1: Pulmonary anatomy and physiology: The basics

OUTLINE

Anatomy, 1

Physiology, 2

Mechanical Aspects of the Lungs and Chest Wall, 2

Ventilation, 5

Circulation, 6

Diffusion, 7

Oxygen Transport, 8

Carbon Dioxide Transport, 10

Ventilation–Perfusion Relationships, 11

Abnormalities in Gas Exchange, 14

Hypoxemia, 14

Hypercapnia, 16

To be effective at gas exchange, the lungs cannot act in isolation. They must interact with the central nervous system (which provides the rhythmic drive to breathe), the diaphragm and muscular apparatus of the chest wall (which respond to signals from the central nervous system and act as a bellows for movement of air), and the circulatory system (which provides blood flow and thus gas transport between the tissues and lungs). The processes of oxygen uptake and carbon dioxide elimination by the lungs depend on proper functioning of all these systems, and a disturbance in any of them can result in clinically important abnormalities in gas exchange. This chapter begins with an initial overview of pulmonary anatomy, followed by a discussion of the mechanical properties of the lungs and chest wall and a consideration of some aspects of the contribution of the lungs and the circulatory system to gas exchange. Additional discussion of pulmonary and circulatory physiology is presented in Chapters 4, 8, and 12; neural, muscular, and chest wall interactions with the lungs are discussed further in Chapter 17.

Anatomy

It is appropriate when discussing the anatomy of the respiratory system to include the entire pathway for airflow from the mouth or nose down to the alveolar sacs. En route to the alveoli, gas flows through the oropharynx or nasopharynx, larynx, trachea, and finally a progressively arborizing system of bronchi and bronchioles of diminishing diameter (Fig. 1.1). The trachea divides at the carina into right and left mainstem bronchi, which branch into lobar bronchi (three on the right, two on the left), segmental bronchi, and an extensive system of subsegmental and smaller bronchi. These conducting airways divide approximately 15 to 20 times down to the level of terminal bronchioles, which are the smallest units that do not actually participate in gas exchange.

FIGURE 1.1 Schematic diagram of airway branching. LLL, left lower lobe

bronchus; LM, left mainstem bronchus; LUL, left upper lobe bronchus; RLL, right

lower lobe bronchus; RM, right mainstem bronchus; RML, right middle lobe

bronchus; RUL, right upper lobe bronchus; Tr, trachea.

Conducting airways include all airways down to the level of the terminal bronchioles.

Beyond the terminal bronchioles, further divisions include the respiratory bronchioles, alveolar ducts, and alveoli. From the respiratory bronchioles on, these divisions form the portion of the lung involved in gas exchange and constitute the terminal respiratory unit or acinus. At this level, inhaled gas comes into contact with alveolar walls (septa), and pulmonary capillary blood loads O2 and unloads CO2 as it courses through the septa.

The acinus includes structures distal to a terminal bronchiole: respiratory bronchioles, alveolar ducts, and alveoli (alveolar sacs).

The surface area for gas exchange provided by the alveoli is enormous. It is estimated that the adult human lung has on the order of 300 million alveoli, with a total surface area approximately the size of a tennis court, more than 2000 square feet or 200 m2. This vast surface area of gas in contact with alveolar walls is a highly efficient mechanism for O2 and CO2 transfer between alveolar spaces and pulmonary capillary blood.

The pulmonary circulation and blood within provide the other crucial requirement for gas exchange: a transportation system for O2 and CO2 to and from other body tissues and organs. After blood arrives at the lungs via the pulmonary artery, it courses through a widely branching system of smaller pulmonary arteries and arterioles to the major locale for gas exchange, the pulmonary capillary network. The capillaries generally allow red blood cells to flow through in single file only, so that gas exchange between each cell and alveolar gas is facilitated. Upon completion of gas exchange and travel through the pulmonary capillary bed, the oxygenated blood flows through pulmonary venules and veins and arrives at the left side of the heart for pumping to the systemic circulation and distribution to the tissues.

Further details about the anatomy of airways, alveoli, and the pulmonary vasculature, particularly with regard to structure–function relationships and cellular anatomy, are given in Chapters 4, 8, and 12.

Physiology

Mechanical aspects of the lungs and chest wall

The discussion of pulmonary physiology begins with an introduction to a few concepts about the mechanical properties of the respiratory system, which have important implications for assessment of pulmonary function and its derangement in disease states.

