Kliegman: Nelson Textbook of Pediatrics, 18th ed.

Copyright 2007 Saunders, An Imprint of Elsevier

Part XVIII Respiratory System

Section 1 Development and Function

Chapter 370 Respiratory Pathophysiology and Regulation Ashok P. Sarnaik Sabrina M. Heidemann The age- and growth-dependent changes in physiology and anatomy of the respiratory control mechanism, airway dynamics, and lung parenchymal characteristics have a profound influence on the pathophysiologic manifestations of the disease process. 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. 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. A child may be identified as being in respiratory distress because of the presence of 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 may not be able to mount sufficient effort to appear in respiratory distress. A child who appears in respiratory distress may not have a respiratory illness; a patient with primary metabolic acidosis (diabetic ketoacidosis) or central nervous system excitatory states (encephalitis) may present in severe respiratory distress without respiratory disease.
370.1 Lung Volumes And Capacities In Health And Disease

Lung volumes are traditionally measured with a spirogram ( Fig. 370-1 ). Tidal volume (VT) is the amount of air moved in and out of the lungs during each breath. At rest, it is usually 67 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 370-1 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 resid ual 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 volu me.

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. 370-2 ). FRC acts as a buffer, minimizing the changes in P AO2 and P ACO2 during inspiration and expiration. FRC represents the environment available for pulmonary capillary blood for gas exchange at all times. 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 dissociation curve, which is sigmoid shaped ( Fig. 370-3 ). Since most of the oxygen in blood is combined with the hemoglobin, it is the percentage of oxyhemoglobin (SO2) that gets averaged rather than the PO2. While an increase in arterial PO2 cannot increase oxygen-hemoglobin saturation more than 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 370-2 Alveolar PO2 rises and P CO2 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 O 2 and add CO2 from the alveoli without atmospheric enrichment. Note that during the early part of inspiration, alveolar PO 2 continues to fall and P CO2 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, 2nd ed. Chicago, Year Book Medical Publishers, 1974, p 12.)

Figure 370-3 Oxygen-hemoglobin dissociation curve. P 50 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 Pa O2< 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. 370-4 ). Pulmonary compliance is decreased at abnormally low or high FRC.

Figure 370-4 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 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.
370.2 Chest Wall

One important area where an infant's respiratory system differs from that of an older child or adult is its chest wall. 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. Since 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 ( Fig. 370-5 ). The measured FRC in infants is higher than expected because respiratory muscles of infants maintain the thoracic cage in a slight inspiratory position at all times. Additionally, some amount of air trapping during expiration occurs in young infants.

Figure 370-5 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 stabilization of the chest wall and restoration of FRC. 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 [see Chapters 416.3 and 698 ], achondroplasia [see Chapter 416.4 ]) have markedly diminished lung volumes and capacities.
370.3 Pulmonary Mechanics And Work Of Breathing In Health And Disease

For air to move in and out of the lungs, a sufficient pressure gradient is needed between alveoli and atmosphere during both 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 ( P) change in volume ( V). 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 ( V P) 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: R = 8 l r4 where R is resistance, l length, viscosity, and r 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 will increase 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 Re = 2rvd where r is radius, v velocity, d density, and 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 1416/min for older children and adults. Welastis 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. 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. Since 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 autoPEEP or intrinsic PEEP. Such patients are therefore best ventilated with relatively slower rates and larger tidal volumes.
370.4 Airway Dynamics In Health And Disease

The trachea and airways of an infant are much more compliant than those of older children and adults, thus 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 [see Chapter 373 ], retropharyngeal abscess, laryngotracheobronchitis [see Chapter 382 ]), 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. 370-6A ). 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 distension of the extrathoracic airway and amelioration of obstruction ( Fig. 370-6 B).

Figure 370-6 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 obstructi on 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 + 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 classical 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 [see Chapter 383 ], 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. 370-7A ).

Figure 370-7 A, In intrathoracic -extrapulmonary airway obstruction, the increased negative pressure during inspiration is transmitted up to the site of obstruction. This results in the distension of the intrathoracic airway above the lesion since 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 i s subjected to mar kedly 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. 370-7B ). 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/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 even contributes to its severity, but 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. 370-8 ).

