The principal physiologic role of the lungs is to make oxygen available to tissues for metabolism and to remove the main byproduct of that metabolism, carbon dioxide. The lungs perform this function by moving inspired air into close proximity to the pulmonary capillary bed to enable gas exchange by simple diffusion. This is accomplished at a minimal workload, is regulated efficiently over a wide range of metabolic demand, and takes place with close matching of ventilation to lung perfusion. The extensive surface area of the respiratory system must also be protected from a broad variety of infectious or noxious environmental insults.

Humans possess a complex and efficient respiratory system that satisfies these diverse requirements. When injury to components of the respiratory system occurs, the integrated function of the whole is disrupted. The consequences can be profound. Airway injury or dysfunction results in obstructive lung diseases, including bronchitis and asthma, whereas parenchymal lung injury can produce restrictive lung disease or pulmonary vascular disease. To understand the clinical presentations of lung disease, it is necessary first to understand the anatomic and functional organization of the lungs that determines normal function.

Anatomy

The mature respiratory system consists of visceral pleura-covered lungs contained by the chest wall and diaphragm, the latter serving under normal conditions as the principal bellows muscle for ventilation. The lungs are divided into lobes, each demarcated by intervening visceral pleura. Each lung possesses an upper and lower lobe; the middle lobe and lingula are the third lobes in the right and left lungs, respectively. At end expiration, most of the volume of the lungs is air (Table 9–1), whereas almost half of the mass of the lungs is accounted for by blood volume. It is a testament to the delicate structure of the gas-exchanging region of the lungs that alveolar tissue has a total weight of only 250 g but a total surface area of 75 m².

Connective tissue fibers and surfactant serve to maintain the anatomic integrity of this large and complex surface area. The connective tissue fibers are highly organized collagen and elastic structures that radiate into the lungs. These fibers divide segments, invest airways and vessels, and support alveolar walls with a delicate, elastic fibrous network. The multidirectional elastic support provided by this network allows the lung, from alveoli to conducting airways, to support itself and retain airway patency despite large changes in volume.

Surfactant is a complex material produced by type II alveolar cells and composed of multiple phospholipids and specific associated proteins. The physiologic function of surfactant is to enhance the anatomic stability of the lungs. The presence of surfactant covering the alveolar epithelial surface reduces surface tension, allowing expansion of alveoli with a transpulmonary distending pressure of less than 5 cm H₂O. In the absence of this surface-active layer, increasing surface tension associated with a reduction of alveolar volume during expiration would collapse alveoli. The distending pressure required to reexpand these alveoli would be greater than normal ventilatory effort could produce.

Airway & Epithelial Anatomy

Further anatomic division of the lungs is based primarily on the separation of the tracheobronchial tree into conducting airways, which provide for movement of air from the external environment to areas of gas exchange, and terminal respiratory units, or acini, the airways and associated alveolar structures participating directly in gas exchange (Figure 9–1). The proximal conducting airways are lined by ciliated pseudostratified columnar epithelial cells, are supported by a cartilaginous skeleton in their walls, and contain secretory glands in the epithelial wall. The ciliated epithelium has a uniform orientation of cilia that beat in unison toward the pharynx. This ciliary action, together with the mucus layer produced by submucosal mucous secretory glands, provides a mechanism for the continuous transport of contaminating or excess material out of the lungs. Circumferential airway smooth muscle is also present but, as with secretory glands, is reduced and then lost as the airways branch farther into the lung and diminish in caliber. The smallest conducting airways are nonrespiratory bronchioles. They are characterized by a loss of smooth muscle and cartilage but retention of a cuboidal epithelium that may be ciliated and is not a site of gas exchange. The lobes of the lung are divided into less distinct lobules, defined as collections of terminal respiratory units incompletely bounded by connective tissue septa. Terminal respiratory units are the final physiologic and anatomic unit of the lung, with walls of thin alveolar epithelial cells that provide gas exchange with the alveolar-capillary network.

The principal site of resistance to airflow in the lungs is in medium-sized bronchi (Figure 9–2). This seems counterintuitive because one would expect smaller caliber airways to be the major site of resistance. Repetitive branching of the small airways leads to a profound increase in cross-sectional area that does not contribute significantly to airway resistance in healthy individuals (Figure 9–3). Under pathologic conditions such as asthma, in which smaller bronchi and bronchioles become narrowed, airway resistance can increase dramatically.

The pulmonary arteries are found in close association with the branching bronchial tree in the lungs (Figure 9–4). Both arterial blood flow and bronchial airflow are actively regulated by changing vessel or airway caliber. The anatomic relationship between arteries and bronchi provides an ideal setting for the continuous matching of ventilation and perfusion to different lung segments.

