The vascular system of the body consists of separate pulmonary and systemic circulations operating in series (Figure 6-1). Each circulation receives its blood from the other; each has its own reservoir, pump, and set of vessels. The right ventricle receives mixed venous blood through the tricuspid valve from its reservoir, the right atrium, and pumps it through the pulmonic valve, which marks the beginning of the pulmonary circulation.¹ This relatively deoxygenated blood flows through pulmonary arteries and arterioles to an immense alveolar capillary bed where it is reoxygenated. The capillary bed consists of extremely short, interconnected segments spreading 75 to 100 mL of blood over a 70-m² area, or about half the size of a tennis court.¹ Comroe² described the capillary bed as two sheets of endothelium held apart in places by posts, similar to an underground parking garage. Rather than flowing through numerous individual tubes (as in systemic capillaries), pulmonary blood flows more like a sheet over the alveoli, maximizing its exposure to alveolar gases. This structural arrangement shortens the distance for oxygen and carbon dioxide diffusion between air and blood to one tenth of the diffusion distance that exists between systemic capillaries and tissue cells.¹

Figure 6-1 Comparison of pulmonary and systemic blood flows and pressures. (Adapted from Thibodeau GA, Patton KT: *Anatomy & physiology,* ed 5, St Louis, 2003, Mosby.)

After leaving the alveoli, the capillaries converge to form venules and veins. The newly oxygenated blood flows through four major pulmonary veins (two from each lung) into the left atrium, the reservoir for the left ventricle. The pulmonary vein orifices in the left atrial wall mark the end of the pulmonary circulation.¹ Blood continues to flow out of the left atrium through the mitral valve into the left ventricle, which pumps the blood through the aortic valve into the aorta. The aortic valve marks the beginning of the systemic circulation. The aorta distributes the oxygenated blood through its many branches to systemic arteries, arterioles, and capillary beds throughout the body, supplying oxygen to tissue cells and removing the carbon dioxide they produce. Beyond the capillary beds, systemic venules and veins converge to return the oxygen-poor blood to the right atrium via the vena cavae, which mark the end of the systemic circulation.

The total cardiac output (Q˙t) is simultaneously pumped through both circulations each minute. Right and left ventricular outputs must be essentially equal over time; otherwise, blood would accumulate in one of the circulations. Small differences in outputs may occur briefly for a few heartbeats, but over time, individual ventricular outputs are equal in healthy hearts. Figure 6-1 illustrates pulmonary and systemic circulations with their associated pressures.

The pulmonary arteries and arterioles have much thinner walls and less smooth muscle than systemic arteries and arterioles. Therefore, pulmonary arterioles cannot constrict as effectively as systemic arterioles. Pulmonary veins and venules also have sparse smooth muscle, differing little in structure from pulmonary arteries and arterioles. Pulmonary arteries generally follow a course parallel with bronchi, whereas pulmonary veins leave the lung through different routes. Without this anatomical difference, distinguishing pulmonary arteries from veins on a chest x-ray image would be difficult because of their structural similarities.²

Pulmonary capillaries also differ significantly from systemic capillaries; as noted previously, pulmonary capillary blood flows in thin sheets, as opposed to the distinctly tubular flow in systemic capillaries. The thin walls of pulmonary vessels and vast area of the capillary bed make the pulmonary vasculature highly distensible compared with the systemic vasculature.

Bronchial Vasculature

The supporting tissues of the tracheobronchial tree, including airways down through the terminal bronchioles, are supplied with oxygenated blood through the systemic bronchial arteries. (See the section on blood supply to the lungs in Chapter 1.) Bronchial systemic venous blood drains directly into the pulmonary veins, mixing oxygen-poor blood with freshly oxygenated pulmonary venous blood on its way to the left ventricle.³ Bronchial blood flow is only 1% to 2% of the cardiac output, which means that the anatomical shunt from this source is usually less than 2%; this also means that left ventricular output is about 1% to 2% greater than right ventricular output.³

CONCEPT QUESTION 6-1

Explain the way anatomical shunt through the bronchial circulation causes an oxygen pressure (PO₂) difference between alveolar gas and arterial blood.

Pulmonary and Systemic Pressures

Figure 6-1 shows that the pulmonary circulation is a low-pressure, low-resistance system compared with the systemic circulation. The lower resistance in the pulmonary circulation is manifested by the fact that its pressures are lower even though it receives the same cardiac output as the systemic circulation receives. The resistance to blood flow in the pulmonary circulation is about one tenth as great as it is in the systemic circulation.¹

Blood flow through the pulmonary circulation is highly pulsatile rather than continuous as in systemic capillaries. The total volume of blood in the pulmonary circulation is about 450 mL, which is only 9% of the total circulating blood volume. About 70 mL of this blood is in the capillaries at any given moment; the rest is distributed equally between pulmonary arterial and venous vessels.³ The capillary blood volume of 70 mL is about equal to the volume ejected by the right ventricle with each contraction (the right ventricular stroke volume). Pulmonary capillary blood is thus almost completely replaced with each heartbeat, which means a red blood cell travels through the capillaries in about 0.75 second. Pulmonary blood flow almost stops between each ventricular beat, which explains its pulsatile nature.^1,3

The highly expandable pulmonary vascular bed serves as a backup reservoir that shields the left atrium from sudden changes in right ventricular output. If venous return to the right ventricle increases suddenly, as would occur during sudden strenuous exercise, left ventricular filling pressure increases gradually over two or three cardiac cycles rather than increasing abruptly.

Clinical Measurement of Pulmonary Blood Pressures and Flows

Measurement of Pulmonary Blood Pressures

Systemic blood pressure is easily measured by simple noninvasive means. However, measurement of pressures in the pulmonary circulation requires an invasive procedure called pulmonary artery catheterization. The special catheter used for this purpose was the subject of a study published in 1970 by Swan, Ganz, and others. Since then, the catheter has been marketed under the brand name Swan-Ganz, and the term Swan-Ganz catheter has become synonymous with pulmonary artery catheter. This catheter is a very thin, multilumen flexible tube with a balloon located at its distal end. The balloon can be inflated through a separate channel inside the catheter. The catheter contains at least two additional internal channels: the distal channel, leading to an opening at the tip of the catheter, and the proximal channel, leading to an opening located several centimeters back from the tip. Pressures can be measured or blood can be withdrawn through these channels via the proximal and distal ports of the catheter (Figure 6-2).

Figure 6-2 Typical quadruple channel pulmonary artery catheter. After insertion, the distal lumen rests in the pulmonary artery, and the proximal lumen rests in the right atrium. Both communicate with their respective injection ports. (From Wilkins RL, Stoller JK, Kacmarek RM: *Egan’s fundamentals of respiratory care,* ed 9, St Louis, 2009, Mosby.)

A physician inserts the catheter under surgically sterile conditions, sometimes at the bedside of a critically ill patient in a hospital intensive care unit. Proximal and distal channels are first filled with sterile fluid to remove all air; the catheter is then inserted into a large systemic vein, usually the right internal jugular or subclavian vein, and advanced until the tip enters the right atrium. At this point the balloon is inflated, allowing the bloodstream to direct the catheter tip across the tricuspid valve into the right ventricle—hence, the term flow-directed, balloon-tipped catheter. The physician advances the catheter until the bloodstream carries it through the pulmonic valve and into the pulmonary artery (Figure 6-3). During insertion, pressures at the catheter tip are continuously recorded by an electronic pressure transducer connected to the distal port. The stationary fluid column inside the distal channel reflects these pressures precisely because it is in direct contact with the blood at the catheter’s tip. The pressure waveforms are continuously displayed on the bedside monitor as the catheter is advanced; this helps the physician identify the position of the catheter tip because each cardiovascular structure produces unique pressure waveforms (Figure 6-4, A and B).