Figure 370-8 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 o bstruction 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.
370.5 interpretation of clinical signs to localize the site of pathology

Appropriate interpretation of clinical findings is the 1st step in establishing the diagnosis of respiratory disease. 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-Barr syndrome or myasthenia gravis, and those with an abnormal respiratory drive may develop severe respiratory failure but are not able to mount sufficient effort to appear in respiratory distress. In these patients, respirations are ineffective or may 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 370-1 and Fig. 370-9 ). 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.

TABLE 370-1 -- Interpreting the Clinical Signs of Respiratory Disease INTRATHORACIC EXTRATHORA EXTRAPULMONA INTRAPULMONA PARENCHYM CIC AIRWAY RY AIRWAY RY AIRWAY AL SIGN OBSTRUCTION OBSTRUCTION OBSTRUCTION PATHOLOGY Tachypne + a + ++ ++++

SIGN

INTRATHORACIC EXTRATHORA EXTRAPULMONA INTRAPULMONA PARENCHYM CIC AIRWAY RY AIRWAY RY AIRWAY AL OBSTRUCTION OBSTRUCTION OBSTRUCTION PATHOLOGY ++ ++ +++ ++ ++++ ++ ++++ +++ -

Retractio ++++ ns Stridor Wheezin g Grunting ++++

Figure 370-9 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 physic al 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 .

370.6 Ventilation-Perfusion (V/Q) Relationship in Health and Disease

During tidal respiration, alveoli and airways in the nondependent parts (the upper lobes in upright position) of the lung are subjected to greater negative intrapleural pressure, and therefore kept relatively more inflated, compared to the dependent alveoli and airways (the lower lobes in upright position). This is because of the gravitational force pulling 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 V/Q ratios favor ventilation in the nondependent portions and perfusion in the dependent portions. Since 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 V/Q relationship is adversely affected in a variety of pathophysiologic states ( Fig. 37010 ). 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 may exceed the FRC. In such situations, perfusion of poorly ventilated alveoli during tidal respiration results in venous admixture.

Figure 370-10 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 alveo lar PO2 of 100 mm mL/min 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 PO 2 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 a lveolar PO2 is equivalent to that of the venous blood, which travels through the unit unaltered. The o xygen 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 arte rial 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 PO 2 by raising the alveolar PO 2 in lung units that, like B, have a ventilation-perfusion ratio greater than zero.

370.7 Gas Exchange in Health and Disease

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, venti lation, 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 37C 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 VT and respiratory rate. Part of the VT 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 (VT - 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: PAO2 = PiO2 - (PACO2 R); 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) gradient 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, however, is different from that in the alveoli, even in normal conditions. This is because there is a certain amount of dead space ventila tion 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. 370-10 ). 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 percent of oxyhemoglobin

saturation. The relationship of PO2and the amount of oxygen carried by the hemoglobin is the basis of the oxygen-hemoglobin (O2-Hb) dissociation curve (see Fig. 370-3 ). The PO2 at which hemoglobin is 50% saturated is referred to as P50. At a normal pH, hemoglobin is 94% saturated at PO2of 70, and little further gain in saturation is accomplished at a higher PO2. At PO2 below 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 PO 2 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.
370.8 Interpretation of Blood Gases

Interpretation of blood gas values is important in localizing the site of the lesion and estimating its severity, especially when considered with clinical observations ( Table 370-2 ). 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 P ACO2 of 20 torr will decrease PAO2 by 20 1.25 or 25 torr. In the absence of a 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 (see Fig. 370-9 ). Such patients can be easily distinguished from those with airway obstruction by their poor respiratory effort.