Vascular & Lymphatic Anatomy

The pulmonary vascular system includes two distinct circuits that distribute blood through the lungs, the pulmonary and bronchial circulations. The right ventricle pumps its entire output of mixed venous blood through pulmonary arteries toward alveolar capillaries. Pulmonary arteries and arterioles are smooth muscle–invested vessels located adjacent to bronchi within the pulmonary bronchovascular bundle. Pulmonary arterioles are very sensitive to alveolar PO₂, with a prominent vasoconstrictor response to hypoxia. Hypoxic pulmonary vasoconstriction allows matching of alveolar perfusion to ventilation (see below). Pulmonary veins arise from alveolar capillaries to form vessels that traverse the intralobular septa to return oxygenated blood to the left atrium.

Bronchial arteries that arise from the aorta and intercostal arteries deliver oxygenated blood at systemic pressures to nearly all of the intrapulmonary structures proximal to the terminal bronchioles, including the bronchial tree, hilar structures, pulmonary arteries and veins, pulmonary nervous system and lymphatics, connective tissue septa, and visceral pleura. Most lung tumors receive their blood supply from the bronchial circulation. There are abundant bronchopulmonary anastomoses at the arteriolar and capillary levels that are silent in health but may enlarge in disease to contribute to hemoptysis. Drainage of the bronchial circulation occurs both to the right atrium via the azygos vein and to the left atrium via the pulmonary veins. The latter represents an anatomic shunt of deoxygenated blood, typically representing less than 5% of cardiac output.

Pulmonary lymphatics arise in connective tissue spaces beneath the visceral pleura and in deep plexuses at the junction of the terminal bronchioles and alveoli. Lymphatics do not enter the alveolar peri-interstitial space (Figure 9–4). As a result, fluid in the alveolar interstitium must move to the region of terminal bronchioles to gain access to draining lymphatics. Lymphatic ducts travel principally in the peribronchovascular sheath back to hilar and mediastinal lymph nodes before entering the left thoracic duct or right lymphatic duct. Lymphatic drainage of the pleural space occurs through plexuses investing the costal, diaphragmatic, and mediastinal parietal pleura that are anatomically separate from pulmonary lymphatics.

Pulmonary Nervous System

The lungs are richly innervated with neural fibers from parasympathetic (vagal), sympathetic, and the so-called nonadrenergic, noncholinergic (NANC) systems. Efferent fibers include the following: (1) parasympathetic fibers, with muscarinic cholinergic efferents that mediate bronchoconstriction, pulmonary vasodilation, and mucous gland secretion; (2) sympathetic fibers, whose stimulation produces bronchial smooth muscle relaxation, pulmonary vasoconstriction, and inhibition of secretory gland activity; and (3) the NANC system, with multiple transmitters implicated, including adenosine triphosphate (ATP), nitric oxide (NO), and peptide neurotransmitters such as substance P and vasoactive intestinal peptide (VIP). The NANC system participates in inhibitory events, including bronchodilation, and may function as the predominant reciprocal balance to the excitatory cholinergic system.

Pulmonary afferents consist principally of the vagal sensory fibers. These include the following:

1. 
   

   Fibers from bronchopulmonary stretch receptors, located in the trachea and proximal bronchi. Stimulation of these fibers by lung inflation results in bronchodilation and an increased heart rate.

   
   
2. 
   

   Fibers from irritant receptors, which are also found in proximal airways. Stimulation of these fibers by diverse nonspecific stimuli elicits efferent responses, including cough, bronchoconstriction, and mucus secretion.

   
   
3. 
   

   C fibers, or fibers from juxtacapillary (J) receptors, are unmyelinated fibers ending in lung parenchyma and bronchial walls and respond to mechanical and chemical stimuli. The reflex responses associated with stimulation of C fibers include a rapid shallow breathing pattern, mucus secretion, cough, and heart rate slowing with inspiration.

Immune Structure & Function

Of all the body’s organs, the lungs have a unique exposure to environmental insults. Nonexertional ventilation in an adult totals about 7500 L of air per day, an amount that is increased substantially with activity. This exposure to an open, nonsterile environment imposes an ongoing risk of toxic, infectious, and inflammatory insults. Furthermore, the pulmonary circulation contains the only capillary bed through which the entire circulating blood volume must flow in each cardiac cycle. As a consequence, the lung is an obligatory vascular sieve and functions as a principal site of defense against hematogenous spread of infection or other noxious influences. Protection of the lungs from environmental and infectious injury involves a set of complex responses capable of providing timely and successful defense against attack via the airways or the vascular bed. As outlined in Table 9–2, it is convenient for discussion purposes to separate these responses into two major categories—nonspecific physical and chemical protections and specific immune structures and actions—all functioning to prevent injury to or microbial invasion of the very large epithelial and vascular area of the lung.

