Physiology of the Airway

Distribution of Pulmonary Perfusion

Contraction of the right ventricle imparts kinetic energy manifested as the ejection of blood into the main pulmonary artery, with subsequent flow into the right and left pulmonary arteries and the subsequent branches. As this energy is dissipated in climbing a vertical hydrostatic gradient, the absolute pressure in the pulmonary artery (Ppa) decreases by 1 cm H ₂ O per centimeter of vertical distance up the lung ( Fig. 5.1 ). At some height above the heart, Ppa becomes zero (i.e., equal to atmospheric pressure), and still higher in the lung Ppa becomes relatively negative (lower than atmospheric pressure). In this region the alveolar pressure (P a ) exceeds Ppa and pulmonary venous pressure (Ppv), which is relatively negative at this vertical height. Because the pressure outside the vessels is greater than the pressure inside, the vessels in this region of the lung are collapsed, and no blood flow occurs; this has been described by John West as zone 1 (P a > Ppa > Ppv). Because there is no blood flow through zone 1 capillaries, gas exchange does not occur, and the region functions as alveolar dead space, or wasted ventilation. Little or no zone 1 exists in the lung under normal conditions, but the amount of zone 1 lung can be greatly increased if Ppa is reduced, as in hypovolemic shock, or if P a is increased, as in the application of excessively large tidal volumes (V t ) or levels of positive end-expiratory pressure (PEEP) during positive-pressure ventilation.

Further down the lung, absolute Ppa becomes positive, and blood flow begins when Ppa exceeds P a ( zone 2 , Ppa > P a > Ppv). At this vertical level in the lung, P a exceeds Ppv, and blood flow is determined by the mean Ppa − P a difference rather than by the more conventional Ppa − Ppv difference (see later discussion). In zone 2, the relationship between blood flow and alveolar pressure has physical characteristics similar to a waterfall flowing over a dam. The height of the upstream river (before reaching the dam) is equivalent to Ppa, and the height of the dam is equivalent to P a . The rate of water flow over the dam is proportional to only the difference between the height of the upstream river and the dam (Ppa − P a ), and it does not matter how far below the dam the downstream riverbed (Ppv) is. This phenomenon has various names, including the waterfall, Starling resistor, weir (dam made by beavers), and sluice effect. Because mean Ppa increases down this region of the lung, but mean P a is relatively constant, the mean driving pressure (Ppa − P a ) increases linearly; therefore, mean blood flow increases linearly as one descends down this portion of the lung. Respiration and pulmonary blood flow, however, are cyclic phenomena. Therefore, absolute instantaneous Ppa, Ppv, and P a are changing continuously, and the relationships among Ppa, Ppv, and P a are dynamically determined by the phase lags between the cardiac and respiratory cycles. Consequently, a specific point in zone 2 may actually be in either a zone 1 or a zone 3 condition at a given moment, depending on where the patient is in respect to respiratory systole and diastole, as well as cardiac systole and diastole.

Still lower in the lung is a vertical level at which Ppv becomes positive and also exceeds P a . In this region, blood flow is governed by the pulmonary arteriovenous pressure difference, Ppa − Ppv ( zone 3 , Ppa > Ppv > P a ), for here both of these vascular pressures exceed P a , and the capillary systems are thus permanently open and blood flow is continuous. In descending zone 3, gravity causes both absolute Ppa and Ppv to increase at the same rate, so the perfusion pressure (Ppa − Ppv) is unchanged. However, the pressure outside the vessels—namely, pleural pressure (Ppl)—increases less than Ppa and Ppv. Therefore, the transmural distending pressures (Ppa − Ppl and Ppv − Ppl) increase down zone 3, the vessel radii increase, vascular resistance decreases, and blood flow consequently increases further.

Finally, whenever pulmonary vascular pressures (Ppa) are extremely high—as they are in a severely volume-overloaded patient, in an extremely dependent lung (far below the vertical level of the left atrium), and in patients with pulmonary embolism or mitral stenosis—fluid can transude out of the pulmonary vessels and into the pulmonary interstitial compartment. In addition, pulmonary interstitial edema can be caused by extremely negative Ppl and perivascular hydrostatic pressure, such as may occur in a spontaneously breathing patient with an obstructed airway due to obstructive sleep apnea (OSA), laryngospasm, upper airway masses (e.g., tumors, hematoma, abscess, edema), strangulation, infectious processes (e.g., epiglottitis, pharyngitis, croup), or vocal cord paralysis; with rapid reexpansion of the lung; or with the application of very negative Ppl during thoracentesis. ^, Transudated pulmonary interstitial fluid can alter the distribution of pulmonary blood flow by exerting pressure on pulmonary capillaries.

When the flow of fluid into the interstitial space is excessive and the fluid cannot be cleared adequately by the lymphatics, it accumulates in the interstitial connective tissue compartment around the vessels and airways and forms peribronchial and periarteriolar edema fluid cuffs. The transuded pulmonary interstitial fluid fills the pulmonary interstitial space and may eliminate the normally present negative and radially expanding interstitial tension on the extraalveolar pulmonary vessels. Expansion of the pulmonary interstitial space by fluid causes pulmonary interstitial pressure (P isf ) to become positive and to exceed Ppv ( zone 4 , Ppa > P isf > Ppv > P a ). ^, In addition, the vascular resistance of extraalveolar vessels may be increased at a very low lung volume (i.e., residual volume); at such volumes, the tethering action of the pulmonary tissue on the vessels is also lost, and as a result P isf increases positively (see later discussion of lung volume). ^, Consequently, zone 4 blood flow is governed by the arteriointerstitial pressure difference (Ppa − P isf ), which is less than the Ppa − Ppv difference, and therefore zone 4 blood flow is less than zone 3 blood flow. In summary, zone 4 is a region of the lung from which a large amount of fluid has transuded into the pulmonary interstitial compartment or is possibly at a very low lung volume. Both circumstances produce positive interstitial pressure, which causes compression of extraalveolar vessels, increased extraalveolar vascular resistance, and decreased regional blood flow.

