Chapter 4. Blood Flow to the Lung

The reader knows the structure, function, distribution, and control of the blood supply of the lung.

• Compares and contrasts the bronchial circulation and the pulmonary circulation.
• Describes the anatomy of the pulmonary circulation, and explains its physiologic consequences.
• Compares and contrasts the pulmonary circulation and the systemic circulation.
• Describes and explains the effects of lung volume on pulmonary vascular resistance.
• Describes and explains the effects of elevated intravascular pressures on pulmonary vascular resistance.
• Lists the neural and humoral factors that influence pulmonary vascular resistance.
• Describes the effect of gravity on pulmonary blood flow.
• Describes the interrelationships of alveolar pressure, pulmonary arterial pressure, and pulmonary venous pressure, as well as their effects on the regional distribution of pulmonary blood flow.
• Predicts the effects of alterations in alveolar pressure, pulmonary arterial and venous pressure, and body position on the regional distribution of pulmonary blood flow.
• Describes hypoxic pulmonary vasoconstriction and discusses its role in localized and widespread alveolar hypoxia.
• Describes the causes and consequences of pulmonary edema.

The lung receives blood flow via both the bronchial circulation and the pulmonary circulation. Bronchial blood flow constitutes a very small portion of the output of the left ventricle and supplies part of the tracheobronchial tree with systemic arterial blood. Pulmonary blood flow (PBF) constitutes the entire output of the right ventricle and supplies the lung with the mixed venous blood draining all the tissues of the body. It is this blood that undergoes gas exchange with the alveolar air in the pulmonary capillaries. Because the right and left ventricles are arranged in series in normal adults, PBF is approximately equal to 100% of the output of the left ventricle. That is, PBF is equal to the cardiac output—normally about 3.5 L/min/m2 of body surface area at rest.

There is about 250 to 300 mL of blood per square meter of body surface area in the pulmonary circulation. About 60 to 70 mL/m2 of this blood is located in the pulmonary capillaries. It takes a red blood cell about 4 to 5 seconds to travel through the pulmonary circulation at resting cardiac outputs; about 0.75 of a second of this time is spent in pulmonary capillaries. Pulmonary capillaries have average diameters of around 6 μm; that is, they are slightly smaller than the average erythrocyte, which has a diameter of about 8 μm. Erythrocytes must therefore change their shape slightly as they pass through the pulmonary capillaries. An erythrocyte passes through a number of pulmonary capillaries as it travels through the lung. Gas exchange starts to take place in smaller pulmonary arterial vessels, which are not truly capillaries by histologic standards. These arterial segments and successive capillaries may be thought of as functional pulmonary capillaries. In most cases in this book, pulmonary capillaries refer to functional pulmonary capillaries rather than to anatomic capillaries.

About 280 billion pulmonary capillaries supply approximately 300 million alveoli, resulting in a potential surface area for gas exchange estimated to be 50 to 100 m2. As shown in Figure 1–4, the alveoli are completely enveloped in pulmonary capillaries. The capillaries are so close to one another that some researchers have described pulmonary capillary blood flow as resembling blood flowing through 2 parallel sheets of endothelium held together by occasional connective tissue supports.

The bronchial arteries arise variably, either directly from the aorta or from the intercostal arteries. They supply arterial blood to the tracheobronchial tree and to other structures of the lung down to the level of the terminal bronchioles. They also provide blood flow to the hilar lymph nodes, visceral pleura, pulmonary arteries and veins, vagus, and esophagus. Lung structures distal to the terminal bronchioles, including the respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli, receive oxygen directly by diffusion from the alveolar air and receive nutrients from the mixed venous blood in the pulmonary circulation. The bronchial circulation may be important in the “air-conditioning” of inspired air, which is discussed in Chapter 10.

The blood flow in the bronchial circulation constitutes about 2% of the output of the left ventricle. Blood pressure in the bronchial arteries is the same as that in the other systemic arteries (disregarding differences due to hydrostatic effects, which will be discussed later in this chapter). This is much greater than the blood pressure in the pulmonary arteries (Figure 4–1). The reasons for this difference will be discussed in the next section.

The venous drainage of the bronchial circulation is unusual. Although some of the bronchial venous blood enters the azygos and hemiazygos veins, a substantial portion of bronchial venous blood enters the pulmonary veins. The blood in the pulmonary veins has undergone gas exchange with the alveolar air—that is, the pulmonary veins contain “arterial” blood. Therefore, the bronchial venous blood entering the pulmonary venous blood is part of the normal anatomic right-to-left shunt, which will be discussed in Chapter 5. Histologists have also identified anastomoses, or connections, between some bronchial capillaries and pulmonary capillaries and between bronchial arteries and branches of the pulmonary artery. These connections probably play little role in a healthy person but may open in pathologic states, such as when either bronchial or PBF to a portion of lung is occluded. For example, if PBF to an area of the lung is blocked by a pulmonary embolus, bronchial blood flow to that area increases. Bronchial blood flow increases after lung injury, and in inflammatory and proliferative diseases. The bronchial circulation is also the primary source of new vessels for the lung after injury. The main anatomic features of the bronchial circulation are illustrated in Figure 4–2.