TABLE 370-2 -- Interpretation of Arterial Blood Gas (ABG) Values LESION EFFECT TYPICAL ABG Central (above the carina) airway obstruction, or Depressed respiratory center, or Ineffective neuromuscular function Intrapulmonary airway obstruction Venous admixture V/Q mismatch Uniform alveolar hypoventilation
*

Early increase in PCO2 Proportionate decrease in PO2 depending on alveolar air equation Response to supplemental oxygen: Excellent Mild: PCO2, PO2 Moderate: Normal PCO2, Severe: PCO2, PO2 PO2

* * *

Response to supplemental oxygen: Good

LESION Alveolar-interstitial pathology

EFFECT Diffusion defect R L shunt

TYPICAL ABG
*

Early decrease in PO2 depending on severity Normal or low PCO2, PCO2 if fatigue develops Response to supplemental oxygen: Fair to poor

V/Q, ventilation-perfusion.

In intrapulmonary airway obstruction (asthma, bronchiolitis), blood gases reflect ventilation perfusion 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 P CO2 can compensate for the higher PCO2 since the hemoglobinCO2 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. 370-10 ). 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 may also have an area of atelectasis; the arterial blood gas reflects both processes. The blood gas values reflect the more dominant lesion.
370.9 Pulmonary Vasculature in Health and Disease

During intrauterine fetal development, the tunica media of pulmonary arteries become more muscular in the last trimester of pregnancy (see Chapter 101.1 ). 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, there is a further decline in PVR and, therefore, the pulmonary artery pressure, as pulmonary arterial musculature in the tunica media involutes. 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; see Chapter 101.8 ). 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 (see Chapter 426 ). Such infants do not usually manifest heart failure until 23 mo after birth, when PVR has sufficiently declined. Premature infants, with 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 development of 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 (see Chapter 433.2 ). Pulmonary hypertension can develop without a well-defined etiology (primary pulmonary hypertension) or as a consequence of an underlying disease (secondary pulmonary hypertension) (see Chapter 433 ). 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 such as cystic fibrosis and bronchopulmonary dysplasia. Pulmonary arterial involvement is sometimes encountered in collagen vascular diseases such as scleroderma (see Chapter 159 ) and dermatomyositis (see Chapter 158 ). Functional or structural upper airway obstruction may 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 (see Chapter 433 ).
370.10 Immune Response of the Lung to Injury

Various disease entities, local or systemic, 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- (TNF- ) and interleukin 1 (IL-1 ). 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 alveolararterial (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) [see Chapter 69 ]. The clinician must consider the potential adverse effects of therapeutic interventions such as oxygen, endotracheal intuba tion, 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, in and of 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 (68 mL/kg) tidal volume.
370.11 Regulation of Respiration

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 receive and integrate the afferent information from sensors, and send 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.
CENTRAL RESPIRATORY CONTROLLER.

The respiratory controller mechanism comprises 2 functionally and anatomically distinct groups of neurons located in the CNS: 1 for voluntary and the other for automatic control. These areas of respiratory control can function independently but are also capable of interacting with each other. Voluntary control of respiration resides in the cerebral motor cortex and limbic forebrain structure. Information is received from sensory neurons such as pain, touch, temperature, smell, vision, and emotions, and impulses are sent directly to the respiratory muscles through corticobulbar and corticospinal tracts. Voluntary control of respiration is important for protection from aspiration and inhalation of noxious gases. A certain level of consciousness is necessary to exercise voluntary control of respiration. Patients with CNS injury and toxic/metabolic encephalopathies lose voluntary control of respirations to varying degrees, depending on the extent of CNS dysfunction. Automatic control of respiration resides in the brainstem. A group of 150200 neurons, designated as the pre-Botzinger complex (preBotC), are located in the medullary region. PreBotC is responsible for maintaining respiratory rhythmicity and it can be considered the pacemaker for the automatic respiratory activity. PreBotC neurons are responsible for various patterns of respiration, including eupneic gasping and sighing, depending on the afferent input. These neurons have specific receptors for neurotransmitters, which may stimulate, inhibit, or modify their activity; such receptors include those for substance P (neurokinin), acetylcholine (nicotinic), glutamate, and opioid receptors. Several genes such as Hox paralogs and Hox-regulating genes kreisler/mafB and Krox20 regulate the embryonic generation of brainstem neurons and their intrinsic connections. A group of neurons located in the lower pons is collectively termed the apneustic center, which stimulates preBotC, resulting in prolonged inspiratory gasps (apneuses) interrupted by transient expiratory efforts. Another group of neurons in the upper pons, called the pneumotaxic center, is involved in inhibiting the activity of preBotC. The role of apneustic and pneumotaxic centers is to finetune the rhythmic respiratory activity generated by preBotC neurons. Abnormalities of respirations are commonly encountered in CNS dysfunction. Global CNS depression may manifest as slow and shallow respirations with resultant hypoventilation and respiratory acidosis. Bihemispheric and diancephalic pathology can lead to Cheyne-Stokes respirations, characterized by periods of apnea interspersed with hyperventilation. Injuries within the rostral brainstem or tegmentum can lead to central neurogenic hyperventilation and respiratory alkalosis. Mid to caudal pontine lesion can result in an apneustic breathing pattern characterized by a prolonged inspiratory pause. Medullary lesions result in ataxic, irregular breathing or apnea.
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 bloodbrain barrier, which is relatively impermeable to H+ and HCO3- ions, but 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 chronic obstructive lung disease 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 (1) decreased PaO2, (2) decreased blood flow (low cardiac output), and (3) impaired oxygen utilization (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. 370-11 ).