Physiology

At rest, the lungs take 4 L/min of air and 5 L/min of blood, direct them within 0.2 μm of each other, and then return both to their respective pools. With maximal exercise, flow may increase to 100 L/min of ventilation and 25 L/min of cardiac output. The lungs thereby perform their primary physiologic function of making oxygen available to the tissues for metabolism and removing the major byproduct of that metabolism, carbon dioxide. The lungs perform this task largely free of conscious control while maintaining PaCO₂ within 5% tolerance. It is a magnificent feat of evolutionary plumbing and neurochemical control.

Static Properties: Compliance & Elastic Recoil

The lung maintains its extremely thin parenchyma over an enormous surface area by means of an intricate supporting architecture of collagen and elastin fibers. Anatomically, as well as physiologically and functionally, the lung is an elastic organ.

The lungs inflate and deflate in response to changes in volume of the semirigid thoracic cage in which they are suspended. An analogy would be to inflate a blacksmith’s bellows by pulling the handles apart, thus increasing the volume of the bellows, lowering pressure, and causing inflow of air. Air enters the lungs when pressure in the pleural space is reduced by the expansion of the chest wall. The volume of air entering the lungs depends on the change in pleural pressure and the compliance of the respiratory system. Compliance is an intrinsic elastic property that relates a change in volume to a change in pressure. The compliance of both the chest wall and the lungs contribute to the compliance of the respiratory system (Figure 9–5). The compliance of the chest wall does not change significantly with thoracic volume, at least within the physiologic range. The compliance of the lungs varies inversely with lung volume. At functional residual capacity (FRC), the lungs are normally very compliant, approximately 200 mL/cm H₂O. Thus, a reduction of only 5 cm H₂O pressure in the pleural space will draw a breath of 1 L.

The tendency of a deformable body to return to its baseline shape is its elastic recoil. The elastic recoil of the chest wall is determined by the shape and structure of the thoracic cage. Lung elastic recoil is determined by two factors, tissue elasticity and the forces needed to change the shape of the air-liquid interface of the alveolus (Figure 9–6). Expanding the lungs requires overcoming local surface forces that are directly proportionate to alveolar surface tension. Surface tension is a physical property that reflects the greater attraction between molecules of a liquid than between molecules of that liquid and adjacent gas. At the air-liquid interface of the lung, molecules of water at the interface are more strongly attracted to each other than they are to the air above. This creates a net force drawing water molecules together in the plane of the interface. If the interface is stretched over a curved surface, that force acts to collapse the curve. The law of Laplace quantifies this force: The pressure needed to keep open the curve (in this case represented by a sphere) is directly proportionate to the surface tension at the interface and inversely proportionate to the radius of the sphere (Figure 9–7).

Surfactant is a mixture of phospholipid (predominantly dipalmitoylphosphatidylcholine [DPPC]) and specific surfactant proteins. These hydrophobic molecules displace water molecules from the air-liquid interface, thereby reducing surface tension. This reduction has three physiologic implications. First, it reduces the elastic recoil pressure of the lungs, thereby reducing the pressure needed to inflate them. This results in reduced work of breathing. Second, it allows surface forces to vary with alveolar surface area, thereby promoting alveolar stability and protecting against atelectasis (Figure 9–7). Third, it limits the reduction of hydrostatic pressure in the pericapillary interstitium caused by surface tension. This reduces the forces promoting transudation of fluid and the tendency to accumulate interstitial edema.

Pathologic states may result from changes in lung elastic recoil related to an increase in compliance (emphysema), a decrease in compliance (pulmonary fibrosis), or a disruption of surfactant with an increase in surface forces (infant respiratory distress syndrome [IRDS]) (Figure 9–8).

Dynamic Properties: Flow & Resistance

Inflation of the lungs must overcome three opposing forces: elastic recoil, including surface forces; inertia of the respiratory system; and resistance to airflow. Since inertia is negligible, the work of breathing can be divided into work to overcome elastic forces and work to overcome flow resistance.

Increased elastic forces predominate in two common disorders, diffuse parenchymal fibrosis and obesity. The reduction in lung compliance in fibrotic lung disease, and in chest wall and respiratory system compliance in obesity, increases the work of breathing. Obese subjects also experience increased airflow resistance, largely though not entirely because of their tendency to breathe at lower lung volumes.

Flow resistance depends on the nature of the flow. Under conditions of laminar or streamlined flow, resistance is described by the Poiseuille equation: Resistance is directly proportionate to the length of the airway and the viscosity of the gas, and inversely proportionate to the fourth power of the radius. A reduction by one half of airway radius leads to a 16-fold increase in airway resistance. Airway caliber is, therefore, the principal determinant of airway resistance under laminar flow conditions. Under conditions of turbulent flow, the driving pressure needed to achieve a given flow rate is proportionate to the square of the flow rate. Turbulent flow is also dependent on gas density and not on gas viscosity.