Both the lungs and chest wall have elastic properties. Each has a particular resting size (or volume) it would assume if no internal or external pressure were exerted on it, and any deviation from this volume requires some additional influencing force. If the lungs were removed from the chest and no longer had the external influences of the chest wall and pleural space acting on them, they would collapse to the point of being almost airless; they would have a much lower volume than they have within the thoracic cage. To expand these lungs, positive pressure would have to be exerted on the air spaces, as could be done by putting positive pressure through the airway. (It is similar to a balloon, which is essentially airless unless positive pressure is exerted on the opening to distend the elastic wall and fill it with air.)

Alternatively, instead of positive pressure exerted on alveoli through the airways, negative pressure could be applied outside the lungs to cause their expansion. Thus, what increases the volume of the isolated lungs from the resting, essentially airless, state is application of a positive transpulmonary pressure—the pressure inside the lungs relative to the pressure outside. Either the internal pressure can be made positive or the external pressure can be made negative; the net effect is the same. With the lungs inside the chest wall, the internal pressure is alveolar pressure (Palv), whereas external pressure is the pressure within the pleural space (Fig. 1.2). Therefore, transpulmonary pressure is defined as Palv minus pleural pressure (Ppl). For air to be present in the lungs, Ppl must be negative compared with Palv, resulting in a positive transpulmonary pressure.

FIGURE 1.3 A, Relationship between lung volume and distending

(transpulmonary) pressure, the compliance curve of the lung. B, Relationship

between volume enclosed by chest wall and distending (transchest wall) pressure,

the compliance curve of the chest wall. C, Combined compliance curves of lung and

chest wall showing relationship between respiratory system volume and distending

(transrespiratory system) pressure. FRC, functional residual capacity; RV, residual

volume; TLC, total lung capacity.

The chest wall also has an effect on lung volume. If the lungs were removed from the chest, the chest wall would expand to a larger size when no external or internal pressures were exerted on it. Thus, the chest wall has a springlike character that is not intuitively obvious. The resting volume is relatively high, and distortion to either a smaller or larger volume requires alteration of either the external or internal pressures acting on it. The pressure across the chest wall is akin to the transpulmonary pressure. With the lungs inside the chest wall, the pressure across the chest wall is the Ppl (internal pressure) minus the external pressure surrounding the chest wall (atmospheric pressure).

The compliance curve of the chest wall relates the volume enclosed by the chest wall to the pressure across the chest wall (see Fig. 1.3B). The curve becomes relatively flat at low lung volumes, at which the chest wall becomes stiff. Further decrease in pressure across the chest wall causes little further decrement in volume.

At RV, either outward recoil of the chest wall or closure of airways prevents further expiration.

RV, Residual volume.

Ventilation

To maintain normal gas exchange to the tissues, an adequate volume of air must pass through the lungs for provision of O2 to and removal of CO2 from the blood. An average-sized adult male at rest typically breathes approximately 500 mL and an average adult female approximately 400 mL of air per breath at a

frequency of 12 to 16 times per minute, resulting in a ventilation of 6 to 8 L/min (minute ventilation [ ]) for males and slightly less for females.a (The subscript “E” indicates that the minute ventilation is measured from expired gas, rather than by how much gas is inspired; these values are slightly different if the patient’s respiratory quotient is not exactly 1.)

The volume of each breath (tidal volume [VT]) is not used entirely for gas exchange; a portion stays in the conducting airways and does not reach the distal part of the lung where gas exchange occurs. The portion of the VT that is “wasted” (in the sense of gas exchange) is termed the volume of dead space (VD), and the volume that reaches the gas-exchanging portion of the lung is the alveolar volume (VA). The anatomic dead space, which includes the larynx, trachea, and bronchi down to the level of the terminal bronchioles, is approximately 150 mL in an average-sized male; thus, 30% of a VT of 500 mL is wasted.

The volume of each breath (tidal volume [VT]) is divided into dead space volume (VD) and alveolar volume (VA).

As for CO2 elimination by the lung, alveolar ventilation ( ), which is equal to the breathing frequency (f) multiplied by VA, bears a direct relationship to the amount of CO2 removed from the body.

In fact, the partial pressure of CO2 (PaCO2) in arterial blood is inversely proportional to ; as increases, PaCO2 decreases. In addition, PaCO2 is affected by the body’s rate of CO2 production ( );

if increases without any change in , PaCO2 shows a proportional increase. Thus, it is easy to understand the relationship given in Eq. 1.1:

This defines the major factors determining PaCO2. When a normal individual exercises,

increases, but increases proportionately so that PaCO2 remains relatively constant.

