365.1 Lung Volumes and Capacities in Health and Disease

Ashok P. Sarnaik and Sabrina M. Heidemann

Traditionally, lung volumes are measured with a spirogram (Fig. 365-1). Tidal volume (V_T) is the amount of air moved in and out of the lungs during each breath; at rest, tidal volume is normally 6-7 mL/kg body weight. Inspiratory capacity (IC) is the amount of air inspired by maximum inspiratory effort after tidal expiration. Expiratory reserve volume (ERV) is the amount of air exhaled by maximum expiratory effort after tidal expiration. The volume of gas remaining in the lungs after maximum expiration is residual volume (RV). Vital capacity (VC) is defined as the amount of air moved in and out of the lungs with maximum inspiration and expiration. VC, IC, and ERV are decreased in lung pathology but are also effort dependent. Total lung capacity (TLC) is the volume of gas occupying the lungs after maximum inhalation.

Figure 365-1 Spirogram showing lung volumes and capacities. FEV_1.0 is the maximum volume exhaled in 1 sec after maximum inspiration. Restrictive diseases are usually associated with decreased lung volumes and capacities. Intrathoracic airway obstruction is associated with air trapping and abnormally high functional residual capacity and residual volume. FEV_1.0 and vital capacity are decreased in both restrictive and obstructive diseases. The ratio of FEV_1.0 to vital capacity is normal in restrictive disease but decreased in obstructive disease. FEV, forced expiratory volume.

Flow volume relationship offers a valuable means at the bedside or in an office setting to detect abnormal pulmonary mechanics and response to therapy with relatively inexpensive and easy-to-use devices. After maximum inhalation, the patient forcefully exhales through a mouthpiece into the device until residual volume is reached followed by maximum inhalation (Fig. 365-2). Flow is plotted against volume. Maximum forced expiratory flow (FEF max) is generated in the early part of exhalation, and it is a commonly used indicator of airway obstruction in asthma and other obstructive lesions. Provided maximum pressure is generated consistently during exhalation, a decrease in flow is a reflection of increased airway resistance. The total volume exhaled during this maneuver is forced vital capacity (FVC). Volume exhaled in one second is referred to as FEV₁. FEV₁/FVC is expressed as a percentage of FVC. FEF_25%-75% is the mean flow between 25% and 75% of FVC and is considered relatively effort independent. Individual values and shapes of flow-volume curves show characteristic changes in obstructive and restrictive respiratory disorders (Fig. 365-3). In intrapulmonary airway obstruction such as asthma or cystic fibrosis, there is a reduction of FEF_max, FEF_25%-75%, FVC, and FEV₁/FVC. Also, there is a characteristic concavity in the middle part of the expiratory curve. In restrictive lung disease such as interstitial pneumonia, FVC is decreased with relative preservation of airflow and FEV₁/FVC. The flow volume curve assumes a vertically oblong shape compared to normal. Changes in shape of the flow volume loop and individual values depend on the type of disease and the extent of severity.

Figure 365-2 Flow volume loop in a normal person performed after maximal inspiration followed by forced complete expiration and forced complete inhalation. FEF_max represents maximum flow during expiration. This is attained soon after initiation of the expiration. Fall in expiratory flow is gradual until it reaches zero after exhalation is complete. FEF_25%-75% represents mean flow from 25% (FEF_25%) to 75% (FEF_75%) of exhaled forced expiratory volume (FEV), also termed forced vital capacity (FVC). FEV₁ is amount of volume after 1 sec of forced exhalation. Normally FEV₁ is around 80% of FVC.

Figure 365-3 Flow volume loops in intrapulmonary airway obstruction and restrictive disorders. Note that in intrapulmonary airway obstruction, there is a decrease in FEF_max, FEF_25%-75, and FEV₁/FVC%. The middle part of expiratory loop appears concave. In restrictive disorder, the flow volume loop assumes a more vertically oblong shape with reduction in FVC but not the FEV₁/FVC%. Expiratory and inspiratory flow rates are relatively unaffected. FEF, forced expiratory flow; FEV, forced expiratory volume; FVC, forced vital capacity.

Functional residual capacity (FRC) is the amount of air left in the lungs after tidal expiration. FRC has important pathophysiologic implications. Alveolar gas composition changes during inspiration and expiration. Alveolar PO₂ (PAO₂) increases and alveolar PCO₂ (PACO₂) decreases during inspiration as fresh atmospheric gas enters the lungs. During exhalation, PAO₂ decreases and PACO₂ increases as pulmonary capillary blood continues to remove oxygen from and add CO₂ into the alveoli (Fig. 365-4). FRC acts as a buffer, minimizing the changes in PAO₂ and PACO₂ during inspiration and expiration. FRC represents the environment available for pulmonary capillary blood for gas exchange at all times.

Figure 365-4 Alveolar PO₂ rises and PCO₂ falls during inspiration as fresh atmospheric gas is brought into the lungs. During expiration, the opposite changes occur as pulmonary capillary blood continues to remove O₂ and add CO₂ from the alveoli without atmospheric enrichment. Note that during the early part of inspiration, alveolar PO₂ continues to fall and PCO₂ continues to rise because of inspiration of the dead space that is occupied by the previously exhaled gas.

(Modified from Comroe JH: Physiology of respiration, ed 2, Chicago, 1974, Year Book Medical Publishers, p 12.)

A decrease in FRC is often encountered in alveolar interstitial diseases and thoracic deformities. The major pathophysiologic consequence of decreased FRC is hypoxemia. Reduced FRC results in a sharp decline in PAO₂ during exhalation because a limited volume is available for gas exchange. PO₂ of pulmonary capillary blood therefore falls excessively during exhalation, leading to a decline in arterial PO₂ (PaO₂). Any increase in PAO₂ (and therefore PaO₂) during inspiration cannot compensate for the decreased PaO₂ during expiration. The explanation for this lies in the shape of O₂-hemoglobin (Hb) dissociation curve, which is sigmoid shaped (Fig. 365-5). Because most of the oxygen in blood is combined with Hb, it is the percentage of oxyhemoglobin (SO₂) that gets averaged rather than the PO₂. Although an increase in arterial PO₂ cannot increase O₂-Hb saturation >100%, there is a steep desaturation of hemoglobin below a PO₂ of 50 torr; thus, decreased SO₂ during exhalation as a result of low FRC leads to overall arterial desaturation and hypoxemia. The adverse pathophysiologic consequences of decreased FRC are ameliorated by application of positive end expiratory pressure (PEEP) and increasing the inspiratory time during mechanical ventilation.