Figure 370-11 Significant stimulation of carotid bodies occurs with Pa O2 level <100 torr. A subjective feeling of dyspnea does not occur, however, until Pa O2 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 individuals 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 Pa O2 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 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 may 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 hyper-carbia. 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.
LUNG RECEPTORS.

Stretch receptors are located within the airway smooth muscle. They are stimulated by lung inflation and the impulse is conducted via the vagus nerve. The main effect of these receptors is to decrease the respiratory rate due to an inhibition of inspiratory muscle activity and an increase in exhalation time. This reflex is termed Hering-Breuer inflation reflex. HeringBreuer deflation reflex stimulates inspiratory muscle activity in response to deflation of the lung. These reflexes are not operative during normal breathing in adults but may be important in newborns. Stretch receptors play an important role in minimizing the energy required for the work of breathing in respiratory disease. In diseases in which airway resistance is increased (asthma), more energy is needed to overcome airway resistance. Slow and deep breathing is most economical in such a situation because of relatively lower flow rate, and greater alveolar inflation is possible without stretching of the airway smooth muscle earlier during inspiration. In diseases of compliance, (pulmonary edema), rapid and shallow breathing is most economical to keep the elastic work at minimum. Because of the stiffer alveoli in such situations, the transpulmonary pressure is transmitted to the airway smooth muscle earlier during inspiration, stimulating the stretch receptors and turning off inspiration. Irritant receptors are present in between the epithelial cells in the airway mucous membrane. They are stimulated by particulate matter, noxious gases, and chemical fumes in the inspired gas, and also by cold air. The vagus nerve is responsible for conducting the impulse. Stimulation of irritant receptors results in bronchoconstriction and hyperpnea. J receptors derive their name because of their juxta-capillary location. They lie in the alveolar walls close to the pulmonary capillaries. Pulmonary capillary engorgement and interstitial and alveolar wall edema provide stimuli for activation of the J receptors, resulting in shallow and rapid respirations and dyspnea. This is seen in left heart failure, ARDS, and interstitial diseases. Muscle receptors important for regulation of respirations are those in the diaphragm and the intercostals. Stretch of the muscle sensed by the muscle spindle is used to control the strength of contraction. Excessive distortion of the diaphragm and the intercostals inhibits inspiratory activity when large negative intrathoracic pressure is required to move air, such as in airway

obstruction. The soft chest walls of newborns and young infants are more susceptible to distortion; such children may respond to upper airway obstruction by premature cessation of inspiration and apnea rather than by the prolongation of inspiration required to move sufficient air past the obstruction. Arterial baroreceptors located in aortic arch and carotid sinuses can influence respiration depending on arterial blood pressure. A decrease in blood pressure results in hyperventilation and an increased blood pressure causes hypoventilation. Pain and temperature receptors also influence respirations and they are especially pronounced in the neonates and young infants. A painful stimulus causes breath holding followed by hyperventilation. Increased skin temperature causes hyperventilation and hypothermia results in hypoventilation. In the context of cold stimulus, the facial area is most important in causing apnea.
EFFECTORS.