Most of the resistance to normal breathing arises in medium-sized bronchi and not in smaller bronchioles (Figure 9–2). There are three main reasons for this counterintuitive finding. First, airflow in the normal lung is not laminar but turbulent, at least from the mouth to the small peripheral airways. Thus, where flow is highest (in segmental and subsegmental bronchi), resistance is dependent chiefly on flow rates. Second, in small peripheral airways, where airway caliber is the principal determinant of resistance, repetitive branching creates a very large number of small airways arranged in parallel. Their resistance is reciprocally additive, making their contribution to total airway resistance minor under normal conditions. Third, there is a transition to laminar flow approaching the terminal bronchioles as a consequence of increased cross-sectional area and decreased flow rates (Figure 9–3). In the respiratory bronchioles and alveoli, bulk flow of gas ceases and gas movement occurs by diffusion.

Airway resistance is determined by several factors. Many disease states affect bronchial smooth muscle tone and cause bronchoconstriction, producing an abnormal narrowing of the airways. Airways may also be narrowed by hypertrophy (chronic bronchitis) or infiltration (sarcoidosis) of the airway mucosa. Physiologically, the radial traction of the lung interstitium supports the airways and increases their caliber as lung volume increases. Conversely, as lung volume decreases, airway caliber also decreases and resistance to airflow increases. Patients with airflow obstruction often breathe at large lung volumes because higher volumes tend to increase elastic lung recoil, maximize airway caliber, and minimize flow resistance.

Analysis in terms of laminar and turbulent flow assumes that airways are rigid tubes. In fact, they are highly compressible. The compressibility of the airways underlies the important phenomenon of effort-independent flow; airflow rates during expiration can be increased with effort only up to a certain point. Beyond that point, further increases in effort do not increase flow rates. The explanation for this phenomenon relies on the concept of an equal pressure point. Pleural pressure is generally negative (sub-atmospheric) throughout quiet breathing. Peribronchiolar pressure, the pressure surrounding small, noncartilaginous conducting airways, is closely related to pleural pressure. Hence, during quiet breathing, conducting airways are surrounded by negative pressure that helps to keep them open. Pleural and peribronchiolar pressure becomes positive during forced expiration, subjecting distensible conducting airways to positive pressure. The equal pressure point occurs where the surrounding peribronchiolar pressure equals or exceeds pressure inside the airway, causing dynamic compression of the airways, which leads to instability and potential airway collapse (Figure 9–9).

The equal pressure point is not an anatomic site but a functional result that helps to clarify different mechanisms of airflow obstruction. Because the driving pressure of expiratory airflow is principally lung elastic recoil pressure, a loss of lung elasticity that reduces recoil pressure without changing pleural or peribronchiolar pressure will lead to dynamic compression at higher lung volumes. The resultant air trapping contributes to symptomatic dyspnea in patients with obstructive lung disease. Patients with emphysema lose lung elastic recoil and may have severely impaired expiratory flow even with airways of normal caliber. The presence of airway disease will increase the drop in driving pressure along the airways and may generate an equal pressure point at even higher lung volumes. Conversely, an increase in recoil pressure will oppose dynamic compression. Patients with pulmonary fibrosis may have abnormally high flow rates despite severely reduced lung volumes.

The Work of Breathing

A constant minute ventilation can be achieved through multiple combinations of respiratory rate and tidal volume. The two components of the work of breathing—elastic forces and resistance to airflow—are affected in opposite ways by changes in frequency and depth of breathing. Elastic resistance is minimized by frequent, shallow breaths; resistive forces are minimized by fewer, larger tidal volume breaths. Figure 9–10 shows how these two components can be summed to provide a total work of breathing for different frequencies at a fixed minute ventilation. The set point for basal respiration is that point at which the total work of breathing is minimized. In normal humans, this occurs at a frequency of approximately 15 breaths/min. In different diseases, this pattern is altered to compensate for the underlying physiologic abnormality.

The amount of energy needed to maintain the respiratory muscles during quiet breathing is small, approximately 2% of basal oxygen consumption. In patients with lung disease, the energy requirements are greater at rest and increase dramatically with exercise. Patients with emphysema may not be able to increase their ventilation by more than a factor of 2 because the oxygen cost of breathing exceeds the additional oxygen made available to the body.