Figure 365-5 Oxygen-hemoglobin dissociation curve. P₅₀ of adult blood is around 27 torr. Under basal conditions, mixed venous blood has PO₂ of 40 torr and oxygen-hemoglobin saturation of 75%. In arterial blood, these values are 100 torr and 97.5%, respectively. Note that there is a steep decline in oxygen-hemoglobin saturation at PaO₂<50 torr, but relatively little increase in saturation is gained at PO₂>70 torr.

The lung pressure–volume relationship is markedly influenced by FRC (Fig. 365-6). Pulmonary compliance is decreased at abnormally low or high FRC.

Figure 365-6 Lung compliance is significantly influenced by the functional residual capacity (FRC). The same change in pressure is associated with less change in volume when FRC is abnormally decreased (a) or abnormally increased (c) compared to the normal state (b).

FRC is abnormally increased in intrathoracic airway obstruction, which results in incomplete exhalation, and abnormally decreased in alveolar-interstitial diseases. At excessively low or high FRC, tidal respiration requires higher inflation pressures compared to normal FRC. Abnormalities of FRC result in increased work of breathing with spontaneous respiration and increased barotrauma in mechanical ventilation.

365.2 Chest Wall

Ashok P. Sarnaik and Sabrina M. Heidemann

The chest wall and diaphragm of an infant are mechanically disadvantaged compared to that of an adult when required to increase thoracic (and therefore the lung) volume. The infant’s ribs are oriented much more horizontally and the diaphragm is flatter and less domed. The infant is therefore unable to duplicate the efficiency of upward and outward movement of obliquely oriented ribs and downward displacement of the domed diaphragm in an adult to expand the thoracic capacity. Additionally, the infant’s rib cage is softer and thus more compliant compared to an adult’s. Although a soft, highly compliant chest wall is beneficial to a baby in its passage through the birth canal and allows future lung growth, it places the young infant in a vulnerable situation under certain pathologic conditions. Chest wall compliance is a major determinant of FRC. Because the chest wall and the lungs recoil in opposite directions at rest, FRC is reached at the point where the outward elastic recoil of the thoracic cage counterbalances the inward lung recoil. This balance is attained at a lower lung volume in a young infant because of the extremely high thoracic compliance compared to older children (see Fig. 365-7 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). The measured FRC in infants is higher than expected because respiratory muscles of infants maintain the thoracic cage in an inspiratory position at all times. Additionally, some amount of air trapping during expiration occurs in young infants.

Figure 365-7 Schematic representation of interaction between chest wall and lung recoil in infants compared to adults. The elastic recoil of a relatively more compliant chest wall is balanced by the lung recoil at a lower volume (FRC) in infants compared to adults. FRC, functional residual capacity.

The increased chest wall compliance is a distinct disadvantage to the young infant under several pathologic conditions. A decrease in muscle tone, as occurs in rapid eye movement (REM) sleep or with CNS depression, allows greater chest wall retraction because of less opposition to the lung recoil; the FRC decreases in such states. The respiratory muscles of infants are poorly equipped to sustain large workloads. They are more easily fatigued than those of older children, limiting their ability to maintain adequate ventilation in lung disease. In diseases of poor lung compliance (atelectasis, pulmonary edema), excessive lung recoil results in greater retraction of the soft chest wall and more loss of FRC than occurs in older children and adults with stiffer chest walls. Increased negative intrathoracic pressure required to overcome airway resistance in obstructive lung disease also produces greater chest wall recoil and reduced FRC in young infants. Application of PEEP is beneficial in such states for stabilizing the chest wall and restoring FRC.

Young infants do not tolerate sustained respiratory loads as well as older children and adults. Respiratory muscle ontogeny is characterized by changes in the composition of muscle fiber types in the diaphragm and intercostals throughout infancy. Type I fibers are slow-twitch and high-oxidative in nature, whereas type II fibers are fast-twitch and low-oxidative. Type I fibers have low contractility but are fatigue resistant. Type II fibers have high contractility but are more prone to fatigue. The proportion of type I fibers in the diaphragm and intercostals of premature infants is only around 10%. This increases to around 25% in full-term newborns and around 50% in children >2 years. Respiratory muscles of premature babies and young infants are therefore more susceptible to fatigue, resulting in earlier decompensation.

Abnormalities of the chest wall are encountered in certain pathologic conditions. Chest wall instability can result from trauma (fractured ribs, thoracotomy) and neuromuscular diseases that lead to intercostal and diaphragmatic muscle weakness. The increased chest wall compliance makes such children more vulnerable to respiratory decompensation when faced with similar pulmonary pathology compared to older children and adults with stiffer chest walls. Children with rigid, noncompliant chest wall (asphyxiating thoracic dystrophy of Jeune [Chapters 411.3 and 691], achondroplasia [Chapter 411.4]) have markedly diminished lung volumes and capacities.

365.3 Pulmonary Mechanics and Work of Breathing in Health and Disease

Ashok P. Sarnaik and Sabrina M. Heidemann

The movement of air in and out of the lungs requires a sufficient pressure gradient between alveoli and atmosphere during inspiration and expiration. Part of the pressure gradient is required to overcome the lung and chest wall elastance; another part is needed to overcome airway resistance. Elastance refers to the property of a substance to oppose deformation or stretching. It is calculated as a change in pressure (ΔP) ÷ change in volume (ΔV). Elastic recoil is a property of a substance that enables it to return to its original state after it is no longer subjected to pressure. Compliance (ΔV ÷ ΔP) is the reciprocal of elastance. In the context of the pulmonary parenchyma, airways, and the chest wall, the compliance refers to their distensibilty. Resistance is calculated as the amount of pressure required to generate flow of gas across the airways. Resistance to laminar flow is governed by Poiseuille’s law stated as:

where R is resistance, l is length, η is viscosity, and r is the radius. The practical implication of pressure-flow relationship is that airway resistance is inversely proportional to its radius raised to the 4th power. If the airway lumen is decreased in half, the resistance increases 16-fold. Newborns and young infants with their inherently smaller airways are especially prone to marked increase in airway resistance from inflamed tissues and secretions. In diseases in which airway resistance is increased, flow often becomes turbulent. Turbulence depends to a great extent on the Reynolds number (Re), a dimensionless entity, which is calculated as

where r is radius, v is velocity, d is density, and η is viscosity. Turbulence in gas flow is most likely to occur when Re exceeds 2000. Resistance to turbulent flow is greatly influenced by density. A low-density gas such as helium-oxygen mixture decreases turbulence in obstructive airway diseases such as viral laryngotracheobronchitis and asthma. Neonates and young infants are predominantly nose breathers and therefore even a minimal amount of nasal obstruction is poorly tolerated.

