The importance of pulmonary physiology to anesthetic practice is obvious. The most commonly used anesthetics—the inhalation agents—depend on the lungs for uptake and elimination. The most important side effects of both inhalation and intravenously administered anesthetics are primarily respiratory. Moreover, muscle paralysis, unusual positioning during surgery, and techniques such as one-lung anesthesia and cardiopulmonary bypass profoundly alter normal pulmonary physiology.
Functional Respiratory Anatomy
Rib Cage & Muscles of Respiration
The rib cage contains the two lungs, each surrounded by its own pleura. The apex of the chest is small, allowing only for entry of the trachea, esophagus, and blood vessels, whereas the base is formed by the diaphragm. Contraction of the diaphragm—the principal pulmonary muscle—causes the base of the thoracic cavity to descend 1.5-7 cm and its contents (the lungs) to expand. Diaphragmatic movement normally accounts for 75% of the change in chest volume. Accessory respiratory muscles also increase chest volume (and lung expansion) by their action on the ribs. Each rib (except for the last two) articulates posteriorly with a vertebra and is angulated downward as it attaches anteriorly to the sternum. Upward and outward rib movement expands the chest.
During normal breathing, the diaphragm, and, to a lesser extent, the external intercostal muscles are responsible for inspiration; expiration is generally passive. With increasing effort, the sternocleidomastoid, scalene, and pectoralis muscles can be recruited during inspiration. The sternocleidomastoid muscles assist in elevating the rib cage, whereas the scalene muscles prevent inward displacement of the upper ribs during inspiration. The pectoralis muscles can assist chest expansion when the arms are placed on a fixed support. Expiration is normally passive in the supine position, but becomes active in the upright position and with increased effort. Exhalation may be facilitated by the abdominal muscles (rectus abdominis, external and internal oblique, and transversus) and perhaps the internal intercostal muscles—aiding the downward movement of the ribs.
Although not usually considered respiratory muscles, some pharyngeal muscles are important in maintaining the patency of the airway. Tonic and reflex inspiratory activity in the genioglossus keeps the tongue away from the posterior pharyngeal wall. Tonic activity in the levator palati, tensor palati, palatopharyngeus, and palatoglossus prevents the soft palate from falling back against the posterior pharynx, particularly in the supine position.
The trachea serves as a conduit for ventilation and the clearance of tracheal and bronchial secretions. The trachea begins at the lower border of the cricoid cartilage and extends to the level of the carina and has an average length of 10-13 cm. It is composed of C-shaped cartilaginous rings, which form the anterior and lateral walls of the trachea and are connected posteriorly by the membranous wall of the trachea. The external diameters of the trachea measure approximately 2.3 cm coronally and 1.8 cm sagitally in men, with corresponding values of 2.0 cm and 1.4 cm, respectively, in women. The cricoid cartilage is the narrowest part of the trachea, with an average diameter of 17 mm in men and 13 mm in women.
The trachea bifurcates at the carina into the right and left main stem bronchi. The tracheal lumen narrows slightly as it progresses toward the carina, with the tracheal bifurcation located at the level of the sternal angle. The right main stem bronchus lies in a more vertical orientation relative to the trachea, whereas the left main stem bronchus lies in a more horizontal orientation. The right main stem bronchus continues as the bronchus intermedius after the take-off of the right upper lobe bronchus. The distance from the tracheal carina to the take-off of the right upper lobe bronchus is an average of 2.0 cm in men and approximately 1.5 cm in women. One in every 250 individuals in the general population may have an abnormal take-off of the right upper lobe bronchus emerging from above the tracheal carina on the right side. The left main stem bronchus is longer than the right main stem bronchus and measures an average of 5.0 cm in men and 4.5 cm in women. The left main stem bronchus divides into the left upper lobe bronchus and the left lower lobe bronchus.
Humidification and filtering of inspired air are functions of the upper airway (nose, mouth, and pharynx). The function of the tracheobronchial tree is to conduct gas flow to and from the alveoli. Dichotomous division (each branch dividing into two smaller branches), starting with the trachea and ending in alveolar sacs, is estimated to involve 23 divisions, or generations (Figure 23-1). With each generation, the number of airways is approximately doubled. Each alveolar sac contains, on average, 17 alveoli. An estimated 300 million alveoli provide an enormous membrane (50-100 m2) for gas exchange in the average adult.
A: Dichotomous division of the airways. (Reproduced, with permission, from Guyton AC: Textbook of Medical Physiology, 7th ed. W.B. Saunders, 1986.) B: The segmental bronchi. (Reproduced, with permission, from Minnich DJ, Mathisen DJ: Anatomy of the trachea, carina, and bronchi. Thorac Surg Clin 2007 Nov;17(4):571-585.)
With each successive division, the mucosal epithelium and supporting structures of the airways gradually change. The mucosa makes a gradual transition from ciliated columnar to cuboidal and finally to flat alveolar epithelium. Gas exchange can occur only across the flat epithelium, which begins to appear on respiratory bronchioles (generations 17-19). The wall of the airway gradually loses its cartilaginous support (at the bronchioles) and then its smooth muscle. Loss of cartilaginous support causes the patency of smaller airways to become dependent on radial traction by the elastic recoil of the surrounding tissue; as a corollary, airway diameter becomes dependent on total lung volume.
Cilia on the columnar and cuboidal epithelium normally beat in a synchronized fashion, such that the mucus produced by the secretory glands lining the airway (and any associated bacteria or debris) moves up toward the mouth.
Alveolar size is a function of both gravity and lung volume. The average diameter of an alveolus is thought to be 0.05-0.33 mm. In the upright position, the largest alveoli are at the pulmonary apex, whereas the smallest tend to be at the base. With inspiration, discrepancies in alveolar size diminish.
Each alveolus is in close contact with a network of pulmonary capillaries. The walls of each alveolus are asymmetrically arranged (Figure 23-2). On the thin side, where gas exchange occurs, the alveolar epithelium and capillary endothelium are separated only by their respective cellular and basement membranes; on the thick side, where fluid and solute exchange occurs, the pulmonary interstitial space separates alveolar epithelium from capillary endothelium. The pulmonary interstitial space contains mainly elastin, collagen, and perhaps nerve fibers. Gas exchange occurs primarily on the thin side of the alveolocapillary membrane, which is less than 0.4 μm thick. The thick side (1-2 μm) provides structural support for the alveolus.
The pulmonary interstitial space, with a capillary passing between the two alveoli. The capillary is incorporated into the thin (gas-exchanging) side of the alveolus on the right. The interstitial space is incorporated into the thick side of the alveolus on the left. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
The pulmonary epithelium contains at least two cell types. Type I pneumocytes are flat and form tight (1-nm) junctions with one another. These tight junctions are important in preventing the passage of large oncotically active molecules such as albumin into the alveolus. Type II pneumocytes, which are more numerous than type I pneumocytes (but because of their shape occupy less than 10% of the alveolar space), are round cells that contain prominent cytoplasmic inclusions (lamellar bodies). These inclusions contain surfactant, an important substance necessary for normal pulmonary mechanics (see below). Unlike type I cells, type II pneumocytes are capable of cell division and can produce type I pneumocytes if the latter are destroyed. They are also resistant to O2 toxicity.
Other cell types present in the lower airways include pulmonary alveolar macrophages, mast cells, lymphocytes, and amino precursor uptake and decarboxylation (APUD) cells. Neutrophils are also typically present in smokers and patients with acute lung injury.
Pulmonary Circulation & Lymphatics
The lungs are supplied by two circulations, pulmonary and bronchial. The bronchial circulation arises from the left heart and sustains the metabolic needs of the tracheobronchial tree. The bronchial circulation provides a small amount of blood flow (ie, less than 4% of the cardiac output). Branches of the bronchial artery supply the wall of the bronchi and follow the airways as far as the terminal bronchioles. Along their courses, the bronchial vessels anastomose with the pulmonary arterial circulation and continue as far as the alveolar duct. Below that level, lung tissue is supported by a combination of the alveolar gas and pulmonary circulation. Except for the main bronchi within the mediastinum, almost all the blood carried by the bronchial arteries enters the pulmonary circulation.
The pulmonary circulation normally receives the total output of the right heart via the pulmonary artery, which divides into right and left branches to supply each lung. Deoxygenated blood passes through the pulmonary capillaries, where O2 is taken up and CO2 is eliminated. The oxygenated blood is then returned to the left heart by four main pulmonary veins (two from each lung). Although flows through the systemic and pulmonary circulations are equal, the lower pulmonary vascular resistance results in pulmonary vascular pressures that are one-sixth of those in the systemic circulation; as a result, both pulmonary arteries and veins normally have thinner walls than systemic vessels with less smooth muscle.
There are connections between the bronchial and the pulmonary circulations. Direct pulmonary arteriovenous communications, bypassing the pulmonary capillaries, are normally insignificant but may become important in certain pathological states. The importance of the bronchial circulation in contributing to the normal venous admixture is discussed below.
Pulmonary capillaries are incorporated into the walls of alveoli. The average diameter of these capillaries (about 10 μm) is barely enough to allow passage of a single red cell. Because each capillary network supplies more than one alveolus, blood may pass through several alveoli before reaching the pulmonary veins. Because of the relatively low pressure in the pulmonary circulation, the amount of blood flowing through a given capillary network is affected by both gravity and alveolar size. Large alveoli have a smaller capillary cross-sectional area and consequently increased resistance to blood flow. In the upright position, apical capillaries tend to have reduced flows, whereas basal capillaries have higher flows.