It should be evident that as Ppa and Ppv increase, three important changes take place in the pulmonary circulation—namely, recruitment or opening of previously unperfused vessels, distention or widening of previously perfused vessels, and transudation of fluid from very distended vessels. ^, Thus, as mean Ppa increases, zone 1 arteries may become zone 2 arteries, and as mean Ppv increases, zone 2 veins may become zone 3 veins. The increase in both mean Ppa and Ppv distends zone 3 vessels according to their compliance and decreases the resistance to flow through them. Zone 3 vessels may become so distended that they leak fluid and become converted to zone 4 vessels. In general, pulmonary capillary recruitment is the principal change as Ppa and Ppv increase from low to moderate levels; distention is the principal change as Ppa and Ppv increase from moderate to high levels; and transudation is the principal change when Ppa and Ppv increase from high to very high levels.

Distribution of Ventilation

Gravity also causes differences in vertical Ppl, which in turn causes differences in regional alveolar volume, compliance, and ventilation. The vertical gradient of Ppl can best be understood by imagining the lung as a plastic bag filled with semifluid contents; in other words, it is a viscoelastic structure. Without the presence of a supporting chest wall, the effect of gravity on the contents of the bag would cause the bag to bulge outward at the bottom and inward at the top (i.e., it would assume a globular shape). Inside the supporting chest wall, the lung cannot assume a globular shape. However, gravity still exerts a force on the lung to assume a globular shape; this force creates relatively more negative pressure at the top of the pleural space (where the lung pulls away from the chest wall) and relatively more positive pressure at the bottom of the lung (where the lung is compressed against the chest wall) ( Fig. 5.2 ). The density of the lung determines the magnitude of this pressure gradient. Because the lung has about one-fourth the density of water, the gradient of Ppl (in cm H ₂ O) is about one-fourth the height of the upright lung (30 cm). Thus, Ppl increases positively by 30/4 = 7.5 cm H ₂ O from the top to the bottom of the lung.

Because P a is the same throughout the lung, the Ppl gradient causes regional differences in transpulmonary distending pressure (P a − Ppl). Ppl is most positive in the dependent basilar lung regions, so alveoli in these regions are more compressed and are, therefore, considerably smaller than the superior, relatively noncompressed apical alveoli (the volume difference is approximately fourfold). If regional differences in alveolar volume are translated to a pressure-volume (compliance) curve for normal lung ( Fig. 5.3 ), the dependent small alveoli are on the midportion, and the nondependent large alveoli are on the upper portion of the S-shaped compliance curve. Because the different regional slopes of the composite curve are equal to the different regional lung compliance values, dependent alveoli are relatively compliant (steep slope), and nondependent alveoli are relatively noncompliant (flat slope). Therefore, most of the V t is preferentially distributed to dependent alveoli that expand more per unit of pressure change than the nondependent alveoli.

Ventilation/Perfusion Ratio

Blood flow and ventilation (both shown on the left vertical axis of Fig. 5.4 ) increase linearly with distance down the normal upright lung. The ventilation/perfusion ratio (V˙ a /Q˙, right vertical axis of Fig. 5.4 ) describes the amount of ventilation relative to perfusion in any given lung region. Because blood flow increases from a very low value and more rapidly than ventilation does with distance down the lung, V˙ a /Q˙, which is very high at the top of the lung, decreases rapidly at first and then more slowly toward the bottom of the lung, where V˙ a /Q˙ is low (V˙ a /Q˙ < 1).

Fig. 5.5 shows the calculated ventilation (V˙ a ) and blood flow (Q˙), the V˙ a /Q˙ ratio, and the alveolar partial pressures of oxygen (P ao ₂ ) and carbon dioxide (P aco ₂ ) for horizontal slices from the top (7% of lung volume), middle (11% of lung volume), and bottom (13% of lung volume) of the lung. P ao ₂ increases by more than 40 mm Hg, from 89 mm Hg at the base to 132 mm Hg at the apex, whereas P aco ₂ decreases by 14 mm Hg, from 42 mm Hg at the bottom to 28 mm Hg at the top. Therefore, in keeping with the regional V˙ a /Q˙ ratio, the bottom of the lung is relatively hypoxic and hypercapnic compared with the top of the lung.

V˙ a /Q˙ inequalities have different effects on arterial CO ₂ tension (Pa co ₂ ) than on arterial oxygen tension (Pa o ₂ ). Blood passing through underventilated alveoli tends to retain its CO ₂ and does not take up enough oxygen; blood traversing overventilated alveoli gives off an excessive amount of CO ₂ but cannot take up a proportionately increased amount of oxygen because of the flatness of the oxygen-hemoglobin (oxy-Hb) dissociation curve in this region (see Fig. 5.25 ). A lung with uneven V˙ a /Q˙ relationships can eliminate CO ₂ from the overventilated alveoli to compensate for the underventilated alveoli. As a result, with uneven V˙ a /Q˙ relationships, P aco ₂ -to-Pa co ₂ gradients are small; whereas, P ao ₂ -to-P ao ₂ gradients are usually large.

In 1974, Wagner and colleagues described a method of determining the continuous distribution of V˙ a /Q˙ ratios within the lung based on the pattern of elimination of a series of intravenously infused inert gases. Gases of differing solubility are dissolved in physiologic saline solution and infused into a peripheral vein until a steady state is achieved (20 minutes). Toward the end of the infusion period, samples of arterial and mixed expired gas are collected, and total ventilation and total cardiac output (Q˙ t ) are measured. For each gas, the ratio of arterial to mixed venous concentration (retention) and the ratio of expired to mixed venous concentration (excretion) are calculated, and retention-solubility and excretion-solubility curves are drawn. The retention- and excretion-solubility curves can be regarded as fingerprints of the particular distribution of V˙ a /Q˙ ratios that give rise to them.