The diaphragm is the major muscle of respiration. When additional work of breathing (WOB) is required, intercostal and other accessory muscles of respirations also contribute to the increased work. The tidal volume and respiratory rate are adjusted, both in health and disease, to maintain the required minute volume with the least amount of energy expenditure. The total WOB (necessary to create pressure gradients to move air) is divided into 2 parts. The 1st part is to overcome the lung and chest wall elastance and is referred to as elastic work (W_elast). The 2nd part is to overcome airway and tissue resistance, and is referred to as resistive work (W_resist). W_elast is directly proportional to tidal volume, whereas W_resist is determined by the rate of airflow and, therefore, the respiratory rate. The total WOB is lowest at a rate of 35-40/min for neonates and 14-16/min for older children and adults. W_elast is disproportionately increased in diseases with decreased compliance and W_resist is increased in airway obstruction. Respirations are therefore shallow (low V_T) and rapid in diseases of low compliance and deep and relatively slow (low flow rate) in diseases of increased resistance.

Compared to older children, young infants have disproportionately greater W_elast because the negative intrapleural pressure during inspiration causes the retractile (more compliant) chest wall to collapse and pose an impediment to air entry. Young infants increase their respiratory rate with any mechanical abnormality. Other examples of compliant chest wall being a disadvantage include flail chest resulting from rib fractures, thoracotomy, and neuromuscular weakness. One of the salutary effects of continuous positive airway pressure in such situations is the stabilization of the chest wall. Under normal conditions, the energy cost of WOB contributes to only approximately 2% of total caloric expenditure. In children with chronic lung disease or congestive heart failure the, WOB can contribute to as much as 40% of total energy expenditure during physical activity, thus increasing their caloric needs.

Time constant, measured in seconds, is a product of compliance and resistance. It is a reflection of the amount of time required for proximal airway pressure (and therefore volume) to equilibrate with alveolar pressure. It takes 3 time constants for 95%, and 5 time constants for 99% of pressure equilibration to occur. Because airways expand during inspiration and narrow during expiration, expiratory time constant is longer than inspiratory time constant. Diseases characterized by decreased compliance (pneumonia, pulmonary edema, atelectasis) are associated with a shorter time constant and therefore require less time for alveolar inflation and deflation. Diseases associated with increased resistance (asthma, bronchiolitis, aspiration syndromes) have prolonged time constant and therefore require more time for alveolar inflation and deflation. Pathologic alterations in time constants have practical significance during mechanical ventilation. Patients with shorter time constants are best ventilated with relatively smaller tidal volumes and faster rates to minimize peak inflation pressure. In patients with increased airway resistance, a fast respiratory rate (and, therefore, less time) does not allow enough pressure equilibration to occur between the proximal airway and the alveoli. Inadequate inspiratory time results in lower tidal volume, whereas insufficient exhalation time results in inadvertent PEEP, often referred to as auto-PEEP or intrinsic PEEP. Such patients are therefore best ventilated with relatively slower rates and larger tidal volumes.

365.4 Airway Dynamics in Health and Disease

Ashok P. Sarnaik and Sabrina M. Heidemann

Because the trachea and airways of an infant are much more compliant than those of older children and adults, changes in intrapleural pressure result in much greater changes in airway diameter. The airway can be divided into 3 anatomic parts: the extrathoracic airway extends from the nose to the thoracic inlet, the intrathoracic-extrapulmonary airway extends from the thoracic inlet to the main stem bronchi, and the intrapulmonary airway is within the lung parenchyma. During normal respirations, intrathoracic airways expand in inspiration as intrapleural pressure becomes more negative and narrow in expiration as they return to their baseline at FRC. The changes in diameter are of little significance in normal respiration. In diseases characterized by airway obstruction, much greater changes in intrapleural pressure are required to generate adequate airflow, resulting in greater changes in airway lumen. The changes in the size of airway during respiration are accentuated in young infants with their softer, more compliant airways.

In extrathoracic airway obstruction (choanal atresia [Chapter 368], retropharyngeal abscess, laryngotracheobronchitis [Chapter 377]), the high negative intrapleural pressure during inspiration is transmitted up to the site of obstruction, after which there is a rapid dissipation of pressure. Therefore, the extrathoracic airway below the site of obstruction has markedly increased negative pressure inside, resulting in its collapse, which makes the obstruction worse (Fig. 365-8A). This produces inspiratory difficulty, prolongation of inspiration, and inspiratory stridor. Also, the increased negative intrapleural pressure results in chest wall retractions. During expiration, the increased positive intrapleural pressure is again transmitted up the airways to the site of obstruction, leading to a distention of the extrathoracic airway and amelioration of obstruction (Fig. 365-8B).

Figure 365-8 A, In extrathoracic airway obstruction, the increased negative pressure during inspiration is transmitted up to the site of obstruction. This results in collapse of the extrathoracic airway below the site of obstruction, making the obstruction worse during inspiration. Note that the pressures are compared to the atmospheric pressure, which is traditionally represented as 0 cm. Terminal airway pressure is calculated as intrapleural pressure plus lung recoil pressure. Lung recoil pressure is arbitrarily chosen as 5 cm for the sake of simplicity. B, During expiration, the positive pressure below the site of obstruction results in distention of extrathoracic airway and amelioration of symptoms.