The most important effectors of respiration are the diaphragm, intercostals, and abdominal muscles. They receive impulses from the controller and effect ventilation. Accessory effectors such as sternocleidomastoids and paraspinal muscles may be called on to make additional contribution to the respiratory efforts in times of need. The effectors can be seriously impaired in malnutrition, spinal injury, and neuromuscular disease.
SLEEP STATES.

Respiratory regulation is considerably affected by sleep. Sleep, in general, decreases central chemosensitivity to CO2. PaCO2 is increased by a few torr compared to that in the wakeful state. Two broad categories of sleep states exist: nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (see Chapter 18 ). NREM sleep is characterized by high-voltage, slow waves on electroencephalogram (EEG), and is associated with fragmented mental activity. Muscle tone and movements are relatively unaffected. NREM sleep is likened to a relatively inactive brain in a movable body. REM sleep is so termed because of the presence of episodic bursts of rapid eye movements. The most clinically significant aspect of REM sleep is marked suppression of postural muscle tone and lack of spontaneous movements. REM sleep is likened to a highly activated brain in a paralyzed body. Descending axons from the dorsal pontine tegmentum region are responsible for the REM sleep-specific characteristic atonia and paralysis. The predominant sleep pattern in premature babies is REM sleep. A full-term newborn has 50% REM sleep. Most of the sleep maturation occurs in the 1st 6 mo of life. Older children and adults spend 20% of their sleep in the REM state. Sleep-related respiratory abnormalities are encountered predominantly in REM sleep. Depression of muscle tone during REM sleep has 2 major effects. The relaxed and therefore increasingly compliant chest wall retracts inward much more during inspiration than a less compliant chest wall would, resulting in an impediment to air inflow and s paradoxical (seesaw) pattern of breathing, in which the abdomen and the chest wall move asynchronously. The 2nd effect is that of relaxation of the genioglossus, palatal, and other upper airway muscles, causing airway obstruction. REM sleep-related respiratory abnormalities are commonly encountered in premature infants and those children with coexistent anatomic upper airway obstruction, obesity, and neuromuscular dysfunction.
REGULATION OF RESPIRATION IN SPECIAL SITUATIONS. Fetus, Newborns, and Young Infants.

At various stages of development, the response to chemoreceptor and mechanoreceptor stimulation and the efficiency of effectors are markedly different. Unlike adults who show an immediate and sustained response to hypoxemia characterized by hyperventilation, the newborn exhibits a biphasic response. After an initial brief period (12 min) of hyperventilation, the neonate and young infant develop hypoventilation and apnea when hypoxemia is sustained. This explains why such infants are much more prone to develop respiratory arrest in hypoxic states than are older children and adults. Lower gestational age of the infant is associated with a more pronounced and earlier apneic response to hypoxemia. Fetal respiratory activity, for example, is switched off when faced with oxygen deprivation. Maturation of carotid chemoreceptors may be an explanation for the differences in hypoxic response at various stages of development. Sensitivity of CO2 sensors also undergoes maturation. Compared to adults and older children, neonates and young infants have decreased CO2 responsiveness, as measured by an increase in minute alveolar ventilation for a given increase in PaCO2. Theophylline and caffeine have been shown to increase the central chemoreceptor ventilatory response to CO2 and decrease the number of apneic spells in premature babies. The neonatal respiratory muscles are poorly equipped to sustain large workloads; they are more easily fatigued than in older children, and this significantly limits their ability to maintain adequate ventilation in lung disease. Also, the excessive inward retraction of the relatively soft infantile chest wall stimulates the intercostal muscles' stretch receptors, sending inhibitory impulses to the respiratory center. Young infants are therefore at greater risk of developing apnea when respiratory muscles are subjected to large elastic loads, such as in upper airway obstruction. Many neurotransmitters involved in regulation of respiration also undergo developmental maturational changes. Serotonergic neurons located in the raphe nuclei possess chemosensitive properties and respond to a decrease in pH. An increase in population of these neurons is associated with increasing chemosensitivity in the developing animal. Abnormalities of the arcuate nucleus, the human equivalent of the rat and cat medullary raphe, have been demonstrated at autopsy on infants dying of sudden infant death syndrome (SIDS; see Chapter 372 ). Cohort studies of Japanese, African-American, and white victims of SIDS have implicated a homozygous gene that encodes for the long allele of the serotonin transporter promoter. SIDS victims are more likely to express the long allele of the serotonin transporter promoter and miss the short allele compared to controls. The delay in development of serotonergic neurons or overexpression of the long allele for serotonin transporter promoter may explain the abnormal respiratory response to adverse conditions, which results in SIDS. Central chemoreception is also severely impaired in congenital central hypoventilation syndrome.
Chronic Hypoxia and Hypercarbia.