Fig. 5.6 shows the types of distributions found in young, healthy subjects breathing air in the semirecumbent position. The distributions of both ventilation and blood flow are relatively narrow. The upper and lower 9% limits shown (vertical interrupted lines) correspond to V˙ a /Q˙ ratios of 0.3 and 2.1, respectively. Note that these young, healthy subjects had no blood flow perfusion areas with very low V˙ a /Q˙ ratios, nor did they have any blood flow to unventilated or shunted areas (V˙ a /Q˙ = 0) or unperfused areas (V˙ a /Q˙ = 8). Fig. 5.6 also shows P ao ₂ and P aco ₂ in respiratory units with different V˙ a /Q˙ ratios. Within the 95% range of V˙ a /Q˙ ratios (i.e., 0.3 to 2.1), P ao ₂ ranges from 60 to 123 mm Hg, whereas the corresponding P aco ₂ range is 44 to 33 mm Hg.

Passive Processes

Cardiac Output

The pulmonary vascular bed is a high-flow, low-pressure system under normal health conditions. As total pulmonary blood flow (cardiac output [Q˙ t ]) increases, pulmonary vascular pressures increase minimally. However, increases in Q˙ t distend open vessels and recruit previously closed vessels. Accordingly, pulmonary vascular resistance (PVR) drops because the normal pulmonary vasculature is quite distensible (and partly because of the addition of previously unused vessels to the pulmonary circulation). As a result of the distensibility of the normal pulmonary circulation, an increase in Ppa increases the radius of the pulmonary vessels, which causes PVR to decrease ( Fig. 5.7 ). Conversely, the opposite effect occurs within the pulmonary vessels during a decrease in Q˙ t . As Q˙ t decreases, pulmonary vascular pressures decrease, the radii of the pulmonary vessels are reduced, and PVR consequently increases. In contrast to the normal situation, the pulmonary vessels of patients with significant pulmonary arterial hypertension (PAH) are less distensible, acting more like rigid pipes. In this setting, Ppa will increase sharply with any increase in Q˙ t because PVR in these stiff vessels does not decrease significantly due to minimal expansion of their radii.

Understanding the relationships among Ppa, PVR, and Q˙ t during passive events is a prerequisite to recognition of active vasomotion in the pulmonary circulation (see section “Lung Volume” ). Active vasoconstriction occurs whenever Q˙ t decreases and Ppa either remains constant or increases. Increased Ppa and PVR have been found to be “a universal feature of acute respiratory failure.”

Active pulmonary vasoconstriction can increase Ppa and Ppv, contributing to the formation of pulmonary edema, and in that way it has a role in the pathophysiology of adult respiratory distress syndrome (ARDS). Active vasodilation occurs whenever Q˙ t increases and Ppa either remains constant or decreases. When deliberate hypotension is achieved with sodium nitroprusside or nitroglycerine infusions, Q˙ t often remains constant or increases, but Ppa decreases, and therefore so does PVR.

Lung Volume

Lung volume and PVR have an asymmetric, U-shaped relationship because of the varying effect of lung volume on small intraalveolar and large extraalveolar vessels, which in both cases is minimal at functional residual capacity (FRC). FRC is defined as the volume of gas in the lungs at end-expiration during normal tidal breathing. Ideally, this means that the patient is inspiring a normal V t , with minimal or no muscle activity or pressure difference between the alveoli and atmosphere at end-expiration. Total PVR is increased when lung volume is either increased or decreased from FRC ( Fig. 5.8 ). The increase in total PVR above FRC results from alveolar compression of small intraalveolar vessels, which results in an increase in small-vessel PVR (i.e., creation of zone 1 or zone 2). As a relatively small counterbalancing effect to the compression of small vessels, the large extraalveolar vessels can be expanded by the increased tethering of interstitial connective tissue that occurs at high lung volumes (and, with spontaneous ventilation only, the negativity of perivascular pressure at high lung volumes). The increase in total PVR with lung volumes below FRC results from an increase in the PVR of large extraalveolar vessels (passive effect). The increase in large-vessel PVR is partly due to mechanical tortuosity or kinking of these vessels (passive effect). In addition, small or grossly atelectatic lungs become hypoxic, and it has been shown that the increased large-vessel PVR in these lungs is also caused by an active vasoconstrictive mechanism known as hypoxic pulmonary vasoconstriction (HPV). The effect of HPV (discussed in greater detail in the section “Alveolar Gases” ) is significant whether the chest is open or closed and whether ventilation is by positive pressure or spontaneous.

Active Processes and Pulmonary Vascular Tone

Four major categories of active processes affect the pulmonary vascular tone of normal patients: (1) local tissue (endothelial- and smooth muscle–derived) autocrine or paracrine products, which act on smooth muscle ( Table 5.1 ); (2) alveolar gas concentrations (chiefly hypoxia), which also act on smooth muscle; (3) neural influences; and (4) humoral (or hormonal) effects of circulating products within the pulmonary capillary bed. The neural and humoral effects work by means of either receptor-mediated mechanisms involving the autocrine/paracrine molecules listed in Table 5.1 or related mechanisms ultimately affecting the smooth muscle cell. These four interrelated systems, each affecting pulmonary vascular tone, are briefly reviewed in sequence.

