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PULMONARY MECHANICS AND GAS EXCHANGE
The major function of the lung is to deliver oxygen to and remove carbon dioxide from the blood as it passes through the pulmonary capillary bed. This function is achieved through a series of complex and highly integrated series of processes. The first step in this essential gas exchange process is the contraction of the inspiratory muscles, producing the force (pressure decrease or pressure difference) to overcome the resistance of the lung and chest wall and resulting in the passage of air down a negative pressure gradient from the airway opening (mouth or nose) along the tracheobronchial tree into the alveoli of the lung. The exchange of respiratory gases with the blood and pulmonary capillaries is aided by an ultrathin alveolar-capillary membrane where oxygen diffuses across the membrane into the blood. Carbon dioxide passes in the opposite direction. The adequacy of gas exchange can be determined from the tensions of oxygen and carbon dioxide in the blood leaving the lungs that supply the organs of the body.
Assessment of the mechanical properties of the lung and chest wall and evaluation of the efficiency of gas exchange in the lungs are clinically important. When abnormalities are revealed early, impairment may still be reversible or at least treatable. Pulmonary function testing is also helpful in elucidating the basis for breathlessness, a common symptom of pulmonary disease, as well as important in characterizing the pathophysiology and providing a measure of the severity of pulmonary diseases. Pulmonary function testing is also an excellent measure of general health and the risk of mortality from all causes. The range of pulmonary function tests, their accepted symbols, techniques of performance, and interpretation are summarized in Plates 3-1 and 3-2 .
RESPIRATORY MUSCLES
The chest expands and the lungs are filled with air by the contraction of the inspiratory muscles that create a negative pressure within the chest cavity and a negative pressure gradient down the airways (see Plate 2-1 ). The diaphragm is the principal muscle of inspiration and provides the pressure gradient for the movement of much of the air that enters the lungs during quiet breathing. Contraction of the diaphragm causes the left and right domes to descend downward and the chest to expand upward and outward. At the same time, because of the vertically oriented attachments of the diaphragm to the costal margins, diaphragmatic contraction also serves to elevate the lower ribs.
Contraction of the intercostal muscles, the external intercostal muscles, and the parasternal intercartilaginous muscles raises the ribs during inspiration. As the ribs are elevated, the anteroposterior and transverse dimensions of the chest enlarge because of the anatomic movement of the ribs around the axis of their necks. This is commonly referred to as the bucket handle effect . Upward displacement of the upper ribs is accompanied by an increase in the anteroposterior dimension similar to the motion of a “water pump handle,” and elevation of the lower ribs is associated with an increase in the transverse dimension of the chest.
In addition to the diaphragm and intercostal muscles, other accessory inspiratory muscles contribute to the movement of the chest in other situations. The scalene muscles make their major contribution during high levels of ventilation when the upper parts of the chest are maximally enlarged. These muscles arise from the transverse processes of the lower five cervical vertebrae and insert into the upper aspect of the first and second ribs. Contraction of these muscles elevates and fixes the uppermost part of the rib cage.
Another accessory muscle, the sternomastoid (sternocleidomastoid), normally also becomes active only at high levels of ventilation. Contraction of the sternomastoid muscle is frequently apparent during severe asthma and with other disorders that obstruct the movement of air into the lungs. The sternomastoid muscle elevates the sternum and slightly enlarges the anteroposterior and longitudinal dimensions of the chest.
In contrast to inspiration, expiration during quiet breathing occurs as a more passive process as a result of recoil of the lung. However, at higher levels of ventilation or when movement of air out of the lungs is impeded, expiration becomes active. Muscles involved in active expiration include the internal intercostal muscles, which depress the ribs; the external and internal oblique abdominal muscles; and the transversus and rectus abdominis muscles, which compress the abdominal contents, depress the lower ribs, and pull down the anterior part of the lower chest. These expiratory muscles also play important and complex roles in regulating breathing and lung volume during talking, singing, coughing, defecation, and parturition.
The strength of the respiratory muscles can be determined from maximal static respiratory pressures (i.e., maximal pressure generated during a forced inspiratory or expiratory maneuver against a manometer or pressure gauge). Pressure developed during an isometric contraction of the respiratory muscles is a function of the length of those muscles and is therefore related to the lung volume at which the maneuver is performed. Maximal inspiratory static pressure is measured when the inspiratory muscles are optimally lengthened after a complete expiration to residual volume (RV). Similarly, maximal static expiratory pressure is determined after a full inspiration to total lung capacity (TLC) when the expiratory muscles are in their most mechanically advantageous position.
Measurement of maximal static respiratory pressures can be clinically useful in the evaluation of patients with neuromuscular disorders. Respiratory muscle weakness, when severe, can reduce the ventilatory capacity and result in breathlessness, even when lung function is otherwise normal.
LUNG VOLUMES AND SUBDIVISIONS
Lung Volumes and Capacities
The forced expiratory volume in 1 second (FEV 1 ) (see Plate 3-1 ) is largely determined by size of the forced vital capacity (FVC), which in turn is determined by the factors that determine TLC and RV; hence, the size of the lung is important. There is significant correlation between the size of the FVC and respiratory disease progression as well as death from all causes.
Determination of the size of the lung is made by measuring lung volumes and lung capacities. A lung capacity is defined as two or more lung volumes. There are four lung capacities: TLC, inspiratory capacity (IC), functional residual capacity (FRC), and vital capacity (VC). There are four separate lung volumes: RV, expiratory reserve volume (ERV), tidal volume (TV), and inspiratory reserve volume (IRV).
TLC is the maximal amount of air in the lung after a full inspiration. TLC is made up of four lung volumes: RV + ERV + TV + IRV or two capacities FRC + IC and other combinations.