The pulmonary artery and its branches are much thinner-walled than corresponding parts of the systemic circulation. The pulmonary artery rapidly subdivides into terminal branches that have thinner walls and greater internal diameters than do corresponding branches of the systemic arterial tree. There is much less vascular smooth muscle in the walls of the vessels of the pulmonary arterial tree, and there are no highly muscular vessels that correspond to the systemic arterioles. The pulmonary arterial tree rapidly subdivides over a short distance, ultimately branching into the approximately 280 billion pulmonary capillaries, where gas exchange occurs.

Determination of Pulmonary Vascular Resistance

PVR cannot be measured directly but must be calculated. Poiseuille’s law, which states that for a Newtonian fluid flowing steadily through a nondistensible tube,

For the pulmonary circulation, then,

That is, the PVR is equal to the mean pulmonary artery pressure (MPAP) minus the mean left atrial pressure (MLAP), with the result divided by PBF, which is equal to the cardiac output.

This formula, however, is only an approximation because blood is not a Newtonian fluid, because PBF is pulsatile (and may also be turbulent), because the pulmonary circulation is distensible (and compressible), and because the pulmonary circulation is a very complex branching structure. (Remember that resistances in series add directly; resistances in parallel add as reciprocals.) Furthermore, the MLAP may not be the effective downstream pressure for the calculation of PVR under all lung conditions (see the section on zones of the lung later in this chapter).

The intravascular pressures in the pulmonary circulation are lower than those in the systemic circulation (Figure 4–1). This is particularly striking with respect to the arterial pressures of the 2 circuits.

Because the right and left circulations are in series, the outputs of the right and left ventricles must be approximately equal to each other over the long run. (If they are not, blood and fluid will build up in the lungs or periphery.) If the 2 outputs are the same and the measured pressure drops across the systemic circulation and the pulmonary circulation are about 98 and 10 mm Hg, respectively, then the PVR must be about one tenth that of the systemic vascular resistance (SVR) (see Figure 4–1). (SVR is sometimes called TPR for total peripheral resistance.) This low resistance to blood flow offered by the pulmonary circulation is due to the structural aspects of the pulmonary circulation already discussed. The pulmonary vasculature is thinner walled, has much less vascular smooth muscle, and is generally more distensible than the systemic circulation.

Distribution of Pulmonary Vascular Resistance

The distribution of PVR can be seen by looking at the pressure drop across each of the 3 major components of the pulmonary vasculature: the pulmonary arteries, the pulmonary capillaries, and the pulmonary veins. In Figure 4–1, the resistance is fairly evenly distributed among the 3 components. At rest, about one third of the resistance to blood flow is located in the pulmonary arteries, about one third is located in the pulmonary capillaries, and about one third is located in the pulmonary veins. This is in contrast to the systemic circulation, in which about 70% of the resistance to blood flow is located in the systemic arteries, mostly in the highly muscular systemic arterioles.

Consequences of Differences in Pressure between the Systemic and Pulmonary Circulations

The pressure at the bottom of a column of a liquid is proportional to the height of the column times the density of the liquid times gravity. Thus, when the normal mean systemic arterial blood pressure is stated to be about 100 mm Hg, the pressure developed in the aorta is equivalent to the pressure at the bottom of a column of mercury that is 100 mm high (it will push a column of mercury up 100 mm). Mercury is chosen for pressure measurement when high pressures are expected because it is a very dense liquid. Water is used when lower pressures are to be measured because mercury is 13.6 times as dense as water. Therefore, lower pressures, such as alveolar and pleural pressures, are expressed in centimeters of water.

Nevertheless, when mean arterial blood pressure is stated to be 100 mm Hg, this is specifically with reference to the level of the left atrium. Blood pressure in the feet of a person who is standing is much higher than 100 mm Hg because of the additional pressure exerted by the “column” of blood from the heart to the feet. In fact, blood pressure in the feet of a standing person of average height with a mean arterial blood pressure of 100 mm Hg is likely to be about 180 mm Hg. Because venous pressure is similarly increased in the feet (about 80 mm Hg), the pressure difference between arteries and veins is unaffected. Conversely, pressure decreases with distance above the heart (“above” with respect to gravity), so that blood pressure at the top of the head may only be 40 to 50 mm Hg.

The left ventricle, then, must maintain a relatively high mean arterial pressure because such high pressures are necessary to overcome hydrostatic forces and pump blood “uphill” to the brain. The apices of the lungs are a much shorter distance above the right ventricle, and so such high pressures are unnecessary.

A second consequence of the high arterial pressure in the systemic circulation is that it allows the redistribution of left ventricular output and the control of blood flow to different tissues. Because the left ventricle supplies all the tissues of the body with blood, it must be able to meet varying demands for blood flow in different tissues under various circumstances. For example, during exercise the blood vessels supplying the exercising muscle dilate in response to the increased local metabolic demand (and blood flow to the skin also increases to aid in thermoregulation). Blood pressure is partly maintained by increasing the resistance to blood flow in other vascular beds. A high-pressure head is thus necessary to allow such redistributions by altering the vascular resistance to blood flow in different organs; also, these redistributions help maintain the pressure head. In the pulmonary circulation, redistributions of right ventricular output are usually unnecessary because all alveolar-capillary units that are participating in gas exchange are performing the same function. The pressure head is low and the small amount of smooth muscle in the pulmonary vessels (which is in large part responsible for the low pressure head) makes such local redistributions unlikely. An exception to this will be seen in the section on hypoxic pulmonary vasoconstriction.