Oxygen Transport

Oxygen is poorly soluble in blood. At a temperature of 37°C and an oxygen partial pressure of 100 mm Hg (PaO₂ = 100), total oxygen dissolved in 100 mL of whole blood is approximately 0.3 mL. Because basal oxygen consumption in the average adult human is approximately 250 mL/min, dissolved oxygen content would be inadequate to meet metabolic demands. Instead, the high oxygen needs of complex internal organs are met by a soluble protein that binds oxygen rapidly, reversibly, and with a high storage capacity, namely, hemoglobin.

Hemoglobin is a complex tetramer of two alpha and two beta polypeptide chains, each of which contains a heme group with an iron atom in the ferrous form (Fe²⁺) at its center capable of binding molecular oxygen (O₂). Each molecule of hemoglobin can bind four oxygen molecules. Under physiologic conditions, 1 g of fully saturated hemoglobin can carry approximately 1.34 mL of oxygen. Therefore, 100 mL of blood containing 15 g/dL of saturated hemoglobin contains 20.1 mL of O₂, nearly 70 times the amount in solution. The conventional way to represent oxygen bound to hemoglobin is the hemoglobin saturation (SO₂), the ratio of oxygen bound to hemoglobin divided by the total oxygen binding capacity, typically expressed as a percentage. Note that SO₂ alone does not determine oxygen content. Blood oxygen content is the sum of two terms, dissolved oxygen and oxygen bound to hemoglobin. Dissolved oxygen is a linear function of the oxygen partial pressure (PO₂) and solubility, while oxygen bound to hemoglobin is the product of three terms, oxygen-carrying capacity, hemoglobin concentration, and hemoglobin saturation (SO₂):

CO₂ = (0.003 × PO₂) + (1.34 × [Hemoglobin] × SO₂)

This equation explains why oxygen content and tissue oxygen delivery may be low despite 100% SO₂ if hemoglobin concentration is markedly reduced.

Because of its physical chemistry, hemoglobin saturation has a complex relationship with the partial pressure of oxygen. Interactions among the four polypeptide chains in the heme molecule increase overall affinity for oxygen as each oxygen binding site is filled. If we graph PO₂ against SO₂ to represent the oxyhemoglobin dissociation curve, we see that the relationship is not linear but S-shaped or sigmoidal (Figure 9–11). The curve is very steep in the physiologic range, between 10 and 70 mm Hg PO₂, at which point it flattens out. This relationship explains the suitability of hemoglobin for its primary physiologic role, the reversible binding to oxygen with uptake in the lungs and release in the tissues. Above 70 mm Hg, PO₂ may vary widely with illness or altitude with minimal effect on oxygen content. From 70 to 40 mm Hg, a fall in PO₂ is associated with a proportionally larger increase in the release of oxygen while retaining a relatively high end-capillary PO₂ to promote oxygen diffusion into tissues. Below 40 mm Hg, small changes in PO₂ continue to release oxygen to tissues, down to very low PO₂ levels encountered in some capillary beds.

Distribution of Ventilation & Perfusion

Inhaled air and pulmonary arterial blood flow are not distributed equally to all lung regions. In healthy individuals, heterogeneous distribution is due principally to two factors: the effects of gravity and the fractal geometry of repetitive branching of airways and vessels.

Pleural pressure varies from the top to the bottom of the lung by approximately 0.25 cm H₂O/cm. It is more negative at the apex and more positive at the base. The effect is shifted to an anteroposterior distribution in the supine position and is greatly diminished (although not abolished) at zero gravity. Regional ventilation is dependent on regional pleural pressure (Figure 9–12). More negative pleural pressure at the lung apex causes greater expansion of apical alveoli. Because lung compliance is higher at lower lung volumes, ventilation is preferentially distributed to the lower lobes at FRC.

Pulmonary blood flow is a low-pressure system that functions in a gravitational field across 30 vertical centimeters. In the upright position, there is a nearly linear increase in blood flow from the top to the bottom of the lung. Within any horizontal (isogravitational) plane, however, there is significant heterogeneity of blood flow because of the fractal geometry of repetitive branching of vessels, resulting in heterogeneous resistance. Details of distribution are portrayed in Figure 9–13.

One additional factor that regulates blood flow is hypoxic pulmonary vasoconstriction. The smooth muscle cells of pulmonary arterioles are sensitive to alveolar PO₂ (much more so than to arterial PO₂). As alveolar PO₂ falls, there is arteriolar constriction, an increase in local resistance to flow, and redistribution of flow to regions of higher alveolar PO₂. When regionalized, this is an effective mechanism to diminish local blood flow without a significant increase in mean pulmonary arterial pressure. When it affects more than 20% of the pulmonary circulation, such as in the setting of global alveolar hypoxia, widespread pulmonary vasoconstriction increases mean pulmonary arterial pressure and may result in pulmonary hypertension.