Alveolar Gases

Hypoxia-induced pulmonary vasoconstriction constitutes a fundamental difference between pulmonary vessels and all systemic blood vessels (which vasodilate in the presence of hypoxia). Alveolar hypoxia of in vivo and in vitro whole lung, unilateral lung, lobe, or lobule of lung results in localized pulmonary vasoconstriction. This phenomenon is widely referred to as HPV and was first described more than 70 years ago by Von Euler and Liljestrand. The HPV response is present in all mammalian species and serves as an adaptive mechanism for diverting blood flow from poorly ventilated to better ventilated regions of the lung and thereby improving V˙ a /Q˙ ratios. The HPV response is also critical for fetal development because it minimizes perfusion of the unventilated lung.

The HPV response occurs primarily in pulmonary arterioles of about 200 µm internal diameter (ID) in humans (60 to 700 µm ID in other species). These vessels are advantageously situated anatomically in close relation to small bronchioles and alveoli, which permits rapid and direct detection of alveolar hypoxia. Indeed, blood may actually become oxygenated in small pulmonary arteries because of the ability of oxygen to diffuse directly across the small distance between the contiguous air spaces and vessels. This direct access that gas in the airways has to small arteries makes possible a rapid and localized vascular response to changes in gas composition.

The oxygen tension at the HPV stimulus site (Ps o ₂ ) is a function of both P ao ₂ and mixed venous oxygen pressure (Pv– o ₂ ). The Ps o ₂ -HPV response curve is sigmoidal, with a 50% response when P ao ₂ , Pv– o ₂ , and Ps o ₂ are approximately 30 mm Hg. Usually, P ao ₂ has a much greater effect than Pv– o ₂ does because oxygen uptake is from the alveolar space to the blood in the small pulmonary arteries.

Numerous theories have been developed to explain the mechanism of HPV. ^, Many vasoactive substances have been proposed as mediators of HPV, including leukotrienes, prostaglandins, catecholamines, serotonin, histamine, angiotensin, bradykinin, and ET-1, but none has been identified as the primary mediator. In 1992, Xuan proposed that NO has a pivotal role in modulating PVR. NO is involved, but not precisely in the way that Xuan first proposed. There are multiple sites of oxygen sensing with variable contributions from the NO, ET-1, and eicosanoid systems (previously described). In vivo, HPV is currently thought to result from the synergistic action of molecules produced in both endothelial cells and smooth muscle cells. However, HPV can proceed in the absence of intact endothelium, suggesting that the primary oxygen sensor is in the smooth muscle cell and that endothelium-derived molecules modulate only the primary HPV response.

The precise mechanism(s) of HPV continue to be studied. However, abundant data support the smooth muscle mitochondrial electron transport chain as the HPV sensor ( Fig. 5.9 ). In addition, reactive oxygen species (including H ₂ O ₂ and superoxide) are released from complex III of the electron transport chain and probably serve as second messengers to increase calcium in pulmonary artery smooth muscle cells during acute hypoxia. Alternative (less likely) mechanisms are also being investigated. One alternative hypothesis suggests that smooth muscle microsomal reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidoreductase or sarcolemmal NADPH oxidase is the sensing mechanism. Although the precise oxygen sensing and signal transduction mechanisms remain under investigation, it is now clear that the mitochondria of the pulmonary artery smooth muscle cells are the focus of these effects. Indeed, a recent study by Zhou and colleagues demonstrated that transplantation of mitochondria from femoral arterial smooth muscle cells into the pulmonary artery smooth muscle cells attenuates the HPV response.

In summary, HPV results from a direct action of alveolar hypoxia on pulmonary smooth muscle cells, sensed by the mitochondrial electron transport chain, with reactive oxygen species (probably H ₂ O ₂ or superoxide) serving as second messengers to increase calcium and smooth muscle vasoconstriction. The endothelium-derived products serve to both potentiate (ET-1) and attenuate (NO, PGI ₂ ) to achieve the HPV response. Additional mechanisms (humoral and neurogenic influences) modulate baseline pulmonary vascular tone and affect the magnitude of the HPV response.

Elevated Pa co ₂ has a pulmonary vasoconstrictor effect. Both respiratory acidosis and metabolic acidosis augment HPV, whereas respiratory and metabolic alkalosis cause pulmonary vasodilation and serve to reduce HPV.

The clinical effects of HPV in humans can be classified under three basic mechanisms. First, life at high altitude or whole-lung respiration of a low F io ₂ increases Ppa. This is true for newcomers to high altitude, for the acclimatized, and for natives. The vasoconstriction is considerable; in healthy people breathing 10% oxygen, Ppa doubles, whereas pulmonary wedge pressure remains constant. The increased Ppa increases perfusion of the apices of the lung (through recruitment of previously unused vessels), which results in gas exchange in a region of lung not normally used (i.e., zone 1). Therefore, with a low F io ₂ , P ao ₂ is greater and the alveolar-arterial oxygen tension difference and the ratio between dead space and tidal volume (V d /V t ) are less than would be expected or predicted on the basis of a normal (sea level) distribution of ventilation and blood flow. High-altitude PAH is an important component in the development of mountain sickness subacutely (hours to days) and cor pulmonale chronically (weeks to years). There is now good evidence that in both patients with chronic obstructive pulmonary disease (COPD) and those with OSA, nocturnal episodes of arterial oxygen desaturation (caused by episodic hypoventilation) are accompanied by elevations in Ppa that can eventually lead to sustained PAH and cor pulmonale.

Second, hypoventilation (low V˙ a /Q˙ ratio), atelectasis, or nitrogen ventilation of any region of the lung usually causes a diversion of blood flow away from the hypoxic to the nonhypoxic lung (40% to 50% in one lung, 50% to 60% in one lobe, 60% to 70% in one lobule) ( Fig. 5.10 ). The regional vasoconstriction and blood flow diversion are important in minimizing transpulmonary shunting and normalizing regional V˙ a /Q˙ ratios during unilateral lung disease, one-lung ventilation (see Chapter 26 ), inadvertent intubation of a mainstem bronchus, and lobar collapse.