A final consequence of the pressure difference between the systemic and pulmonary circulations is that the workload of the left ventricle (stroke work equals stroke volume times arterial pressure) is much greater than that of the right ventricle. The metabolic demand of the left ventricle is also much greater than that of the right ventricle. The difference in wall thickness of the left and right ventricles of the adult is a reminder of the much greater workload of the left ventricle.

The relatively small amounts of vascular smooth muscle, low intravascular pressures, and high distensibility of the pulmonary circulation lead to a much greater importance of extravascular effects (“passive factors”) on PVR. Gravity, body position, lung volume, alveolar and intrapleural pressures, intravascular pressures, and right ventricular output all can have profound effects on PVR without any alteration in the tone of the pulmonary vascular smooth muscle.

The Concept of a Transmural Pressure Difference

For distensible-compressible vessels, the transmural pressure difference is an important determinant of the vessel diameter. As the transmural pressure difference (which is equal to pressure inside minus pressure outside) increases, the vessel diameter increases and resistance falls; as the transmural pressure difference decreases, the vessel diameter decreases and the resistance increases. Negative transmural pressure differences lead to compression or even collapse of the vessel.

Lung Volume and Pulmonary Vascular Resistance

Two different groups of pulmonary vessels must be considered when the effects of changes in lung volume on PVR are analyzed: those vessels that are exposed to the mechanical influences of the alveoli and the larger vessels that are not—the alveolar and extraalveolar vessels (Figure 4–3).

As lung volume increases during a normal negative-pressure inspiration, the alveoli increase in volume. While the alveoli expand, the vessels found between them, mainly pulmonary capillaries, are elongated. As these vessels are stretched, their diameters decrease, just as stretching a rubber tube causes its diameter to narrow. Resistance to blood flow through the alveolar vessels increases as the alveoli expand because the alveolar vessels are longer (resistance is directly proportional to length) and because their radii are smaller (resistance is inversely proportional to radius to the fourth power). At high lung volumes, then, the resistance to blood flow offered by the alveolar vessels increases greatly; at low lung volumes, the resistance to blood flow offered by the alveolar vessels decreases. This can be seen in the “alveolar” curve in Figure 4–4.

One group of the extraalveolar vessels, the larger arteries and veins, is exposed to the intrapleural pressure. As lung volume is increased by making the intrapleural pressure more negative, the transmural pressure difference of the larger arteries and veins increases and they distend. Another factor tending to decrease the resistance to blood flow offered by the extraalveolar vessels at higher lung volumes is radial traction by the connective tissue and alveolar septa holding the larger vessels in place in the lung. (Look at the small branch of the pulmonary artery at the bottom of Figure 1–3.) Thus, at high lung volumes (attained by normal negative-pressure breathing), the resistance to blood flow offered by the extraalveolar vessels decreases (Figure 4–4). During a forced expiration to low lung volumes, however, intrapleural pressure becomes very positive. Extraalveolar vessels are compressed, and as the alveoli decrease in size, they exert less radial traction on the extraalveolar vessels. The resistance to blood flow offered by the extraalveolar vessels increases greatly (see left side of Figure 4–4).

Because the alveolar and extraalveolar vessels may be thought of as 2 groups of resistances in series with each other, the resistances of the alveolar and extraalveolar vessels are additive at any lung volume. Thus, the effect of changes in lung volume on the total PVR gives the U-shaped curve seen in Figure 4–4.

A second type of extraalveolar vessel is the so-called corner vessel, or extraalveolar capillary (see the circled asterisk in Figure 1–3). Although these vessels are found between alveoli, their locations at junctions of alveolar septa give them different mechanical properties. Expansion of the alveoli during inspiration increases the wall tension of the alveolar septa, and the corner vessels are distended by increased radial traction, whereas the alveolar capillaries are compressed.

Also note that during mechanical positive-pressure ventilation, alveolar pressure (PA) and intrapleural pressure are positive during inspiration. In this case, both the alveolar and extraalveolar vessels are compressed as lung volume increases, and the resistance to blood flow offered by both alveolar and extraalveolar vessels increases during lung inflation. This is especially a problem during mechanical positive-pressure ventilation with positive end-expiratory pressure (PEEP). During PEEP, airway pressure (and thus alveolar pressure) is kept positive at end expiration to help prevent atelectasis. In this situation, alveolar pressure and intrapleural pressure are positive during both inspiration and expiration. PVR is elevated in both alveolar and extraalveolar vessels throughout the respiratory cycle. In addition, because intrapleural pressure is always positive, the other intrathoracic blood vessels are subjected to decreased transmural pressure differences; the venae cavae, which have low intravascular pressure, are also compressed. If cardiovascular reflexes are unable to adjust to this situation, cardiac output may fall precipitously because of decreased venous return and high PVR.