Because of the increased positive intrapleural pressure, the chest wall tends to bulge out, which produces the classic paradoxical respiration, in which the chest retracts during inspiration and bulges out during expiration. The younger the child, the softer is the chest wall and the more marked is the paradoxical respiration of extrathoracic airway obstruction. A pattern of seesaw respiration may also be evident in newborns and young infants as the compliant chest wall is sucked in and the abdomen bulges out during inspiration, with the converse happening during expiration.

In obstruction of intrathoracic-extrapulmonary airway (vascular ring [Chapter 378], mediastinal tumors) and intrapulmonary airway (asthma, bronchiolitis), the increased negative intrapleural pressure results in a distention of intrathoracic airways during inspiration, thus providing some relief from obstruction (Fig. 365-9A).

Figure 365-9 A, In intrathoracic-extrapulmonary airway obstruction, the increased negative pressure during inspiration is transmitted up to the site of obstruction. This results in the distention of the intrathoracic airway above the lesion because it is surrounded by an even greater negative intrapleural pressure. B, During expiration, the increased positive airway pressure rapidly dissipates above the obstruction. Consequently, there is a collapse of the intrathoracic airway above the obstruction as it is subjected to markedly increased positive intrapleural pressure, making the obstruction worse during expiration.

During expiration, the increased positive intrathoracic pressure is transmitted up to the site of obstruction, after which it dissipates rapidly. The intrathoracic airway above the site of obstruction is therefore subjected to much greater intrapleural pressure from outside, which cannot be adequately balanced by enough positive pressure inside, resulting in collapse above the site of obstruction (Fig. 365-9B).

The site at which pressures inside and outside the airway during exhalation are equal is referred to as the equal pressure point (EPP). With intrathoracic airway obstruction, the EPP is shifted distally toward the alveolus, causing airway collapse above. Marked inspiratory and expiratory changes in a young infant’s airway lumen above the EPP is often termed collapsible trachea. Tracheal collapse is often a sign of airway obstruction, and it even contributes to its severity, but it is rarely the primary abnormality. With intrapulmonary airway obstruction, an even wider portion of intrathoracic airway is subjected to pressure swings during inspiration and expiration (Fig. 365-10).

Figure 365-10 A and B, In intrapulmonary airway obstruction, even a wider segment of intrathoracic airway is subjected to pressure changes compared to those observed in intrathoracic-extrapulmonary airway obstruction. Such lesions are associated with marked increase in airway obstruction during expiration.

Both intrathoracic-extrapulmonary and intrapulmonary airway obstruction result in increasing difficulty during expiration, prolongation of expiration, and expiratory wheezing. Any airway obstruction within the thorax results in expiratory wheezing.

365.5 Interpretation of Clinical Signs to Localize the Site of Pathology

Ashok P. Sarnaik and Sabrina M. Heidemann

The 1st step in establishing the diagnosis of respiratory disease is appropriate interpretation of clinical findings. Respiratory distress can occur without respiratory disease, and severe respiratory failure can be present without significant respiratory distress. Diseases characterized by CNS excitation, such as encephalitis, and neureoexcitatory drugs are associated with central neurogenic hyperventilation. Similarly, diseases that produce metabolic acidosis, such as diabetic ketoacidosis, salicylism, and shock, result in hyperventilation as a compensatory response. Patients in either group could be considered clinically to have respiratory distress; they are distinguished from patients with respiratory disease by their increased tidal volume as well as the respiratory rate. Their blood gas values reflect a low PaCO₂ and a normal PaO₂. Patients with neuromuscular diseases, such as Guillain-Barré syndrome or myasthenia gravis, and those with an abnormal respiratory drive can develop severe respiratory failure but are not able to mount sufficient effort to appear in respiratory distress. In these patients, respirations are ineffective or can even appear normal in the presence of respiratory acidosis and hypoxemia.

The rate and depth of respiration and the presence of retractions, stridor, wheezing, and grunting are valuable signs in localizing the site of respiratory pathology (Table 365-1 and Fig. 365-11). Rapid and shallow respirations (tachypnea) are characteristic of parenchymal pathology, in which the elastic work of breathing is increased disproportionately to the resistive work of breathing. Chest wall, intercostal, and suprasternal retractions are most striking, with increased negative intrathoracic pressure during inspiration. This occurs in extrathoracic airway obstruction as well as diseases of decreased compliance. Inspiratory stridor is a hallmark of extrathoracic airway obstruction. Expiratory wheezing is characteristic of intrathoracic airway obstruction, either extrapulmonary or intrapulmonary. Grunting is produced by expiration against a partially closed glottis and is an attempt to maintain positive airway pressure during expiration for as long as possible. Such prolongation of positive pressure is most beneficial in alveolar diseases that produce widespread loss of FRC, such as in pulmonary edema, hyaline membrane disease, and pneumonia. Grunting is also effective in small airway obstruction (bronchiolitis) to maintain a higher positive pressure in the airway during expiration, decreasing the airway collapse.

Figure 365-11 Presentation profiles of respiratory failure in childhood. When a mechanical dysfunction is present (by far, the most common circumstance), arterial hypoxemia and hypercapnia (and hence, pH) are sensed by peripheral (carotid bodies) and central (medullary) chemoreceptors. After being integrated with other sensory information from the lungs and chest wall, chemoreceptor activation triggers an increase in the neural output to the respiratory muscles (vertical arrows), which results in the physical signs that characterize respiratory distress. When the problem resides with the respiratory muscles (or their innervation), the same increase in neural output occurs (arrow), but the respiratory muscles cannot increase their effort as demanded; therefore, the physical signs of distress are more subtle. Finally, when the control of breathing is itself affected by disease, the neural response to hypoxemia and hypercapnia is absent or blunted and the gas exchange abnormalities are not accompanied by respiratory distress.