The pulmonary capillary endothelium has relatively large junctions (5 nm wide), allowing the passage of large molecules such as albumin. As a result, pulmonary interstitial fluid is relatively rich in albumin. Circulating macrophages and neutrophils are able to pass through the endothelium, as well as the smaller alveolar epithelial junctions, with relative ease. Pulmonary macrophages are commonly seen in the interstitial space and inside alveoli; they serve to prevent bacterial infection and to scavenge foreign particles.
Lymphatic channels in the lung originate in the interstitial spaces of large septa and are close to the bronchial arteries. Bronchial lymphatics return fluids, lost proteins, and various cells that have escaped in the peribronchovascular interstitium into the blood circulation, thus ensuring homeostasis and permitting lung function. Because of the large endothelial junctions, pulmonary lymph has a relatively high protein content, and total pulmonary lymph flow may be as much as 20 mL/hr. Large lymphatic vessels travel upward alongside the airways, forming the tracheobronchial chain of lymph nodes. Lymphatic drainage channels from both lungs communicate along the trachea.
The diaphragm is innervated by the phrenic nerves, which arise from the C3-C5 nerve roots. Unilateral phrenic nerve block or palsy only modestly reduces most indices of pulmonary function (about 25%) in normal subjects. Although bilateral phrenic nerve palsies produce more severe impairment, accessory muscle activity may maintain adequate ventilation in some patients. Intercostal muscles are innervated by their respective thoracic nerve roots. Cervical cord injuries above C5 are incompatible with spontaneous ventilation because both phrenic and intercostal nerves are affected.
The vagus nerves provide sensory innervation to the tracheobronchial tree. Both sympathetic and parasympathetic autonomic innervation of bronchial smooth muscle and secretory glands is present. Vagal activity mediates bronchoconstriction and increases bronchial secretions via muscarinic receptors. Sympathetic activity (T1-T4) mediates bronchodilation and also decreases secretions via β2-receptors. The nerve supply of the larynx is reviewed in Chapter 19.
Both α- and β-adrenergic receptors are present in the pulmonary vasculature, but the sympathetic system normally has little effect on pulmonary vascular tone. α1-Activity causes vasoconstriction; β2-activity mediates vasodilation. Parasympathetic vasodilatory activity seems to be mediated via the release of nitric oxide.
The periodic exchange of alveolar gas with the fresh gas from the upper airway reoxygenates desaturated blood and eliminates CO2
. This exchange is brought about by small cyclic pressure gradients established within the airways. During spontaneous ventilation, these gradients are secondary to variations in intrathoracic pressure; during mechanical ventilation, they are produced by intermittent positive pressure in the upper airway.
Normal pressure variations during spontaneous breathing are shown in Figure 23-3. The pressure within alveoli is always greater than the surrounding (intrathoracic) pressure unless the alveoli are collapsed. Alveolar pressure is normally atmospheric (zero for reference) at end-inspiration and end-expiration. By convention in pulmonary physiology, pleural pressure is used as a measure of intrathoracic pressure. Although it may not be entirely correct to refer to the pressure in a potential space, the concept allows the calculation of transpulmonary pressure. Transpulmonary pressure, or Ptranspulmonary, is then defined as follows:
Ptranspulmonary = Palveolar − Pintrapleural
Changes in intrapleural and alveolar pressures during normal breathing. Note that at end inspiration, volume is maximal; flow is zero; and alveolar pressure is atmospheric. (Adapted from West JB: Respiratory Physiology—The Essentials, 6th ed. Williams & Wilkins, 2000.)
At end-expiration, intrapleural pressure normally averages about −5 cm H2O, and because alveolar pressure is 0 (no flow), transpulmonary pressure is +5 cm H2O.
Diaphragmatic and intercostal muscle activation during inspiration expands the chest and decreases intrapleural pressure from −5 cm H2O to −8 or −9 cm H2O. As a result, alveolar pressure also decreases (between −3 and −4 cm H2O), and an alveolar-upper airway gradient is established; gas flows from the upper airway into alveoli. At end-inspiration (when gas inflow has ceased), alveolar pressure returns to zero, but intrapleural pressure remains decreased; the new transpulmonary pressure (5 cm H2O) sustains lung expansion.
During expiration, diaphragmatic relaxation returns intrapleural pressure to −5 cm H2O. Now the transpulmonary pressure does not support the new lung volume, and the elastic recoil of the lung causes a reversal of the previous alveolar-upper airway gradient; gas flows out of alveoli, and original lung volume is restored.
Most forms of mechanical ventilation intermittently apply positive airway pressure at the upper airway. During inspiration, gas flows into alveoli until alveolar pressure reaches that in the upper airway. During the expiratory phase of the ventilator, the positive airway pressure is removed or decreased; the gradient reverses, allowing gas flow out of alveoli.
The movement of the lungs is passive and determined by the impedance of the respiratory system, which can be divided into the elastic resistance of tissues and the gas-liquid interface and the nonelastic resistance to gas flow. Elastic resistance governs lung volume and the associated pressures under static conditions (no gas flow). Resistance to gas flow relates to frictional resistance to airflow and tissue deformation. The work necessary to overcome elastic resistance is stored as potential energy, but the work necessary to overcome nonelastic resistance is lost as heat.
Both the lungs and the chest have elastic properties. The chest has a tendency to expand outward, whereas the lungs have a tendency to collapse. When the chest is exposed to atmospheric pressure (open pneumothorax), it usually expands about 1 L in adults. In contrast, when the lung is exposed to atmospheric pressure, it collapses completely and all the gas within it is expelled. The recoil properties of the chest are due to structural components that resist deformation and chest wall muscle tone. The elastic recoil of the lungs is due to their high content of elastin fibers, and, even more important, the surface tension forces acting at the air-fluid interface in alveoli.
The gas-fluid interface lining the alveoli causes them to behave as bubbles. Surface tension forces tend to reduce the area of the interface and favor alveolar collapse. Laplace’s law can be used to quantify these forces:
The pressure derived from the equation is that within the alveolus. Alveolar collapse is therefore directly proportional to surface tension. Fortunately, in contrast to a bubble, pulmonary surfactant decreases alveolar surface tension. Moreover, the ability of the surfactant to lower surface tension is directly proportional to its concentration within the alveolus, resulting in lower intraalveolar pressure in smaller alveoli. As alveoli become smaller, the surfactant within becomes more concentrated, and surface tension is more effectively reduced. Conversely, when alveoli are overdistended, surfactant becomes less concentrated, and surface tension increases. The net effect is to stabilize alveoli; small alveoli are prevented from getting smaller, whereas large alveoli are prevented from getting larger.
Elastic recoil is usually measured in terms of compliance (C), which is defined as the change in volume divided by the change in distending pressure. Compliance measurements can be obtained for either the chest, the lung, or both together (Figure 23-4). In the supine position, chest wall compliance (Cw) is reduced because of the weight of the abdominal contents against the diaphragm. Measurements are usually obtained under static conditions, (ie, at equilibrium). (Dynamic lung compliance [Cdyn,L], which is measured during rhythmic breathing, is also dependent on airway resistance.) Lung compliance (CL) is defined as
CL is normally 150-200 mL/cm H2O. A variety of factors, including lung volume, pulmonary blood volume, extravascular lung water, and pathological processes (eg, inflammation and fibrosis) affect CL
where transthoracic pressure equals atmospheric pressure minus intrapleural pressure.
The pressure-volume relationship for the chest wall, lung, and both together in the upright (A) and supine (B) positions. (Modified and reproduced, with permission, from Scurr C, Feldman S: Scientific Foundations of Anesthesia. Heinemann, 1982.)
Normal chest wall compliance is 200 mL/cm H2O. Total compliance (lung and chest wall together) is 100 mL/cm H2O and is expressed by the following equation:
Lung volumes are important parameters in respiratory physiology and clinical practice (Table 23-1 and Figure 23-5). The sum of all of the named lung volumes equals the maximum to which the lung can be inflated. Lung capacities are clinically useful measurements that represent a combination of two or more volumes.
Table 23-1 Lung Volumes and Capacities. ||Download (.pdf)
Table 23-1 Lung Volumes and Capacities.
|Measurement||Definition||Average Adult Values (mL)|
|Tidal volume (VT)||Each normal breath||500|
|Inspiratory reserve volume (IRV)||Maximal additional volume that can be inspired above VT||3000|
|Expiratory reserve volume (ERV)||Maximal volume that can be expired below VT||1100|
|Residual volume (RV)||Volume remaining after maximal exhalation||1200|
|Total lung capacity (TLC)||RV + ERV + VT + IRV||5800|
|Functional residual capacity (FRC)||RV + ERV||2300|
Spirogram showing static lung volumes. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
Functional Residual Capacity
The lung volume at the end of a normal exhalation is called functional residual capacity (FRC). At this volume, the inward elastic recoil of the lung approximates the outward elastic recoil of the chest (including resting diaphragmatic tone). Thus, the elastic properties of both chest and lung define the point from which normal breathing takes place. Functional residual capacity can be measured by nitrogen washout or helium washin technique or by body plethysmography. Factors known to alter the FRC include the following:
- Body habitus: FRC is directly proportional to height. Obesity, however, can markedly decrease FRC (primarily as a result of reduced chest compliance).