IC is the maximal volume of air inhaled from the end of a normal breath (FRC) to TLC. IC = TV + IRV.
FRC is the volume of air in the lung at the end of a normal breath. FRC = ERV + RV.
VC is the volume of air exhaled after a complete expiration from TLC. This effort ends when the RV is reached. VC = IRV + TV + ERV or IC + ERV. When the effort is done with a maximal force, it is termed the FVC.
IRV is the volume of air inhaled from the end of a normal tidal breath to TLC.
TV (or V T ) is the volume of air that is inhaled and exhaled during normal breathing.
ERV is maximal volume of air exhaled from the end of a normal breath and is terminated when the RV is reached.
RV is the volume of air that remains in the lung at the end of a maximal expiration. A spirometer is a device that measures the volume of air inhaled into and exhaled out of the lung (see Plate 2-2 ).
Spirometers come in two general types; based on the measurement principle used, they can measure either volume or flow. In the volume-type spirometer, air is captured as a displacement of some physical container (e.g., the vertical displacement of a bell in a water seal or displacement of a dry bellows). With the flow-type spirometer, volume is determined by the electrical integration of a flow signal ( Plate 2-2 ). Other types of instruments measure flow or volume in a variety of ways such as using temperature probes, turbines, or vanes. To measure lung volumes and specifically the VC, the patient sits and breathes into the spirometer. A technician then instructs the patient to inhale and exhale maximally with either a slow effort or a maximally generated effort. The volume of air inhaled and exhaled is at ambient temperature, pressure, saturated (ATPS) but by convention is expressed to body temperature, pressure, saturated (BTPS). A spirometer can only measure three volumes (IRV, ERV, and TV) and two capacities (IC and VC), but in practice, usually only the VC is measured. A low VC is often observed in patients with either restrictive or obstructive diseases, so other volumes and capacities must be measured, but to measure the TLC, FRC, and RV, the FRC needs to be determined.
FRC is generally measured by two very different techniques: inert gas dilution or applying Boyle's law during gas compression.
MEASURING LUNG VOLUMES (see Plate 2-3 )
The inert gas dilution method involves the measurement of FRC be determining the dilution of an inert gas. The inert gas helium is used most often, but other inert gases can be used as well. Helium is both inert and insoluble. A breathing circuit is filled with a gas mixture that contains oxygen and a known percentage of helium. The patient is switched to this gas mixture at end expiration (FRC). As the helium or other inert gas in the circuit mixes with the air in the lung, the concentration of helium falls to a new or diluted level. Because helium does not cross the alveolar-capillary membrane, the total amount of helium in the system does not change during the test period. Consequently, the initial concentration of helium (He initial ) multiplied by the volume of gas in the spirometer at the start of the test (V spirometer ) equals the final concentration of helium (He final ) multiplied by the volume of gas in the spirometer at the end of the test plus the volume of air in the lung (i.e., FRC). The equation can be written as follows:
Solving for FRC, the equation becomes
The open-circuit nitrogen washout technique is another inert gas dilution method in which nitrogen is completely displaced from the lungs during a period of 100% oxygen breathing. All expired air is collected, and the volume and nitrogen concentration of the sample are measured. Because the total volume of nitrogen in the expired air equals the volume of nitrogen in the lung before the start of the test, the volume of expired air multiplied by the nitrogen concentration of the expired air equals the volume of air in the lung (FRC) multiplied by the initial concentration of nitrogen in the lung.
Both of these inert gas dilution techniques measure the gas (FRC) that communicates with the room air. What is not measured is the gas trapped in the lung behind closed or obstructed airways. For example, in a patient with emphysema, this trapped gas can be quite large (>1 L) and represents the gas trapped in the emphysematous bullae.
The body plethysmograph technique , or Boyle's law technique, uses a closed chamber within which the patient is seated (see Plate 2-3 ).
At the end of a normal breath (FRC), a shutter closes, and the patient gently pants against the closed shutter. During the subsequent inspiratory and expiratory efforts against the closed shutter, the pressure in the airways and alveoli falls or rises below atmospheric levels, and the gas in the lung undergoes decompression and compression. Because the plethysmograph is sealed, the resulting increase and decrease in lung volume is reflected by an increase or decrease in the pressure within the plethysmograph.
Thoracic gas volume is then determined by applying Boyle's law, which states that for a gas at a constant temperature, the product of pressure and volume in two different states (compressed or decompressed) is constant. PV = P 1 V 1 . Boyle's law can also be expressed as follows:
where P = initial pressure, V = initial volume, ΔP is a change in pressure, and ΔV is a corresponding change in volume. This expression can be simplified, solving for V:
With respect to the respiratory system, V represents the initial volume of gas in the thorax (i.e., FRC), P represents the pressure in the alveoli at the end of a normal expiration (i.e., atmospheric pressure), ΔP represents the change in alveolar pressure during breathing efforts against a closed shutter, and ΔV represents the change in thoracic gas volume resulting from gas expansion or compression during obstructed breathing. Changes in alveolar pressure are determined from changes in mouth pressure (ΔP = ΔPm), and changes in the volume of thoracic gas are reflected by changes in the pressure within the plethysmograph (ΔV = ΔPp). Because changes in alveolar pressure during the gentle breathing maneuver against a closed shutter are extremely small as compared with atmospheric pressure, FRC can be calculated from the following simplified equation:
FRC measured by the body plethysmograph measures all the gas within the lung whether it communicates with the atmosphere or not. So in the situation of excessive trapped gas, the FRC determined by the body plethysmograph is greater than the FRC determined by inert gas dilution.