Third, in patients who have COPD, asthma, pneumonia, or mitral stenosis without bronchospasm, administration of pulmonary vasodilator drugs such as isoproterenol, nitroprusside, or nitroglycerin inhibits HPV and causes a decrease in Pa o ₂ and PVR and an increase in right-to-left transpulmonary shunt. The mechanism for these changes is thought to be deleterious inhibition of preexisting and, in some conditions, geographically widespread HPV without concomitant bronchodilation. In accordance with the latter two lines of evidence (one-lung or regional hypoxia and vasodilator drug effects on generalized or whole-lung disease), HPV can divert blood flow away from hypoxic regions of the lung, thereby serving as an autoregulatory mechanism that protects Pa o ₂ by favorably adjusting regional V˙ a /Q˙ ratios. Factors that inhibit regional HPV are extensively discussed by other authors, ^, and further explained in this chapter (In Section Inhibition of Hypoxic Pulmonary Vasoconstriction (pp. 151–152)).

Alternative (Nonalveolar) Pathways of Blood Flow Through the Lung

Blood can also traverse the lung from the right to the left side of the heart without being fully oxygenated or oxygenated at all. For example, blood flow through poorly ventilated alveoli (regions of low V˙ a /Q˙ with an F io ₂ < 0.3) have a right-to-left shunt effect on oxygenation, and blood flow through nonventilated alveoli (in atelectatic or consolidated regions, V˙ a /Q˙ = 0) does not contribute to gas exchange at any F io ₂ values; both are sources of right-to-left transpulmonary shunting. Low-V˙ a /Q˙ and atelectatic lung units occur in conditions in which the FRC is less than the closing capacity (CC) of the lung (see section “ Lung Volume , Functional Residual Capacity, and Closing Capacity”).

In addition, several right-to-left blood flow pathways traverse the lungs and heart without passing by or involving alveoli at all. The bronchial and pleural circulations originate from systemic arteries and empty directly into the left side of the heart without being oxygenated; these circulations constitute the 1% to 3% true right-to-left shunt normally present. With chronic bronchitis, and in cases of severe chronic thromboembolic pulmonary hypertension (CTEPH), the bronchial circulation can markedly increase, carrying as much as 10% of the cardiac output, and with pleuritis the pleural circulation can increase to carry 5% of the cardiac output. Consequently, as much as a 10% or 15% obligatory right-to-left shunt can be present under pathologic conditions.

Intrapulmonary arteriovenous anastomoses are normally closed, but in the presence of acute PAH, such as may be caused by a pulmonary embolus, they may open and result in a direct increase in right-to-left shunting. A patent foramen ovale (PFO) is present in 20% to 30% of individuals, but it usually remains functionally closed because left atrial pressure normally exceeds right atrial pressure. When a PFO is present, any condition that causes right atrial pressure to be greater than left atrial pressure can produce a right-to-left shunt, with resultant hypoxemia and possible paradoxical embolization. Such conditions include PAH, the use of high levels of PEEP, pulmonary embolization, COPD, pulmonary valvular stenosis, congestive heart failure, and postpneumonectomy states. Even such common events as mechanical ventilation and reaction to the presence of an endotracheal tube (ETT) during the excitement phase of emergence from anesthesia have caused right-to-left shunting across a PFO and severe arterial desaturation (with the potential for paradoxical embolization). ^, Transesophageal echocardiography (TEE) has been demonstrated to be a sensitive modality for diagnosing a PFO in anesthetized patients with elevated right atrial pressure.

Esophageal to mediastinal to bronchial to pulmonary vein pathways of right-to-left shunt have been described and may explain, in part, the hypoxemia associated with portal hypertension and cirrhosis. Thebesian vessels nourish the left ventricular myocardium and originate and empty into the left side of the heart. There are no known conditions that selectively increase thebesian blood flow.

Pulmonary Compliance

For air to flow into the lungs, a pressure gradient (ΔP) must be developed to overcome the elastic resistance of the lungs and chest wall to expansion. These structures are arranged concentrically, and their elastic resistance is therefore additive. The relationship between ΔP and the resultant volume increase (ΔV) of the lungs and thorax is independent of time and is known as total compliance (C _T ), as expressed in the following equation:C _T (L/cm H ₂ O) = ΔV (L)/ΔP (cm H ₂ O)(1)

The C _T of lung plus chest wall is related to the individual compliance of the lungs (C _L ) and of the chest wall (C _CW ) according to the following expression:1/C _T = 1/C _L + 1/C _CW [or C _T = (C _L )(C _CW )/C _L + C _CW ](2)

Normally, C _L and C _CW each equal 0.2 L/cm H ₂ O; hence C _T = 0.1 L/cm H ₂ O. To determine C _L , ΔV and the transpulmonary pressure gradient (P a − Ppl, the ΔP for the lung) must be known; to determine C _CW , ΔV and the transmural pressure gradient (Ppl − P _ambient , the ΔP for the chest wall) must be known; and to determine C _T , ΔV and the transthoracic pressure gradient (P a − P _ambient , the ΔP for the lung and chest wall together) must be known. In clinical practice, only C _T is measured, which can be done dynamically or statically, depending on whether a peak or a plateau inspiratory ΔP (respectively) is used for the C _T calculation.