- Sex: FRC is reduced by about 10% in females compared with males.
- Posture: FRC decreases as a patient is moved from an upright to a supine or prone position. This is the result of reduced chest compliance as the abdominal contents push up against the diaphragm. The greatest change occurs between 0° and 60° of inclination. No further decrease is observed with a head-down position of up to 30°.
- Lung disease: Decreased compliance of the lung, chest, or both is characteristic of restrictive pulmonary disorders all of which are associated with a low FRC.
- Diaphragmatic tone: This normally contributes to FRC.
As described above (see the section on Functional Respiratory Anatomy), small airways lacking cartilaginous support depend on radial traction caused by the elastic recoil of surrounding tissue to keep them open; patency of these airways, particularly in basal areas of the lung, is highly dependent on lung volume. The volume at which these airways begin to close in dependent areas of the lung is called the closing capacity. At lower lung volumes, alveoli in dependent areas continue to be perfused but are no longer ventilated; intrapulmonary shunting of deoxygenated blood promotes hypoxemia (see below).
Closing capacity is usually measured using a tracer gas (xenon-133), which is inhaled near residual volume and then exhaled from total lung capacity.
Closing capacity is normally well below FRC (Figure 23-6), but rises steadily with age (Figure 23-7). This increase is probably responsible for the normal age-related decline in arterial O2
tension. At an average age of 44 years, closing capacity equals FRC in the supine position; by age 66, closing capacity equals or exceeds FRC in the upright position in most individuals. Unlike FRC, closing capacity is unaffected by posture.
The relationship between functional residual capacity, closing volume, and closing capacity. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
The effect of age on closing capacity and its relationship to functional residual capacity (FRC). Note that FRC does not change. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
Vital capacity (VC) is the maximum volume of gas that can be exhaled following maximal inspiration. In addition to body habitus, VC is also dependent on respiratory muscle strength and chest-lung compliance. Normal VC is about 60-70 mL/kg.
Airway Resistance to Gas Flow
Gas flow in the lung is a mixture of laminar and turbulent flow. Laminar flow can be thought of as consisting of concentric cylinders of gas flowing at different velocities; velocity is highest in the center and decreases toward the periphery. During laminar flow,
where Raw is airway resistance.
Turbulent flow is characterized by random movement of the gas molecules down the air passages. Mathematical description of turbulent flow is considerably more complex:
Resistance is not constant but increases in proportion to gas flow. Moreover, resistance is directly proportional to gas density and inversely proportional to the fifth power of the radius. As a result, turbulent gas flow is extremely sensitive to airway caliber.
Turbulence generally occurs at high gas flows, at sharp angles or branching points, and in response to abrupt changes in airway diameter. Whether turbulent or laminar flow occurs can be predicted by the Reynolds number, which results from the following equation:
A low Reynolds number (<1000) is associated with laminar flow, whereas a high value (>1500) produces turbulent flow. Laminar flow normally occurs only distal to small bronchioles (<1 mm). Flow in larger airways is probably turbulent. Of the gases used clinically, only helium has a significantly lower density-to-viscosity ratio, making it useful clinically during severe turbulent flow (as caused by upper airway obstruction). A helium-O2 mixture not only is less likely to cause turbulent flow but also reduces airway resistance when turbulent flow is present (Table 23-2).
Table 23-2 Physical Properties of Several Gas Mixtures.1
Table 23-2 Physical Properties of Several Gas Mixtures.1
Normal total airway resistance is about 0.5-2 cm H2O/L/sec, with the largest contribution coming from medium-sized bronchi (before the seventh generation). Resistance in large bronchi is low because of their large diameters, whereas resistance in small bronchi is low because of their large total cross-sectional area. The most important causes of increased airway resistance include bronchospasm, secretions, and mucosal edema as well as volume-related and flow-related airway collapse.
Volume-Related Airway Collapse
At low lung volumes, loss of radial traction increases the contribution of small airways to total resistance; airway resistance becomes inversely proportional to lung volume (Figure 23-8). Increasing lung volume up to normal with positive end-expiratory pressure (PEEP) can reduce airway resistance.
The relationship between airway resistance and lung volume. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
Flow-Related Airway Collapse
During forced exhalation, reversal of the normal transmural airway pressure can cause collapse of these airways (dynamic airway compression). Two contributing factors are responsible: generation of a positive pleural pressure and a large pressure drop across intrathoracic airways as a result of increased airway resistance. The latter is in turn due to high (turbulent) gas flow and the reduced lung volume. The terminal portion of the flow/volume curve is therefore considered to be effort independent (Figure 23-9).
Gas flow (A) during forced exhalation from total lung capacity with varying effort and (B) with maximal effort from different lung volumes. Note that regardless of initial lung volume or effort, terminal expiratory flows are effort independent. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
The point along the airways where dynamic compression occurs is called the equal pressure point. It is normally beyond the eleventh to thirteenth generation of bronchioles where cartilaginous support is absent (see above). The equal pressure point moves toward smaller airways as lung volume decreases. Emphysema or asthma predisposes patients to dynamic airway compression. Emphysema destroys the elastic tissues that normally support smaller airways. In patients with asthma, bronchoconstriction and mucosal edema intensify airway collapse and promote reversal of transmural pressure gradients across airways. Patients may terminate exhalation prematurely or purse their lips to increase expiratory resistance at the mouth. Premature termination of exhalation may increase FRC above normal, resulting in air trapping and auto-PEEP.
Measuring vital capacity as an exhalation that is as forceful and rapid as possible (Figure 23-10) provides important information about airway resistance. The ratio of the forced expiratory volume in the first second of exhalation (FEV1) to the total forced vital capacity (FVC) is proportional to the degree of airway obstruction. Normally, FEV1/FVC is ≥80%.
Whereas both FEV1
and FVC are effort dependent, forced midexpiratory flow (FEF25-75%
) is more effort independent and may be a more reliable measurement of obstruction.
The normal forced exhalation curve. FEF25-75% is also called the maximum midexpiratory flow rate (MMF25-75%). FRC, functional residual capacity; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.
This component of nonelastic resistance is generally underestimated and often overlooked, but may account for up to half of total airway resistance. It seems to be primarily due to viscoelastic (frictional) resistance of tissues to gas flow.
Because expiration is normally entirely passive, both the inspiratory and the expiratory work of breathing is performed by the inspiratory muscles (primarily the diaphragm). Three factors must be overcome during ventilation: the elastic recoil of the chest and lung, frictional resistance to gas flow in the airways, and tissue frictional resistance.
Respiratory work can be expressed as the product of volume and pressure (Figure 23-11). During inhalation, both inspiratory airway resistance and pulmonary elastic recoil must be overcome; nearly 50% of the energy expended is stored pulmonary elastic recoil. During exhalation, the stored potential energy is released and overcomes expiratory airway resistance. Increases in either inspiratory or expiratory resistance are compensated by increased inspiratory muscle effort. When expiratory resistance increases, the normal compensatory response is to increase lung volume such that Vt breathing occurs at an abnormally high FRC. The greater elastic recoil energy stored at a higher lung volume overcomes the added expiratory resistance. Excessive amounts of expiratory resistance also activate expiratory muscles (see above).
The work of breathing and its components during inspiration. (Reproduced, with permission, from Guyton AC: Textbook of Medical Physiology, 7th ed. W.B. Saunders, 1986.)
Respiratory muscles normally account for only 2% to 3% of O2 consumption but operate at about 10% efficiency. Ninety percent of the work is dissipated as heat (due to elastic and airflow resistance). In pathological conditions that increase the load on the diaphragm, muscle efficiency usually progressively decreases, and contraction may become uncoordinated with increasing ventilatory effort; moreover, a point may be reached whereby any increase in O2 uptake (because of augmented ventilation) is consumed by the respiratory muscles themselves.
The work required to overcome elastic resistance increases as VT increases, whereas the work required to overcome airflow resistance increases as respiratory rate (and, necessarily, expiratory flow) increases. Faced with either condition, patients minimize the work of breathing by altering the respiratory rate and VT (Figure 23-12). Patients with reduced compliance tend to have rapid, shallow breaths, whereas those with increased airflow resistance have a slow, deep breathing pattern.
The work of breathing in relation to respiratory rate for normal individuals, patients with increased elastic resistance, and patients with increased airway resistance. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
Effects of Anesthesia on Pulmonary Mechanics
The effects of anesthesia on breathing are complex and relate to changes both in position and anesthetic agent.
Effects on Lung Volumes & Compliance
Changes in lung mechanics due to general anesthesia occur shortly after induction. The supine position reduces the FRC by 0.8-1.0 L, and induction of general anesthesia further reduces the FRC by 0.4-0.5 L. FRC reduction is a consequence of alveolar collapse and compression atelectasis due to loss of inspiratory muscle tone, change in chest wall rigidity, and upward shift of the diaphragm. The mechanisms may be more complex; for example, only the dependent (dorsal) part of the diaphragm in the supine position moves cephalad. Other factors are likely due to a change in intrathoracic volume secondary to increased blood volume in the lung and changes in chest wall shape (Figure 23-13). The higher position of the dorsal diaphragm and changes in the thoracic cavity itself decrease lung volumes. This decrease in FRC is not related to anesthetic depth and may persist for several hours or days after anesthesia. Steep head-down (Trendelenburg) position (>30°) may reduce FRC even further as intrathoracic blood volume increases. In contrast, induction of anesthesia in the sitting position seems to have little effect on FRC. Muscle paralysis does not seem to change FRC significantly when the patient is already anesthetized.