Figure 6-3 Pulmonary artery catheter in place. The *dotted circle* represents the wedge position. The heart is in diastole in this schematic. (From Martin L: *Pulmonary physiology in clinical practice,* St Louis, 1987, Mosby.)

Figure 6-4 Correlation between pulmonary artery catheter positions (A) and pressure waveforms (B). *RA,* Right atrium; *RV,* right ventricle; *PA,* pulmonary artery; *PAWP,* pulmonary artery wedge pressure. (From Wilkins RL, Stoller JK, Kacmarek RM: *Egan’s fundamentals of respiratory care,* ed 9, St Louis, 2009, Mosby.)

When the catheter is advanced far enough to wedge in a small branch of the pulmonary artery, the inflated balloon completely blocks blood flow to the downstream vessels supplied by that artery (see Figure 6-3, dotted circle). The pressure measured from the catheter tip in this wedged position is called the pulmonary capillary wedge pressure (PCWP). (When the balloon is deflated, flow resumes, and the catheter tip simply measures the pulmonary artery pressure [PAP].) The vessels extending beyond the artery blocked by the inflated balloon are in direct communication with the pulmonary capillaries and the pulmonary veins. Pulmonary venous pressure is nearly equal to left atrial pressure (LAP), which is essentially equal to left ventricular end-diastolic pressure (LVEDP), the pressure inside the filled ventricle just before it contracts (see Figure 6-3). This so-called filling pressure is also known as preload of the left ventricle. The PCWP is only slightly greater than the filling pressure of the left ventricle.³ The PCWP accurately reflects changes in LAP (or ventricular filling pressure) because the stationary fluid column inside the catheter is functionally extended from the catheter tip to the left atrium. For this reason, the PCWP is commonly used to assess the pumping function of the left ventricle. For example, if the left ventricle fails to contract with normal force, blood flowing into it dams up in the left atrium, pulmonary veins, and capillaries; consequently, the PCWP increases. In certain rare circumstances, the PCWP might not accurately reflect left atrial pressure: (1) if the pulmonary veins constrict and downstream resistance beyond the catheter tip increases or (2) if the catheter tip is in an area in the lung where alveolar pressure exceeds pulmonary venous pressure, as might occur in positive pressure mechanical ventilation. In the latter instance, high alveolar pressure compresses capillaries distal to the catheter tip, blocking its communication with the left atrium.

CONCEPT QUESTION 6-2

Why would a narrowed (stenotic) mitral valve affect the PCWP? (See Figure 6-3.)

CLINICAL FOCUS 6-1 Causes of Pulmonary Artery Catheter Pressure Waveform Shapes

Proper positioning of the pulmonary artery catheter is confirmed by waveform patterns produced as the catheter is advanced into the pulmonary artery (see Figure 6-4). The first waveform appears on the monitor when the tip of the catheter reaches the great vessels. This is known as the central venous pressure (CVP) and reflects pressure in the vena cava and right atrium. A normal value for CVP is about 2 mm Hg; this produces the low-amplitude waveform in Figure 6-4, B. In the right atrium, the balloon is inflated for two reasons: (1) to decrease the risk of cardiac arrhythmias induced by the catheter tip hitting the ventricular walls and (2) to allow blood flow to catch the balloon and carry the catheter forward.

The catheter passes through the tricuspid valve into the right ventricle. The pressure waveform increases in height as the ventricle contracts (systole) and decreases sharply to near 0 as the ventricle relaxes (diastole) (see Figure 6-4, B). During diastole, the pressure waveform slowly rises as blood flows into the right ventricle through the tricuspid valve. Normal right ventricular pressure is about 25/0 mm Hg (systolic/diastolic).

The striking difference between pulmonary artery pressure (PAP) tracings and tracings created by the right ventricle is the diastolic pressure in the pulmonary artery. Closure of the pulmonic valve prevents PAP from decreasing as much as it does in the right ventricle (see Figure 6-4). The ejection of blood from the right ventricle creates a steep rise in the systolic portion of the curve. After systole, PAP decreases sharply until the pulmonic valve closes. Closure of this valve abruptly stops blood backflow, creating a shock wave responsible for the dicrotic notch on the downslope of the waveform. Normal PAPs are about 25/10 mm Hg.

As the catheter floats into a small branch of the pulmonary artery, the inflated balloon blocks blood flow. The pressure tracing is similar to right atrial waveforms but is of even lower amplitude; this is known as pulmonary capillary wedge pressure (PCWP). Normal PCWP is 4 to 12 mm Hg and is about the same as pressure in the left atrium. If pulmonary vascular resistance (PVR) is normal, the pulmonary artery diastolic pressure is about equal to the PCWP.

The pulmonary artery catheter also can be used to assess right ventricular preload and pumping function because the proximal channel (see Figure 6-2) communicates with the right atrium. The pressure measured at the catheter’s proximal port reflects right atrial pressure (RAP), sometimes called central venous pressure (CVP).

Blood drawn from the proximal channel is a mixture of superior and inferior vena cava venous blood. Because oxygen contents of these two sources may differ considerably, proximal channel blood is not a clinically acceptable mixed venous blood sample for purposes of measuring the average venous oxygen content of the body. A thoroughly mixed venous blood sample reflecting the true average venous oxygen content of the body must be obtained from the pulmonary artery, through the distal channel of the catheter (see Figure 6-2). By comparing the oxygen content of mixed venous blood with the oxygen content of systemic arterial blood, the oxygen consumption of the body can be assessed. (This is discussed in Chapters 8 and 12.)

By measuring and comparing pressures obtained from the pulmonary artery catheter (RAP, PAP, and PCWP), the

CLINICAL FOCUS 6-2 Differentiating Causes of High Pulmonary Artery Pressure

You have two patients with the following cardiac pressure values.

Patient A

Pulmonary artery (PA) systolic	38 mm Hg
PA diastolic	25 mm Hg
Pulmonary capillary wedge pressure (PCWP)	21 mm Hg

Patient B

PA systolic	40 mm Hg
PA diastolic	25 mm Hg
PCWP	10 mm Hg

Although both patients have elevated pulmonary artery pressures (PAPs), the reasons for this are quite different. The PCWP helps differentiate origins of high PAPs.