MECHANICS OF VENTILATORY APPARATUS (see Plate 2-4 )
The respiratory system or ventilatory apparatus consists of the lungs and surrounding chest wall. The chest wall includes not only the rib cage but also the diaphragm and abdominal wall. The lungs fill the chest such that the visceral pleurae are in contact with the parietal pleurae of the chest cage where the pleural space is filled with a small amount of liquid and is therefore really only a potential space. As a result of their close physical contact, the lungs and chest wall act in unison. From a mechanical point of view, the respiratory system or ventilatory apparatus may be regarded as a pump that can be characterized by its elastic (E), flow-resistive (R), and inertial (I) properties (see Plates 2-4 and 2-5 ). Dynamically, the total pressure developed by the contracting muscles must overcome three resistances:
where P E is pressure attributable to elastic resistance (E), P R is pressure attributable to flow-resistance (R), and P I is pressure attributable to inertia (I).
In terms of flow and volume:
At the end of a normal expiration, the respiratory muscles are at rest. The elastic recoil of the lung, which is inward and favors deflation, is balanced by the elastic recoil of the chest, which is directed outward and favors inflation, and these opposing forces generate a subatmospheric pressure of approximately 5 cm H 2 O in the pleural space between the visceral and parietal pleurae. At the point of no flow, the pressure along the entire airway from the mouth to the alveoli is at atmospheric level. The difference between alveolar and pleural pressure or the pressure difference across the lung structures is the transpulmonary pressure (P TP ).
As the inspiratory muscles contract during inspiration and the chest expands, the pleural pressure becomes increasingly negative or subatmospheric. Because of the resistance (Raw) offered by the tracheobronchial tree to the flow of air into the lung, the alveolar pressure also becomes subatmospheric. At a given rate of airflow, the difference between alveolar pressure and the pressure at the airway opening, which remains at atmospheric level, is used to measure of the flow resistance of the airways:
or
Movement of air into the lungs continues until the alveolar pressure again reaches or equilibrates with atmospheric level or the alveolar pressure minus the airway opening pressure equals zero, which is when the pressure difference between the alveoli and the airway opening no longer exists.
Elastic Properties of the Lung (see Plate 2-5 )
The compliance or distensibility of the lungs is determined from the relationship between changes in lung volume and changes in transpulmonary pressure.
At the end of inspiration, when flow is zero, the volume of air in the lungs is greater, and the pleural pressure is more subatmospheric than at FRC when the breath begins. At this point, the difference between alveolar and pleural pressure—the transpulmonary pressure—is increased. This change in transpulmonary pressure required to effect a given change in the volume of air in the lungs is a measure of the elastic resistance of the lungs:
or:
The inverse of which is lung compliance:
The forces required to overcome elastic resistance are stored within the elastic elements; expiration then occurs when these forces are released. When the respiratory muscles stop contracting and start relaxing, the recoil of the lung causes the alveolar pressure to exceed the pressure at the mouth, the pressure gradient is reversed, and air flows out of the lung.
The elastic properties of the lungs (see Plate 2-5 ) are determined statically when airflow is stopped. Under these no-flow conditions, alveolar pressure equals the pressure at the mouth; pleural pressure is determined indirectly from the pressure in the lower third of the esophagus by means of a balloon catheter. In practice, the subject inhales to TLC and then slowly exhales, airflow is then periodically interrupted, and static measurements are made of lung volume and transpulmonary pressure. From the measurements of volume and transpulmonary pressure, lung compliance (C L = ΔV/ΔP TP ) or its inverse elastance (E L + ΔP TP /ΔVol) is determined.
Pressure-volume characteristics of the lung are nonlinear. Thus, compliance of the lung is decreased at high volumes and greatest as RV is approached. Forces favoring further collapse of the lung can be demonstrated throughout the range of VC, even at low lung volumes. If the inflationary forces of the chest wall on the lung are eliminated by removing the lung from the thorax or by opening the chest (pneumothorax), the lung will collapse to a virtually airless state upon reaching an equilibrium position.
Lung tissue elasticity arises in part from the fibers of elastin and collagen that are present in the alveolar walls and that surround both the bronchioles and pulmonary capillaries. The elastin fibers can approximately double their resting length; in contrast, the collagen fibers are poorly extensible and act primarily to limit expansion at high lung volumes. Lung expansion occurs through an unfolding and geometric rearrangement of the fibers analogous to the way a nylon stocking is easily stretched even though the individual fibers are elongated very little.
The distensibility of the lungs increases (compliance increases) with advancing age as a result of alterations in the elastin and collagen fibers in the lung. Pulmonary emphysema, which destroys alveolar walls and enlarges alveolar spaces, similarly increases lung compliance. In contrast, compliance of the lung is reduced by disorders such as pulmonary fibrosis, which affect the interstitial tissues of the lung, and by diffuse alveolar consolidation and edema, which also interfere with expansion of the lung.
SURFACE TENSION (see Plate 2-6 )
The elastic behavior of the lung also depends on the surface tension of the film lining the alveoli. The attractive forces between molecules of the liquid film are stronger than those between the film and the gas in the alveoli. Consequently, the area of the surface film shrinks. The behavior of the surface film has been examined in experimental animals by comparing pressure-volume relationships of air-filled lungs with those of saline-filled lungs. Because saline eliminates the liquid-air interface without affecting tissue elasticity, lungs distended with liquid require a substantially lower transpulmonary pressure to maintain a given lung volume than do lungs inflated with air. Thus, surface forces make a major contribution to the retractive forces of the lung.
Surface forces can be characterized by Laplace's law (see Plate 2-6 ). Laplace's law states that the pressure inside a spherical structure such as an alveolus is directly proportional to the tension in the wall and inversely proportional to the radius of curvature. When the liquid-air interface and surface tension forces are abolished by instillation of saline into the alveolar spaces, the pressure required to maintain a given lung volume is markedly reduced.