With induction of anesthesia in the supine position, the abdominal contents exert cephalad pressure on the diaphragm. At end-expiration, the dorsal portion of the diaphragm is more cephalad and the ventral portion is more caudal than when awake, the thoracic spine is more lordotic, and the rib cage moves inward, all secondary to loss of motor tone.
The effects of anesthesia on closing capacity are more variable. Both FRC and closing capacity, however, are generally reduced to the same extent under anesthesia. Thus, the risk of increased intrapulmonary shunting under anesthesia is similar to that in the conscious state; it is greatest in the elderly, in obese patients, and in those with underlying pulmonary disease.
Effects on Airway Resistance
The reduction in FRC associated with general anesthesia would be expected to increase airway resistance. Increases in airway resistance are not usually observed, however, because of the bronchodilating properties of the volatile inhalation anesthetics. Increased airway resistance is more commonly due to pathological factors (posterior displacement of the tongue; laryngospasm; bronchoconstriction; or secretions, blood, or tumor in the airway) or equipment problems (small tracheal tubes or connectors, malfunction of valves, or obstruction of the breathing circuit).
Effects on the Work of Breathing
Increases in the work of breathing under anesthesia are most often secondary to reduced lung and chest wall compliance, and, less commonly, increases in airway resistance (see above). The problems of increased work of breathing are usually circumvented by controlled mechanical ventilation.
Effects on the Respiratory Pattern
Regardless of the agent used, light anesthesia often results in irregular breathing patterns; breath holding is common. Breaths become regular with deeper levels of anesthesia. Inhalation agents generally produce rapid, shallow breaths, whereas nitrous-opioid techniques result in slow, deep breaths.
Ventilation is usually measured as the sum of all exhaled gas volumes in 1 min (minute ventilation, or
Minute ventilation = Respiratory rate × Tidal volume
For the average adult at rest, minute ventilation is about 5 L/min.
Not all of the inspired gas mixture reaches alveoli; some of it remains in the airways and is exhaled without being exchanged with alveolar gases. The part of the VT not participating in alveolar gas exchange is known as dead space (VD). Alveolar ventilation (
) is the volume of inspired gases actually taking part in gas exchange in 1 min.
= Respiratory rate × Vt − Vd
Dead space is actually composed of gases in nonrespiratory airways (anatomic dead space) and alveoli that are not perfused (alveolar dead space). The sum of the two components is referred to as physiological dead space. In the upright position, dead space is normally about 150 mL for most adults (approximately 2 mL/kg) and is nearly all anatomic. The weight of an individual in pounds is roughly equivalent to dead space in milliliters. Dead space can be affected by a variety of factors (Table 23-3).
Table 23-3 Factors Affecting Dead Space. ||Download (.pdf)
Table 23-3 Factors Affecting Dead Space.
|Position of airway|
|Pulmonary vascular disease |
Because VT in the average adult is approximately 450 mL (6 mL/kg), VD/VT is normally 33%. This ratio can be derived by the Bohr equation:
where Paco2 is the alveolar CO2 tension and Peco2 is the mixed expired CO2 tension. This equation is useful clinically if arterial CO2 tension (Paco2) is used to approximate the alveolar concentration and the CO2 tension in expired air gases is the average measured over several minutes.
Distribution of Ventilation
Regardless of body position, alveolar ventilation is unevenly distributed in the lungs. The right lung receives more ventilation than the left lung (53% vs 47%), and the lower (dependent) areas of both lungs tend to be better ventilated than do the upper areas because of a gravitationally induced gradient in intrapleural pressure (transpulmonary pressure). Pleural pressure decreases about 1 cm H2O (becomes less negative) per 3-cm decrease in lung height. This difference places alveoli from different areas at different points on the pulmonary compliance curve (Figure 23-14). Because of a higher transpulmonary pressure, alveoli in upper lung areas are near-maximally inflated and relatively noncompliant, and they undergo little expansion during inspiration. In contrast, the smaller alveoli in dependent areas have a lower transpulmonary pressure, are more compliant, and undergo greater expansion during inspiration.
The effect of gravity on alveolar compliance in the upright position.
Airway resistance can also contribute to regional differences in pulmonary ventilation. Final alveolar inspiratory volume is solely dependent on compliance only if inspiratory time is unlimited. In reality, inspiratory time is necessarily limited by the respiratory rate and the time necessary for expiration; consequently, an excessively short inspiratory time will prevent alveoli from reaching the expected change in volume. Moreover, alveolar filling follows an exponential function that is dependent on both compliance and airway resistance. Therefore, even with a normal inspiratory time, abnormalities in either compliance or resistance can prevent complete alveolar filling.
Lung inflation can be described mathematically by the time constant, τ.
τ = Total compliance × Airway resistance
Regional variations in resistance or compliance not only interfere with alveolar filling but can cause asynchrony in alveolar filling during inspiration; some alveolar units may continue to fill as others empty.
Variations in time constants within the normal lung can be demonstrated in normal individuals breathing spontaneously during abnormally high respiratory rates. Rapid shallow breathing reverses the normal distribution of ventilation, preferentially favoring upper (nondependent) areas of the lung over the lower areas.
Of the approximately 5 L/min of blood flowing through the lungs, only about 70-100 mL at any one time are within the pulmonary capillaries undergoing gas exchange. At the alveolar-capillary membrane, this small volume forms a 50-100 m2-sheet of blood approximately one red cell thick. Moreover, to ensure optimal gas exchange, each capillary perfuses more than one alveolus.
Although capillary volume remains relatively constant, total pulmonary blood volume can vary between 500 mL and 1000 mL. Large increases in either cardiac output or blood volume are tolerated with little change in pressure as a result of passive dilation of open vessels and perhaps some recruitment of collapsed pulmonary vessels. Small increases in pulmonary blood volume normally occur during cardiac systole and with each normal (spontaneous) inspiration. A shift in posture from supine to erect decreases pulmonary blood volume (up to 27%); Trendelenburg positioning has the opposite effect. Changes in systemic capacitance also influence pulmonary blood volume: systemic venoconstriction shifts blood from the systemic to the pulmonary circulation, whereas vasodilation causes a pulmonary-to-systemic redistribution. In this way, the lung acts as a reservoir for the systemic circulation.
Local factors are more important than the autonomic system in influencing pulmonary vascular tone (above). Hypoxia is a powerful stimulus for pulmonary vasoconstriction (the opposite of its systemic effect). Both pulmonary arterial (mixed venous) and alveolar hypoxia induce vasoconstriction, but the latter is a more powerful stimulus. This response seems to be due to either the direct effect of hypoxia on the pulmonary vasculature or increased production of leukotrienes relative to vasodilatory prostaglandins. Inhibition of nitric oxide production may also play a role. Hypoxic pulmonary vasoconstriction is an important physiological mechanism in reducing intrapulmonary shunting and preventing hypoxemia (see below). Hyperoxia has little effect on the pulmonary circulation in normal individuals. Hypercapnia and acidosis have a constrictor effect, whereas hypocapnia causes pulmonary vasodilation, the opposite of what occurs in the systemic circulation.
Distribution of Pulmonary Perfusion
Pulmonary blood flow is also not uniform. Regardless of body position, lower (dependent) areas of the lung receive greater blood flow than upper (nondependent) areas. This pattern is the result of a gravitational gradient of 1 cm H2O/cm lung height. The normally low pressures in the pulmonary circulation allow gravity to exert a significant influence on blood flow. Also, in vivo perfusion scanning in normal individuals has shown an “onion-like” layering distribution of perfusion, with reduced flow at the periphery of the lung and increased perfusion toward the hilum.
Although the pulmonary perfusion pressure is not uniform across the lung, the alveolar distending pressure is relatively constant. The interplay of these pressures results in the dividing of the lung into four distinct zones (ie, the West Zones) (Figure 23-15). In zone 1 (PA > Pa > Pv), alveolar pressure (PA) is greater than both the arterial pulmonary pressure (PA) and venous pulmonary pressure (Pv), resulting in obstruction of blood flow and creation of alveolar dead space. Zone 1 is fairly small in a spontaneously breathing individual, but can enlarge during positive pressure ventilation. In lower areas of the lungs, Pa progressively increases due to lower elevation above the heart. In zone 2 (Pa > PA > Pv), Pa is higher than PA, but Pv remains lower than both, resulting in blood flow that is dependent on the differential between Pa and PA. The bulk of the lung is described by zone 3 (Pa > Pv > PA), where both Pa and Pv are higher than PA, resulting in blood flow independent of the alveolar pressure. Zone 4, the most dependent part of the lung, is where atelectasis and/or interstitial pulmonary edema occur, resulting in blood flow that is dependent on the differential between Pa and pulmonary interstitial pressure.