Discussion

In the following discussion, PCWP is used as a substitute for the left atrial pressure (LAP). PCWP (i.e., LAP) is elevated in Patient A and normal in Patient B. Pulmonary artery end-diastolic pressure (PAEDP) in Patient A is only 4 mm Hg higher than PCWP, whereas PAEDP in Patient B is 15 mm Hg higher than PCWP. In healthy people, the PAEDP is almost equal to the PCWP (PCWP = LAP) because pressures across the pulmonary capillary bed have enough time to equalize during diastole. High pulmonary vascular resistance (PVR) creates an increased PAEDP-PCWP difference because the resistance is located between the pulmonary artery and left atrium. In Patient B, PVR must be high, as shown by the high PAEDP-PCWP difference. The normal PCWP in Patient B suggests normal left ventricular pumping action. In Patient A, PVR must be normal because the difference between PAEDP and PCWP is small. The elevated PCWP (i.e., LAP) is transmitted back across the pulmonary capillaries, creating a proportionately high PAEDP, preserving the PAEDP-PCWP difference. Causes of increased PAP in Patient A may be left ventricular pumping failure or mitral valve narrowing. Causes of increased PVR in Patient B may be a pulmonary embolus or vasoconstriction induced by hypoxemia.

clinician can evaluate right and left ventricular function, differentiate the causes of increased PAP, and assess the risk of pulmonary edema. PAP might be increased because of excessive blood volume (hypervolemia) or because of left ventricular pumping failure in which blood dams up in the entire pulmonary circulation. The PAP might also be increased as a result of increased pulmonary vascular resistance (PVR). Increased pressures in either ventricle at the end of diastole, coupled with a low cardiac output, signal a loss of ventricular pumping ability, or a loss of contractility. Increased PCWP, regardless of the cause, means that the pulmonary capillaries are engorged with blood, increasing the likelihood that fluid will be forced into interstitial lung spaces and cause pulmonary edema. Understanding these relationships is essential for taking appropriate therapeutic actions.

Measurement of Pulmonary Blood Flow or Cardiac Output

The amount of blood the heart pumps each minute can be clinically measured with a pulmonary artery catheter via a thermodilution technique. In this method, a known volume of room temperature fluid (e.g., saline) is rapidly injected into the right atrium through the proximal injection port (see Figure 6-2). This volume of cool fluid rapidly flows into the right ventricle where it is pumped into the pulmonary artery. A temperature-sensing thermistor near the end of the catheter (see Figure 6-2) in the pulmonary artery records a sudden decrease in temperature as the bolus of cool saline passes by. If cardiac output is increased, blood temperature rapidly returns to its original value; if it is decreased, the temperature increases more slowly to the original value. A microprocessor receives information from the thermistor and computes the area under the temperature-time curve. The area under the curve is small for rapid blood flow and large for slow blood flow. The microprocessor uses the area under the curve and the volume of the injected fluid to compute the blood flow rate, or the cardiac output (Q˙t). Several determinations of cardiac output can be made within minutes in this fashion.

Pulmonary Vascular Resistance

PVR is measured in millimeters of mercury per liter per minute (mm Hg/[L/min]). PVR is the resistance that the vessels pose to blood flowing through the pulmonary circulation—it is the resistance against which the right ventricle pumps. Any factor that increases PVR increases right ventricular work. An increased PVR does not affect left ventricular work because this ventricle is situated on the downstream side of the pulmonary vessels.

Calculation of Pulmonary Vascular Resistance

PVR is calculated by dividing the mean pressure difference between beginning and ending points of the pulmonary circulation by the pulmonary blood flow. This is shown as follows:

PVR(mm Hg/[L/min])=meanPAP−LAPQ˙t

Clinically, values for calculating PVR are obtained from pulmonary artery catheter measurements. Cardiac output is obtained via the thermodilution technique, and PCWP is substituted for LAP. A microprocessor computes the mean PAP from the PAP waveform. The clinical equation is as follows:

PVR=mean PAP−PCWPQ˙t

For example, at a Q˙t of 5 L per minute, a mean PAP of 14 mm Hg, and a PCWP of 8 mm Hg, PVR is calculated as follows:

14mm Hg−8mm Hg5 L/min=1.2mm Hg/(L/min)

A pressure of 1.2 mm Hg is needed to produce a flow of 1 L per minute through the pulmonary circulation. In classic physics, pressure is measured in dynes per square centimeter (force per unit of area), and blood flow is measured in milliliters per second (cubic centimeters per second). Using these measurement units, PVR is calculated as follows:²

dynes/cm2cm3/sec=dynescm2×seccm3=dynes×seccm5=dynes•sec•cm−5

The resistance term dynes • sec • cm⁻⁵ is traditionally used in clinical hemodynamic measurements. To convert mm Hg/(L/min) to its equivalent units in dynes • sec • cm⁻⁵, one multiplies mm Hg/(L/min) by 80. Thus, the PVR of 1.2 mm Hg/(L/min) calculated previously is equivalent to 96 dynes • sec • cm⁻⁵.

The pressure difference between beginning and ending points of the systemic circulation is the difference between mean arterial pressure (MAP) and RAP (or CVP). Systemic vascular resistance (SVR) is calculated as follows (using values from Figure 6-1):

SVR=MAP−RAPQ˙tSVR=93∗−25=18.2mm Hg/(L/min)

^∗

A pressure gradient of 18.2 mm Hg is needed to drive 1 L per minute of blood through the systemic circulation (compared with 1.2 mm Hg in the pulmonary circulation). This pressure converts to about 1456 dynes • sec • cm⁻⁵. PVR is normally less than one tenth of SVR.¹ Thus, right ventricular work is about one tenth of left ventricular work, which explains why the left ventricular muscle mass is normally much greater than the right ventricular mass.

CONCEPT QUESTION 6-3

Which of the following does an increased PVR influence more: PAP or PCWP? Explain.

Distribution of Pulmonary Vascular Resistance

Figure 6-1 shows that the pressure decreases from the pulmonary arterioles to the pulmonary capillaries to the pulmonary veins are similar—that is, from 12 mm Hg to 10 mm Hg to 9 mm Hg as shown in the right lung of the diagram in Figure 6-1. This means the individual resistances of these three components are nearly equal; at rest, each accounts for about one third of the total PVR. In contrast to the more muscular systemic arterioles, pulmonary arterioles do not normally function to regulate and redistribute blood flow.⁴ In contrast to the pulmonary vasculature, systemic arterioles account for about two thirds of the total SVR.

Factors Affecting Pulmonary Vascular Resistance

Passive or active factors may change pulmonary vessel diameters and vascular resistance. Passive changes occur in response to pressure differences across vessel walls. Because pulmonary vessels are thin and distensible, they are especially susceptible to pressure-induced diameter changes. Active changes in the vessel diameter and resistance occur when vascular smooth muscle contracts or relaxes.

Passive Factors

Lung Volume: Effects on Alveolar and Extraalveolar Vessels

Pulmonary vessels can be classified into two groups: vessels in direct contact with alveoli, exposed to alveolar pressure (alveolar vessels), and vessels not in contact with alveoli, exposed to intrapleural pressure (extraalveolar vessels). Alveolar vessels are pulmonary capillaries in intimate contact with alveolar walls. The state of alveolar inflation determines the diameters of alveolar vessels. As the lung inflates, alveolar vessels are compressed, and their resistances increase (Figure 6-5, A and B).^1,3

Figure 6-5 Schematic drawing of alveolar and extraalveolar (corner) vessels during normal, quiet inspiration (A) and deep inspiration (B). High lung volumes (B) compress alveolar vessels and dilate extraalveolar vessels. A, Alveoli; P, pleural pressure. (Redrawn from Fishman AP: *Assessment of pulmonary function,* New York, 1980, McGraw-Hill.)

Extraalveolar vessels include all pulmonary arteries, arterioles, venules, and veins not in direct contact with alveoli. The lung’s elastic fibers have a tethering effect on these vessels (similar to their effect on small airways), stretching them to larger diameters as the lung inflates. In addition, during lung inflation, subatmospheric intrapleural pressure increasingly dilates these vessels, decreasing their resistance.1,3 Extraalveolar vessels also include certain capillaries between alveoli in corners formed by the junctions of adjacent alveoli (see Figure 6-5, A and B). As the lung inflates, these corner spaces enlarge, stretching and dilating the “corner vessels” (see Figure 6-5, B).