365.6 Ventilation-Perfusion Relationship in Health and Disease

Ashok P. Sarnaik and Sabrina M. Heidemann

Alveoli and airways in the nondependent parts (the upper lobes in upright position) of the lung are subjected to greater negative intrapleural pressure during tidal respiration and are therefore kept relatively more inflated compared to the dependent alveoli and airways (the lower lobes in upright position). Gravitational force pulls the lung away from the nondependent part of the parietal pleura. The nondependent alveoli are less compliant because they are already more inflated. During tidal inspiration, ventilation therefore occurs preferentially in the dependent portions of the lung that are more amenable to expansion. Although perfusion is also greater in the dependent portions of the lung because of greater pulmonary arterial hydrostatic pressure due to gravity, the increase in perfusion is greater than the increase in ventilation in the dependent portions of the lung. Thus, the ratios favor ventilation in the nondependent portions and perfusion in the dependent portions. Because the airways in the dependent portion of the lung are narrower, they close earlier during expiration. The lung volume at which the dependent airways start to close is referred to as the closing capacity. In normal children, the FRC is greater than the closing capacity. During tidal respiration, airways remain patent both in the dependent and the nondependent portions of the lung. In newborns, the closing capacity is greater than the FRC, resulting in perfusion of poorly ventilated alveoli during tidal respiration; therefore, normal neonates have a lower PaO₂ compared to older children.

The relationship is adversely affected in a variety of pathophysiologic states (Fig. 365-12). Air movement in areas that are poorly perfused is referred to as dead space ventilation. Examples of dead space ventilation include pulmonary thromboembolism and hypovolemia. Perfusion of poorly ventilated alveoli is referred to as intrapulmonary right-to-left shunting or venous admixture. Examples include pneumonia, asthma, and hyaline membrane disease. In intrapulmonary airway obstruction, the closing capacity is abnormally increased and can exceed the FRC. In such situations, perfusion of poorly ventilated alveoli during tidal respiration results in venous admixture.

Figure 365-12 Diagram demonstrating the effects of decreased ventilation-perfusion ratios on arterial oxygenation in the lungs. Three alveolar-capillary units are illustrated. Unit A has normal ventilation and an alveolar PO₂ of 100 mm Hg (shown by the number in the middle of the space). The blood that circulates through this unit raises its oxygen saturation from 75% (the saturation of mixed venous blood) to 99%. Unit B has a lower ventilation-perfusion ratio and a lower alveolar PO₂ of 60 mm Hg. The blood that circulates through this unit reaches a saturation of only 90%. Finally, unit C is not ventilated at all. Its alveolar PO₂ is equivalent to that of the venous blood, which travels through the unit unaltered. The oxygen saturation of the arterial blood reflects the weighted contributions of these 3 units. If it is assumed that each unit has the same blood flow, the arterial blood would have a saturation of only 88%. Ventilation-perfusion mismatch is the most common mechanism of arterial hypoxemia in lung disease. Supplemental oxygen increases the arterial PO₂ by raising the alveolar PO₂ in lung units that, like B, have a ventilation-perfusion ratio >0.

365.7 Gas Exchange in Health and Disease

Ashok P. Sarnaik and Sabrina M. Heidemann

The main function of the respiratory system is to remove carbon dioxide from and add oxygen to the systemic venous blood brought to the lung. The composition of the inspired gas, ventilation, perfusion, diffusion, and tissue metabolism have a significant influence on the arterial blood gases.

The total pressure of the atmosphere at sea level is 760 torr. With increasing altitude, the atmospheric pressure decreases. The total atmospheric pressure is equal to the sum of partial pressures exerted by each of its component gases. Alveolar air is 100% humidified and, therefore, for alveolar gas calculations, the inspired gas is also presumed to be 100% humidified. At a temperature of 37°C and 100% humidity, water vapor exerts pressure of 47 torr, regardless of altitude. In a natural setting, the atmosphere consists of 20.93% oxygen. Partial pressure of oxygen in inspired gas (PiO₂) at sea level is therefore (760 − 47) × 20.93% = 149 torr. When breathing 40% oxygen at sea level, PiO₂ is (760 − 47) × 40% = 285 torr. At higher altitudes, breathing different concentrations of oxygen, PiO₂ is less than at sea level, depending on the prevalent atmospheric pressures. In Denver (altitude of 5,000 feet and barometric pressure of 632 torr), PiO₂ in room air is (632 − 47) × 20.93% = 122 torr, and in 40% oxygen, it is (632 − 47) × 40% = 234 torr.

Minute volume is a product of V_T and respiratory rate. Part of the V_T occupies the conducting airways (anatomic dead space), which does not contribute to gas exchange in the alveoli. Alveolar ventilation is the volume of atmospheric air entering the alveoli and is calculated as (V_T − dead space) × respiratory rate. Alveolar ventilation is inversely proportional to alveolar PCO₂ (PACO₂). When alveolar ventilation is halved, PACO₂ is doubled. Conversely, doubling of alveolar ventilation decreases PACO₂ by 50%. Alveolar PO₂ (PAO₂) is calculated by the alveolar air equation as follows:

where R is the respiratory quotient. For practical purposes, PACO₂ is substituted by arterial PCO₂ (PaCO₂) and R is assumed to be 0.8. According to the alveolar air equation, for a given PiO₂, a rise in PaCO₂ of 10 torr results in a decrease in PAO₂ by 10 ÷ 0.8 or 10 × 1.25 or 12.5 torr. Thus, proportionately inverse changes in PAO₂ occur to the extent of 1.25× the changes in PACO₂ (or PaCO₂).

After the alveolar gas composition is determined by the inspired gas conditions and process of ventilation, gas exchange occurs by the process of diffusion and equilibration of alveolar gas with pulmonary capillary blood. Diffusion depends on the alveolar capillary barrier and amount of available time for equilibration. In health, the equilibration of alveolar gas and pulmonary capillary blood is complete for both oxygen and carbon dioxide. In diseases in which alveolar capillary barrier is abnormally increased (alveolar interstitial diseases) and/or when the time available for equilibration is decreased (increased blood flow velocity), diffusion is incomplete. Because of its greater solubility in liquid medium, carbon dioxide is 20 times more diffusible than oxygen. Therefore, diseases with diffusion defects are characterized by marked alveolar-arterial oxygen (A-aO₂) gradients and hypoxemia. Significant elevation of CO₂ does not occur as a result of a diffusion defect unless there is coexistent hypoventilation.