Recruitment and Distention

During exercise, cardiac output can increase several-fold without a correspondingly great increase in MPAP. Although the MPAP does increase, the increase is only a few millimeters of mercury, even if cardiac output has doubled or tripled. Since the pressure drop across the pulmonary circulation is proportional to the cardiac output times the PVR (ie,

Like the effects of lung volume on PVR, this decrease appears to be passive—that is, it is not a result of changes in the tone of pulmonary vascular smooth muscle caused by neural mechanisms or humoral agents. In fact, a fall in PVR in response to increased blood flow or even an increase in perfusion pressure can be demonstrated in a vascularly isolated perfused lung, as was used to obtain the data summarized in Figure 4–5.

In this experiment, the blood vessels of the left lung of a dog were isolated, cannulated, and perfused with a pump. The lung was ventilated with a mechanical respirator. Blood flow to the lung and MPAP were elevated by increasing the pump output. As can be seen from the graph, increasing the blood flow to the lung caused a decrease in the calculated PVR. Increasing the left atrial pressure also decreased PVR in these studies.

Recruitment

As indicated in the diagram, at resting cardiac outputs, not all the pulmonary capillaries are perfused. A substantial proportion of capillaries, perhaps as large as one half to two thirds, is probably not perfused because of hydrostatic effects that will be discussed later in this chapter. Others may be unperfused because they have a relatively high critical opening pressure. That is, these vessels, because of their high vascular smooth muscle tone or other factors such as positive alveolar pressure, require a higher perfusion pressure than that solely necessary to overcome hydrostatic forces. Under normal circumstances, it is not likely that the critical opening pressures for pulmonary blood vessels are very great because they have so little smooth muscle.

Increasing blood flow increases the MPAP, which opposes hydrostatic forces and exceeds the critical opening pressure in previously unopened vessels. This series of events opens new parallel pathways for blood flow, which lowers the PVR. This opening of new pathways is called recruitment. Note that decreasing the cardiac output or pulmonary artery pressure can result in a derecruitment of pulmonary capillaries.

Distention

The distensibility of the pulmonary vasculature has already been discussed in this chapter. As perfusion pressure increases, the transmural pressure gradient of the pulmonary blood vessels increases, causing distention of the vessels. This increases their radii and decreases their resistance to blood flow.

Recruitment or Distention?

The answer to the question of whether it is recruitment or distention that causes the decreased PVR seen with elevated perfusion pressure is probably both. Perhaps recruitment of pulmonary capillaries occurs with small increases in pulmonary vascular pressures and distention at higher pressures. Note that recruitment increases the surface area for gas exchange and may decrease alveolar dead space. Derecruitment caused by low right ventricular output or high alveolar pressures decreases the surface area for gas exchange and may increase alveolar dead space.

Control of Pulmonary Vascular Smooth Muscle

Pulmonary vascular smooth muscle is responsive to both neural and humoral influences. These produce “active” alterations in PVR, as opposed to those “passive” factors discussed in the previous section. A final passive factor, gravity, will be discussed later in this chapter. The main “passive” and “active” factors that influence PVR are summarized in Tables 4–1 and 4–2.

Neural Effects

The pulmonary vasculature is innervated by both sympathetic and parasympathetic fibers of the autonomic nervous system. The innervation of pulmonary vessels is relatively sparse in comparison with that of systemic vessels. There is relatively more innervation of the larger vessels and less of the smaller, more muscular vessels. There appears to be no innervation of vessels smaller than 30 μm in diameter. There does not appear to be much innervation of intrapulmonary veins and venules.

The effects of stimulation of the sympathetic innervation of the pulmonary vasculature are somewhat controversial. Some investigators have demonstrated an increase in PVR with sympathetic stimulation of the innervation of the pulmonary vasculature, whereas others have shown only a decreased distensibility with no change in calculated PVR. Stimulation of the parasympathetic innervation of the pulmonary vessels generally causes vasodilation, although its physiologic function is not known.

Humoral Effects

The catecholamines epinephrine and norepinephrine both increase PVR when injected into the pulmonary circulation. Histamine, found in the lung in mast cells, is a pulmonary vasoconstrictor. Certain prostaglandins and related substances, such as PGF2α, PGE2, and thromboxane, are also pulmonary vasoconstrictors, as is endothelin, a 21-amino acid peptide synthesized by the vascular endothelium. Alveolar hypoxia and hypercapnia also cause pulmonary vasoconstriction, as will be discussed later in this chapter. Acetylcholine, the β-adrenergic agonist isoproterenol, nitric oxide (NO), and certain prostaglandins, such as PGE1 and PGI2 (prostacyclin), are pulmonary vasodilators.

Determinations of the regional distribution of PBF have shown that gravity is another important “passive” factor affecting local PVR and the relative perfusion of different regions of the lung. The interaction of the effects of gravity and extravascular pressures may have a profound influence on the relative perfusion of different areas of the lung.

Measurement of Total Pulmonary Blood Flow

The total PBF (which is the cardiac output) can be determined clinically in several ways, the more accurate of which have the disadvantage of being invasive to the patient (ie, requiring minor surgery).

