Chapter 365 Respiratory Pathophysiology and Regulation
The main function of the respiratory system is to supply sufficient oxygen to meet metabolic demands and remove carbon dioxide. A variety of processes including ventilation, perfusion, and diffusion are involved in tissue oxygenation and carbon dioxide removal. Abnormalities in any one of these mechanisms can lead to respiratory failure. The pathophysiologic manifestations of respiratory disease processes are profoundly influenced by age- and growth-dependent changes in the physiology and anatomy of the respiratory control mechanisms, airway dynamics, and lung parenchymal characteristics. Smaller airways, a more compliant chest wall, and poor hypoxic drive render a younger infant more vulnerable compared to an older child with similar severity of disease.
Respiratory distress may be diagnosed from signs such as cyanosis, nasal flaring, grunting, tachypnea, wheezing, chest wall retractions, and stridor. Respiratory failure can be present without respiratory distress; a patient with abnormalities of central nervous system (CNS) or neuromuscular disease might not be able to mount sufficient effort to appear in respiratory distress. A child who appears in respiratory distress might not have a respiratory illness; a patient with primary metabolic acidosis (diabetic ketoacidosis) or CNS excitatory states (encephalitis) can present in severe respiratory distress without respiratory disease.
Traditionally, lung volumes are measured with a spirogram (Fig. 365-1). Tidal volume (VT) 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. FEV1.0 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. FEV1.0 and vital capacity are decreased in both restrictive and obstructive diseases. The ratio of FEV1.0 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. FEF25%-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 FEFmax, FEF25%-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. FEFmax 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. FEF25%-75% represents mean flow from 25% (FEF25%) to 75% (FEF75%) 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 FEFmax, FEF25%-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.
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.
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 (Welast). The 2nd part is to overcome airway and tissue resistance, and is referred to as resistive work (Wresist). Welast is directly proportional to tidal volume, whereas Wresist 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. Welast is disproportionately increased in diseases with decreased compliance and Wresist is increased in airway obstruction. Respirations are therefore shallow (low VT) 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 Welast 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.
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,