The surface tension of the film lining the alveolar walls depends on lung volume; surface tension is high when the lungs are inflated and low at small lung volumes. These variations in surface tension with changes in lung volume require that the surface film contain a unique type of surface-active material. If the surface tension remained constant instead of changing with lung volume, a greater pressure would be required to keep an alveolus open as its radius of curvature diminished with decreasing lung volume. The surface-active material lining the alveoli, or surfactant , is a product of the type II granular pneumocyte and has dipalmitoyl lecithin as an important constituent. Surfactant serves a number of important functions. Without surfactant, small alveoli would empty into communicating larger ones, and atelectasis would occur. Indeed, this is the situation in premature infants who lack surfactant. Surfactant's low surface tension, particularly at low lung volumes, increases the compliance of the lung and facilitates expansion during the subsequent breath; hence, the stability of alveoli at low lung volumes is maintained.
Elastic Properties of the Chest Wall and Total Respiratory System (see Plate 2-7 )
The elastic recoil of the chest wall is outward and favors inflation. If the chest is unopposed by the lungs, it enlarges to approximately 70% of the TLC, and this point represents the equilibrium or resting position of the chest wall. At this point, the pressure across the chest wall (the difference between pleural pressure and the pressure at the surface of the chest when the respiratory muscles are completely at rest) is zero. If the thorax expands beyond this equilibrium point, the chest wall, similar to the lung, will recoil inward, resisting expansion and favoring a return to the equilibrium position. On the other hand, at all volumes less than 70% of TLC, the recoil of the chest is opposite to that of the lung such that it is directly outward and favors inflation.
The lung and chest wall are considered to be in series, so that the recoil pressure of the total respiratory system (P RS ) is the algebraic sum of the pressures exerted by the recoil of the lung (P L ) and the recoil of the chest wall (P W ).
The P L is determined from the difference between alveolar pressure (Palv) and pleural pressure (Ppl). The P W when the respiratory muscles are at rest is determined from the difference between pleural pressure (Ppl) and the pressure at the external surface of the chest (Patm). Thus, the recoil of the entire respiratory system can be expressed as follows:
When the respiratory muscles are completely at rest and the pressure at the surface of the chest is at atmospheric levels:
The elastic properties of the total respiratory system can be evaluated in a number of ways. Each method requires that a given lung volume be maintained during complete relaxation of all the respiratory muscles and is generally accomplished by application of external forces such as positive pressure to the airways or negative pressure around the chest or through voluntary relaxation of the respiratory muscles while the airway opening is occluded.
FRC therefore represents the unique equilibrium or resting position where the recoil pressure is zero. At this one point (FRC), the increased (deflation) recoil pressure of the lung is equal but opposite to the outward (inflation) recoil pressure of the chest wall. At any volume above FRC, the recoil pressure exceeds atmospheric levels, favoring a decrease in lung volume; at volumes below FRC, the recoil pressure is less than atmospheric pressure and the respiratory system tends to retract outward in an attempt to increase lung volume. FRC is therefore a measure of the elastic forces of the respiratory system.
Elastic recoil properties of the chest wall, which play an important role in determining the subdivisions of lung volume, may be rendered abnormal by disorders such as marked obesity, kyphoscoliosis, and ankylosing spondylitis.
Distribution of Airflow Resistance (see Plate 2-8 )
The motion of gas from the alveoli to the airway opening requires pressure dissipation. The ratio of transpulmonary pressure (difference between pleural and mouth pressures) to flow defines pulmonary resistance , which is the sum of the viscous resistance caused by the gas movement through the airways ( airway resistance ) and the viscoelastic resistance offered by lung tissue displacement ( tissue resistance ).
Pulmonary resistance is inversely related to breathing frequency, attributable to the frequency dependence of tissue resistance, and to lung volume, attributable to the volume dependence of airway resistance.
During normal tidal breathing at rest, tissue resistance represents a major component of pulmonary resistance, and it may be further increased in diseases affecting the lung parenchyma, such as pulmonary fibrosis. Tissue resistance is defined as the ratio of the pressure difference between pleural surface and alveoli to airflow and thus cannot be directly measured in vivo.
The driving pressure producing airflow along the airways is the difference between alveolar (Palv) and airway opening (Pao) pressures. Airway resistance (Raw) is thus defined as the ratio of this driving pressure to airflow ( 
) according to the equation:
Airway resistance can be readily determined in vivo by whole-body plethysmography, which allows measurement of changes in Palv while mouth flow is simultaneously measured by a pneumotachograph. In normal subjects, a large proportion of airway resistance is offered by the upper respiratory tract. During tidal breathing at rest, the contributions of nose and larynx to airway resistance sum up to 40% to 60%, a variability likely attributable to anatomical differences. The larynx contributes to resistance more on expiration than inspiration because the vocal cords are abducted during the latter, and the nose contributes more on inspiration than expiration.
The resistance of intrathoracic airways is mainly attributable to bronchi proximal to the seventh airway generation. With more distal branching, the number of airways increases exponentially much more than their diameter decreases. Thus, the total cross-sectional area of the tracheobronchial tree is also exponentially increasing toward the periphery. As a consequence, the airways with a diameter smaller than 2 mm contribute to about 10% of the total airway resistance of a normal lung. In diseased conditions, the resistance of these peripheral airways may increase considerably, but it should be more than doubled to result in an increase of total airway resistance exceeding 10%.