As mentioned earlier, the dead space comprises that amount of each breath going to parts of the tracheobronchial tree not involved in gas exchange. The anatomic dead space consists of the conducting airways. However, in disease states, areas of lung that normally participate in gas exchange (parts of the

terminal respiratory unit) may not receive normal blood flow, even though they continue to be ventilated. In these areas, some of the ventilation is wasted; such regions contribute additional volume to the dead space.

Hence, a more useful clinical concept than anatomic dead space is physiologic dead space, which takes into account the volume of each breath not involved in gas exchange, whether at the level of the conducting airways or the terminal respiratory units. Primarily in certain disease states, in which there may be areas with normal ventilation but decreased or no perfusion, the physiologic dead space is larger than the anatomic dead space.

Quantitation of the physiologic dead space or, more precisely, the fraction of the VT represented by the dead space (VD/VT), can be made by measuring PCO2 in arterial blood (PaCO2) and expired gas (PECO2) and by using Eq. 1.2, known as the Bohr equation for physiologic dead space:

The Bohr equation can be used to quantify the fraction of each breath that is wasted, the dead space-to- tidal volume ratio (VD/VT).

For gas coming directly from alveoli that have participated in gas exchange, PCO2 approximates that of arterial blood. For gas coming from the dead space, PCO2 approximates 0 because the expired gas from that region never came into contact with pulmonary capillary blood.

Consider the two extremes. If the expired gas came entirely from perfused alveoli, PECO2 would equal PaCO2, and according to the equation, VD/VT would equal 0. On the other hand, if expired gas came totally from the dead space, it would contain no CO2, PECO2 would equal 0, and VD/VT would equal 1. In practice, this equation is used in situations between these two extremes, and it quantifies the proportion of expired gas coming from alveolar gas (PCO2 = PaCO2) versus dead space gas (PCO2 = 0).

In summary, each normal or VT breath can be divided into alveolar volume (VA) and dead space (VD), just as the total ventilation ( ) can be divided into alveolar ventilation ( ) and wasted (or dead space) ventilation ( ). Elimination of CO2 by the lungs is proportional to ; therefore, PaCO2 is

inversely proportional to and not to . The wasted ventilation can be quantified by the Bohr equation, using the principle that increasing amounts of dead space ventilation augment the difference between PCO2 in arterial blood and expired gas.

Circulation

Normally, because the entire cardiac output flows from the right ventricle to the lungs and back to the left side of the heart, the pulmonary circulation handles a blood flow of approximately 5 L/min. If the pulmonary vasculature were similar in structure to the systemic vasculature, large pressures would have to be generated because of the thick walls and high resistance offered by systemic-type arteries. However, pulmonary arteries are quite different in structure from systemic arteries, with thin walls that provide much less resistance to flow. Thus, despite equal right and left ventricular outputs, the normal mean pulmonary artery pressure of 15 mm Hg is much lower than the normal mean aortic pressure of approximately 95 mm Hg.

One important feature of blood flow in the pulmonary capillary bed is the distribution of flow in

different areas of the lung. The pattern of flow is explained to a large degree by the effect of gravity and

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the necessity for blood to be pumped “uphill” to reach the apices of the lungs. In an upright person the apex of each lung is approximately 25 cm higher than the base, so the pressure in pulmonary vessels at the apex is 25 cm H2O (19 mm Hg) lower than that in pulmonary vessels at the bases. Because flow through these vessels depends on the perfusion pressure, the capillary network at the bases receives much more flow than the capillaries at the apices. In fact, flow at the lung apices falls to 0 during the part of the cardiac cycle when pulmonary artery pressure is insufficient to pump blood up to the apices.

As a result of gravity, there is more blood flow to dependent regions of the lung.

West developed a model of pulmonary blood flow that divides the lung into zones, based on the relationships among pulmonary arterial, venous, and alveolar pressures (Fig. 1.4). As stated earlier, the vascular pressures (i.e., pulmonary arterial and venous) depend in part on the vertical location of the vessels in the lung because of the hydrostatic effect. Apical vessels have much lower pressure than basilar vessels, the difference being the vertical distance between them (divided by a correction factor of 1.3 to convert from cm H2O to mm Hg).

FIGURE 1.4 Three-zone model of pulmonary blood flow showing relationships

among alveolar pressure (PA), arterial pressure (PA), and venous pressure (PV) in each zone. Blood flow (per unit volume of lung) is shown as function of vertical

distance on the right. Source: (From West, J. B., Dollery, C. T., & Naimark, A.

(1964). Distribution of blood flow in isolated lung; relation to vascular and alveolar

pressures. Journal of Applied Physiology, 19, 713–724.)