To visualize this phenomenon, think of a basket of small half-inflated balloons. Similar to the balloons, the spherical alveoli touch each other, but spaces exist between them. Extraalveolar corner vessels occupy these spaces. During inspiration, the balloons (alveoli) enlarge, increasing the amount of space between them. Alveolar recoil forces attempt to increase this space further. The pressure in these spaces decreases, dilating the corner vessels and reducing their resistance.

Because alveolar and extraalveolar vessel resistances are in series with each other, their effects are additive.¹ Thus, total PVR is the composite of alveolar and extraalveolar vessel resistances, creating a U-shaped curve (Figure 6-6). Overall, PVR is lowest at functional residual capacity (FRC). At volumes less than FRC, elastic retractile forces and subatmospheric intrapleural pressures are weak, allowing extraalveolar vessels to narrow, shorten, and kink. The resulting increase in extraalveolar vessel resistance predominates, increasing total PVR. At volumes greater than FRC, increased alveolar vessel resistance caused by capillary compression becomes the predominant factor, again increasing total PVR (see Figure 6-6).

Figure 6-6 Relative changes in alveolar vessel, extraalveolar vessel, and total pulmonary vascular resistance as the lung volume increases. *RV,* Residual volume; FRC, functional residual capacity; *TLC,* total lung capacity. (Redrawn from Murray JF: *The normal lung,* ed 2, Philadelphia, 1986, Saunders.)

Vascular Pressure: Recruitment and Distention

An increase in either PAP or LAP decreases PVR. One reason is that both PAP and LAP cause an increase in distending pressure across vessel walls (transmural pressure), which dilates them.1,4 This dilating effect is amplified if PAP and LAP increase together (Figure 6-7).^1,3 For example, consider an increasing LAP caused by inadequate left ventricular pumping action; the elevated LAP is reflected back throughout the pulmonary veins, capillaries, and arteries, dilating them and decreasing their vascular resistance.

Figure 6-7 Effects of pulmonary artery pressure changes on pulmonary vascular resistance. High left atrial pressure (*LAP*) exaggerates the effect. (From Berne RM, Levy MN: *Physiology, international edition,* ed 2, St Louis, 1988, Mosby.)

The second mechanism responsible for the decrease in PVR when vascular pressures increase is recruitment.1,4 Under normal resting conditions, some pulmonary capillaries in the upper regions of the lungs are completely collapsed.^1,4 As intravascular pressure increases, these collapsed capillaries are forced open (recruited), increasing the total cross-sectional area of the pulmonary capillary bed. As vascular pressures increase further, individual capillaries widen or distend, decreasing PVR even more. If vascular pressure increases from an initially low level, recruitment is the chief mechanism whereby PVR decreases; conversely, if vascular pressure increases further from an initially high level when all vessels are already open, distention is the main reason why PVR decreases.⁴ Recruitment and distention help explain why PAP changes little during exercise. As cardiac output increases, recruitment and distention dramatically decrease PVR, allowing PAP to increase only a few millimeters of mercury. The opposite effect is equally important; decreased cardiac output and vascular pressures cause derecruitment, or collapse, of pulmonary capillaries.

CONCEPT QUESTION 6-4

In what circumstance may a decreased cardiac output be associated with increased pulmonary vascular pressures and pulmonary capillary distention?

Blood Volume

Pulmonary blood volume is generally constant, but it may change under certain circumstances. For example, a sustained Valsalva maneuver (forced expiration against a closed glottis) can squeeze 250 mL of blood into the systemic circulation.³ Systemic blood loss can also decrease pulmonary blood volume. Left ventricular failure causes blood to dam up in pulmonary vessels, potentially increasing pulmonary blood volume by 100%.³ Regardless of the mechanism, increased blood volume distends and recruits capillaries, decreasing the PVR.

Active Factors

Neurogenic Stimuli

There is little evidence to suggest that neurogenic stimuli play a role in controlling pulmonary blood flow in healthy adults.1,4 Although sympathetic and parasympathetic nerves innervate the pulmonary vasculature (mostly larger arteries), their functional significance is marginally important and not well understood.¹ Some investigators have shown that sympathetic stimulation causes a slight increase in PVR, but others have shown only a stiffening of the arteries with no change in calculated resistance.⁴ Parasympathetic (vagal) stimulation causes a slight decrease in vascular resistance, but its physiological significance is unknown. Overall, the effects of autonomic stimulation on the pulmonary circulation are controversial and not well understood; autonomic stimulation produces only minor changes in the smooth muscle tone of vessels in the adult lung.¹

Humoral Agents and Nitric Oxide

The most important substance that regulates pulmonary vascular tone is nitric oxide (NO), derived from the endothelial cells lining the blood vessels.⁵ Naturally occurring (endogenous) humoral substances in the body produce vasodilation by stimulating the production of NO, previously called endothelium-derived relaxing factor (EDRF). Endogenous substances include acetylcholine, bradykinin, histamine, thrombin, serotonin, adenosine diphosphate (ADP), and some prostaglandins.⁶ In 1987, Furchgott⁶ noted that acetylcholine did not cause smooth muscle relaxation in vessels stripped of their endothelium; he postulated that endothelial cells produce a smooth muscle relaxing factor. Palmer et al.⁷ and Ignarro et al.⁸ later identified EDRF as NO. The 1998 Nobel Prize in physiology or medicine was awarded to Furchgott, Ignarro, and Murad for their discovery of the role of NO in the human body.⁹

Nitric oxide is a potent vasodilator in the human circulation, and it plays an important role in regulating pulmonary vascular smooth muscle tone.⁵ The endogenous substances previously listed are considered to be endothelial-dependent vasodilators because they depend on the endothelial release of NO for their effects. The elaboration of NO accounts for the vasodilating mechanism of nitrate drugs such as nitroglycerin (used to improve coronary blood flow) and nitroprusside (used to treat dangerously high blood pressure).¹⁰

NO is produced in vascular endothelial cells (Figure 6-8) by oxidation of an amino acid, l-arginine, catalyzed by an enzyme, nitric oxide synthase (NOS).^11–13 As stated in Chapter 1, there are three forms of NOS: neuronal NOS (nNOS), which is constituted in nonadrenergic noncholinergic neurons (a form of constitutive NOS [cNOS]); inducible NOS (iNOS), which is induced in airway epithelial cells by inflammation; and endothelial NOS (eNOS), another constitutive form of NOS that is generated in vascular endothelial cells (referred to as cNOS in Figure 6-8).^5,13 Production of eNOS is controlled by endothelial cell surface receptors that are stimulated by the various humoral substances previously listed. Besides these substances, mechanical factors such as stretching and shear stress stimulate cell surface receptors.¹¹ Whether the stress is humoral or mechanical, receptor stimulation activates eNOS but only in the presence of calcium ions (Ca⁺⁺). Calcium-activated cNOS catalyzes the oxidation of l-arginine, producing small bursts of NO.

Figure 6-8 Endothelial production of nitric oxide (NO) in the pulmonary arteriole. Various stimuli may activate endothelial surface receptors, initiating a chain of biochemical events that produce NO and subsequent vascular smooth muscle relaxation. *ADP,* Adenosine diphosphate; *cNOS,* constitutive nitric oxide synthase; *cGMP,* cyclic guanosine monophosphate.