The airways are nonrigid structures and are compressed or distended when a pressure difference exists between their lumina and the surrounding space ( transmural pressure ). The pressure surrounding the intrathoracic airways approximates pleural pressure because these airways are exposed to the force required to distend the lung ( transpulmonary pressure ). Thus, the transmural pressure of a given airway varies directly with transpulmonary pressure, and its diameter changes in proportion to the cube root of lung volume changes. Because the resistance of a given airway is inversely proportional to the fourth power of its radius, a hyperbolic inverse relationship exists between airway resistance and lung volume. In normal individuals, the product of airway resistance and lung volume ( specific airway resistance ) and its inverse ( specific airway conductance ) are relatively constant and are used to correct airway resistance for the volume at which it is measured. If the lung elastic recoil is reduced, as in pulmonary emphysema, both transmural pressure and airway caliber decrease, and airway resistance increases.
The effects of changes in transmural pressure on airway caliber also depend on the airway wall compliance; this in turn depends on the structural support of a given airway. The trachea has a cartilage layer in its anterior and lateral walls that prevents complete collapse even when transmural pressure is negative. Whereas the bronchi are less supported by incomplete cartilaginous rings and plates, bronchioles have no cartilage. Nevertheless, their excessive narrowing upon maximal airway smooth muscle activation is, in normal subjects, prevented by internal and external elastic loads, the former being represented by airway wall structures, the latter by the force of interdependence provided by the alveolar attachments to the outer airway walls. If alveolar attachments are destroyed, such as in emphysema, the force of interdependence is reduced, and the airway caliber is less for any given airway smooth muscle tone.
Airway caliber may also be reduced and airway resistance increased in patients with lung disease such as asthma and chronic bronchitis (chronic obstructive pulmonary disease) because of mucosal edema, hypertrophy or hyperplasia of mucous glands, changes in mucus properties, or hypertrophy or hyperplasia of bronchial smooth muscle.
Patterns of Airflow (see Plate 2-9 )
The relationship between driving pressure and the resulting airflow along the tracheobronchial tree is extremely complicated because the airways are a system of irregularly branching tubes that are neither rigid nor perfectly circular.
The driving pressure required to overcome friction depends on the rate and pattern of airflow. There are two major patterns of airflow. Laminar flow is characterized by streamlines that are parallel to the sides of the tube and sliding over each other. The streamlines at the center of the tube move faster than those closest to the walls so that the flow profile is parabolic. The pressure-flow characteristics of laminar flow depend on length (l) and radius (r) of the tube and the viscosity of gas (μ) according to the Poiseuille equation:
where P is driving pressure and
is flow. The above equation shows that driving pressure is directly proportional to flow (ΔP ∝ μ
) and highly dependent on tube radius. If the radius of the tube is halved, the pressure required to maintain a given flow rate must be increased 16 times. Laminar flow dominates in the periphery of the lung, where
is low because the airway caliber is small but the total cross-section area is large. Turbulent flow occurs at high flow rates and is characterized by a complete disorganization of streamlines. The molecules of gas may then move laterally, collide with each other, and change their velocities. Under these circumstances, the pressure-flow relationships change. The airflow is no longer directly proportional to the driving pressure as with laminar flow; rather, the driving pressure to produce a given rate of airflow is proportional to the square of flow (ΔP∝ρ
2 ). Also, the driving pressure is dependent on gas density but is little affected by viscosity. Turbulent flow dominates in the more central airways, where
is high because airway caliber is large but the total cross-section area is small.
Whether the pattern of flow is laminar or turbulent is determined from the Reynolds number (Re), a dimensionless number that depends on the rate of airflow ( ), the density (ρ) and viscosity (μ) of gas, and the radius of the tube (r), according to the equation:
In straight, smooth, rigid tubes, turbulence results when the Reynolds number exceeds 2000. It is apparent that turbulence is most likely to occur when the rate of airflow and the gas density are high, the viscosity is low, and the tube radius is small. However, even at low flow during expiration, particularly at branches in the tracheobronchial tree where flow in two separate tubes comes together into a single one, the parabolic profile of laminar flow may become blunted, the streamlines may separate from the walls of the tube, and minor eddy formations may develop. This is referred to as a mixed or transitional flow pattern. With a mixed flow pattern, the driving pressure to produce a given flow depends on both the viscosity and the density of the gas.
In addition to pressure dissipation to generate flow, expiration requires some energy to accelerate the gas moving from the large cross-sectional area of the respiratory zone to the smaller cross-sectional area of conducting zone (bronchi, trachea). The ΔP caused by convective acceleration is described by the Bernoulli equation, ΔP=½ρ( /A) 2 , where A is cross-section area.
In a normal lung, the laminar flow pattern occurs only in the very small peripheral airways, where the flow through any given airway is extremely low. In the remainder of the tracheobronchial tree, flow is transitional, and in the trachea, turbulence regularly occurs.
Determinants of Maximal Expiratory Flow (see Plate 2-10 )
An assessment of the flow-resistive properties of the airways is obtained from the flow-volume relationship during a forced expiratory maneuver. An individual inhales maximally to TLC and then exhales to RV as rapidly as possible. During this maneuver, the airflow rises quickly to a maximal value at a lung volume close to TLC. As lung volume decreases, its recoil pressure decreases, the intrathoracic airways narrow, the airway resistance increases, and the airflow decreases almost linearly.