Venous blood brought to the lungs is “arterialized” after diffusion is complete. After complete arterialization, the pulmonary capillary blood should have the same PO₂ and PCO₂ as in the alveoli. The arterial blood gas composition is different from that in the alveoli, even in normal conditions because there is a certain amount of dead space ventilation as well as venous admixture in a normal lung. Dead space ventilation results in a higher PaCO₂ than PACO₂, whereas venous admixture or right-to-left shunting results in a lower PaO₂ compared to the alveolar gas composition (see Fig. 365-11). PaO₂ is a reflection of the amount of oxygen dissolved in blood, which is a relatively minor component of total blood oxygen content. For every 100 torr PO₂, there is 0.3 mL of dissolved O₂ in 100 mL of blood. The total blood oxygen content is composed of the dissolved oxygen and the oxygen bound to hemoglobin. Each gram of hemoglobin carries 1.34 mL of O₂ when 100% saturated with oxygen. Thus, 15 g of hemoglobin carries 20.1 mL of oxygen. Arterial oxygen content (CaO₂), expressed as mL O₂/dL blood, can be calculated as (PaO₂ × 0.003) + (Hb × 1.34 × SO₂), where Hb is grams of hemoglobin per dL blood and SO₂ is percentage of oxyhemoglobin saturation. The relationship of PO₂ and the amount of oxygen carried by the hemoglobin is the basis of the O₂-Hb dissociation curve (see Fig. 365-5). The PO₂ at which hemoglobin is 50% saturated is referred to as P₅₀. At a normal pH, hemoglobin is 94% saturated at PO₂ of 70, and little further gain in saturation is accomplished at a higher PO₂. At PO₂ <50, there is a steep decline in saturation and therefore the oxygen content.

Oxygen delivery to the tissues is a product of oxygen content and cardiac output. When hemoglobin is near 100% saturated, the blood contains ∼20 mL oxygen per 100 mL or 200 mL/L. In a healthy adult, the cardiac output is ∼5 L/min, oxygen delivery 1,000 mL/min, and oxygen consumption 250 mL/min. Mixed venous blood returning to the heart has a PO₂ of 40 torr and is 75% saturated with oxygen. Blood oxygen content, cardiac output, and oxygen consumption are important determinants of mixed venous oxygen saturation. Given a steady-state blood oxygen content and oxygen consumption, the mixed venous saturation is an important indicator of cardiac output. A declining mixed venous saturation in such a state indicates decreasing cardiac output.

365.8 Interpretation of Blood Gases

Ashok P. Sarnaik and Sabrina M. Heidemann

Clinical observations and interpretation of blood gas values are critical in localizing the site of the lesion and estimating its severity (see Table 365-2 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). In airway obstruction above the carina (subglottic stenosis, vascular ring), blood gases reflect overall alveolar hypoventilation. This is manifested by an elevated PACO₂ and a proportionate decrease in PAO₂ as determined by the alveolar air equation. A rise in PACO₂ of 20 torr decreases PAO₂ by 20 × 1.25 or 25 torr. In the absence of significant parenchymal disease and intrapulmonary shunting, such lesions respond very well to supplemental oxygen in reversing hypoxemia. Similar blood gas values, demonstrating alveolar hypoventilation and response to supplemental oxygen, are observed in patients with a depressed respiratory center and ineffective neuromuscular function, resulting in respiratory insufficiency. Such patients can be easily distinguished from those with airway obstruction by their poor respiratory effort.

Table 365-2 INTERPRETATION OF ARTERIAL BLOOD GAS VALUES

In intrapulmonary airway obstruction (asthma, bronchiolitis), blood gases reflect imbalance and venous admixture. In these diseases, the obstruction is not uniform throughout the lungs, resulting in areas that are hyperventilated and others that are hypoventilated. Pulmonary capillary blood coming from hyperventilated areas has a higher PO₂ and lower PCO₂, whereas that coming from hypoventilated regions has a lower PO₂ and higher PCO₂. A lower blood PCO₂ can compensate for the higher PCO₂ because the Hb-CO₂ dissociation curve is relatively linear. In mild disease, the hyperventilated areas predominate, resulting in hypocarbia. An elevated PaO₂ in hyperventilated areas cannot compensate for the decreased PaO₂ in hypoventilated areas because of the shape of the O₂-Hb dissociation curve. This results in venous admixture, arterial desaturation, and decreased PaO₂ (see Fig. 365-12). With increasing disease severity, more areas become hypoventilated, resulting in normalization of PaCO₂ with a further decrease in PaO₂. A normal or slightly elevated PaCO₂ in asthma should be viewed with concern as a potential indicator of impending respiratory failure. In severe intrapulmonary airway obstruction, hypoventilated areas predominate, leading to hypercarbia, respiratory acidosis, and hypoxemia. The degree to which supplemental oxygenation raises PaO₂ depends on the severity of the illness and the degree of venous admixture.

In alveolar and interstitial diseases, blood gas values reflect both intrapulmonary right-to-left shunting and a diffusion barrier. Hypoxemia is a hallmark of such conditions occurring early in the disease process. PaCO₂ is either normal or decreased. An increase in PaCO₂ is observed only later in the course, as muscle fatigue and exhaustion result in hypoventilation. Response to supplemental oxygen is relatively poor with shunting and diffusion disorders compared to other lesions.

Most clinical entities present with mixed lesions. A child with a vascular ring might also have an area of atelectasis; the arterial blood gas reflects both processes. The blood gas values reflect the more dominant lesion.

365.9 Pulmonary Vasculature in Health and Disease

Ashok P. Sarnaik and Sabrina M. Heidemann

The tunica media of the pulmonary arteries of the fetus become more muscular in the last trimester of pregnancy (Chapter 95.1). Up to 90% of the systemic venous return is shunted away from the pulmonary arterial circulation to the systemic arterial circulation through the foramen ovale and the ductus arteriosus. After birth, with functional closure of the foramen ovale and the ductus arteriosus, and dilatation of the pulmonary arterial circulation with consequent decrease in pulmonary vascular resistance (PVR), all of the right ventricular output passes through the lung. The PVR is ∼50% of the systemic arterial resistance 3 days after birth. In the next several wk after birth as pulmonary arterial musculature in the tunica media involutes, there is a further decline in PVR and therefore in pulmonary artery pressure. Two to 3 mo after birth, the PVR and the pulmonary artery pressure are ∼15% of the systemic values, a relationship that exists through childhood and adolescence. Pulmonary vasculature constricts in response to hypoxemia, acidosis, and hypercarbia and dilates with increased alveolar and arterial PO₂, alkalosis, and hypocarbia. Younger infants, with their relatively muscular pulmonary arteries, are especially susceptible to pulmonary vasoconstrictive stimuli.