Pulmonary blood flow distribution relative to the alveolar pressure (PA), the pulmonary arterial pressure (Pa), the pulmonary venous pressure (Pv), and the interstitial pressure (Pis) at various gravitation levels. A: Classic West Zones of blood flow distribution in the upright position. (Modified and reproduced, with permission, from West JB: Respiratory Physiology: The Essentials, 6th edition. Williams and Wilkins, 2000. p. 37.). B: In vivo perfusion scanning illustrating central-to-peripheral, in addition to gravitational blood flow distribution, in the upright position. (Reproduced, with permission, from Lohser J: Evidence based management of one lung ventilation. Anesthesiol Clin 2008;26:241.)
Because alveolar ventilation (
) is normally about 4 L/min, and pulmonary capillary perfusion (
) is 5 L/min, the overall
ratio is about 0.8.
for individual lung units (each alveolus and its capillary) can range from 0 (no ventilation) to infinity (no perfusion); the former is referred to as intrapulmonary shunt, whereas the latter constitutes alveolar dead space.
normally ranges between 0.3 and 3.0; the majority of lung areas, however, are close to 1.0 (Figure 23-16A). Because perfusion increases at a greater rate than ventilation, nondependent (apical) areas tend to have higher
ratios than do dependent (basal) areas (Figure 23-16B).
The distribution of
ratios for the whole lung (A
) and according to height (B
) in the upright position. Note that blood flow increases more rapidly than ventilation in dependent areas. (Reproduced, with permission, from West JB: Ventilation/Blood Flow and Gas Exchange
, 3rd ed. Blackwell, 1977.)
The importance of
ratios relates to the efficiency with which lung units resaturate venous blood with O2
and eliminate CO2
. Pulmonary venous blood (the effluent) from areas with low ratios has a low O2 tension and high CO2 tension—similar to systemic mixed venous blood
. Blood from these units tends to depress arterial O2
tension and elevate arterial CO2
tension. Their effect on arterial O2
tension is much more profound than that on CO2
tension; in fact, arterial CO2
tension often decreases from a hypoxemia-induced reflex increase in alveolar ventilation. An appreciable compensatory increase in O2
uptake cannot take place in remaining areas where
is normal, because pulmonary end-capillary blood is usually already maximally saturated with O2
Shunting denotes the process whereby desaturated, mixed venous blood from the right heart returns to the left heart without being resaturated with O2
in the lungs (Figure 23-17). The overall effect of shunting is to decrease (dilute) arterial O2
content; this type of shunt is referred to as right-to-left. Left-to-right shunts (in the absence of pulmonary congestion), however, do not produce hypoxemia.
A three-compartment model of gas exchange in the lungs, showing dead space ventilation, normal alveolar-capillary exchange, and shunting (venous admixture). (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
Intrapulmonary shunts are often classified as absolute or relative. Absolute shunt refers to anatomic shunts and lung units where
is zero. A relative shunt is an area of the lung with a low
ratio. Clinically, hypoxemia from a relative shunt can usually be partially corrected by increasing the inspired O2
concentration; hypoxemia caused by an absolute shunt cannot.
Venous admixture refers to a concept rather than an actual physiological entity. Venous admixture is the amount of mixed venous blood that would have to be mixed with pulmonary end-capillary blood to account for the difference in O2 tension between arterial and pulmonary end-capillary blood. Pulmonary end-capillary blood is considered to have the same concentrations as alveolar gas. Venous admixture is usually expressed as a fraction of total cardiac output (
). The equation for
may be derived with the law for the conservation of mass for O2
across the pulmonary bed:
The simplified equation is
The formula for calculating the O2 content of blood is given below.
can be calculated clinically by obtaining mixed venous and arterial blood gas measurements; the former requires a pulmonary artery catheter. The alveolar gas equation is used to derive pulmonary end-capillary O2 tension. Pulmonary capillary blood is usually assumed to be 100% saturated for an FIO2 ≥ 0.21.
The calculated venous admixture assumes that all shunting is intrapulmonary and due to absolute shunts (
= 0). In reality, neither is ever the case; nonetheless, the concept is useful clinically. Normal
is primarily due to communication between deep bronchial veins and pulmonary veins, the thebesian circulation in the heart, and areas of low
in the lungs (Figure 23-18). The venous admixture in normal individuals (physiological shunt) is typically less than 5%.
Components of the normal venous admixture. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
Effects of Anesthesia on Gas Exchange
Abnormalities in gas exchange during anesthesia are common. They include increased dead space, hypoventilation, and increased intrapulmonary shunting. There is increased scatter of
ratios. Increases in alveolar dead space are most commonly seen during controlled ventilation, but may also occur during spontaneous ventilation.
General anesthesia commonly increases venous admixture to 5% to 10%, probably as a result of atelectasis and airway collapse in dependent areas of the lung. Inhalation agents, including nitrous oxide, also can inhibit hypoxic pulmonary vasoconstriction
in high doses; for volatile agents, the ED50
is about 2 minimum alveolar concentration (MAC). Elderly patients seem to have the largest increases in
. Inspired O2
tensions of 30% to 40% usually prevent hypoxemia, suggesting anesthesia increases relative shunt. PEEP is often effective in reducing venous admixture and preventing hypoxemia during general anesthesia, as long as cardiac output is maintained. Prolonged administration of high inspired O2
concentrations may be associated with atelectasis formation and increases in absolute shunt. Atelectasis in this situation is known as resorption atelectasis and appears in areas with a low
ratio ventilated at an O2
-inspired concentration close to 100%. Perfusion results in O2
being transported out of the alveoli at a rate faster than it enters the alveoli, leading to an emptying of the alveoli and collapse.
Alveolar, Arterial, & Venous Gas Tensions
When dealing with gas mixtures, each gas is considered to contribute separately to total gas pressure, and its partial pressure is directly proportional to its concentration. Air has an O2 concentration of approximately 21%; therefore, if the barometric pressure is 760 mm Hg (sea level), the partial pressure of O2 (Po2) in air is normally 159.6 mm Hg:
760 mm Hg × 0.21 = 159.6 mm Hg
In its general form, the equation may be written as follows:
where Pb = barometric pressure and Fio2 = the fraction of inspired O2.
Two general rules can also be used:
- Partial pressure in millimeters of mercury approximates the percentage × 7
- Partial pressure in kilopascals is approximately the same as the percentage.
With every breath, the inspired gas mixture is humidified at 37°C in the upper airway. The inspired tension of O2 (PIO2) is therefore reduced by the added water vapor. Water vapor pressure is dependent only upon temperature and is 47 mm Hg at 37°C. In humidified air, the normal partial pressure of O2 at sea level is 149.7 mm Hg:
(760 − 47) × 0.21 = 149.1 mm Hg
PIO2 = (PB − PH2O) × FIO2
where PH2O = the vapor pressure of water at body temperature.
In alveoli, the inspired gases are mixed with residual alveolar gas from previous breaths, O2 is taken up, and CO2 is added. The final alveolar O2 tension (Pao2) is therefore dependent on all of these factors and can be estimated by the following equation:
where Paco2 = arterial CO2 tension and Rq = respiratory quotient.
Rq is usually not measured.
Note that large increases in Paco2
(>75 mm Hg) readily produce hypoxia (Pao2
< 60 mm Hg) at room air, but not at high inspired O2
A yet simpler method of approximating Pao2 in millimeters of mercury is to multiply the percentage of inspired O2 concentration by 6. Thus, at 40%, Pao2 is 6 × 40, or 240 mm Hg.
Pulmonary End-Capillary Oxygen Tension
For all practical purposes, pulmonary end-capillary O2 tension (Pc′o2) may be considered identical to Pao2; the Pao2-Pc′o2 gradient is normally minute. Pc′o2 is dependent on the rate of O2 diffusion across the alveolar-capillary membrane, as well as on pulmonary capillary blood volume and transit time. The large capillary surface area in alveoli and the 0.4-0.5 μm thickness of the alveolar-capillary membrane greatly facilitate O2 diffusion. Enhanced O2 binding to hemoglobin at saturations above 80% also augments O2 diffusion (see below). Capillary transit time can be estimated by dividing pulmonary capillary blood volume by cardiac output (pulmonary blood flow); thus, normal capillary transit time is 70 mL ÷ 5000 mL/min (0.8 s). Maximum Pc′o2 is usually attained after only 0.3 sec, providing a large safety margin.
The binding of O2
to hemoglobin seems to be the principal rate-limiting factor in the transfer of O2
from alveolar gas to blood. Therefore, pulmonary diffusing capacity reflects not only the capacity and permeability of the alveolar-capillary membrane, but also pulmonary blood flow. Moreover, O2
uptake is normally limited by pulmonary blood flow, not O2
diffusion across the alveolar-capillary membrane; the latter may become significant during exercise in normal individuals at high altitudes and in patients with extensive destruction of the alveolar-capillary membrane.
O2 transfer across the alveolar-capillary membrane is expressed as O2 diffusing capacity (Dlo2):
Because Pc′o2 cannot be measured accurately, measurement of carbon monoxide diffusion capacity (Dlco) is used instead to assess gas transfer across the alveolar-capillary membrane. Because carbon monoxide has a very high affinity for hemoglobin, there is little or no CO in pulmonary capillary blood, so that even when it is administered at low concentration, Pc′co can be considered zero. Therefore,
Reductions in DLCO imply an impediment in gas transfer across the alveolar-capillary membrane. Such impediments may be due to abnormal
ratios, extensive destruction of the gas alveolar-capillary membrane, or very short capillary transit times. Abnormalities are accentuated by increases in O2
consumption and cardiac output, such as occurs during exercise.