Matching of Ventilation to Perfusion

The functional role of the lungs is to place ambient air in close proximity to circulating blood to permit gas exchange by simple diffusion. To accomplish this, air and blood flow must be directed to the same place at the same time. Optimum functioning of the respiratory system requires that ventilation be matched to perfusion.

In the normal individual, typical resting alveolar ventilation is approximately 4 L/min, whereas pulmonary artery blood flow is 5 L/min. This yields an overall ratio of ventilation to perfusion of 0.8. As noted above, ventilation and perfusion are both preferentially distributed to dependent regions at rest, although the increase in gravity-dependent flow is more marked with perfusion than with ventilation. Hence, the ratio of ventilation to perfusion is highest at the apex and lowest at the base (Figure 9–14).

Regional alterations in this overall distribution of ventilation and perfusion are referred to as V̇/Q̇ mismatch and are an extremely important phenomenon that underlies the functional impairment of many disease states. A distribution may favor high V̇/Q̇ ratios, with the limiting case being alveolar dead space (ventilation without perfusion, or V̇/Q̇ = ∞) or it may favor low V̇/Q̇ ratios, with the limiting case being a shunt (perfusion without ventilation, or V̇/Q̇ = 0). These two types of V̇/Q̇ mismatch affect respiratory function very differently.

In the normal individual, approximately one third of resting minute ventilation fills the main conducting airways. This is the anatomic dead space; it represents ventilation to areas that do not participate in gas exchange. If participating gas-exchanging regions of the lung are ventilated but not perfused, as may occur in pulmonary embolism, pulmonary vascular disease, or emphysema, these regions will also fail to function in gas exchange. Distributions shifted toward high V̇/Q̇ ratios are referred to as alveolar dead space or wasted ventilation (Figure 9–15, lower panel). Functionally, a shift toward high V̇/Q̇ ratios means that more work of breathing supports ventilation that does not participate in gas exchange, reducing the overall efficiency of ventilation.

In the absence of respiratory compensation, the primary effect of a shift toward high V̇/Q̇ ratios will be a rise in arterial PCO₂; PaO₂ may fall slightly as well. Because the respiratory control center is exquisitely sensitive to small changes in PaCO₂, however, the most common integrated response to increasing wasted ventilation is to increase total minute ventilation, thereby maintaining PaCO₂ nearly constant. PaO₂ remains normal or may be reduced if the fraction of wasted ventilation is large. The A-a ΔPO₂ is increased (discussed below). This adaptive response may be done unconsciously, but it presents a clinical problem when the individual can no longer sustain an increased minute ventilation, as in the patient with advanced emphysema.

A shift toward low V̇/Q̇ ratios occurs when regional ventilation is reduced or eliminated but perfusion persists, as might happen with atelectatic lung or in areas of lung consolidation where alveoli are filled with fluid or infected debris (Figure 9–15, mid panel). A shunt is the limiting case of a low V̇/Q̇ area where ventilation is absent and the ratio goes to zero. Pulmonary arterial (mixed venous) blood will then pass to the systemic arterial circulation without coming into contact with alveolar gas. The primary physiologic effect of such a right-to-left shunt is to reduce arterial PO₂.

Ventilation/perfusion mismatching commonly occurs between the limiting cases of true shunts and alveolar dead space. The effect on arterial blood gases of shifts in the distribution of V̇/Q̇ ratios can be predicted from the discussion of the limiting cases (Figure 9–16). At the top of Figure 9–16 is a respiratory unit where on one side (B) ventilation has been reduced but perfusion maintained. This defines an area of low V̇/Q̇ ratio. The effect on lung function can be understood by dividing it into an area with a normal V̇/Q̇ ratio (A) and an area of shunted blood (C). The physiologic effect of low V̇/Q̇ areas is similar to the effect of shunts: hypoxemia without hypercapnia. The difference between low V̇/Q̇ areas and true shunts can also be seen in this schematic. Shunted blood comes into no contact with inspired air; therefore, no amount of additional oxygen supplied to inspired air will reverse the fall in systemic arterial PO₂. A low V̇/Q̇ area does come in contact with inspired air and can be reversed with increased inspired oxygen.

At the bottom of Figure 9–16 is a respiratory unit where on one side blood flow has been decreased (B) but ventilation maintained. This defines an area of high V̇/Q̇ ratio. The effect on lung function can be understood by dividing the unit into an area with a normal V̇/Q̇ ratio (A) and an area of dead space or wasted ventilation (C). The physiologic effect of high V̇/Q̇ ratios is to increase PCO₂, typically leading to increased respiration to return PaCO₂ to normal.