NO is highly soluble in cell membranes and diffuses instantly into vascular smooth muscle cells. In vascular smooth muscle cells, NO activates another enzyme, guanylate cyclase, which catalyzes the production of cyclic guanosine monophosphate (cGMP), as shown in Figure 6-8. cGMP causes vascular smooth muscle relaxation. Physical exercise induces cNOS production, presumably by increasing vascular pressure, and may be a factor, along with recruitment and distention, in preventing significant increases in PVR during exercise.¹¹

CONCEPT QUESTION 6-5

Predict the physiological effect of a drug that inhibits the action of NOS.

Endothelial cells synthesize NO in small amounts on demand, exerting a regulatory vasodilating influence on pulmonary arterioles under normal resting conditions.11,12 A calcium-independent form of NOS (inducible NOS [iNOS]) can be induced in endothelial and inflammatory cells by endotoxins associated with bacterial blood infections (septicemia) and by various other inflammatory mediators in the body.⁵ In contrast to eNOS, which is released in small pulses as needed, iNOS is always “turned on,” releasing large, continuous amounts of NO not controlled by cell receptor–dependent mechanisms. Excessive induced NO production is linked to the massive vasodilation and hypotension of septic shock syndrome.^14,15 Sepsis-induced vasodilation does not respond well to vasoconstrictor drugs. If an effective iNOS-inhibiting drug could be given to patients with septic shock, it would seem that the vasodilation and associated hypotension might be reversed, increasing the blood pressure.

This hypothesis was studied in a large multicenter clinical trial in which humans with septic shock were given a drug known to inhibit NOS activity. The NOS inhibitor reduced blood nitrate levels, increased pulmonary and systemic vascular tone, maintained systemic blood pressure in an acceptable range, and reduced the need for conventional vasoconstrictor drugs, such as norepinephrine.¹⁴ However, overall patient outcome was not improved. Although general inhibition of NOS is not ultimately beneficial in septic shock, selective inhibition of the inducible form (iNOS) was found to be more beneficial than norepinephrine in an animal study.¹⁶

Inhaled NO gas in extremely low concentrations has been used therapeutically to treat severe pulmonary hypertension and to selectively dilate pulmonary vessels in well-ventilated regions of the lungs. In the latter instance, inhaled NO of necessity enters the best-ventilated lung areas, selectively lowering vascular resistance in those regions. Because blood flow follows the path of least resistance, it is diverted from poorly ventilated to well-ventilated areas. NO inhalation has been especially beneficial in treating infants with persistent pulmonary hypertension of the newborn (PPHN) (see Chapter 16).

Chemical Factors

The most important chemical factor causing pulmonary vasoconstriction is low alveolar oxygen pressure (P_AO₂)—that is, alveolar hypoxia. A P_AO₂ of less than 70 mm Hg usually elicits this effect, known as hypoxic pulmonary vasoconstriction (HPV).¹ HPV is brought about by alveolar hypoxia, as opposed to arterial or mixed venous hypoxemia. The elements of the vasculature that constrict are predominantly the small precapillary arterioles; small pulmonary veins also constrict to some extent but produce only 20% or less of the HPV-induced increase in PVR.¹⁷ This constrictive venous response might explain the acute pulmonary edema sometimes seen in individuals who travel to high altitudes in the mountains where atmospheric oxygen pressure is low; hypoxia-induced venous constriction could increase pulmonary capillary pressure, which is a feature of high-altitude pulmonary edema.¹⁷

The constrictive response to hypoxia is unique to the pulmonary circulation; hypoxia evokes vasodilation in the systemic circulation. High P_AO₂ (hyperoxia) has little effect on normal pulmonary circulation, probably because pulmonary vessels in normal lungs have little muscle tone, and their vasodilating ability is minimal.¹⁸ However, in hypoxic individuals, improved oxygenation markedly dilates pulmonary vessels and dramatically decreases PVR.

HPV is enhanced by low arterial blood pH (acidemia); HPV becomes progressively greater for a given P_AO₂ as pH decreases. At a normal arterial pH of 7.40, the maximal vasoconstrictive response occurs at a P_AO₂ of 60 to 70 mm Hg ¹⁸; this corresponds with a PaO₂ of about 50 to 60 mm Hg when the normal alveolar-to-arterial PO₂ gradient is taken into account. A classic animal experiment showed that at arterial pH less than 7.30, a PaO₂ less than 50 mm Hg causes a sudden, sharp increase in PVR (Figure 6-9).¹⁹ At a normal PaO₂, arterial pH must decrease to less than 7.25 to cause a significant increase in PVR.¹⁸ High PaCO₂ increases PVR indirectly by generating carbonic acid, which causes acidemia. HPV is also enhanced by NOS-inhibiting agents, suggesting that reduced endothelial NO release may be an underlying mechanism in HPV.¹⁷

Figure 6-9 Effects of low arterial pH and hypoxemia on pulmonary vascular resistance (*PVR*) in newborn calves. The greater the acidemia, the greater the vascular resistance at any PO₂ value. Note the abrupt increase in PVR at PO₂ less than 50 mm Hg, especially at pH less than 7.40. (Redrawn from Rudolph AM, Yaun S: *J Clin Invest* 45[3]:407, 1966.)

HPV is inhibited by various mediators present in the blood that cause vasodilation, such as the endothelial-derived substances NO and prostacyclin.¹⁷ HPV is also inhibited by drugs that block alpha-adrenergic or stimulate beta-adrenergic receptors. In addition, it is inhibited by increased LAP (a vascular distending effect), high alveolar pressure, and high blood pH (alkalemia).¹⁷

Physiological Function of Hypoxic Pulmonary Vasoconstriction

The physiological function of HPV is to match blood flow with ventilation better (i.e., to divert pulmonary arterial blood away from poorly ventilated, hypoxic regions to the better ventilated areas. If HPV or a similar mechanism did not exist, pulmonary arterial blood would remain poorly oxygenated as it flows unchecked past underventilated alveoli. This blood would mix with and decrease the PO₂ of blood leaving well-ventilated alveoli, causing systemic arterial hypoxia. Thus, HPV has a beneficial effect, even though it increases the PVR. If the entire lung is uniformly hypoxic (e.g., at high altitudes), HPV is widespread throughout the lung, increasing vascular resistance and pressures. HPV still may be physiologically helpful because elevated pressures recruit previously nonperfused pulmonary capillaries, increasing the surface area for gas exchange.

CONCEPT QUESTION 6-6

Scintiphotography, a special imaging technique, allows ventilation or blood flow distribution to be seen in the lungs (ventilation or perfusion scans). Why does regional alveolar hypoxia caused by mucous plugging produce a perfusion scan similar to one produced by a pulmonary embolus that blocks blood pulmonary flow, and how might one distinguish between these two conditions?

Mechanism of Hypoxic Pulmonary Vasoconstriction

The exact mechanism of HPV is poorly understood.¹ The response is localized, occurring only in areas of alveolar hypoxia. HPV does not depend on nervous or humoral control because it occurs in surgically removed, mechanically perfused lungs ventilated with hypoxic gas mixtures¹⁷; this explains why HPV occurs even in patients who receive heart-lung transplants.