At the apex of the lung (see zone 1 in Fig. 1.4), alveolar pressure exceeds arterial and venous pressures and no flow results. Normally, such a condition does not arise unless pulmonary arterial pressure is decreased or alveolar pressure is increased (by exogenous pressure applied to the airways and alveoli).

In preparation for this discussion, an understanding of the concepts of partial pressure, gas content, and percent saturation is essential. The partial pressure of any gas is the product of the ambient total gas pressure and the proportion of total gas composition made up by the specific gas of interest. For example, air is composed of approximately 21% O2. Assuming a total pressure of 760 mm Hg at sea level and no water vapor pressure, the partial pressure of O2 (PO2) is 0.21 × 760, or 160 mm Hg. If the gas is saturated with water vapor at body temperature (37°C), the water vapor has a partial pressure of 47 mm Hg. The partial pressure of O2 is then calculated on the basis of the remaining pressure: 760 − 47 = 713 mm Hg. Therefore, when room air is saturated at body temperature, PO2 is 0.21 × 713 = 150 mm Hg. Because inspired gas is normally humidified by the upper airway, it becomes fully saturated by the time it reaches the trachea and bronchi, where inspired PO2 is approximately 150 mm Hg.

In clinical situations, we also must consider the concept of partial pressure of a gas within a body fluid, primarily blood. When a gas mixture is in contact with a liquid, the partial pressure of a particular gas in the liquid is the same as its partial pressure in the gas mixture, assuming full equilibration has taken place. Some of the gas molecules will dissolve in the liquid, and the amount of dissolved gas reflects the partial pressure of gas in the liquid. Therefore, the partial pressure of the gas acts as the driving force for the gas to be taken up by the liquid phase.

However, the quantity of a gas carried by a liquid medium depends not only on the partial pressure of the gas in the liquid but also on the “capacity” of the liquid for that particular gas. If a specific gas is quite soluble within a liquid, more of that gas is carried for a given partial pressure than a less soluble gas. In addition, if a component of the liquid is also able to bind the gas, more of the gas is transported at a particular partial pressure. For example, this is true of the interaction of hemoglobin and O2. Hemoglobin in red blood cells vastly increases the capacity of blood to carry O2, as a more detailed discussion will show.

The content of a gas in a liquid, such as blood, is the actual amount of the gas contained within the liquid. For O2 in blood, the content is expressed as milliliters of O2 per 100 mL blood. The percent saturation of a gas is the ratio of the actual content of the gas to the maximal possible content if there is a limit or plateau in the amount that can be carried.

Oxygen is transported in blood in two ways: either dissolved in the blood or bound to the heme portion of hemoglobin. Oxygen is not very soluble in plasma, and only a small amount of O2 is carried this way under normal conditions. The amount dissolved is proportional to the partial pressure of O2, with 0.0031 mL dissolved for each millimeter of mercury of partial pressure. The amount bound to hemoglobin is a function of the oxyhemoglobin dissociation curve, which relates the driving pressure (PO2) to the quantity of O2 bound. This curve reaches a plateau, indicating that hemoglobin can hold only so much O2 before it becomes fully saturated (Fig. 1.5). At PO2 = 60 mm Hg, hemoglobin is approximately 90% saturated, so only relatively small amounts of additional O2 are transported at a PO2 above this level.

FIGURE 1.5 Oxyhemoglobin dissociation curve, relating percent hemoglobin

saturation and partial pressure of oxygen (PO2). Oxygen content can be determined on the basis of hemoglobin concentration and percent hemoglobin saturation (see

text). Normal curve is depicted with solid line. Curves shifted to right or left (and

conditions leading to them) are shown with broken lines. 2,3-DPG, 2,3-

diphosphoglycerate; PCO2, partial pressure of carbon dioxide.

Almost all O2 transported in the blood is bound to hemoglobin; only a small fraction is dissolved in plasma.

Hemoglobin is 90% saturated with O2 around an arterial PO2 of 60 mm Hg.

This curve can shift to the right or left, depending on a variety of conditions. Thus, the relationships between arterial PO2 and saturation are not fixed. For instance, a decrease in pH or an increase in PCO2 (largely by a pH effect), temperature, or 2,3-bisphosphoglycerate (2,3-BPG; also called 2,3- diphosphoglycerate [2,3-DPG]) shifts the oxyhemoglobin dissociation curve to the right, making it easier to unload (or harder to bind) O2 for any given PO2 (see Fig. 1.5). The opposite changes in pH, PCO2, temperature, or 2,3-BPG shift the curve to the left and make it harder to unload (or easier to bind) O2 for any given PO2. These properties help to ensure that oxygen is released preferentially to tissues that are more metabolically active because intense anaerobic metabolism results in decreased pH and elevations in 2,3-BPG, whereas increased heat and CO2 are generated by intense aerobic metabolism.