A family of flow-volume curves can be obtained by repeating full expiratory maneuvers over the entire VC at different levels of effort. At lung volumes close to TLC, the airflow increases progressively with increasing effort. At intermediate and low lung volumes, expiratory flow reaches maximal levels with moderate efforts and thereafter increases no further despite increasing efforts. If pleural pressure is measured during such maneuvers, the relationship among lung volume, effort, and expiratory airflow can be explored by plotting a family of isovolume pressure-flow curves . At all lung volumes, pleural pressure becomes less subatmospheric and subsequently exceeds atmospheric pressure as the expiratory effort is progressively increased. Correspondingly, the airflow increases. At lung volumes greater than 75% of VC, the airflow increases continuously with increasing pleural pressure and is thus considered to be effort dependent. In contrast, at volumes below 75% of VC, flow levels off as pleural pressure exceeds atmospheric pressure but does not increase further with increases in effort and is thus considered to be effort independent. Because airflow remains constant despite an increase in driving pressure, it follows that the resistance to airflow must also be increasing proportionally with pleural pressure, probably because of compression and narrowing of intrathoracic airways.
An explanation of this phenomenon is illustrated by a simple model of the lung. Alveoli are represented by an elastic sac and intrathoracic airways by a compressible tube, both enclosed within a pleural space. At a given end-inspiratory lung volume, when airflow is arrested, pleural pressure is subatmospheric and counterbalances the elastic recoil pressure of the lung. The alveolar pressure (i.e., the sum of the elastic recoil pressure of the lung and pleural pressure) is zero. Because airflow has ceased, pressures along the entire airway are also at atmospheric levels. During a forced expiration, pleural pressure increases above atmospheric pressure and increases alveolar pressure. Airway pressure decreases progressively from the alveolus toward the airway opening to overcome viscous resistance. At a point along the airway, referred to as the equal pressure point , the decrease in airway pressure from that in the alveolus equals the recoil pressure of the lung. At this point, the intraluminal pressure equals the pressure surrounding the airways (i.e., the pleural pressure). Downstream, the intraluminal pressure decreases below pleural pressure, thus resulting in a negative transmural pressure, and the airways are dynamically compressed.
The airways can be divided into two segments arranged in series, one upstream (i.e., from alveoli to the equal pressure point) and one downstream (i.e., from the equal pressure point to the airway opening). As soon as maximal expiratory flow is achieved, further increases in pleural pressure with increasing expiratory force simply produce more compression of the downstream segment but do not affect airflow through the upstream segment.
The driving pressure of the upstream segment (i.e., the pressure decrease from alveoli to equal pressure point) equals the lung elastic recoil pressure. Consequently, the airflow during forced expiration ( max ) represents the ratio of lung elastic recoil pressure (P L ) to the resistance of the upstream segment (Rus), according to the equation:
However, because the caliber of a given airway at the flow-limiting site also depends on airway wall stiffness, the maximal flow ( 
max ) during forced expiration will be:
The quantity (A/ρ · ΔP/ΔA) 1/2t is the speed that a small wave propagates in a compressible tube and is related to tube area (A), gas density (ρ), and tube wall stiffness (ΔP/ΔA). The wave speed theory of flow limitation thus demonstrates that maximal flow is increased for airways with greater area or greater wall stiffness and gases of lower density.
Forced Expiratory Maneuver (see Plate 2-11 )
The magnitude of airflow during a forceful expiration from TLC to RV provides an indirect measure of the flow-resistive properties of the lung. This is because a maximal effort is not required to achieve maximal flow at intermediate and low lung volumes. Thus, parameters measured over most of a forced expiratory maneuver are little affected by suboptimal efforts and are good, albeit indirect, indexes of airway resistance. This so-called FVC maneuver is usually recorded as volume exhaled against time ( spirogram ). For clinical purposes, the volume exhaled during the first second (i.e., FEV 1 ) is measured and expressed as a ratio to FVC.
The FEV 1 /FVC ratio is generally taken as an index of airway function; a decrease in FEV 1 below the normal range with less or no change in FVC is consistent with an obstructive disorder, (e.g., bronchial asthma, chronic bronchitis, emphysema). A normal FEV 1 /FVC ratio in the presence of similar decrements of both FEV 1 and FVC may be taken as suggestive of a restrictive disorder (pulmonary fibrosis, obesity, neuromuscular disease), but it may occasionally occur in airflow obstruction, when the only abnormality is an increase in RV caused by airway closure. Therefore, the diagnosis of restrictive abnormality requires the measurement of TLC. The reduction of FEV 1 is generally taken as an estimate of severity for either obstructive or restrictive abnormalities as determined by spirometry.
A forced expiratory VC maneuver can be also displayed as airflow against expired volume. This plot, called maximal expiratory flow-volume curve , is particularly useful for quality control of forced expiratory maneuver. In obstructive disorders, the descending limb of the expiratory flow-volume curve shows an upward concavity, a shape that can be numerically described by taking instantaneous flows at specific lung volumes, such as 75%, 50%, and 25% of FVC, but their clinical significance is debated, and they should not be used for diagnosis.
Comparing tidal with forced expiratory flow-volume curves allows one to estimate the occurrence of expiratory flow limitation during breathing. This mechanism is responsible for dynamic lung hyperinflation, which is an increase of FRC above the relaxation volume of the system. When maximal flow is attained during tidal breathing because of bronchoconstriction or exercise hyperpnea, the only way to maintain or increase minute ventilation is to breathe at increased lung volume, at which greater expiratory flows can be generated. Occurrence or relief of dynamic lung hyperinflation and expiratory flow limitation during tidal breathing can be simply inferred from changes in inspiratory capacity (difference between FRC and TLC).
Flow limitation during tidal expiration may be present either in obstructive disorders because maximal flows are reduced or in restrictive disorders because breathing occurs at low lung volume. In restrictive disorders, all lung volumes are reduced, and flow is low throughout expiration even if, with respect to absolute lung volume, it may be greater than normal.
Dynamic Lung Compliance and Work of Breathing (see Plate 2-12 )
Changes in lung volume and pleural pressure during a breathing cycle, displayed as a pressure-volume loop , describe elastic and flow-resistive properties of the lung as well as the work performed by the respiratory muscles on the lung.