Failure of the pulmonary arterial circulation to dilate after birth results in persistent pulmonary hypertension of the newborn (PPHN; Chapter 95.7). Because of the persistently high PVR, the systemic venous blood returning to the right side of the heart continues to be shunted across the foramen ovale and the ductus arteriosus to the systemic arterial circulation, leading to a vicious cycle of hypoxemia, acidosis, and further pulmonary vasoconstriction.

The relatively high PVR opposes excessive left-to-right shunting in full-term neonates with ventricular septal defect and patent ductus arteriosus (Chapter 420). Such infants do not usually manifest heart failure until 2-3 mo after birth, when PVR has sufficiently declined. Premature infants who have lesions capable of left-to-right shunting are susceptible to developing heart failure earlier in life because of less musculature in pulmonary artery tunica media and, therefore, a lower PVR. Persistent and long-term left-to-right shunting carries the risk of developing secondary pulmonary vascular disease characterized by the postnatal development of medial muscular hypertrophy followed by intimal proliferation and increased PVR. Early changes in pulmonary vasculature are reversible with correction of the congenital heart defect responsible for left-to-right shunting. Advanced pulmonary vascular disease is characterized by irreversible intimal and medial changes. When PVR is increased to suprasystemic levels, right-to-left shunting occurs and is characterized by a cyanotic state (Eisenmenger syndrome), making the heart defect inoperable in the absence of an accompanying lung transplantation (Chapter 427.2).

Pulmonary hypertension can develop without a well-defined etiology (primary pulmonary hypertension) or as a consequence of an underlying disease (secondary pulmonary hypertension) (Chapter 427). Adverse effects of pulmonary hypertension are related to an increased right ventricular afterload, decreased cardiac output, and heart failure characterized by increased systemic venous pressure, hepatomegaly, and edema. In an acute situation, right ventricular failure and decreased cardiac output can worsen oxygen delivery and hypoxemia. Right ventricular failure secondary to pulmonary pathology is referred to as cor pulmonale. Secondary pulmonary hypertension is a common occurrence in end-stage chronic obstructive pulmonary disease (COPD) such as cystic fibrosis and bronchopulmonary dysplasia. Pulmonary arterial involvement is sometimes encountered in collagen vascular diseases such as scleroderma (Chapter 154) and dermatomyositis (Chapter 153). Functional or structural upper airway obstruction can also produce right ventricular failure. Children with marked obesity are also susceptible to chronic alveolar hypoventilation and right heart failure, termed Pickwickian syndrome. Treatment of the underlying cause is the 1st priority in patients with secondary pulmonary hypertension (Chapter 427).

365.10 Immune Response of the Lung to Injury

Ashok P. Sarnaik and Sabrina M. Heidemann

Local and systemic diseases can potentially induce an inflammatory response in the lung. Local diseases of the lung capable of inducing the inflammatory response include infectious processes, aspiration, asphyxia, pulmonary contusion, and inhalation of chemical irritants; systemic diseases include sepsis, shock, trauma, and cardiopulmonary bypass. This inflammatory response is mediated through the release of cytokines and other mediators. In the lung, alveolar macrophages are the chief architects of the early cytokine response, producing tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). These cytokines are involved in initiating the inflammatory cascade, resulting in the production of other cytokines, prostaglandins, reactive oxygen species, and upregulating cell adhesion molecules, which, in turn, leads to white cell migration into the lung tissue. The pathophysiologic consequences of the inflammatory response include injury to pulmonary capillary endothelium and the alveolar epithelial cells. Various cytokines and eicosanoids produce pulmonary vasoconstriction, resulting in pulmonary hypertension and increased right ventricular afterload. Injury to the capillary endothelium results in increased permeability and exudation of protein-rich fluid into the pulmonary interstitium and alveoli. Cellular debris and fibrin form the characteristic eosinophilic hyaline membranes along the walls of the alveolar duct. There is sloughing of type 1 pneumocytes. Interstitial and alveolar edema results in decreased FRC, diffusion barrier, intrapulmonary right-to-left shunting across poorly ventilating alveoli, and increase in the alveolar-arterial (A-aO₂) gradient. Clinically, A-aO₂ gradient >200 is characterized as acute lung injury and a gradient >300 is termed acute respiratory distress syndrome (ARDS) (Chapter 65).

The pediatrician must consider the potential adverse effects of therapeutic interventions such as oxygen, endotracheal intubation, and mechanical ventilation as part of the pathophysiologic consequences of ARDS. High concentrations of inspired oxygen have a risk of pulmonary capillary and epithelial cell injury; the concentration of oxygen below which it can be considered safe has not been established. In addition to the potential for nosocomial pneumonia, mechanical ventilation carries the risk of ventilator-induced lung injury due to physical stress applied to terminal airways, alveolar epithelium, and pulmonary capillaries. Excessive tidal volume can itself result in mechanical disruption capable of perpetuating the inflammatory response. If alveoli are allowed to deflate excessively during exhalation, they are subjected to greater stress injury from alveolar recruitment and derecruitment. The mechanical ventilation strategy aimed at minimizing ventilator-induced lung injury in ARDS includes alveolar recruitment and maintenance of adequate FRC throughout the respiratory cycle with an optimum PEEP, and ventilation with relatively low (6-8 mL/kg) tidal volume.