CLINICAL FOCUS 6-3 Chronic Hypoxia and Right Ventricular Failure

You are called to assess a patient admitted with chronic obstructive pulmonary disease (COPD). A physician has just examined the patient and tells you that physical findings include obvious pulmonary disease, distended neck veins, ankle edema, and hepatomegaly (enlarged liver). Arterial blood gas values indicate chronic hypoxia, and the chest radiograph shows hyperinflation of the lungs with right ventricular enlargement (hypertrophy). The admitting diagnosis is COPD with right ventricular hypertrophy. What is the relationship between this patient’s lung disease and cardiac function?

Discussion

Chronic hypoxia characterizes COPD. COPD is often associated with anatomical destruction of alveoli and associated capillaries, decreasing the functional surface area for gas exchange. The resulting hypoxia induces pulmonary vasoconstriction, increasing pulmonary artery pressure (PAP). The destruction of the alveolar-capillary membrane area contributes further to increased PAP by reducing the cross-sectional area of the pulmonary vasculature. High PAP poses an increased opposition to blood flow coming from the right ventricle. The muscle mass of the right ventricle increases in response to the increased workload, but it may ultimately fail to pump blood effectively into the high-resistance pulmonary vascular system. A failing right ventricle causes blood to back up into the right atrium, vena cava, jugular veins, liver, and veins in the legs and ankles; this accounts for liver enlargement (hepatomegaly) and ankle edema (pedal edema). Right heart failure induced by pulmonary disease is called cor pulmonale. This condition often improves with continuous oxygen therapy, which relieves hypoxic vasoconstriction and decreases pulmonary vascular resistance.

Animal and human studies strongly suggest that lack of normal NO release by the endothelium plays a role in the HPV mechanism. Decreased PO₂ in vascular endothelial cells diminishes NO synthesis, suggesting that reduced NO formation is a mechanism underlying HPV.1, 20 HPV is abolished by breathing NO gas mixtures or by drugs that stimulate endothelial NO production.^{1, 20} Conversely, blocking NO synthesis enhances HPV, which means that NO must have a regulating effect on HPV, holding its severity in check.¹⁷ Even in persons without hypoxia, drugs inhibiting NO synthesis induce pulmonary vasoconstriction, confirming that the normally oxygenated pulmonary vasculature is in a continuous state of NO-mediated dilation.²⁰

Whatever the cause of HPV, Ca⁺⁺ entry into the vascular smooth muscle cell must be involved to cause muscle contraction.¹ A mechanism has been proposed whereby hypoxia directly affects vascular smooth muscle; it has been shown that hypoxia depolarizes smooth muscle cell membranes, probably by inhibiting potassium ion (K⁺) channels, which is accompanied by the opening of Ca⁺⁺ channels and Ca⁺⁺ entry into the cell.^1,17 Ca⁺⁺ are essential in the smooth muscle contraction process. Consistent with this proposed mechanism is the fact that Ca⁺⁺ channel blocking drugs inhibit HPV, whereas Ca⁺⁺ agonists enhance it.¹

Loss of Hypoxic Pulmonary Vasoconstriction

The HPV response is often diminished in patients with acute lung injuries, such as burn and smoke inhalation, sepsis, and acute respiratory distress syndrome (ARDS).13,14,17,21,22 This diminished response may account for the severe systemic hypoxemia these diseases cause. Acute lung injury causes the release of inflammatory mediators that induce formation of iNOS and subsequent NO release; this prevents the normal vasoconstrictive response of vessels in hypoxic lung regions. When the HPV response is lost, poorly oxygenated mixed venous blood flows unchecked through underventilated and nonventilated lung regions, creating severe shunting and systemic arterial hypoxemia. This type of intrapulmonary shunting responds poorly to oxygen inhalation because the supplemental oxygen cannot enter nonventilated alveoli.

Inflammatory mediators are also released in response to overinflation of the alveoli, which has implications for patients who are dependent on mechanical ventilatory assistance. Patients with acute lung injuries often require positive pressure mechanical ventilation. High pressures during mechanical ventilation can overstretch and injure the alveoli. This type of stretch injury is known to release inflammatory cytokines that induce iNOS and subsequent NO release, which counteracts HPV.23–25

A purely mechanical explanation for why acute lung injury might diminish the effect of HPV also has been proposed.²¹ Injury to the alveolar-capillary membrane increases its permeability, allowing fluid to enter the alveolus and deactivate surfactant. The resulting high surface tension causes alveoli to shrink and collapse. Animal studies using an in vivo microscope revealed that as alveoli shrink, they place a tethering force on the extraalveolar vessels, causing them to dilate. In this way, portions of the pulmonary vasculature are mechanically dilated in injured, poorly ventilated lung regions, possibly negating or minimizing the effects HPV might have.²¹

Inhaled Vasodilators in Acute Respiratory Distress Syndrome

Despite the reduction of the effectiveness of HPV in acute lung injury, the overall PVR is nevertheless often elevated in ARDS.¹⁷ For this reason, inhaled NO and other pulmonary vasodilators have been used clinically to decrease PVR. Besides decreasing PVR, an added benefit of inhaled vasodilators (as a gas or an aerosol mist) is that they selectively dilate pulmonary vessels only in well-ventilated lung regions, diverting mixed venous blood to these areas. The effect is to match blood flow with ventilation better, reducing intrapulmonary shunt and improving arterial oxygenation—in effect, enhancing the benefits of HPV. Selective dilation occurs because inhaled vasodilators can enter only ventilated portions of the lung.

Alternatives to inhaled NO have been sought because of the complex technology associated with NO administration, high NO costs, potential NO toxicity, and the failure of NO to decrease overall mortality in patients with ARDS.²⁶ Some of these alternative vasodilators, which are inhaled as aerosols,

CLINICAL FOCUS 6-4 Different Therapy for Different Causes of Increased Pulmonary Artery Pressure

Increased pulmonary artery pressures (PAPs) occur for different reasons. What are the different reasons, and how does therapy differ?

Discussion

When PAP is elevated as a result of high pulmonary vascular resistance (PVR), therapy is aimed at reducing the PVR. For example, if hypoxic pulmonary vasoconstriction (HPV) in chronic hypoxemia causes high PVR and right ventricular strain, continuous oxygen therapy might be appropriate. Oxygen therapy relieves the hypoxia, removing the stimulus for pulmonary vasoconstriction.

An elevated PAP caused by left heart failure (i.e., loss of left ventricular pumping action) may be treated with inotropic drugs, which increase the heart’s contractility and pumping effectiveness. Diuretics decrease the blood volume by enhancing urine production and reducing venous return to the heart. Vasodilators decrease the resistance against which the left ventricle must pump, allowing it to pump blood more effectively.