During a positive- or negative-pressure inspiration of sufficient duration, transthoracic ΔP first increases to a peak value and then decreases to a lower plateau value. The peak transthoracic pressure value is the pressure required to overcome both elastic and airway resistance (see section “Airway Resistance” ). Transthoracic pressure decreases to a plateau value after the peak value because, with time, gas is redistributed from stiff alveoli (which expand only slightly and therefore have only a short inspiratory period) into more compliant alveoli (which expand a great deal and therefore have a long inspiratory period). Because the gas is redistributed into more compliant alveoli, less pressure is required to contain the same volume of gas, which explains why the pressure decreases. In practical terms, dynamic compliance is the volume change divided by the peak inspiratory transthoracic pressure, and static compliance is the volume change divided by the plateau inspiratory transthoracic pressure. Therefore, static C _T is usually greater than dynamic C _T , because the former calculation uses a smaller denominator (lower pressure) than the latter. If the patient is receiving PEEP, that pressure must first be subtracted from the peak or plateau pressure before thoracic compliance is calculated (i.e., compliance is equal to the volume delivered divided by the peak or plateau pressure—PEEP).

Alveolar pressure deserves special comment. The alveoli are lined with a layer of liquid. When a curved surface (a sphere or cylinder, such as the alveoli, bronchioles, and bronchi) is lined with liquid, a surface tension is created that tends to make the surface area that is exposed to the atmosphere as small as possible. Simply stated, water molecules crowd much closer together on the surface of a curved layer of water than elsewhere in the fluid. As the alveolar size decreases, the degree of curvature and the retractive surface tension will increase.

According to the Laplace expression, shown in Eq. 3 , the pressure in an alveolus (P, in dynes/cm ² ) is higher than ambient pressure by an amount that depends on the surface tension of the lining liquid (T, in dynes/cm) and the radius of curvature of the alveolus (R, in cm). This relationship is expressed in the following equation:

Although surface tension contributes to the elastic resistance and retractive forces of the lung, two difficulties must be resolved. First, the pressure inside a small alveolus should be higher than that inside a large alveolus, a conclusion that stems directly from the Laplace equation (R in the denominator). From this reasoning, one would expect a progressive discharge of each small alveolus into a larger one until eventually only one gigantic alveolus would be left ( Fig. 5.11A ). The second problem concerns the relationship between lung volume and transpulmonary ΔP (P a − Ppl). Theoretically the retractive forces of the lung should increase as lung volume decreases. If this were true, lung volume would decrease in a vicious circle, with an increasingly progressive tendency to collapse as lung volume diminishes.

These two problems are resolved by the fact that the surface tension of the fluid lining the alveoli is variable and decreases as its surface area is reduced. The substance responsible for the reduction (and variability) in alveolar surface tension is secreted by the intraalveolar type II pneumocyte; it is a lipoprotein called surfactant , which floats as a 50-Å-thick film on the surface of the fluid lining the alveoli. When the surface film is reduced in area and the concentration of surfactant at the surface is increased, the surface-reducing pressure is increased and counteracts the surface tension of the fluid lining the alveoli.

The surface tension of alveolar fluid can reach levels that are well below the normal range for body fluids such as water and plasma. When an alveolus decreases in size, the surface tension of the lining fluid falls to an extent greater than the corresponding reduction in radius; as a result, the transmural pressure gradient (equal to 2T/R) diminishes. This explains why small alveoli do not discharge their contents into large alveoli (see Fig. 5.11B ) and why the elastic recoil of small alveoli is less than that of large alveoli.

Airway Resistance

For air to flow into the lungs, a ΔP must also be developed to overcome the nonelastic airway resistance (R _AW ) of the lungs to airflow. The R _AW describes the relationship between ΔP and the rate of airflow (V˙).

The ΔP along the airway depends on the caliber of the airway and the rate and pattern of airflow. There are three main patterns of airflow. Laminar flow occurs when the gas passes down parallel-sided tubes at less than a certain critical velocity. With laminar flow, the pressure drop down the tube is proportional to the flow rate and may be calculated from the equation derived by Poiseuille:∆P = V˙ × 8 L × μ/πr ⁴ (5)where

ΔP is the pressure drop (in cm H ₂ O), V˙ is the volume flow rate (in mL/s), µ is viscosity (in poises), L is the length of the tube (in cm), and r is the radius of the tube (in cm).

When flow exceeds the critical velocity, it becomes turbulent. The significant feature of turbulent flow is that the pressure drop along the airway is no longer directly proportional to the flow rate but is proportional to the square of the flow rate according to Eq. 6 for turbulent flow:

∆P = V˙ ² ρ f L/4π ² r ⁵ (6)

where

ΔP is the pressure drop (in cm H ₂ O), V˙ is the volume flow rate (in mL/s), ρ is the density of the gas (or liquid), f is a friction factor that depends on the roughness of the tube wall, and r is the radius of the tube (in cm).

With increases in turbulent flow (or orifice flow, as described in the next paragraph), ΔP increases much more than V˙ and therefore R _AW also increases more, as predicted by Eq. 4 .

Orifice flow occurs at severe constrictions such as a nearly closed larynx, subglottic stenosis or stricture, or a kinked ETT. In these situations, the pressure drop is also proportional to the square of the flow rate, but density replaces viscosity as the important factor in the numerator. This explains why a low-density gas such as helium diminishes the resistance to flow (by threefold in comparison to air) in the setting of severe upper airway obstruction.

Because the total cross-sectional area of the airways increases as branching occurs, the velocity of airflow decreases in the distal airways; laminar flow is therefore chiefly confined to the airways below the main bronchi. Orifice flow occurs at the larynx, and flow in the trachea is turbulent during most of the respiratory cycle. By examining the components that constitute each of the preceding airway pressure equations, one can see that many factors can affect the pressure drop down the airways during ventilation. However, variations in diameter of the smaller bronchi and bronchioles are particularly critical, because bronchoconstriction may convert laminar flow to turbulent flow and the pressure drop along the airways can become much more closely related to the flow rate.

