibrium and diffusion limitation. Under abnormal conditions, O2 may become a diffusion-limited gas (Fig. 4).

The reason that some gases are perfusion limited and some are diffusion limited is not related solely to their solubility in blood. All anesthetic gases are perfusion limited, yet they have a wide range of solubility in blood. A gas is a diffusion-limited gas when its effective solubility in blood is significantly greater than its solubility in the blood-gas barrier (which is approximated by its solubility in water or plasma). This is because a gas has to dissolve in the barrier before it can diffuse across the barrier and dissolve in the blood. An analogy is putting a liquid into different-sized containers with different-sized openings. The supply of liquid is assumed to be unlimited, analogous to a constant alveolar partial pressure. The size of the container represents solubility in blood and the size of the opening represents solubility in the membrane. It takes a long time to fill a large container through a small opening.

However, a larger container will not take longer to fill if it also has a larger opening.

In practice, the only diffusion-limited gases are CO and O2 under hypoxic conditions. All other gases are perfusion limited, including O2 under normoxic conditions in healthy lungs. CO is diffusion limited because it is always much more soluble in blood than in the blood-gas barrier. This is also the case for O2 in hypoxia, when the slope of the O2-blood equilibrium curve is much steeper than the slope for physically dissolved O2 in plasma (see Chapter 20, Fig. 1). However, at high PO2 levels, the slope of the blood-O2 equilibrium curve equals the slope of the solubility curve in plasma, and O2 behaves like inert gases.

Measures of Diffusing Capacity

The diffusing capacity of the lung can be measured from the uptake of a diffusion-limited gas like CO. If very low levels of CO are inspired (about 0.1%), then hemoglobin saturation with CO is very low, arterial oxygenation is not disturbed, and there are no toxic effects. Also, the amount of CO entering the capillary blood does not increase blood PCO significantly because CO is so soluble in blood. Therefore, the lung-diffusing capacity for CO (DLCO) can be defined by Fick's first law of diffusion as follows:

Dlco = V co/Paco, where Vco = CO uptake by the lung and the gradient driving CO diffusion equals Paco because average capillary Pco = 0. In theory, Dlco could be used to calculate the DLfor O2 by correcting for physical factors that determine diffusing capacity (MW and solubility). However, only Dlco is reported clinically.

In the steady-state Dlco method, the individual breathes a low level of CO for a couple of minutes. Then CO uptake is calculated from the Fick principle using measurements of ventilation and inspired and expired PCO. Alveolar Pco can be estimated from expired Pco. In the single breath Dlco method, an individual takes a breath with a low concentration of CO and holds the breath for 10 sec. This method also requires a simultaneous measurement of lung volume (e.g., by helium dilution; see Chapter 18, Fig. 7) to calculate Vco from Pco changes in the lung. Alveolar Pco is estimated from expired Pco and corrected for the change that occurs during the breath hold.

A normal Dlco is about 25 mL/(min • mm Hg). Dlco can increase two- to threefold with exercise, as expected for capillary recruitment and distension. Dlco also changes with O2 level because the rate of chemical

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