The respiratory control mechanism is altered when exposed to chronic conditions. In patients with chronic pulmonary insufficiency with elevated PaCO2, the CSF pH has been normalized and the central chemoreceptors become unresponsive to CO2. Furthermore, renal compensation results in bicarbonate retention and relative normalization of blood pH. Arterial hypoxemia remains the chief stimulus for ventilation, which is predominantly dependent on peripheral chemoreceptor stimulation by a low PaO2. Administration of a high amount of oxygen in such patients carries a risk of sudden removal of the hypoxic stimulus, cessation of breathing, exacerbation of hypercarbia and CO2 narcosis, and coma. Patients with chronic

obstructive lung disease and neuromuscular disease are especially susceptible to this complication. Children with bronchopulmonary dysplasia or with muscular dystrophy who have had a high PaCO2, with or without supplemental oxygen, may develop serious hypoventilation and respiratory acidosis when their PaO2 is increased more than their baseline with administration of a higher amount of oxygen. Chronically hypoxic patients such as those living at high altitude and those with cyanotic heart disease and interstitial lung disease have a blunted chemoreceptor function and poor response to further hypoxemia. It is of interest to the clinician that children with poorly controlled asthma also show a blunted hypoxic response and may appear to be breathing relatively comfortably in spite of dangerously low PaO2. Such children and their caretakers are at risk of failing to appreciate the severity of their disease, which can result in delay in the institution of appropriate therapy. Email to ColleaguePrint Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Kliegman: Nelson Textbook of Pediatrics, 18th ed.

Copyright 2007 Saunders, An Imprint of Elsevier Chapter 371 Diagnostic Approach to Respiratory Disease Gabriel G. Haddad Thomas P. Green The appropriate diagnosis of a child presenting with respiratory signs and symptoms depends most heavily on a careful history and physical examination. In some patients, complementary diagnostic tests and modalities are required.
HISTORY

The history should include questions about respiratory symptoms (dyspnea, cough, pain, wheezing, snoring, apnea, cyanosis), chronicity, timing during day or night, and associations with activities such as exercise or food intake. The respiratory system interacts with a number of other systems, and questions related to cardiac, gastrointestinal, central nervous, hematologic, and immune systems may be relevant. Questions related to gastrointestinal reflux or immune status may be important in a patient with repeated pneumonias. The family history is essential and should include inquiries about siblings and other close relatives with similar symptoms or any chronic disease with respiratory components.
PHYSICAL EXAMINATION