Understanding the origins of elevated PAP is important because treatment approaches are completely different for different circumstances.

include prostacyclin (PGI₂), sildenafil (Viagra), nitroprusside, and nitroglycerin.^26–28 Similar to NO, prostacyclin is synthesized in the pulmonary vascular endothelial cells; it exerts its effects by activating specialized endothelial receptors. Sildenafil exerts its effects by inhibiting phosphodiesterase, an enzyme that deactivates cyclic adenosine monophosphate (cAMP); cAMP is the intracellular substance responsible for smooth muscle relaxation. Nitroprusside and nitroglycerin induce the enzymatic release of NO. All of these NO alternatives reduce both pulmonary and systemic blood pressures if given intravenously or orally. Intravenous or oral administration of these agents not only could dangerously lower the systemic blood pressure but also indiscriminately dilate all pulmonary vessels; this would hinder HPV and worsen intrapulmonary shunt and hypoxemia. However, when administered by inhalation, these vasodilators affect only the pulmonary circulation and only in well-ventilated lung regions; this tends to preserve HPV in poorly ventilated areas.²⁶

Distribution of Pulmonary Blood Flow

Gravitational and Pressure Effects: Zones of Blood Flow

Because pressures in the thin, distensible pulmonary blood vessels are low, gravity and pressures surrounding the vessels greatly affect blood flow distribution in the lung. The effects of gravity create three distinct zones of blood flow, as described in the classic model by West ⁴ (shown in Figure 6-10). Blood enters the lung at the hilum through the pulmonary artery. The same average PAP of about 15 mm Hg is applied to arterial vessels in all zones. Arteries in zone III (lung base) are about 12 cm below the hilum. Thus, the weight of a column of blood 12 cm high is added to the pressure in zone III vessels. A column of blood 12 cm high exerts a pressure of about 9 mm Hg, causing arterial pressure in zone III to be 9 mm Hg higher than arterial pressure in zone II (see Figure 6-10). Blood flows down into zone III with the aid of gravity.

Figure 6-10 Gravitational effects create three zones of blood flow patterns in the pulmonary circulation. Zone I has no flow, zone II has intermittent flow, and zone III has continuous flow. (From Berne RM, Levy MN: *Principles of physiology,* ed 2, St Louis, 1996, Mosby.)

In contrast, blood is pumped up into zone I (lung apex) against gravitational forces. Zone I arteries are about 12 cm above the main pulmonary artery, causing the arterial pressures to be 9 mm Hg less than the arterial pressure in the main pulmonary artery. Figure 6-10 shows an upright lung (i.e., the person is standing). If the person is supine, zones I to III are redistributed from anterior to posterior lung regions, rather than from the lung apex to the lung base.⁴

Zone I Blood Flow

To illustrate zone I conditions, which are not normally present in spontaneously breathing individuals, the lung model in Figure 6-10 is receiving positive pressure mechanical ventilation such that the average alveolar pressure is about 8 mm Hg in all alveoli. In the lung apex or zone I, gravitational effects cause both arterial and venous pressures to be lower than alveolar pressure. Consequently, alveolar pressure compresses the surrounding capillaries, totally occluding them and stopping blood flow. Only extraalveolar corner vessels may still have some blood flow in this zone. In zone I, alveoli are ventilated but have no blood flow, which constitutes alveolar dead space ventilation. In spontaneously breathing healthy individuals with normal cardiac outputs and blood pressures, arterial pressures always exceed alveolar pressures, even in the uppermost apical lung regions, and zone I does not exist. However, a severe decrease in blood pressure can lower PAP so much that zone I conditions are created in the lung.

Zone II Blood Flow

Figure 6-10 shows that arterial pressure in zone II considerably exceeds alveolar pressure, but alveolar pressure still exceeds venous pressure; this produces intermittent flow through alveolar capillaries. Blood flows into a capillary at its arterial end because its pressure exceeds the surrounding alveolar pressure. As blood flows down the length of the capillary, approaching the venous end, capillary pressure progressively decreases until it falls below alveolar pressure. At this point, alveolar pressure collapses the capillary, stopping blood flow. (This is similar to the situation described in Chapter 3 in which forced expiration causes dynamic airway compression after an equal pressure point is formed.) The pressure of the stationary column of blood in the capillary quickly equalizes with its source, the arterial pressure, which is greater than alveolar pressure. This action momentarily forces the capillary open, allowing blood flow to resume. As blood flows through the opened capillary, pressure again decreases down its length, falling below alveolar pressure, recollapsing the capillary near its venous end. The cycle repeats, causing capillaries to flutter rapidly between open and closed states, producing intermittent flow.

The pressure gradient for blood flow in zone II is the difference between arterial and alveolar pressure, not arterial and venous pressure (as it is for most other vessels). As long as venous pressure is below alveolar pressure, pulmonary veins are blocked, and venous pressures cannot influence flow. This zone

CLINICAL FOCUS 6-5 Most Likely Location of the Pulmonary Artery Catheter Tip: Zone I, II, or III?

Blood flow must be continuous between the tip of the Swan-Ganz catheter and left atrium to reflect left heart pressure accurately. Uninterrupted blood flow is found only in zone III of the lung, where arterial and venous pressures exceed alveolar pressures. Because the Swan-Ganz catheter is flow directed (i.e., carried into place via continuous blood flow), it is most likely to migrate into zone III. Pulmonary capillary wedge pressure (PCWP) measured when the Swan-Ganz catheter is located in zone I or II does not accurately reflect left atrial pressure (LAP) because alveolar pressure momentarily or continuously stops blood flow in these zones. PCWP measured from zone I or II reflects alveolar pressures instead of LAPs.

II flow characteristic is sometimes called the waterfall effect. In this analogy, the rate of flow over the waterfall’s edge is proportional to the pressure difference between a point upstream (arterial pressure) and a point at the waterfall’s edge (alveolar pressure). Neither the pressure in the stream below the waterfall’s edge (venous pressure) nor the height of the waterfall influences the rate of flow over the edge.

Zone III Blood Flow

The arterial and venous pressures exceed alveolar pressure in zone III because of the effects of gravity. Blood flow is continuous and proportional to the difference between arterial and venous pressures. As long as alveolar pressure is below vascular pressures, it cannot influence blood flow. Gravity causes zone III, the lung bases in the upright person, to have the greatest blood flow.

Factors Affecting Zones of Blood Flow

Blood flow zones are not fixed, anatomical boundaries; rather, they are dependent on physiological conditions. Certain respiratory maneuvers, such as exhaling against a closed glottis, blowing through a wind instrument, or coughing, can momentarily increase alveolar pressures above arterial pressure, creating zone I conditions in gravity-independent (uppermost) lung regions. Positive-pressure mechanical ventilation may increase alveolar pressure enough to convert some zone II regions to zone I. This is one mechanism whereby positive pressure ventilation increases alveolar dead space. Likewise, a loss of blood volume or massive vasodilation, as in septic shock, may decrease PAP enough to create zone I conditions. Conversely, exercise increases cardiac output and PAP, recruiting any zone I to zone II or zone II to zone III. The lung volume also affects regional distribution of blood flow, as implied in the earlier discussion regarding the effect of lung volume on PVR (see Figure 6-7). At total lung capacity when alveoli are maximally expanded, apical regions are more likely to produce zone I conditions.

Normal Matching of Ventilation and Blood Flow

As discussed in Chapter 3, tidal inspiration is preferentially distributed to basal alveoli. This distribution occurs because at FRC, the beginning point for a tidal inspiration, apical alveoli are more distended and less compliant than basal alveoli. Although apical alveoli contain more volume at FRC, their decreased compliance allows less volume change per breath and less ventilation per minute. Similar to blood flow, ventilation is least in the lung apex and greatest in the lung base. However, the decrease in blood flow from base to apex is greater than the corresponding decrease in ventilation, which means that the lung apex has relatively more ventilation than blood flow. Likewise, the lung base has relatively more blood flow than ventilation. As a result, the ventilation-perfusion ratio (V˙/Q˙) increases from the lung base to the lung apex (Figure 6-11).