Invasive Methods

The Fick Principle

In 1870, Adolf Fick pointed out the following relationship, now known as the Fick principle: The total amount of oxygen absorbed by the body per minute

Both arterial and mixed venous (which is equal to pulmonary artery) blood must be sampled in this method. Central venous oxygen saturation (SO2 see Chapter 7) is sometimes used to calculate the approximate mixed venous oxygen content because central venous blood is much easier to obtain than mixed venous—a catheter in the pulmonary artery is not necessary. A low central venous oxygen saturation is also a good indicator of poor tissue oxygenation and may be more useful clinically than determination of the cardiac output.

The Indicator Dilution Technique

In this traditional method, no longer used commonly, a known amount of an indicator dye that stays in the blood vessels, such as indocyanine green, is injected intravenously as a bolus. The systemic arterial dye concentration is monitored continuously with a densitometer as the dye passes through the aorta. Correction must be made for recirculating dye because the concentration change of interest is that which occurs in a single pass through the pulmonary circulation. A curve of the dye concentration as it changes with time is constructed, and then the area under the curve is determined by integration. Dividing this amount by the time of passage of the dye gives the average concentration of dye through the passage. If the cardiac output is high, the dye concentration falls rapidly, and so the area under the curve is small and the average dye concentration is low. If the cardiac output is low, the area under the curve is large and the average dye concentration is high. The cardiac output (

The calculations are usually done automatically in newer densitometers. Both arterial and venous catheters are necessary for this technique.

The Thermal Dilution Technique

This method is similar in principle to the indicator dilution technique. Cold fluid, for example, saline, is injected into a central vein, and the change in temperature of the blood downstream is monitored continuously with a thermistor. With high cardiac outputs, the temperature returns to normal rapidly; with low cardiac outputs, the temperature rises slowly. The advantage of this method is that the insertion of a single intravenous catheter is the only necessary surgical procedure. A type of catheter known as a quadruple-lumen Swan-Ganz catheter is used. One lumen is connected to a tiny inflatable balloon at the end of the catheter. During the insertion of the catheter, the balloon is inflated so that the tip of the catheter “floats” in the direction of blood flow: through the right atrium and ventricle and into the pulmonary artery. The balloon is then deflated. A second lumen carries the thermistor wire to the end of the catheter. A third lumen travels only part of the way down the catheter so that it opens into a central vein. This lumen is used for the injection of the cold solution. The final lumen, at the end of the catheter, is open to the pulmonary artery, and it allows pulmonary artery pressure to be monitored. (It can also be used to sample mixed venous blood.) This monitoring is necessary because the only way the physician knows that the catheter is placed properly is by recognizing the characteristic pulmonary artery pressure trace (unless a fluoroscope is used).

The temperature change after the injection is monitored by a cardiac output “computer” that automatically calculates the cardiac output from the volume and temperature of the injected substance, the original blood temperature, and the temperature change of the blood with time.

If the Swan-Ganz catheter is advanced, with the balloon inflated, until it completely occludes a branch of the pulmonary artery, it is said to be “wedged.” The pressure measured at the tip of the catheter with the balloon still inflated is approximately equal to the pressure in the vascular segment immediately distal to it, the pulmonary capillary pressure. Because there are no valves between the pulmonary capillaries and the lumen of the left atrium, this “pulmonary capillary wedge pressure” is similar to left atrial pressure. When the balloon is deflated, the pressure measured at the tip of the catheter is pulmonary artery pressure. Figure 4–7 shows a pressure trace as a Swan-Ganz catheter is advanced through the right atrium, the right ventricle, the main pulmonary artery, and into a branch of the pulmonary artery until it is “wedged.” The balloon is then deflated to show pulmonary artery pressure.

Noninvasive Methods

Several methods can be used to determine cardiac output noninvasively: some are currently used clinically; others are used experimentally. They include transcutaneous and transesophageal Doppler ultrasonography, thoracic electrical bioimpedance, pulse pressure waveform analysis, and partial CO2 rebreathing. The Doppler ultrasonography methods are more commonly used clinically.

Determination of Regional Pulmonary Blood Flow

Regional PBF can be determined by pulmonary angiography, by lung scans after injection of macroaggregates of albumin labeled with radioactive iodine (131I) or technetium (99mTC), and by lung scans after the infusion of dissolved radiolabeled gases such as 133Xe.

Pulmonary Angiography

A radiopaque substance is injected into the pulmonary artery, and its movement through the lung is monitored during fluoroscopy. Unperfused areas secondary to vascular obstruction by emboli or from other causes are evident because none of the radiopaque substance enters these areas.

Macroaggregates of Albumin

Macroaggregates of albumin labeled with 131I or 99mTC in the size range of 10 to 50 μm are injected in small quantities into a peripheral vein. Most of these become trapped in small pulmonary vessels as they enter the lung. Lung scans for radioactivity demonstrate the perfused areas of the lung. The aggregates fragment and are removed from the lung within a day or so.

133Xe

133Xe is dissolved in saline and injected intravenously. Xenon is not particularly soluble in saline or blood, and so it comes out of solution in the lung and enters the alveoli. If the 133Xe is well mixed in the blood as it enters the pulmonary artery, then the amount of radioactivity coming into a region of the lung is proportional to the amount of blood flow to that area. By making corrections for regional lung volume, the blood flow per unit volume of a region of the lung can be determined.