Hyperventilation of unaffected lung regions can compensate for the increase in PCO₂ from alveolar dead space but cannot compensate for the decrease in PO₂ from areas of shunt. The reason is due to the different ways that oxygen and carbon dioxide are carried in blood, and the different relationships between the content and partial pressure of these gases. Because PCO₂ and CO₂ content are linearly related within the normal physiologic range, increased ventilation to one respiratory unit will reduce the PCO₂ and the CO₂ content of blood leaving that unit. Overall CO₂ content will be the mean of affected and unaffected units. Because PCO₂ is proportionate to the CO₂ content, the reduced CO₂ content of hyperventilated lung regions compensates for elevated content from areas of wasted ventilation. The PCO₂ and CO₂ content of the mixture track together.

Hyperventilation or increasing inspired oxygen to unaffected lung regions does not compensate for the decrease in PO₂ from areas of true shunt. The O₂ content of blood is not linearly related to PO₂ (Figure 9–11). The sigmoidal shape of the oxyhemoglobin dissociation curve indicates that hemoglobin is nearly maximally saturated at a PO₂ of 60. Increasing PO₂ from 60 to 600 increases partial pressure 10-fold but O₂ content by only 10%. Increasing ventilation or increasing alveolar PO₂ to unaffected respiratory units can increase end-capillary PO₂ but will not change the O₂ content of blood leaving those units. Overall O₂ content will be the mean of normal blood oxygen content and shunted, desaturated blood. The reduced oxygen content of the mixture tends to lie on the steep portion of the oxyhemoglobin dissociation curve, with the result that modest decreases in oxygen content lead to large decreases in the PO₂.

Arterial blood gases detect major disturbances in respiratory function. One attempt to assess more subtle abnormalities of gas exchange is to calculate the difference between the alveolar and arterial PO₂. This is referred to as the A-a ΔPO₂ or A-a DO₂. The alveolar-capillary membrane permits full equilibration of alveolar and end-capillary oxygen tension under normal V̇/Q̇ matching. There is nonetheless a small A-a ΔPO₂ in normal individuals as a result of right-to-left shunting through the bronchial veins and the thebesian veins of the left heart. This accounts for approximately 2–5% of resting cardiac output and leads to an A-a ΔPO₂ of 5–8 mm Hg in healthy young adults breathing ambient air at sea level. Increasing the fractional inspired concentration of oxygen (FiO₂) increases this value: A normal A-a ΔPO₂ breathing 100% oxygen is approximately 100 mm Hg. Normal values increase with age, presumably as a result of closure of dependent airways with consequent shift toward low V̇/Q̇ ratios. Further increases in the A-a ΔPO₂ reflect areas of low V̇/Q̇ ratio, including shunting.

Control of Breathing

The lungs inflate and deflate passively in response to changes in pleural pressure. Therefore, control over respiration lies in control of the striated muscles—chiefly the diaphragm but also the intercostals and abdominal wall—that change pleural pressure.

These muscles are under both automatic and voluntary control. The rhythm of spontaneous breathing originates in the brainstem, specifically in several groups of interconnected neurons in the medulla. Research into the generation of the respiratory rhythm has identified that it originates in the neurons in the pre-Bötzinger complex. Respiratory neurons are either inspiratory or expiratory and may fire early, late, or in an accelerating fashion during the respiratory cycle. Their integrated output is an efferent signal via the phrenic nerve (diaphragm) and spinal nerves (intercostals and abdominal wall) to generate rhythmic contraction and relaxation of the respiratory musculature. The result is spontaneous breathing without conscious input. However, by attending to breathing, the reader may alter this pattern. Eating, speaking, singing, swimming, and defecating all rely on voluntary control over automatic breathing.

Sensory Input

The frequency, depth, and timing of spontaneous breathing are modified by information provided to the respiratory center from both chemical and mechanical sensors (Figure 9–17).

There are chemoreceptors in the peripheral vasculature and in the brainstem. The peripheral chemoreceptors are the carotid bodies, located at the bifurcation of the common carotid arteries and the aortic bodies near the arch of the aorta. The carotid bodies are particularly important in humans. They function as sensors of arterial oxygenation. There is a graded increase in firing of the carotid body in response to a fall in the PaO₂. This response is most marked below 60 mm Hg. An increase in the PaCO₂ or a fall in arterial pH potentiates the response of the carotid body to decreases in the PaO₂.

In humans, the carotid bodies are solely responsible for the increased ventilation seen in response to hypoxia. Bilateral carotid body resection, which has been performed to treat disabling dyspnea and may happen as an unintended consequence of carotid thromboendarterectomy, results in a complete loss of this hypoxic ventilatory drive while leaving intact the response to changes in PaCO₂. Central chemoreceptors mediate the response to changes in PaCO₂. There is growing evidence that these chemoreceptors are widely dispersed throughout the brainstem. They are separate from the neurons that generate the respiratory rhythm. The increased ventilatory response to elevation in PaCO₂ is mediated through changes in chemoreceptor pH. The blood-brain barrier permits free diffusion of CO₂ but not hydrogen ions. CO₂ is hydrated to carbonic acid, which ionizes and lowers brain pH. Central chemoreceptors probably respond to these changes in intracellular hydrogen ion concentration.