PaO2 cannot be calculated like PAO2 but must be measured at room air. The alveolar-to-arterial O2 partial pressure gradient (A-a gradient) is normally less than 15 mm Hg, but progressively increases with age up to 20-30 mm Hg. Arterial O2 tension can be approximated by the following formula (in mm Hg):
The range is 60-100 mm Hg (8-13 kPa). Decreases are probably the result of a progressive increase in closing capacity relative to FRC (see above). Table 23-4 lists the mechanisms of hypoxemia (Pao2 <60 mm Hg).
Table 23-4 Mechanisms of Hypoxemia. ||Download (.pdf)
Table 23-4 Mechanisms of Hypoxemia.
- Low alveolar
- Low inspired
- Low fractional inspired concentration
- High altitude
- Alveolar hypoventilation
- Diffusion hypoxia
- Increased alveolar-arterial gradient
- Right-to-left shunting
- Increased areas of low
- Low mixed venous
- Decreased cardiac output
- Decreased hemoglobin concentration
The most common mechanism for hypoxemia is an increased alveolar-arterial gradient. The A-a gradient for O2 depends on the amount of right-to-left shunting, the amount of scatter, and the mixed venous O2 tension (see below). The last depends on cardiac output, O2 consumption, and hemoglobin concentration.
The A-a gradient for O2 is directly proportional to shunt, but inversely proportional to mixed venous O2 tension. The effect of each variable on Pao2 (and consequently the A-a gradient) can be determined only when the other variables are held constant. Figure 23-19 shows the effect of different degrees of shunting on Pao2.
It should also be noted that the greater the shunt, the less likely the possibility that an increase in Fio2
will prevent hypoxemia. Moreover, isoshunt lines seem to be most useful for O2
concentrations between 35% and 100%. Lower O2
concentrations require modification of isoshunt lines to account for the effect of
Isoshunt curves showing the effect of varying amounts of shunt on Pao2. Note that there is little benefit in increasing inspired oxygen concentration in patients with very large shunts. (Modified and reproduced, with permission, from Benatar SR, Hewlett AM, Nunn JF: The use of isoshunt lines for control of oxygen therapy. Br J Anaesth 1973;45:711.)
The effect of cardiac output on the A-a gradient (Figure 23-20) is due not only to its secondary effects on mixed venous O2 tension but also to a direct relationship between cardiac output and intrapulmonary shunting. As can be seen, a low cardiac output tends to accentuate the effect of shunt on Pao2. A reduction in venous admixture may be observed with low-normal cardiac outputs secondary to accentuated pulmonary vasoconstriction from a lower mixed venous O2 tension. On the other hand, high cardiac outputs can increase venous admixture by elevating mixed venous O2 tension, which in turn inhibits hypoxic pulmonary vasoconstriction.
The effect of cardiac output on the alveolar-arterial Po2 difference with varying degrees of shunting.
= 200 mL/min and Pao2
= 180 mm Hg.) (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology
, 4th ed. Butterworth, 2000.)
O2 consumption and hemoglobin concentration can also affect Pao2 through their secondary effects on mixed venous O2 tension (below). High O2 consumption rates and low hemoglobin concentrations can increase the A-a gradient and depress Pao2.
Mixed Venous Oxygen Tension
Normal mixed venous O2 tension () is about 40 mm Hg and represents the overall balance between O2 consumption and O2 delivery (Table 23-5). A true mixed venous blood sample contains venous drainage from the superior vena cava, the inferior vena cava, and the heart; it must therefore be obtained from a pulmonary artery catheter.
Table 23-5 Alterations in Mixed Venous Oxygen Tension (and Saturation). ||Download (.pdf)
Table 23-5 Alterations in Mixed Venous Oxygen Tension (and Saturation).
- Increased O2 consumption
- Malignant hyperthermia
- Thyroid storm
- Decreased O2 delivery
- Decreased cardiac output
- Decreased hemoglobin concentration
- Abnormal hemoglobin
- Left-to-right shunting
- High cardiac output
- Impaired tissue uptake
- Decreased oxygen consumption
- Combined mechanisms
- Sampling error
- Wedged pulmonary artery catheter
Carbon dioxide is a by-product of aerobic metabolism in mitochondria. There are therefore small continuous gradients for CO2 tension from mitochondria to cell cytoplasm, extracellular fluid, venous blood, and alveoli, where the CO2 is finally eliminated.
Mixed Venous Carbon Dioxide Tension
Normal mixed venous CO2 tension (
) is about 46 mm Hg and is the end result of mixing of blood from tissues of varying metabolic activity. Venous CO2
tension is lower in tissues with low metabolic activity (eg, skin), but higher in blood from those with relatively high activity (eg, heart).
Alveolar Carbon Dioxide Tension
Alveolar CO2 tension (Paco2) is generally considered to represent the balance between total CO2 production (
) and alveolar ventilation (elimination):
is alveolar ventilation (Figure 23-21). In reality, Paco2
is related to CO2
elimination rather than production. Although the two are equal in a steady state, an imbalance occurs during periods of acute hypoventilation or hypoperfusion, and the excess CO2
increases total body CO2
content. Clinically, Paco2
is more dependent on alveolar ventilation than is
, because CO2
output does not vary appreciably under most circumstances. Moreover, the body’s large capacity to store CO2
(see below) buffers acute changes in
The effect of alveolar ventilation on alveolar Pco2 at two rates of CO2 production. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
Pulmonary End-Capillary Carbon Dioxide Tension
Pulmonary end-capillary CO2 tension (Pc′co2) is virtually identical to Paco2 for the same reasons as those discussed in the section about O2. In addition, the diffusion rate for CO2 across the alveolar-capillary membrane is 20 times that of O2.
Arterial Carbon Dioxide Tension
Arterial CO2 tension (Paco2), which is readily measurable, is identical to Pc′co2, and, necessarily, Paco2. Normal Paco2 is 38 ± 4 mm Hg (5.1 ± 0.5 kPa); in practice, 40 mm Hg is usually considered normal.
ratios tend to increase Paco2,
ratios tend to decrease it (in contrast to the case for O2
[see above]), significant arterial-to-alveolar gradients for CO2
develop only in the presence of marked
abnormalities (>30% venous admixture); even then the gradient is relatively small (2-3 mm Hg). Moreover, small increases in the gradient appreciably increase CO2
output into alveoli with relatively normal
. Even moderate to severe disturbances usually fail to appreciably alter arterial CO2
because of a reflex increase in ventilation from concomitant hypoxemia.
End-Tidal Carbon Dioxide Tension
Because end-tidal gas is primarily alveolar gas and Paco2 is virtually identical to Paco2, end-tidal CO2 tension (Petco2) is used clinically as an estimate of Paco2. The Paco2-Petco2 gradient is normally less than 5 mm Hg and represents dilution of alveolar gas with CO2-free gas from nonperfused alveoli (alveolar dead space).
Transport of Respiratory Gases in Blood
O2 is carried in blood in two forms: dissolved in solution and in reversible association with hemoglobin.
The amount of O2 dissolved in blood can be derived from Henry’s law, which states that the concentration of any gas in solution is proportional to its partial pressure. The mathematical expression is as follows:
Gas concentration = α × Partial pressure
where α = the gas solubility coefficient for a given solution at a given temperature.
The solubility coefficient for O2 at normal body temperature is 0.003 mL/dL/mm Hg. Even with a Pao2 of 100 mm Hg, the maximum amount of O2 dissolved in blood is very small (0.3 mL/dL) compared with that bound to hemoglobin.
Hemoglobin is a complex molecule consisting of four heme and four protein subunits. Heme is an iron-porphyrin compound that is an essential part of the O2-binding sites; only the divalent form (+2 charge) of iron can bind O2. The normal hemoglobin molecule (hemoglobin A1) consists of two α and two β chains (subunits); the four subunits are held together by weak bonds between the amino acid residues. Each gram of hemoglobin can theoretically carry up to 1.39 mL of O2.
Hemoglobin Dissociation Curve
Each hemoglobin molecule binds up to four O2 molecules. The complex interaction between the hemoglobin subunits results in nonlinear (an elongated S shape) binding with O2 (Figure 23-22). Hemoglobin saturation is the amount of O2 bound as a percentage of its total O2-binding capacity. Four separate chemical reactions are involved in binding each of the four O2 molecules. The change in molecular conformation induced by the binding of the first three molecules greatly accelerates binding of the fourth O2 molecule. The last reaction is responsible for the accelerated binding between 25% and 100% saturation. At about 90% saturation, the decrease in available O2 receptors flattens the curve until full saturation is reached.
The normal adult hemoglobin-oxygen dissociation curve. (Modified and reproduced, with permission, from West JB: Respiratory Physiology—The Essentials, 6th ed. Williams & Wilkins, 2000.)