The Regional Distribution of Pulmonary Blood Flow

If 133Xe is used to determine regional PBF in a person seated upright or standing up, a pattern like that shown in Figure 4–8 is seen.

If the subject lies down, this pattern of regional perfusion is altered so that perfusion to the anatomically upper and lower portions of the lung is roughly evenly distributed, but blood flow per unit volume is still greater in the more gravity-dependent regions of the lung. For example, if the subject were to lie down on his or her left side, the left lung would receive more blood flow per unit volume than would the right lung. Exercise, which increases the cardiac output, increases the blood flow per unit volume to all regions of the lung, but the perfusion gradient persists so that there is still relatively greater blood flow per unit volume in more gravity-dependent regions of the lung.

The reason for this gradient of regional perfusion of the lung is obviously gravity. As already discussed, the pressure at the bottom of a column of a liquid is proportional to the height of the column times the density of the liquid times gravity. Thus, the intravascular pressures in more gravity-dependent portions of the lung are greater than those in upper regions. Because the pressures are greater in the more gravity-dependent regions of the lung, the resistance to blood flow is lower in lower regions of the lung owing to more recruitment or distention of vessels in these regions. It is therefore not only gravity but also the special characteristics of the pulmonary circulation that cause the increased blood flow to more gravity-dependent regions of the lung. After all, the same hydrostatic effects occur to an even greater extent in the left side of the circulation, but the thick walls of the systemic arteries are not affected. Blood travels through the more gravity-dependent regions of the lung at a faster rate. That is, the mean capillary transit time is less in the lower regions of the lung. There is also considerable heterogeneity in PBF at any vertical distance up the lung. That is, there may be significant variations in PBF within a given horizontal plane of the lung. These variations are caused by local factors and mechanical stresses.

The Interaction of Gravity and Extravascular Pressure: The Zones of the Lung

Experiments done on excised, perfused, upright animal lungs have demonstrated the same gradient of increased perfusion per unit volume from the top of the lung to the bottom. When the experiments were done at low pump outputs so that the pulmonary artery pressure was low, the uppermost regions of the lung received no blood flow. Perfusion of the lung ceased at the point at which alveolar pressure (PA) was just equal to pulmonary arterial pressure (Pa). Above this point, there was no perfusion because alveolar pressure exceeded pulmonary artery pressure, and so the transmural pressure across capillary walls was negative. Below this point, perfusion per unit volume increased steadily with increased distance down the lung.

The lower portion of the lung in Figure 4–9 is said to be in zone 3. In this region, the pulmonary artery pressure and the pulmonary vein pressure (Pv) are both greater than alveolar pressure. The driving pressure for blood flow through the lung in this region is simply pulmonary artery pressure minus pulmonary vein pressure. Note that this driving pressure stays constant as one moves further down the lung in zone 3 because the hydrostatic pressure effects are the same for both the arteries and the veins.

The middle portion of the lung in Figure 4–9 is in zone 2. In zone 2, pulmonary artery pressure is greater than alveolar pressure, and so blood flow does occur. However, because alveolar pressure is greater than pulmonary vein pressure, the effective driving pressure for blood flow is pulmonary artery pressure minus alveolar pressure in zone 2. (This is analogous to the situation during dynamic compression of the airways described in Chapter 2: During a forced expiration the driving pressure for airflow is equal to alveolar pressure minus intrapleural pressure.) Notice that in zone 2 (at right in Figure 4–9) the increase in blood flow per distance down the lung is greater than it is in zone 3. This is because the upstream driving pressure, the pulmonary artery pressure, increases according to the hydrostatic pressure increase, but the effective downstream pressure, alveolar pressure, is constant throughout the lung at any instant.

To summarize then: In zone 1,

and there is no blood flow (except perhaps in “corner vessels,” which are not exposed to alveolar pressure); in zone 2,

and the effective driving pressure for blood flow is Pa − PA; in zone 3,

and the driving pressure for blood flow is Pa − Pv.

It is important to realize that the boundaries between the zones are dependent on physiologic conditions—they are not fixed anatomic landmarks. Alveolar pressure changes during the course of each breath. During eupneic breathing these changes are only a few centimeters of water, but they may be much greater during speech, exercise, and other conditions. A patient on a positive-pressure ventilator with PEEP may have substantial amounts of zone 1 because alveolar pressure is always high. Similarly, after a hemorrhage or during general anesthesia, PBF and pulmonary artery pressure are low and zone 1 conditions are also likely. During exercise, cardiac output and pulmonary artery pressure increase and any existing zone 1 should be recruited to zone 2. The boundary between zones 2 and 3 will move upward as well. Pulmonary artery pressure is highly pulsatile, and so the borders between the zones probably even move up a bit with each contraction of the right ventricle.

Changes in lung volume also affect the regional distribution of PBF and will therefore affect the boundaries between zones. Finally, changes in body position alter the orientation of the zones with respect to the anatomic locations in the lung, but the same relationships exist with respect to gravity and alveolar pressure.