Respiratory dysfunction usually produces detectable alterations in the pattern of breathing. Values for normal respiratory rates are presented in Table 66-3 and depend on many factors, most importantly, age. Repeated respiratory rate measurements are necessary because respiratory rates, especially in the young, are exquisitely sensitive to extraneous stimuli. Sleeping respiratory rates are more reproducible in infants than those obtained during feeding

or activity. These rates vary among infants but average 4050 breaths/min in the 1st weeks of life and usually <60 breaths/min in the 1st few days of life. Respiratory control abnormalities may cause the child to breathe at a low rate or periodically. Mechanical abnormalities produce compensatory changes that are generally directed at maintaining or increasing alveolar ventilation. Decreases in lung compliance require increases in muscular force and breathing rate leading to variable increases in chest wall retractions and nasal flaring. The respiratory excursions of children with restrictive disease are shallow. An expiratory grunt is common as the child attempts to raise the functional residual capacity (FRC) by closing the glottis at the end of expiration. Children with obstructive disease take slower, deeper breaths (see Chapter 370 ). When the obstruction is extrathoracic (from the nose to the mid-trachea), inspiration is more prolonged than is expiration, and an inspiratory stridor can usually be heard. When the obstruction is intrathoracic, expiration is more prolonged than is inspiration, and the patient often has to make use of accessory expiratory muscles. Lung percussion has limited value in small infants because it cannot discriminate between noises originating from tissues that are close to each other. In adolescents and adults, percussion is usually dull in restrictive lung disease and with a pleural effusion, pneumonia, and atelectasis, and tympanitic in obstructive disease (asthma, pneumothorax). Auscultation confirms the presence of inspiratory or expiratory prolongation and provides information about the symmetry and quality of air movement. In addition, it often detects abnormal or adventitious sounds such as stridor (a predominant inspiratory monophonic noise), crackles (high pitch, interrupted sounds found during inspiration and more rarely during early expiration, which denote opening of previously closed air spaces), or wheezes (musical, continuous sounds usually caused by the development of turbulent flow in narrow airways) [ Table 371-1 ]. Digital clubbing is a sign of chronic hypoxia ( Fig. 371-1 ) but may be due to nonpulmonary etiologies ( Table 371-2 ).

TABLE 371-1 -- Lung Sound Nomenclature SOUND DISCONTINUOUS Fine (high pitched, low amplitude, short duration) CONTINUOUS High pitched Wheezes Low pitched Rhonchus From Chernick V, Boat TF: Kendig's Disorders of the Respiratory Tract in Children, 6th ed. Philadelphia, WB Saunders, 1998, p 97. Recommendation from the 1985 International Symposium on Lung Sounds in Tokyo for a unified nomenclature of adventitious sounds. (From Cugell DW: Lung sound nomenclature. Am Rev Respir Dis 1987;136:1016, with permission.) Fine crackles Coarse (low pitched, high amplitude, long duration) Coarse crackles

Figure 371-1 Finger clubbing can be measured in different ways. The ratio of the distal phalangeal diameter (DPD) over the interphalangeal diameter (IPD), or the phalangeal depth ratio, is <1 in normal subjects but inc reases to >1 with finger clubbing. The DPD/IPD can be measured with calipers or, more accurately, with finger casts. The hyponychial angle can be measured from lateral projections of the finger contour on a magnifying screen and is usually <180 degrees in normal subjects but >195 degrees in patients with finger clubbing. For bedside clinical assessment, the Schamroth sign is useful. The dorsal surfaces of the t erminal phalanges of similar fingers are placed together. With clubbing, the normal diamond -shaped aperture or window at the bases of the nail beds disappears, and a prominent distal angle forms between the ends of the nails. In normal subjects, this angle is minimal or nonexistent. (From Chernick V, Boat TF: Kendig's Disorders of the Respiratory Tract in Children, 6th ed. Philadelphia, WB Saunders, 1998.)

TABLE 371-2 -- Nonpulmonary Diseases Associated with Clubbing CARDIAC Cyanotic congenital heart disease Subacute bacterial endocarditis

Chronic congestive heart failure HEMATOLOGIC Thalassemia Congenital methemoglobinemia (rare) GASTROINTESTINAL Crohn disease Ulcerative colitis Chronic dysentery, sprue Polyposis coli Severe gastrointestinal hemorrhage Small bowel lymphoma Liver cirrhosis (including OTHER Thyroid deficiency (thyroid acropachy) Chronic pyelonephritis (rare) Toxic (e.g., arsenic, mercury, beryllium) Lymphomatoid granulomatosis Fabry disease Raynaud disease, scleroderma UNILATERAL CLUBBING Vascular disorders (e.g., subclavian arterial aneurysm, brachial arteriovenous fistula) Subluxation of shoulder Median nerve injury Local trauma From Chernick V, Boat TF: Kendig's Disorders of the Respiratory Tract in Children, 6th ed. Philadelphia, WB Saunders, 1998, p 102.
BLOOD GAS ANALYSIS
1-antitrypsin

deficiency)