Figure 6-11 Changes in blood flow, ventilation, and V˙/Q˙ ratio in the upright lung. From the lung base to the lung apex, blood flow decreases more rapidly than ventilation. Consequently, the V˙/Q˙ ratio increases from the lung base to the lung apex. (Modified from West JB: *Ventilation, blood flow and gas exchange,* Oxford, 1965, Blackwell Science; and Martin L: *Pulmonary physiology in clinical practice,* St Louis, 1987, Mosby.)

Dead Space and Shunt Effects in the Normal Lung

Shunt refers to deoxygenated blood flowing through the capillaries of unventilated alveoli; dead space refers to the ventilation of alveoli that have no capillary blood flow. Between these two extremes are shuntlike and dead space–like effects, corresponding with low and high V˙/Q˙ ratios. Because the lung apices have relatively more ventilation than blood flow (high V˙/Q˙), a dead space–like effect is produced. Likewise, because lung bases have relatively less ventilation with respect to blood flow (low V˙/Q˙), a shuntlike effect is produced. The overall average V˙/Q˙ ratio in the normal resting lung is about 0.8, which means ventilation on average is slightly less than blood flow (Figure 6-12). During exercise, the tremendous increase in ventilation causes the V˙/Q˙ ratio to increase. (Ventilation-perfusion relationships and their effects on blood gases are discussed in Chapter 12.)

Figure 6-12 Normal human V˙/Q˙ curves. Overall average V˙/Q˙ for the lung is slightly greater than 0.8, as shown by the *thin vertical line*. On average, blood flow slightly exceeds ventilation. (From Berne RM, Levy MN: *Physiology,* ed 3, St Louis, 1993, Mosby.)

Liquid Movement Across the Alveolar Capillary Membrane

Capillary Fluid Dynamics

Figure 6-13 illustrates hydrostatic and osmotic forces governing fluid movement across pulmonary capillary walls. The pulmonary capillary acts as a semipermeable membrane, freely permeable to water molecules but much less permeable to larger molecules. The capillary endothelial membrane is relatively impermeable to large high-molecular-weight proteins, although the membrane’s leakiness allows some proteins to enter the interstitial space. Large protein molecules create osmotic pressure in solution. The influence of proteins on the osmotic pressure of blood plasma is called oncotic pressure. The greater the protein concentration in blood plasma, the greater the oncotic pressure. One can think of oncotic pressure as a force that “pulls” water molecules from areas of low oncotic pressure into areas of high oncotic pressure. This is the opposite of hydrostatic pressure, a force that “pushes” fluid from high to low pressures.

Figure 6-13 Fluid movement in pulmonary capillaries. Lymphatic vessels normally prevent fluid accumulation in the interstitium. *Outward force* and *inward force* refer to forces moving fluid out of or into the pulmonary capillary. *HP,* Hydrostatic pressure; *OP,* oncotic pressure. (Modified from Guyton AC: *Textbook of medical physiology,* ed 8, Philadelphia, 1991, Saunders.)

As shown in Figure 6-13, pulmonary capillary hydrostatic blood pressure is about 7 mm Hg, and interstitial hydrostatic fluid pressure is about 8 mm Hg. Interstitial fluid pressure is “negative” because inward alveolar recoil and lymphatic removal of fluid from this area create subatmospheric pressure. The combined effect of interstitial and capillary hydrostatic pressures is a force of 15 mm Hg, which tends to move fluid out of the capillary. Adding to this force is an interstitial oncotic pressure of about 14 mm Hg, which tends to pull fluid out of the capillary into the interstitial space. Hydrostatic and oncotic forces combine for a total of 29 mm Hg, favoring fluid movement out of the capillary into the interstitial space. The only force that moves fluid into the capillary is the blood’s oncotic pressure of about 28 mm Hg. The total force favoring fluid movement out of the capillary is 29 mm Hg, whereas the total force favoring inward movement is 28 mm Hg. This yields a net mean filtration pressure of 1 mm Hg.³

The following Starling equation describes fluid movement across the capillary endothelium:⁴

Q˙f=Kf[(Pc−Pis)−α(πpl−πis)]

In this equation, Q˙f represents the net flow of fluid (mL/min) out of the capillary; K_f represents the capillary filtration coefficient, describing capillary fluid permeability characteristics; P_c represents capillary hydrostatic pressure; P_is represents interstitial hydrostatic pressure; σ represents the reflection coefficient, describing how easily the capillary endothelium prevents passage of solute particles (when σ equals 1.0, the membrane is impermeable to solutes); π_pl represents plasma oncotic pressure; and π_is represents interstitial fluid oncotic pressure.

This filtration pressure causes a slight amount of fluid to flow continuously from capillaries into interstitial spaces. The lymphatic system, a natural sump for draining interstitial fluid, immediately removes this fluid. Lymphatic action is extremely important for preventing fluid leakage into alveoli; the alveolar epithelium is so thin and weak that positive interstitial pressure can rupture it, allowing fluid to flow into alveoli.³

CLINICAL FOCUS 6-6 Correlation of Pulmonary Capillary Wedge Pressure with Hydrostatic Pulmonary Edema

Hydrostatic pulmonary edema is also known as cardiogenic pulmonary edema (i.e., arising from left heart failure). The inefficient left ventricle causes blood to back up in the pulmonary circulation, increasing hydrostatic pressure in the pulmonary capillaries, increasing the pulmonary capillary wedge pressure (PCWP). High capillary pressure forces fluid into the interstitium and alveoli. Differentiating between cardiogenic and noncardiogenic pulmonary edema may be difficult because the clinical presentation is similar in both. Clinical signs and symptoms of pulmonary edema (cardiogenic and noncardiogenic) include dyspnea, wheezing, fine crackling breath sounds, and hypoxemia. In cardiogenic pulmonary edema, the PCWP is usually greater than 20 mm Hg. In contrast, PCWP is usually normal in noncardiogenic pulmonary edema. The cause of pulmonary edema in this situation is often hyperpermeability, or leakiness, of the alveolar capillary membrane. A general correlation between PCWP and clinical evidence of pulmonary edema with normal capillary permeability follows.

PCWP (mm Hg)	Clinical Evidence of Hydrostatic Pulmonary Edema
16-18	No physical or x-ray findings evident
18-25	Some x-ray evidence of pulmonary edema (engorged pulmonary vessels and appearance of infiltrates); physical findings evident, including some fine crackling breath sounds
>25	Obvious x-ray evidence of pulmonary edema (greatly increased infiltrates and vascular engorgement); physical findings (clinically significant hypoxemia, tachypnea, respiratory distress, diffuse crackles, and wheezing breath sounds)

hydrostatic blood pressure, such as mitral valve stenosis. In chronic conditions, capillary pressures may reach 35 to 45 mm Hg without causing significant pulmonary edema, whereas an acute capillary pressure increase to 20 mm Hg normally causes significant edema.³ Table 6-1 summarizes the mechanisms causing pulmonary edema.

TABLE 6-1

Mechanisms of Pulmonary Edema

Factor	Value	Type	Clinical Problem
Hydrostatic pressure	Increased	Cardiac	Left ventricular failure
			Fluid overload
			Mitral stenosis
Capillary permeability	Increased	Noncardiac	SepsisOxygen toxicityAcute lung injury
Oncotic pressure	Decreased	Noncardiac	Protein starvation
			Hemodilution
			Renal loss of proteins
Lymphatic drainage	Decreased	Noncardiac	Pulmonary interstitial fibrosis