Perhaps the easiest way to understand O2 transport is to follow O2 and hemoglobin as they course

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through the circulation in a normal person. When blood leaves the pulmonary capillaries, it has already been oxygenated by equilibration with alveolar gas, and the PO2 should be identical to that in the alveoli. Because of O2 uptake and CO2 excretion at the level of the alveolar–capillary interface, alveolar PO2 is less than the 150 mm Hg that was calculated for inspired gas within the airways (see discussion on Hypoxemia and Eq. 1.7). Alveolar PO2 in a normal individual (breathing air at sea level) is approximately 100 mm Hg. However, the PO2 measured in arterial blood is actually slightly lower than this value for alveolar PO2, partly because of the presence of small amounts of “shunted” blood that do not participate in gas exchange at the alveolar level, such as (1) desaturated blood from the bronchial circulation draining into pulmonary veins and (2) venous blood from the coronary circulation draining into the left side of the heart via thebesian veins. Ventilation–perfusion mismatch, as discussed below, also contributes to the difference between alveolar and arterial PO2.

Assuming PO2 = 95 mm Hg in arterial blood, the total O2 content is the sum of the quantity of O2 bound to hemoglobin plus the amount dissolved. To calculate the quantity bound to hemoglobin, the patient’s hemoglobin level and the percent saturation of the hemoglobin with O2 must be known. Because each gram of hemoglobin can carry 1.34 mL O2 when fully saturated, the O2 content is calculated by Eq. 1.3:

Assume that hemoglobin is 97% saturated at PO2 = 95 mm Hg and the individual has a hemoglobin level of 15 g/100 mL blood (Eq. 1.4):

In contrast, the amount of dissolved O2 is much smaller and is proportional to PO2, with 0.0031 mL O2 dissolved per 100 mL blood per mm Hg PO2. Therefore, at an arterial PO2 of 95 mm Hg (Eq. 1.5):

The total O2 content is the sum of the hemoglobin-bound O2 plus the dissolved O2, or 19.5 + 0.3 = 19.8 mL O2/100 mL blood.

Arterial PO2 is not the sole determinant of O2 content; because most of the oxygen is bound to hemoglobin, the hemoglobin level is also crucial. With anemia (reduced hemoglobin level), fewer binding sites are available for O2, and the O2 content falls even though PO2, which reflects the amount of O2 dissolved in the plasma, remains unchanged. In addition, the O2 content of blood is a static measurement of the quantity of O2 per 100 mL blood. The actual delivery of oxygen to tissues is dynamic and depends on blood flow (determined primarily by cardiac output, but also influenced by regulation at the microvascular level of the receiving tissue or organ) as well as O2 content. Thus, three main factors determine tissue O2 delivery: arterial PO2, hemoglobin level, and cardiac output. Disturbances in any one of these factors can result in decreased or insufficient O2 delivery.

FIGURE 1.7 Spectrum of ventilation–perfusion ratios within single alveolar–

capillary unit. A, Ventilation is obstructed, but perfusion is preserved. Alveolar– capillary unit is behaving as a shunt. B, Ventilation and perfusion are well matched.

C, No blood flow is reaching the alveolus, so ventilation is wasted, and the alveolus behaves as dead space. , Ventilation–perfusion ratio.

Source: (Modified from West, J. B. (1977). Ventilation/blood flow and gas exchange (3rd ed., p. 36). Oxford, UK: Blackwell Scientific Publications.)

Ventilation–perfusion ratios within each alveolar–capillary unit range from = ∞ (dead space) to = 0 (shunt).

Again, dealing with the extremes, for an alveolar–capillary unit acting as dead space (ventilation but no perfusion, or = ∞), PO2 in the alveolus is equal to that in air (i.e., 150 mm Hg, taking into account the fact that air in the alveolus is saturated with water vapor), whereas PCO2 in the alveolus approaches 0 because no blood and therefore no CO2 is in contact with alveolar gas. With a region of true dead space, there is no blood flow, so no gas exchange has occurred between this alveolus and blood. If there were a

minute amount of blood flow (i.e., if the ratio approached but did not reach ∞), the blood also would have a PO2 approaching (but slightly less than) 150 mm Hg and a PCO2 approaching (but slightly more than) 0 mm Hg. At the other extreme, for an alveolar–capillary unit acting as a shunt (perfusion but

ratio in an alveolar–capillary unit, the closer the unit comes to behaving like an area of dead space