Mechanism of Hypoxic Pulmonary Vasoconstriction

The mechanism of hypoxic pulmonary vasoconstriction is not completely understood. The response occurs locally, that is, only in the area of the alveolar hypoxia. Connections to the central nervous system are not necessary: An isolated, excised lung, perfused with blood by a mechanical pump with a constant output, exhibits an increased perfusion pressure when ventilated with hypoxic gas mixtures. This indicates that the increase in PVR can occur without the influence of extrinsic nerves. Thus, it is not surprising that hypoxic pulmonary vasoconstriction persists in human patients who had received heart-lung transplants. Hypoxia may cause the release of a vasoactive substance from the pulmonary parenchyma or mast cells in the area. Histamine, serotonin, catecholamines, and prostaglandins have all been suggested as the mediator substance, but none appears to completely mimic the response. Decreased release of a vasodilator such as nitric oxide may also be involved in hypoxic pulmonary vasoconstriction. Possibly several mediators act together. More recent studies have strongly indicated that hypoxia acts directly on pulmonary vascular smooth muscle to produce hypoxic pulmonary vasoconstriction. Hypoxia inhibits an outward potassium current, which causes pulmonary vascular smooth muscle cells to depolarize, allowing calcium to enter the cells. This, in turn, causes them to contract. The potassium channel appears to be open when it is oxidized and closed when it is reduced.

The hypoxic pulmonary vasoconstriction response is graded—constriction begins to occur at alveolar

Physiologic Function of Hypoxic Pulmonary Vasoconstriction

The function of hypoxic pulmonary vasoconstriction in localized hypoxia is fairly obvious. If an area of the lung becomes hypoxic because of airway obstruction or if localized atelectasis occurs, any mixed venous blood flowing to that area will undergo little or no gas exchange (Figure 4–10B) and will mix with blood draining well-ventilated areas of the lung as it enters the left atrium. This mixing will lower the overall arterial

In hypoxia of the whole lung, such as might be encountered at high altitude (see Chapter 11) or in hypoventilation, hypoxic pulmonary vasoconstriction occurs throughout the lung. Even this may be useful in increasing gas exchange because greatly increasing the pulmonary artery pressure recruits many previously unperfused pulmonary capillaries. This increases the surface area available for gas diffusion (see Chapter 6) and improves the matching of ventilation and perfusion, as will be discussed in the next chapter. On the other hand, such a whole-lung hypoxic pulmonary vasoconstriction greatly increases the workload on the right ventricle, and the high pulmonary artery pressure may overwhelm hypoxic pulmonary vasoconstriction in some parts of the lung, increase the capillary hydrostatic pressure in those vessels, and lead to pulmonary edema (see the next section of this chapter).

The mechanism of hypoxic pulmonary vasoconstriction has been controversial, but as noted above many researchers currently believe that inhibition of oxygen-sensitive voltage-gated potassium ion channels depolarizes smooth muscle cells in small branches of the pulmonary artery. This activates voltage-gated calcium ion channels in the smooth muscle cells, allowing influx of calcium ions, which causes the smooth muscle to contract and the vessels to constrict.

Alveolar hypercapnia (high carbon dioxide) also causes pulmonary vasoconstriction. It is not clear whether this occurs by the same mechanism as that of hypoxic pulmonary vasoconstriction.

Pulmonary edema is the extravascular accumulation of fluid in the lung. This pathologic condition may be caused by one or more physiologic abnormalities, but the result is inevitably impaired gas transfer. As the edema fluid builds up, first in the interstitium and later in alveoli, diffusion of gases—particularly oxygen—decreases (see Chapter 6).

The capillary endothelium is much more permeable to water and solutes than is the alveolar epithelium. Edema fluid therefore accumulates in the interstitium before it accumulates in the alveoli.

The Factors Influencing Liquid Movement in the Pulmonary Capillaries

The Starling equation describes the movement of liquid across the capillary endothelium:

where

• Kf = capillary filtration coefficient; this describes the permeability characteristics of the membrane to fluids
• Pc = capillary hydrostatic pressure
• Pis = hydrostatic pressure of the interstitial fluid
• σ = reflection coefficient; this describes the ability of the membrane to prevent extravasation of solute particles
• πpl = colloid osmotic (oncotic) pressure of the plasma
• πis = colloid osmotic pressure of the interstitial fluid
• A = the surface area of the alveolar-capillary barrier

The equation is shown schematically in Figure 4–11. The Starling equation is very useful in understanding the potential causes of pulmonary edema, even though only the plasma colloid osmotic pressure (πpl) can be measured clinically.

Lymphatic Drainage of the Lung

Any fluid that makes its way into the pulmonary interstitium must be removed by the lymphatic drainage of the lung. The pulmonary lymphatic vessels are mainly located in the extra-alveolar interstitium. The volume of lymph flow from the human lung is now believed to be as great as that from other organs under normal circumstances, and it is capable of increasing as much as 10-fold under pathologic conditions. It is only when this large safety factor is overwhelmed that pulmonary edema occurs.

Conditions that May Lead to Pulmonary Edema

The Starling equation provides a useful method of categorizing most of the potential causes of pulmonary edema (Table 4–3).