At the end of both expiration and inspiration, airflow is zero; the difference in pleural pressure between these two points reflects the increasing elastic recoil as lung volume enlarges. The slope of the line connecting end-expiratory and end-inspiratory points on the pressure-volume loop provides a measure of dynamic lung compliance . In addition, during inspiration, the change in pleural pressure at any given lung volume reflects not only the pressure needed to overcome lung elastic recoil but also the pressure required to overcome airway and lung tissue resistances.
In normal individuals, dynamic lung compliance closely approximates static lung compliance and remains essentially unchanged when breathing frequency is increased up to 60 breaths/min. This is because lung units in parallel with each other normally fill and empty evenly and synchronously, even when airflow is high and lung volume changes rapidly. For the distribution of ventilation to parallel lung units to be independent of airflow, their time constants (i.e., the products of resistance and compliance) must be approximately equal. In the presence of uneven distribution of time constants, a given change in pleural pressure produces a smaller overall change in lung volume, and dynamic compliance decreases. However, because the time constants of lung units distal to airways with 2-mm diameter are on the order of 0.01 second, fourfold differences in time constants are necessary to cause dynamic compliance to decrease with increasing frequency. The frequency dependence of dynamic compliance is a time-consuming and technically difficult test, but it is sensitive to changes in peripheral airways when conventional measurements of lung mechanics (i.e., static compliance, overall airway resistance) are still within normal limits.
The mechanical work of breathing (W) performed by the respiratory muscles can be readily evaluated during spontaneous breathing from changes in pleural pressure (P) and lung volume (V) according to the equation:
During quiet breathing, lung elastic recoil is sufficient to overcome nonelastic forces during expiration, which is therefore passive. At high levels of ventilation or when airway resistance is increased, additional mechanical work may be required to overcome nonelastic forces during expiration; pleural pressure must exceed atmospheric pressure, and expiration is no longer passive.
The work of breathing at any given level of ventilation depends on the pattern of breathing. Whereas large TVs increase the elastic work of inspiration, high breathing frequencies increase the work against flow-resistive forces. During quiet breathing and exercise, individuals tend to adjust TV and breathing frequency at values that minimize the work of breathing. Patients with pulmonary fibrosis and increased elastic work of breathing tend to breathe shallowly and rapidly. Patients with airway obstruction tend to breathe at increased lung volume (dynamic lung hyperinflation) to minimize airway resistance, although this is associated with increased elastic work on inspiration.
From the point of view of energy requirements, the work of breathing can be considered as oxygen cost of breathing. In normal individuals, this is approximately 1 mL oxygen per liter of ventilation, which is less than 5% of total oxygen consumption but increases with increasing ventilation. Thus, the oxygen consumed by respiratory muscles can be inferred from the increase in total oxygen consumption when ventilation is increased, either voluntarily or in response to breathing carbon dioxide. Patients with pulmonary disorders demonstrate an increased oxygen cost of quiet breathing as well as a disproportionate increase at elevated levels of ventilation.
Pleural Pressure Gradient and Closing Volume (see Plate 2-13 )
In the upright position, pleural pressure is more negative with respect to atmospheric pressure at the apex of the lung than at the base. Pleural pressure increases by approximately 0.25 cm H 2 O per centimeter of vertical distance from the top to the bottom of the lung because of the weight of the lung and the effects of gravity. Because of these differences in pleural pressure, the transpulmonary pressure is greater at the top than at the bottom of the lung, so at most lung volumes, the alveoli at the lung apices are more expanded than those at the lung bases.
At low lung volumes approaching RV, the pleural pressure at the bottom of the lung actually exceeds intraluminal airway pressure and leads to closure of peripheral airways at the lung bases. The first portion of a breath taken from RV thus enters alveoli at the lung apex. However, in the TV range and above, because of regional variations in lung compliance, ventilation per alveolus is greater at the bottom than at the top of the lung.
The distribution of ventilation and volume at which airways at the lung bases begin to close can be assessed by the single-breath nitrogen washout and closing volume test (see Plate 2-13 ). The concentration of nitrogen at the mouth is measured and plotted against expired lung volume after a single full inspiration of 100% oxygen from RV to TLC. The initial portion of the inspiration, which consists of dead-space gas rich in nitrogen, goes to the upper lung zones, and the remainder of the breath, containing only oxygen, is distributed preferentially to the lower lung zones. The result is that the concentration of oxygen in the alveoli of the lung bases is greater than in those of the lung apices.
During the subsequent expiration, the initial portion of the washout consists of dead space and contains no nitrogen ( phase I ). Then, as alveolar gas containing nitrogen begins to be washed out, the concentration of nitrogen in the expired air rises to reach a plateau. The portion of the curve where the concentration of nitrogen rises steeply is called phase II , and the plateau is referred to as phase III . Provided gas enters and leaves all regions of lung synchronously and equally, phase III will be flat. When the distribution of ventilation is nonuniform, gas coming from different alveoli will have different nitrogen concentrations, producing an increasing nitrogen concentration during phase III.
At low lung volumes, when the airways at the lung bases close, only the alveoli at the top of the lung continue to empty. Because the concentration of nitrogen in the alveoli of the upper lung zones is higher, the slope of the nitrogen-volume curve ( phase IV ) abruptly increases. The volume at which this increase in slope occurs is referred to as the closing volume .
With pathologic changes occurring in peripheral airways less than 2 to 3 mm in diameter, the closing volume and the slope of phase III increase. Although the single-breath nitrogen test is considered sensitive for early diagnosis of small airway disease, its specificity is low because loss of lung elastic recoil also increases the closing volume. This feature accounts for the progressive increase in closing volume seen with advancing age in normal individuals.