Factors Influencing the Hemoglobin Dissociation Curve
Clinically important factors altering O2 binding include hydrogen ion concentration, CO2 tension, temperature, and 2,3-diphosphoglycerate (2,3-DPG) concentration. Their effect on hemoglobin-O2 interaction can be expressed by P50, the O2 tension at which hemoglobin is 50% saturated (Figure 23-23). Each factor shifts the dissociation curve either to the right (increasing P50) or to the left (decreasing P50).
A rightward shift in the oxygen-hemoglobin dissociation curve lowers O2
affinity, displaces O2
from hemoglobin, and makes more O2
available to tissues; a leftward shift increases hemoglobin’s affinity for O2
, reducing its availability to tissues. The normal P50
in adults is 26.6 mm Hg (3.4 kPa).
The effects of changes in acid-base status, body temperature, and 2,3-DPG concentration on the hemoglobin-oxygen dissociation curve.
An increase in blood hydrogen ion concentration reduces O2 binding to hemoglobin (Bohr effect). Because of the shape of the hemoglobin dissociation curve, the effect is more important in venous blood than arterial blood (Figure 23-23); the net result is facilitation of O2 release to tissue with little impairment in O2 uptake (unless severe hypoxia is present).
The influence of CO2 tension on hemoglobin’s affinity for O2 is important physiologically and is secondary to the associated rise in hydrogen ion concentration when CO2 tension increases. The high CO2 content of venous capillary blood, by decreasing hemoglobin’s affinity for O2, facilitates the release of O2 to tissues; conversely, the lower CO2 content in pulmonary capillaries increases hemoglobin’s affinity for O2 again, facilitating O2 uptake from alveoli.
2,3-DPG is a by-product of glycolysis (the Rapoport-Luebering shunt) and accumulates during anaerobic metabolism. Although its effects on hemoglobin under these conditions are theoretically beneficial, its physiological importance normally seems minor. 2,3-DPG levels may, however, play an important compensatory role in patients with chronic anemia and may significantly affect the O2-carrying capacity of blood transfusions.
Abnormal Ligands & Abnormal Forms of Hemoglobins
Carbon monoxide, cyanide, nitric acid, and ammonia can combine with hemoglobin at O2-binding sites. They can displace O2 and shift the saturation curve to the left. Carbon monoxide is particularly potent, having 200-300 times the affinity of O2 for hemoglobin, combining with it to form carboxyhemoglobin. Carbon monoxide decreases hemoglobin’s O2-carrying capacity and impairs the release of O2 to tissues.
Methemoglobin results when the iron in heme is oxidized to its trivalent (+3) form. Nitrates, nitrites, sulfonamides, and other drugs can rarely result in significant methemoglobinemia. Methemoglobin cannot combine with O2 unless reconverted by the enzyme methemoglobin reductase; methemoglobin also shifts the normal hemoglobin saturation curve to the left. Methemoglobinemia, like carbon monoxide poisoning, therefore decreases the O2-carrying capacity and impairs the release of O2. Reduction of methemoglobin to normal hemoglobin is facilitated by such agents as methylene blue or ascorbic acid.
Abnormal hemoglobins can also result from variations in the protein subunit composition. Each variant has its own O2-saturation characteristics. These include fetal hemoglobin, hemoglobin A2, and sickle hemoglobin.
The total O2content of blood is the sum of that in solution plus that carried by hemoglobin. In reality, O2 binding to hemoglobin never achieves the theoretical maximum (see above), but is closer to 1.31 mL O2/dL blood per mm Hg. Total O2 content is expressed by the following equation:
O2 content = ([0.003 mL O2/dL blood per mm Hg] × Po2) + (So2 × Hb × 1.31 mL/dL blood)
where Hb is hemoglobin concentration in g/dL blood, and So2 is hemoglobin saturation at the given Po2.
Using the above formula and a hemoglobin of 15 g/dL, the normal O2 content for both arterial and mixed venous blood and the arteriovenous difference can be calculated as follows:
O2 transport is dependent on both respiratory and circulatory function. Total O2 delivery (
) to tissues is the product of arterial O2
content and cardiac output:
Note that arterial O2 content is dependent on Pao2 as well as hemoglobin concentration. As a result, deficiencies in O2delivery may be due to a low Pao2, a low hemoglobin concentration, or an inadequate cardiac output. Normal O2 delivery can be calculated as follows:
O2 delivery = 20 mL O2/dL blood × 50 dL per blood/min = 1000 mL O2/min
The Fick equation expresses the relationship between O2 consumption, O2 content, and cardiac output:
Rearranging the equation:
Consequently, the arteriovenous difference is a good measure of the overall adequacy of O2 delivery.
As calculated above, the arteriovenous difference (Cao2 -
) is about 5 mL O2
/dL blood (20 mL O2
/dL - 15 mL O2
/dL). Note that the normal extraction fraction for O2
] is 5 mL ÷ 20 mL, or 25%; thus, the body normally consumes only 25% of the O2
carried on hemoglobin. When O2
demand exceeds supply, the extraction fraction exceeds 25%. Conversely, if O2
supply exceeds demand, the extraction fraction falls below 25%.
is even moderately reduced,
usually remains normal because of increased O2
extraction (mixed venous O2
remains independent of delivery. With further reductions in
, however, a critical point is reached beyond which
becomes directly proportional to
. This state of supply-dependent O2 is typically associated with progressive lactic acidosis caused by cellular hypoxia.
The concept of O2 stores is important in anesthesia. When the normal flux of O2 is interrupted by apnea, existing O2 stores are consumed by cellular metabolism; if stores are depleted, hypoxia and eventual cell death follow. Theoretically, normal O2 stores in adults are about 1500 mL. This amount includes the O2 remaining in the lungs, that bound to hemoglobin (and myoglobin), and that dissolved in body fluids. Unfortunately, the high affinity of hemoglobin for O2 (the affinity of myoglobin is even higher), and the very limited quantity of O2 in solution, restrict the availability of these stores. The O2 contained within the lungs at FRC (initial lung volume during apnea), therefore, becomes the most important source of O2. Of that volume, however, probably only 80% is usable.
Apnea in a patient previously breathing room air leaves approximately 480 mL of O2 in the lungs. (If Fio2 = 0.21 and FRC = 2300 mL, O2 content = Fio2 × FRC.) The metabolic activity of tissues rapidly depletes this reservoir (presumably at a rate equivalent to
); severe hypoxemia usually occurs within 90 sec. The onset of hypoxemia can be delayed by increasing the Fio2
prior to the apnea. Following ventilation with 100% O2
, FRC contains about 2300 mL of O2
; this delays hypoxemia following apnea for 4-5 min. This concept is the basis for preoxygenation prior to induction of anesthesia.
Carbon dioxide is transported in blood in three forms: dissolved in solution, as bicarbonate, and with proteins in the form of carbamino compounds (Table 23-6). The sum of all three forms is the total CO2 content of blood (routinely reported with electrolyte measurements).
Table 23-6 Contributions to Carbon Dioxide Transport in 1 L of Whole Blood.1,2 ||Download (.pdf)
Table 23-6 Contributions to Carbon Dioxide Transport in 1 L of Whole Blood.1,2
|Mixed venous whole blood|
|Arterial whole blood|
Carbon dioxide is more soluble in blood than O2, with a solubility coefficient of 0.031 mmol/L/mm Hg (0.067 mL/dL/mm Hg) at 37°C.
In aqueous solutions, CO2 slowly combines with water to form carbonic acid and bicarbonate, according to the following reaction:
H2O + CO2 ↔ H2CO3 ↔ H+ + HCO3−
In plasma, although less than 1% of the dissolved CO2 undergoes this reaction, the presence of the enzyme carbonic anhydrase within erythrocytes and endothelium greatly accelerates the reaction.
As a result, bicarbonate represents the largest fraction of the CO2
in blood (see Table 23-6). Administration of acetazolamide
, a carbonic anhydrase inhibitor, can impair CO2
transport between tissues and alveoli.
On the venous side of systemic capillaries, CO2 enters red blood cells and is converted to bicarbonate, which diffuses out of red cells into plasma; chloride ions move from plasma into red cells to maintain electrical balance. In the pulmonary capillaries, the reverse occurs: chloride ions move out of red cells as bicarbonate ions reenter them for conversion back to CO2, which diffuses out into alveoli. This sequence is referred to as the chloride or Hamburger shift.
Carbon dioxide can react with amino groups on proteins, as shown by the following equation:
R-NH2 + CO2 → RNH − CO2− + H+
At physiological pH, only a small amount of CO2 is carried in this form, mainly as carbaminohemoglobin. Deoxygenated hemoglobin (deoxyhemoglobin) has a greater affinity (3.5 times) for CO2 than does oxyhemoglobin. As a result, venous blood carries more CO2 than does arterial blood (Haldane effect; see Table 23-6). Pco2 normally has little effect on the fraction of CO2 carried as carbaminohemoglobin.
Effects of Hemoglobin Buffering on Carbon Dioxide Transport
The buffering action of hemoglobin also accounts for part of the Haldane effect. Hemoglobin can act as a buffer at physiological pH because of its high content of histidine. Moreover, the acid-base behavior of hemoglobin is influenced by its oxygenation state:
Removal of O2 from hemoglobin in tissue capillaries causes the hemoglobin molecule to behave more like a base; by taking up hydrogen ions, hemoglobin shifts the CO2-bicarbonate equilibrium in favor of greater bicarbonate formation:
CO2 + H2O + HbO2 → HbH+ + HCO3- + O2
As a direct result, deoxyhemoglobin also increases the amount of CO2 that is carried in venous blood as bicarbonate. As CO2 is taken up from tissue and converted to bicarbonate, the total CO2 content of blood increases (see Table 23-6).