Permeability

Infections, circulating or inhaled toxins, oxygen toxicity, and other factors that destroy the integrity of the capillary endothelium can lead to localized or generalized pulmonary edema.

Capillary Hydrostatic Pressure

The capillary hydrostatic pressure is estimated to be about 10 mm Hg under normal conditions. If the capillary hydrostatic pressure increases dramatically, the filtration of fluid across the capillary endothelium will increase greatly, and enough fluid may leave the capillaries to exceed the lymphatic drainage. The pulmonary capillary hydrostatic pressure often increases secondary to problems in the left side of the circulation, such as infarction of the left ventricle, left ventricular failure, or mitral stenosis. As left atrial pressure and pulmonary venous pressure rise because of accumulating blood, the pulmonary capillary hydrostatic pressure also increases. Other causes of elevated pulmonary capillary hydrostatic pressure include overzealous administration of intravenous fluids by the physician and diseases that occlude the pulmonary veins.

Interstitial Hydrostatic Pressure

Some investigators believe the interstitial hydrostatic pressure of the lung to be slightly positive, whereas others have shown evidence that it may be in the range of -5 to -7 mm Hg. Conditions that would decrease the interstitial pressure would increase the tendency for pulmonary edema to develop. These include forced inspiration against an upper airway obstruction and potential actions of the physician, such as rapid evacuation of chest fluids or reduction of pneumothorax. Situations that increase alveolar surface tension, for example, when decreased amounts of pulmonary surfactant are present, could also make the interstitial hydrostatic pressure more negative and increase the tendency for the formation of pulmonary edema. Note that as fluid accumulates in the interstitium, the interstitial hydrostatic pressure increases, which helps limit further fluid extravasation.

The Reflection Coefficient

Any situation that permits more solute to leave the capillaries will lead to more fluid movement out of the vascular space.

Plasma Colloid Osmotic Pressure

Decreases in the colloid osmotic pressure of the plasma, which helps retain fluid in the capillaries, may lead to pulmonary edema. Plasma colloid osmotic pressure, normally in the range of 25 to 28 mm Hg, falls in hypoproteinemia or over administration of intravenous solutions.

Interstitial Colloid Osmotic Pressure

Increased concentration of solute in the interstitium will pull fluid from the capillaries.

Lymphatic Insufficiency

Conditions that block the lymphatic drainage of the lung, such as tumors or scars, may predispose patients to pulmonary edema.

Other Conditions Associated with Pulmonary Edema

Pulmonary edema is often seen associated with head injury, heroin overdose, and high altitude. The causes of the edema formation in these conditions are not known, although high-altitude pulmonary edema may be partly caused by high pulmonary artery pressures secondary to the hypoxic pulmonary vasoconstriction.

A patient’s mean arterial blood pressure is 100 mm Hg and his right atrial pressure is 2 mm Hg. His mean pulmonary artery pressure and pulmonary capillary wedge pressure (≈ left atrial pressure) determined using a Swan-Ganz catheter, are 15 and 5 mm Hg, respectively. If his cardiac output is 5 L/min, calculate his pulmonary vascular resistance and systemic vascular resistance.

The correct answer is:

Pulmonary vascular resistance (PVR):

Systemic vascular resistance (SVR):

From Raff H, Levitzky MG, eds. Medical Physiology: A Systems Approach. New York: McGraw-Hill; 2011:350–351.

A 60-year-old man who had a left ventricular myocardial infarction 3 months ago returns to the cardiologist because of dyspnea on exertion but not at rest, a cough productive of frothy fluid after exercise, and orthopnea (easier breathing in the upright than recumbent position). At rest, his heart rate is 105/min, blood pressure is 120/90, and his respiratory rate is increased at 20/min. His chest radiograph shows evidence of edema in gravity dependent lung regions.

The patient does not have dyspnea (the feeling of difficult breathing or “shortness of breath”) at rest and his blood pressure is within the normal range. His heart rate at rest is slightly above the normal range (50–100/min; tachycardia), and his respiratory rate is high (normally 12–15/min; tachypnea). He does have orthopnea.

He had a left ventricular myocardial infarction 3 months ago and the damaged heart muscle has been replaced with scar tissue that cannot contract. Although his left ventricle can generate a sufficient stroke volume at rest, it cannot match the increased right ventricular output during exercise, leading to increased left atrial pressure. Because there are no valves between the left atrium and the pulmonary veins and capillaries, pulmonary capillary hydrostatic pressure increases. Filtration of fluid from the capillaries into the pulmonary interstitium increases sufficiently to exceed the ability of the pulmonary lymphatic drainage to remove it, resulting in interstitial edema and then alveolar edema.

The dyspnea results from several factors. Pulmonary vascular congestion (excess blood in the pulmonary blood vessels) decreases the compliance of the lungs. Interstitial and alveolar edema increase the alveolar-capillary barrier for gas diffusion. This is particularly a problem for oxygen diffusion, as will be discussed in Chapter 6. Stretch receptors in the pulmonary circulation (J receptors) respond to pulmonary vascular congestion and the arterial chemoreceptors respond to low arterial