There are a variety of pulmonary stretch receptors located in airway smooth muscle and mucosa whose afferent fibers are carried in the vagus nerve. They discharge in response to lung distention. Increasing lung volume decreases the rate of respiration by increasing expiratory time. This is known as the Hering-Breuer reflex. There are unmyelinated C fibers located near the pulmonary capillaries (hence juxtacapillary [J] receptors). These fibers are quiet during normal breathing but can be directly stimulated by intravenous administration of irritant chemicals such as capsaicin. They appear to stimulate the increased respiratory drive in interstitial edema and pulmonary fibrosis. Skeletal movement transmitted by proprioceptors in joints, muscles, and tendons causes an increase in respiration and may have some role in the increased ventilation of exercise. Finally, there are muscle spindle receptors in the diaphragm and intercostals that provide feedback on muscle force. They may be involved in the sensation of dyspnea when the work of breathing is disproportionate to ventilation.

Integrated Responses

Under normal conditions in healthy adults, the hydrogen ion concentration in the region of the central chemoreceptors determines the drive to breathe. Changes in chemoreceptor pH are largely determined by the PaCO₂. The PaO₂ is not an important part of the baseline respiratory drive under normal conditions.

Breathing is stimulated by a fall in the PaO₂, a rise in the PaCO₂, or an increase in the hydrogen ion concentration of arterial blood (fall in arterial pH).

Ventilation increases approximately 2–3 L/min for every 1 mm Hg rise in PaCO₂. This response (Figure 9–18) occurs first through sensitization of the carotid body receptor. The carotid body will increase its firing in response to an increased PaCO₂ even in the absence of changes in the PaO₂. This accounts for approximately 15% of the ventilatory response to hypercapnia. The majority of the response is mediated through pH changes in the region of the central chemoreceptors. Changes in arterial pH are additive to changes in PaCO₂. CO₂ response curves under conditions of metabolic acidosis have an identical slope but are shifted to the left. The ventilatory response to an increased PaCO₂ falls with age, sleep, and aerobic conditioning and with increased work of breathing.

The individual response to hypoxemia is extremely variable. Normally, there is little increase in ventilation until the PaO₂ falls below 50–60 mm Hg. At this point, there is a rapid increase in ventilation that reaches its maximum at approximately 32 mm Hg. Below this level, further decreases in PaO₂ lead to depression of ventilation. The response to hypoxia is affected by the PaCO₂. An increase in the alveolar PCO₂ will shift the isocapnic O₂ response curve upward and to the right (Figure 9–19).

A fall in arterial hydrogen ion concentration increases minute ventilation. This response results chiefly from stimulation of the carotid bodies and is independent of changes in PaCO₂. There is a response to severe metabolic acidosis in the absence of carotid bodies. It is assumed that this response is mediated by central chemoreceptors; it may represent breakdown of the blood-brain barrier.

Special Situations

1. 
   

   Chronic hypercapnia—In patients with chronic hypercapnia, brain pH is returned toward normal by compensatory changes in serum and tissue bicarbonate levels. As a result, central chemoreceptors become less sensitive to further changes in PaCO₂. In this instance, a patient’s basal minute ventilation may depend on tonic stimuli from the carotid bodies. If such a patient were given high concentrations of inspired oxygen, carotid body output may be depressed, leading to a fall in minute ventilation. The change in minute ventilation does not fully account for the hypercapnia in response to supplemental oxygen, suggesting that ablation of hypoxic pulmonary vasoconstriction also plays a role.

   
   
2. 
   

   Chronic hypoxia—Long-term residence at high altitude—or sleep apnea with repeated episodes of severe oxygen desaturation—may blunt the hypoxic ventilatory response. In such individuals, the development of lung disease and hypercapnia may attenuate all endogenous stimuli to breathing. This pattern is seen in patients with obesity-hypoventilation syndrome.

   
   
3. 
   

   Exercise—Exercise may increase minute ventilation up to 25 times the resting level. Strenuous but submaximal exercise in a healthy individual typically causes no change or only a slight rise in PaO₂ as a result of increased pulmonary blood flow and better matching of ventilation and perfusion, with no change or a slight fall in PaCO₂. Changes in arterial oxygenation are, therefore, not a factor behind the increased ventilatory response to exercise. The reason for the increased ventilatory response is not known with certainty. Two contributing factors are the increased production of carbon dioxide and increased afferent discharge from joint and muscle proprioceptors.