365.11 Regulation of Respiration

Ashok P. Sarnaik and Sabrina M. Heidemann

The main function of respiration is to maintain normal blood gas homeostasis to match the metabolic needs of the body with the least amount of energy expenditure. Respiratory rate and tidal volume are regulated by a complex interaction of controllers, sensors, and effectors. The central respiratory controller consists of a group of neurons in the CNS that receives and integrates the afferent information from sensors and sends motor impulses to effectors to initiate and maintain respiration. Sensors are a variety of receptors located throughout the body. They gather chemical and physical information that is sent to the controller either to stimulate or to inhibit its activity. Effectors are the various muscles of respiration that, under the influence of the controller, move air in and out of the lung at a given tidal volume and rate. The respiratory regulatory mechanism itself undergoes a significant maturation process from the neonatal period throughout infancy and early childhood. Sleep states have the potential for profound influences on the control of respiration.

Sensors

Various receptors throughout the body are responsible for sensing afferent information that modulates the activity of the central respiratory controller. These receptors are sensory nerve endings that respond to changes in their environment. They are termed either chemoreceptors or mechanoreceptors, depending on the type of stimulus that is sensed. Chemoreceptors are classified as central or peripheral, depending on their location.

Central chemoreceptors are so termed because of their location within the CNS. Chemoreceptors sense a change in the chemical composition of body fluid to which they are exposed. Central chemoreceptors reside over a wide area that includes the posterior hypothalamus, cerebellum, locus ceruleus, raphe, and multiple nuclei within the brainstem. Central chemoreceptors bathe in the extracellular fluid of the brain and respond to the changes in the H⁺ concentration. Information sensing an increase in H⁺ concentration stimulates ventilatory response of the controller, whereas a decrease inhibits it. The brain’s extracellular fluid, represented by the cerebrospinal fluid (CSF), is separated from the blood by the blood-brain barrier, which is relatively impermeable to H⁺ and HCO₃⁻ ions but is readily permeable to CO₂. A rise in PaCO₂ is quickly reflected in a similar rise in the CSF. The consequent fall in CSF pH is sensed by the central chemoreceptors, causing stimulation of the controller and increase in ventilation. Changes in PaCO₂ result in stimulation or inhibition of ventilation by changes in CSF pH. CSF pH in normal conditions is ∼7.32. Compared to blood, CSF has much less CO₂ buffering capacity because of a much lower protein concentration. Consequently, the change in CSF pH is more pronounced than that in the blood for the same change in PaCO₂. With a persistent elevation in PaCO₂, the CSF pH eventually tends to normalize as HCO₃⁻ equilibrates across the blood-brain barrier. Patients with COPD therefore have a relatively normal CSF pH, and they do not show the ventilatory response that is observed with an acute rise in PaCO₂.

Hypoxia can depress global CNS function; nonetheless, multiple regions in the brain show an excitatory response to hypoxia, which contributes to the increase in ventilation.

Peripheral chemoreceptors are located in carotid bodies just above the bifurcation of the common carotid arteries, and in the aortic bodies above and below the aortic arch; the carotid bodies are the most important in humans. The most important variable in determining the activity of the carotid bodies is changes in PaO₂. Although the carotid bodies have a relatively high metabolic rate, they receive a very high flow for their rather small size. As long as a normal blood flow is maintained, the dissolved oxygen reflected by PaO₂ is sufficient for their metabolism. Stimulation of carotid bodies resulting in increased ventilation occurs when their oxygen supply is decreased below their metabolic requirements. This occurs when there is decreased PaO₂, decreased blood flow (low cardiac output), and impaired oxygen use (cyanide poisoning). In anemia, carbon monoxide poisoning, and methemoglobinemia, carotid bodies are not stimulated as long as the PaO₂ and the cardiac output are not compromised. The relationship of PaO₂ and the stimulation of carotid bodies is nonlinear (Fig. 365-13).

Figure 365-13 Significant stimulation of carotid bodies occurs with PaO₂ level <100 torr. A subjective feeling of dyspnea does not occur, however, until PaO₂ is <50 torr, at which point, stimulation of the carotid bodies increases exponentially.

Carotid bodies are activated at a PaO₂ of <500 torr. This is substantiated by the observation that there is a small but distinct decrease in ventilation when 100% oxygen is breathed by normal persons when PaO₂ exceeds 500 torr. A relatively small increase in ventilation occurs until the PaO₂ reaches 100 torr. Where the PaO₂ is <100 torr, the carotid body stimulation increases significantly. The carotid body receptor response rate is fast enough to alter their discharge rate during the respiratory cycle as a result of small cyclic changes in PaO₂ during inspiration and expiration. At PaO₂ levels <50 torr, carotid body stimulation increases exponentially. The most important effect of carotid body stimulation is an increase in respiratory rate and tidal volume. Additional effects include vasoconstriction, bradycardia, systemic hypertension, release of antidiuretic hormone, and stimulation of the adrenal medulla and adrenal cortex. The bradycardic effect of carotid body stimulation is overshadowed by the pulmonary reflex, which is induced by lung inflation and results in tachycardia. Patients in whom lung inflation is prevented are more likely to develop bradycardia after hypoxic stimulation of carotid bodies. Examples of such situations are fetal hypoxia, CNS depression, neuromuscular blockade, myopathy, neuropathy, and controlled ventilation. The peripheral chemoreceptors are responsible for almost all of the increase in ventilation that occurs in response to hypoxemia.

Peripheral chemoreceptors are also stimulated by an increase in PaCO₂; this response requires a relatively large change in PaCO₂ and results in a smaller rise in minute ventilation compared to the effect of CO₂ on central chemoreceptors. The peripheral chemoreceptors respond much more quickly (within 1 sec), however, whereas the central chemoreceptors can take minutes to respond. Thus peripheral chemoreceptors are important in the immediate rise in ventilation in response to a large and abrupt increase in PaCO₂. Decreased pH also stimulates the peripheral chemoreceptors. The effect of pH is regardless of whether the acidosis is due to respiratory or metabolic causes. Decreased PaO₂, increased PaCO₂, and decreased pH act synergistically on carotid bodies. The combined effect is greater than the sum of their individual actions.

In contrast to the central chemoreceptors, the peripheral chemoreceptors are not easily depressed, such as by anesthesia or opiates. They also do not adapt easily to a persistent stimulus such as hypoxia, as do the central chemoreceptors to hypercarbia. The central chemoreceptors in hypoxic patients are relatively unresponsive to CO₂ at a time when respirations are predominantly stimulated by effects of hypoxia on peripheral chemoreceptors.