In the lungs, the reverse is true. Oxygenation of hemoglobin favors its action as an acid, and the release of hydrogen ions shifts the equilibrium in favor of greater CO2 formation:
O2 + HCO3- + HbH+ → H2O + CO2 + HbO2
Bicarbonate concentration decreases as CO2 is formed and eliminated, so that the total CO2 content of blood decreases in the lungs. Note that there is a difference between CO2 content (concentration per liter) of whole blood (see Table 23-6) and plasma (Table 23-7).
Table 23-7 Carbon Dioxide Content of Plasma (mmol/L).1,2 ||Download (.pdf)
Table 23-7 Carbon Dioxide Content of Plasma (mmol/L).1,2
Carbon Dioxide Dissociation Curve
A CO2 dissociation curve can be constructed by plotting the total CO2 content of blood against Pco2. The contribution of each form of CO2 can also be quantified in this manner (Figure 23-24).
The CO2 dissociation curve for whole blood. (Reproduced, with permission, from Nunn JF: Nunn's Applied Physiology, 4th ed. Butterworth, 2000.)
Carbon dioxide stores in the body are large (approximately 120 L in adults) and primarily in the form of dissolved CO2 and bicarbonate. When an imbalance occurs between production and elimination, establishing a new CO2 equilibrium requires 20-30 min (compared with less than 4-5 min for O2; see above). Carbon dioxide is stored in the rapid-, intermediate-, and slow-equilibrating compartments. Because of the larger capacity of the intermediate and slow compartments, the rate of rise in arterial CO2 tension is generally slower than its fall following acute changes in ventilation.
Spontaneous ventilation is the result of rhythmic neural activity in respiratory centers within the brainstem. This activity regulates respiratory muscles to maintain normal tensions of O2 and CO2 in the body. The basic neuronal activity is modified by inputs from other areas in the brain, volitional and autonomic, as well as various central and peripheral receptors (sensors).
Central Respiratory Centers
The basic breathing rhythm originates in the medulla. Two medullary groups of neurons are generally recognized: a dorsal respiratory group, which is primarily active during inspiration, and a ventral respiratory group, which is active during expiration. The close association of the dorsal respiratory group of neurons with the tractus solitarius may explain reflex changes in breathing from vagal or glossopharyngeal nerve stimulation.
Two pontine areas influence the dorsal (inspiratory) medullary center. A lower pontine (apneustic) center is excitatory, whereas an upper pontine (pneumotaxic) center is inhibitory. The pontine centers appear to fine-tune respiratory rate and rhythm.
The most important of these sensors are chemoreceptors that respond to changes in hydrogen ion concentration.
Central chemoreceptors are thought to lie on the anterolateral surface of the medulla and respond primarily to changes in cerebrospinal fluid (CSF) [H+
]. This mechanism is effective in regulating Paco2
, because the blood-brain barrier is permeable to dissolved CO2
, but not to bicarbonate ions. Acute changes in Paco2
, but not in arterial [HCO3-
], are reflected in CSF; thus, a change in CO2
must result in a change in [H+
Over the course of a few days, CSF [HCO3-] can compensate to match any change in arterial [HCO3-].
Increases in Paco2 elevate CSF hydrogen ion concentration and activate the chemoreceptors. Secondary stimulation of the adjacent respiratory medullary centers increases alveolar ventilation (Figure 23-25) and reduces Paco2 back to normal. Conversely, decreases in CSF hydrogen ion concentration secondary to reductions in Paco2 reduce alveolar ventilation and elevate Paco2. Note that the relationship between Paco2 and minute volume is nearly linear. Also note that very high arterial Paco2 tensions depress the ventilatory response (CO2 narcosis). The Paco2 at which ventilation is zero (x-intercept) is known as the apneic threshold. Spontaneous respirations are typically absent under anesthesia when Paco2 falls below the apneic threshold. (In the awake state, cortical influences prevent apnea, so apneic thresholds are not ordinarily seen.) In contrast to peripheral chemoreceptors (see below), central chemoreceptor activity is depressed by hypoxia.
The normal relationship between Paco2 and minute ventilation. (Reproduced, with permission, from Guyton AC: Textbook of Medical Physiology, 7th ed. W.B. Saunders, 1986.)
Peripheral chemoreceptors include the carotid bodies (at the bifurcation of the common carotid arteries) and the aortic bodies (surrounding the aortic arch). The carotid bodies are the principal peripheral chemoreceptors in humans and are sensitive to changes in Pao
2, pH, and arterial perfusion pressure. They interact with central respiratory centers via the glossopharyngeal nerves, producing reflex increases in alveolar ventilation in response to reductions in Pao
2, arterial perfusion, or elevations in [H+] and Paco
2. Peripheral chemoreceptors are also stimulated by cyanide,
doxapram, and large doses of
nicotine. In contrast to central chemoreceptors, which respond primarily to Paco
2 (really [H+]), the carotid bodies are most sensitive to Pao
2 (Figure 23-26). Note that receptor activity does not appreciably increase until Pao2 decreases below 50 mm Hg. Cells of the carotid body (glomus cells) are thought to be primarily dopaminergic neurons. Anti-dopaminergic drugs (such as phenothiazines), most commonly used anesthetics, and bilateral carotid surgery abolish the peripheral ventilatory response to hypoxemia.
The relationship between Pao2 and minute ventilation at rest and with a normal Paco
2. (Data from Weil JV, Byrne-Quinn E, Sodal IE, et al: Hypoxic ventilatory drive in normal man. J Clin Invest 1970;49:1061-1072; Dripps RD, Comroe JH: The effect of the inhalation of high and low
oxygen concentration on respiration, pulse rate, ballistocardiogram and arterial oxygen saturation (oximeter) of normal individuals. Am J Physiol 1947;149:277-291; Cormac RS, Cunningham DJC, Gee JBL: The effect of carbon dioxide on the respiratory response to want of oxygen in man. Q J Exp Physiol 1957;42:303-316.)
Impulses from these receptors are carried centrally by the vagus nerve. Stretch receptors are distributed in the smooth muscle of airways; they are responsible for inhibition of inspiration when the lung is inflated to excessive volumes (Hering-Breuer inflation reflex) and shortening of exhalation when the lung is deflated (deflation reflex). Stretch receptors normally play a minor role in humans. In fact, bilateral vagal nerve blocks have a minimal effect on the normal respiratory pattern.
Irritant receptors in the tracheobronchial mucosa react to noxious gases, smoke, dust, and cold gases; activation produces reflex increases in respiratory rate, bronchoconstriction, and coughing. J (juxta-capillary) receptors are located in the interstitial space within alveolar walls; these receptors induce dyspnea in response to expansion of interstitial space volume and various chemical mediators following tissue damage.
These include various muscle and joint receptors on pulmonary muscles and the chest wall. Input from these sources is probably important during exercise and in pathological conditions associated with decreased lung or chest compliance.
Effects of Anesthesia on the Control of Breathing
The most important effect of most general anesthetics on breathing is a tendency to promote hypoventilation. The mechanism is probably dual: central depression of the chemoreceptor and depression of external intercostal muscle activity. The magnitude of the hypoventilation is generally proportional to anesthetic depth.
With increasing depth of anesthesia, the slope of the Paco2
/minute ventilation curve decreases, and the apneic threshold increases (Figure 23-27). This effect is at least partially reversed by surgical stimulation.
The effect of volatile agents (halothane) on the Petco2-ventilation response curve (see text). (Data from Munson ES, Larson CP, Babad AA, et al: The effects of halothane, fluroxene and cyclopropane on ventilation: a comparative study in man. Anesthesiology 1966;27:716-728.)
The peripheral response to hypoxemia is even more sensitive to anesthetics than the central CO2 response and is nearly abolished by even subanesthetic doses of most inhalation agents (including
nitrous oxide) and many intravenous agents.
Nonrespiratory Functions of the Lung
Filtration & Reservoir Function
The unique in-series position of the pulmonary capillaries within the circulation allows them to act as a filter for debris in the bloodstream. The lungs’ high content of heparin and plasminogen activator facilitates the breakdown of entrapped fibrin debris. Although pulmonary capillaries have an average diameter of 7 μm, larger particles have been shown to pass through to the left heart.
The role of the pulmonary circulation as a reservoir for the systemic circulation was discussed above.
The lungs are metabolically very active organs. In addition to surfactant synthesis, pneumocytes account for a major portion of extrahepatic mixed-function oxidation. Neutrophils and macrophages in the lung produce O2-derived free radicals in response to infection. The pulmonary endothelium metabolizes a variety of vasoactive compounds, including norepinephrine, serotonin, bradykinin, and a variety of prostaglandins and leukotrienes. Histamine and epinephrine are generally not metabolized in the lungs; in fact the lungs can be a major site of histamine synthesis and release during allergic reactions.
The lungs are also responsible for converting angiotensin I to its physiologically active form, angiotensin II. The enzyme responsible, angiotensin-converting enzyme, is bound on the surface of the pulmonary endothelium.