Different Regional Lung Time Constants

Thus far, the compliance and airway resistance properties of the chest have been discussed separately. In the following analysis, pressure at the mouth is assumed to increase suddenly to a fixed positive value ( Fig. 5.12 ) that overcomes both elastic and airway resistance and to be maintained at this value during inflation of the lungs. The ΔP required to overcome nonelastic airway resistance is the difference between the fixed mouth pressure and the instantaneous height of the dashed line in Fig. 5.12 and is proportional to the flow rate during most of the respiratory cycle.

The ΔP required to overcome nonelastic airway resistance is maximal initially but then decreases exponentially (see Fig. 5.12A , hatched lines ). The rate of filling therefore also declines in an approximately exponential manner. The remainder of the pressure gradient overcomes the elastic resistance (the instantaneous height of the dashed line in Fig. 5.12A ) and is proportional to the change in lung volume. The ΔP required to overcome elastic resistance is minimal initially but then increases exponentially, as does lung volume. Alveolar filling ceases (lung volume remains constant) when the pressure resulting from the retractive elastic forces balances the applied (mouth) pressure (see Fig. 5.12A , dashed line ).

Because only a finite time is available for alveolar filling and because alveolar filling occurs in an exponential manner, the degree of filling depends on the duration of the inspiration. The rapidity of change in an exponential curve can be described by its time constant τ, which is the time required to complete 63% of an exponentially changing function if the total time allowed for the function change is unlimited (2τ = 87%, 3τ = 95%, and 4τ = 98%). For lung inflation, τ = C _T × R; normally, C _T = 0.1 L/cm H ₂ O, R = 2.0 cm H ₂ O/L/s, τ = 0.2 s, and 3τ = 0.6 s.

When this equation is applied to individual alveolar units, the time taken to fill such a unit clearly increases as airway resistance increases. The time required to fill an alveolar unit also increases as compliance increases, because a greater volume of air is transferred into a more compliant alveolus before the retractive force equals the applied pressure. The compliance of individual alveoli differs from top to bottom of the lung, and the resistance of individual airways varies widely depending on their length and caliber. Therefore, various time constants for inflation exist throughout the lung.

Pathways of Collateral Ventilation

Collateral ventilation is another nongravitational determinant of the distribution of ventilation. Four pathways of collateral ventilation are known. First, interalveolar communications (pores of Kohn) exist in most species; their number ranges from 8 to 50 per alveolus, and they may increase with age and with the development of obstructive lung disease. Their precise role has not been defined, but they probably function to prevent hypoxia in neighboring but obstructed lung units. Second, distal bronchiole-to-alveolus communications are known to exist (channels of Lambert); their function in vivo is speculative but may be similar to that of the pores of Kohn. Third, respiratory bronchiole-to-terminal bronchiole connections have been found in adjacent lung segments (channels of Martin) in healthy dogs and in humans with lung disease. Fourth, interlobar connections exist; the functional characteristics of interlobar collateral ventilation through these connections have been described in dogs, and they have been observed in humans as well.

Work of Breathing

The pressure-volume characteristics of the lung also determine the WOB. BecauseWork = Force × DistanceForce = Pressure × Area(7)Distance = Volume/Area

work is defined by the equationWork = (Pressure × Area)(Volume/Area) =(8)Pressure × Volumeand ventilatory work may be analyzed by plotting pressure against volume. In the presence of increased airway resistance or decreased C _L , increased transpulmonary pressure is required to achieve a given V t with a consequent increase in the WOB. The metabolic cost of the WOB at rest constitutes only 1% to 3% of the total oxygen consumption in healthy subjects, but it is increased considerably (up to 50%) in patients with severe lung disease.

Two different pressure-volume diagrams are shown in Fig. 5.13 . During normal inspiration, transpulmonary pressure increases from 0 to 5 cm H ₂ O while 500 mL of air is drawn into the lung. Potential energy is stored by the lung during inspiration and is expended during expiration; consequently, the entire expiratory cycle is passive. The hatched area plus the triangular area ABC represents pressure multiplied by volume and is the WOB during one breath. Line AB is the lower section of the pressure-volume curve of Fig. 5.13 . The triangular area ABC is the work required to overcome elastic forces (C _T ), whereas the hatched area is the work required to overcome airflow or frictional resistance (R). The second graph applies to an anesthetized patient with diffuse obstructive airway disease resulting from the accumulation of mucous secretions. There is a marked increase in both the elastic (triangle AB′C) and the airway (hatched area) resistive components of respiratory work. During expiration, only 250 mL of air leaves the lungs during the passive phase when intrathoracic pressure reaches the equilibrium value of 0 cm H ₂ O. Active effort-producing work is required to force out the remaining 250 mL of air, and intrathoracic pressure becomes positive.

The full WOB over time must include the ventilatory frequency. The following equation depicts the variables included in the WOB equation:

Evaluating each component in the WOB equation, V˙ _E is the minute ventilation (RR × V t ) required to achieve a normal Pa co ₂ . When patients have increased CO ₂ production (as occurs with fever), the V˙ _E , and hence the WOB, will need to be higher. When the dead space (either alveolar or anatomic) is increased, the V˙ _E will need to increase to achieve a normal Pa co ₂ . Similarly, when airway resistance (R _AW ) is increased or compliance (C _L ) is decreased, there will be a corresponding increase in the WOB.

Furthermore, for any constant minute volume, the work done against elastic resistance is increased when breathing is deep and slow. On the other hand, the work done against airflow resistance is increased when breathing is rapid and shallow. If the two components are summed and the total work is plotted against respiratory frequency, there is an optimal respiratory frequency at which the total WOB is minimal ( Fig. 5.14 ). In patients with diseased lungs in which elastic resistance is high (e.g., pulmonary fibrosis, pulmonary edema, or in infants), the optimal frequency is increased, and rapid, shallow breaths are favored. Like other muscles, respiratory muscles can become fatigued, especially with rapid, shallow breathing. When airway resistance is high (e.g., in asthma or COPD), the optimal frequency is decreased, and slow, deep breaths are favored. Although the optimal frequency is slow (allowing a prolonged expiratory phase), a rapid, shallow breathing pattern also develops in these patients when fatigued, which further exacerbates their primary (airway resistance) problem.