PULMONARY CIRCULATION
Mixed venous blood from the systemic circulation is collected in the right atrium and passes to the right ventricle (see Plate 2-14 ). Contraction of the right ventricle delivers the entire cardiac output along the pulmonary arteries to the capillary bed where gas exchange takes place. The pulmonary capillaries consist of a fine network of thin-walled vessels, but because the surface area of the capillary bed is approximately 70 m 2 , it may be regarded as a sheet of flowing blood rather than as individual channels. At any one moment, the pulmonary capillary bed holds only about 100 mL of blood; most of the remainder of the blood in the pulmonary circulation is contained in the compliant pulmonary venules and veins which, along with the left atrium, serve as a reservoir for the left ventricle.
Intravascular Pressure
The systemic circulation distributes blood flow to various organs such as the muscles, kidneys, and gastrointestinal tract in response to their specific requirements. By contrast, the pulmonary circulation is concerned only with blood flow through the lungs. Pulmonary vascular pressures are very low compared with those in the systemic circulation; systolic pulmonary artery pressure is approximately 25 mm Hg, diastolic pressure is 8 mm Hg, and mean arterial pressure is about 14 mm Hg. Pressure in the left atrium is 5 mm Hg, only slightly less than the pressure in the large pulmonary veins. The pressure decrease across the entire pulmonary circulation—the difference between mean pulmonary artery pressure and mean left atrial pressure—constitutes the driving pressure that produces blood flow through the lungs.
Blood Flow
Pulmonary capillary blood flow ( 
c ) can be determined in a number of ways. The Fick method makes use of the principle that the rate of oxygen taken up by the blood ( o 2 ) as it passes through the lungs is given by the product of 
c . The difference in oxygen content between arterial and mixed venous blood (Ca o 2 and Cv o 2 , respectively) c can thus be calculated as:
c can also be measured by the thermodilution and indicator dilution techniques, in which a tracer substance is injected into the venous system, and its concentration in the arterial blood is recorded as a function of time. The Fick and dilution methods measure blood flow averaged over many heartbeats.
Distribution of Pulmonary Blood Flow (see Plate 2-14 )
Gravity has a major effect on the distribution of blood flow throughout the lungs, causing flow to be greater at the bottom than at the top in the upright position. Blood flow is also influenced by the resistance of the vascular pathway it must traverse in moving from artery to vein, and this resistance tends to increase with path length. This causes the pattern of blood flow distribution to decrease with distance from the hilum of the lung. Blood flow becomes more evenly distributed in the supine position and during exercise.
Normally, pulmonary artery pressure is just sufficient to deliver blood to the lung apices at rest. Consequently, a decrease in hydrostatic pressure produced by hemorrhage or shock may lower intravascular pressure at the lung apex below alveolar pressure, causing the highly compliant alveolar blood vessels to become compressed even to the point of complete occlusion. Under these circumstances, this area at the lung apex is called zone 1. Farther down the lung, there is a region called zone 2 within which pulmonary artery pressure is greater than alveolar pressure because of the hydrostatic gradient, but where alveolar pressure is still greater than venous pressure. Still farther down the lung, gravity increases hydrostatic vascular pressures to the point that venous pressure exceeds alveolar pressure. Within this region, known as zone 3, blood flow is determined principally by the difference between pulmonary arterial and venous pressures. Descending through zone 3, the transmural pressure across the capillary wall increases, which causes distension of already open vessels and recruitment of new ones, leading to an increase in flow. Finally, at the very bottom of the lung, these effects are offset by a decrease in the outward elastic recoil forces exerted by the parenchyma on the extraalveolar vessel walls, and overall pulmonary vascular resistance increases again.
Pulmonary Vascular Resistance
Pulmonary vascular resistance (see Plate 2-15 ) is calculated from the decrease in blood pressure across the pulmonary circulation (i.e., the difference between mean pulmonary artery pressure and mean left atrial pressure) and c according to the vascular equivalent of Ohm's law for electric circuits. That is:
Blood flow through the pulmonary circulation is essentially the same as that through the systemic circulation, yet the pressure drop across the pulmonary circulation is only one-tenth that across the systemic circulation. It follows that pulmonary vascular resistance is one-tenth of the systemic resistance. The major sites of pulmonary vascular resistance are the arterioles and capillaries.
The pulmonary circulation is able to accommodate several fold increases in 
c , such as occur during exercise, with only small changes in pulmonary artery pressure. This means that as c increases, pulmonary vascular resistance must decrease. There are two principal mechanisms by which this occurs; blood vessels already conducting blood increase their caliber, and vessels that were previously closed are recruited to increase the number of vessels transporting blood in parallel.
Pulmonary blood vessels are extremely thin walled and compliant, so their caliber is greatly influenced by transmural pressure (i.e., the difference in pressure inside and outside the vessel wall). The smallest pulmonary capillaries are surrounded by alveoli and thus are subjected externally to alveolar pressure. Increases in alveolar pressure produced, for example, by positive-pressure mechanical ventilation can compress these vessels to the point of closure. Even increases in lung volume during spontaneous breathing tend to increase the resistance of these alveolar vessels because the longitudinal stretching that occurs causes the vessel walls to approach each other. By contrast, larger blood vessels are tethered outwardly by the lung parenchyma, which acts like a spring to hold the vessels open. The parenchymal attachments effectively apply pleural pressure to the outside of the vessel wall. Consequently, as lung volume increases, the outward pull on these extraalveolar vessels also increases, causing the vessels to dilate and their resistance to decrease. Overall pulmonary vascular resistance is probably lowest at FRC.
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