Lung Volumes, Functional Residual Capacity, and Closing Capacity

Lung Volumes and Functional Residual Capacity

FRC is defined as the volume of gas in the lung at the end of a normal expiration during normal tidal breathing. At FRC, there is no airflow and P A equals ambient pressure. Under these conditions, expansive chest wall elastic forces are exactly balanced by retractive lung tissue elastic forces ( Fig. 5.15 ).

The FRC includes the expiratory reserve volume (the additional gas beyond the tidal volume that can be forcibly exhaled) along with the residual volume . Therefore, FRC equals residual volume plus expiratory reserve volume ( Fig. 5.16 ). With regard to the other lung volumes shown in Fig. 5.16 , V t , vital capacity, inspiratory capacity, inspiratory reserve volume, and expiratory reserve volume can be measured by simple spirometry. Total lung capacity (TLC), FRC, and residual volume contain a fraction (residual volume) that cannot be measured by simple spirometry. However, if one of these three volumes is measured, the others can easily be derived, because the other lung volumes, which relate these three volumes to one another, can be measured by simple spirometry.

Residual volume, FRC, and TLC can be measured by any of three techniques: (1) nitrogen washout, (2) inert gas dilution (e.g., helium wash-in), and (3) total-body plethysmography. The first method, the nitrogen washout technique, is based on measuring expired nitrogen concentrations before and after the patient breathes pure oxygen for several minutes; the difference is the total quantity of nitrogen eliminated. If, for example, 2 L of N ₂ is eliminated and the initial alveolar N ₂ concentration was 80%, the initial volume of the lung was 2.5 L. The second method, the inert gas dilution technique, uses the wash-in of an inert tracer gas such as helium. If 50 mL of helium is introduced into the lungs and, after equilibration, the helium concentration is found to be 1%, the volume of the lung is 5 L. The third method, the total-body plethysmography technique, uses Boyle’s law (P ₁ V ₁ = P ₂ V ₂ , where P ₁ = initial pressure, V ₁ = initial volume). The subject is confined within a gas-tight box (plethysmograph) so that changes in the volume of the body during respiration may be readily determined as a change in pressure within the sealed box. Although each technique has technical limitations, all are based on sound physical and physiologic principles and provide accurate results in normal patients. Disparity between FRC as measured in the body plethysmograph and as determined by the helium dilution method is often used as a way of detecting large, nonventilating, air-trapped blebs.

Airway Closure and Closing Capacity

As discussed (see section “Distribution of Ventilation” ), Ppl increases when proceeding from the top to the bottom of the lung and determines regional alveolar size, compliance, and ventilation. Of even greater importance to the clinician is the recognition that these gradients in Ppl may lead to airway closure and collapse of alveoli.

Patient with Normal Lungs

Fig. 5.17A illustrates the normal resting end-expiratory (FRC) position of the lung–chest wall combination. The distending transpulmonary ΔP and the intrathoracic air passage transmural ΔP are 5 cm H ₂ O, and the airways remain patent. During the middle of a normal inspiration (see Fig. 5.17B ), there is an increase in transmural ΔP (to 6.8 cm H ₂ O) that encourages distention of the intrathoracic air passages. During the middle of a normal expiration (see Fig. 5.17C ), expiration is passive; P a is attributable only to the elastic recoil of the lung (2 cm H ₂ O), and there is a decrease (to 5.2 cm H ₂ O) but still a favorable (distending) intraluminal transmural ΔP. During the middle of a severe forced expiration (see Fig. 5.17D ), Ppl increases far higher than atmospheric pressure and is communicated to the alveoli, which have a pressure that is still higher because of the elastic recoil of the alveolar septa (an additional 2 cm H ₂ O).

At high gas flow rates, the pressure drop down the air passage is increased, and there is a point at which intraluminal pressure equals either the surrounding parenchymal pressure or Ppl; that point is termed the equal pressure point (EPP). If the EPP occurs in small noncartilaginous air passages (distal to the 11th generation, the airways have no cartilage and are called bronchioles ), they may be held open at that point by the tethering effect of the elastic recoil of the immediately adjacent or surrounding lung parenchyma. If the EPP occurs in large cartilaginous air passages (proximal to the 11th generation, the airways have cartilage and are called bronchi ), they may be held open at that point by their cartilage. Downstream of the EPP (in either small or large airways), transmural ΔP is reversed (−6 cm H ₂ O), and airway closure occurs. Thus, the patency of airways distal to the 11th generation is a function of lung volume, and the patency of airways proximal to the 11th generation is a function of intrathoracic (pleural) pressure. In bronchi, the posterior membranous sheath appears to give first by invaginating into the lumen. If lung volume were abnormally decreased (e.g., because of splinting) and expiration were still forced, the caliber of the airways would be relatively reduced at all times, which would cause the EPP and point of collapse to move progressively from larger to smaller air passages (closer to the alveolus).

In adults with normal lungs, airway closure can still occur even if expiration is not forced, provided that residual volume is approached closely enough. Even in patients with normal lungs, as lung volume decreases toward residual volume during expiration, small airways (0.5 to 0.9 mm in diameter) show a progressive tendency to close, whereas larger airways remain patent. ^, Airway closure occurs first in the dependent lung regions (as directly observed by computed tomography) because the distending transpulmonary pressure is less and the volume change during expiration is greater. Airway closure is most likely to occur in the dependent regions of the lung whether the patient is in the supine or the lateral decubitus position and whether ventilation is spontaneous or positive-pressure ventilation. ^{, ,}

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