An arterial blood gas analysis is probably the single most useful rapid test of pulmonary function. Although this analysis does not specify the cause of the condition or the specific nature of the disease process, it can give an overall assessment of the functional state of the respiratory system and clues about the pathogenesis of the disease. Because the detection of cyanosis is influenced by skin color, perfusion, and blood hemoglobin concentration, the clinical detection by inspections is an unreliable sign of hypoxemia. Arterial hypertension, tachycardia, and diaphoresis are late, and not exclusive, signs of hypoventilation. Blood gas exchange is evaluated most accurately by the direct measurement of arterial PO2, PCO2, and pH (see Chapters 64 , 101.4 , and 370 ). The blood specimen is best collected

anaerobically in a heparinized syringe containing only enough heparin solution to displace the air from the syringe. The syringe should be sealed, placed in ice, and carried to the laboratory for immediate analysis. Although these measurements have no substitute in many conditions, they require arterial puncture and have been replaced to a great extent by noninvasive monitoring. The age and clinical condition of the patient need to be taken into account when interpreting blood gas tensions. With the exception of neonates, values of arterial PO2< 85 mm Hg are usually abnormal for a child breathing room air at sea level. Calculation of the alveolararterial oxygen gradient is useful in the analysis of arterial oxygenation, particularly when the patient is not breathing room air or in the presence of hypercarbia. Values of arterial PCO2> 45 mm Hg usually indicate hypoventilation or a severe ventilation-perfusion mismatch, unless they reflect respiratory compensation for metabolic alkalosis (see Chapter 52 ).
TRANSILLUMINATION OF THE CHEST

In infants up to at least 6 mo of age, a pneumothorax can often be diagnosed by transillumination of the chest wall using a fiberoptic light probe. Free air in the pleural space often results in an unusually large halo of light in the skin surrounding the probe. Comparison with the contralateral chest is often very helpful in interpreting findings. This test is unreliable in older patients or in those with subcutaneous emphysema or atelectasis.
RADIOGRAPHIC TECHNIQUES CHEST ROENTGENOGRAMS.

Whenever possible, a posteroanterior and a lateral view (upright and in full inspiration) should be obtained. Portable films, although useful, can give a somewhat distorted image. Expiratory films can be misinterpreted, although a comparison of expiratory and inspiratory films may be useful in the evaluation of a child with suspected foreign body (localized failure of the lung to empty reflects bronchial obstruction). If pleural fluid is suspected, decubitus films are indicated. Films taken in a recumbent position are difficult to interpret if there is fluid within the pleural space or a cavity.
UPPER AIRWAY FILM.

A lateral view of the neck can yield invaluable information about upper airway obstruction and particularly about the condition of the retropharyngeal, supraglottic, and subglottic spaces (which should also be viewed in an anteroposterior projection). Knowing the phase of respiration during which the film was taken is often essential for accurate interpretation. Magnified airway films are often helpful in delineating the upper airways. Patients with suggested obstruction should not be sent unattended to the radiology department.
SINUS AND NASAL FILMS.

The utility of roentgenographic examination of the sinuses is uncertain. Imaging studies are not necessary to confirm the diagnosis of sinusitis in children <6 yr. CT scans are indicated if surgery is required, in cases of complications due to sinus infection, in immunodeficient patients, and for recurrent infections that are not responsive to medical management.
CHEST CT AND MRI.

CT delineates the internal structure of the thorax in much greater detail than is possible with plain roentgenograms. Technical advances have greatly enhanced the utility of this diagnostic modality (three-dimensional reconstruction is often feasible), and have potentially decreased radiation exposure. CT scans are of particular importance in the evaluation of mediastinal and pleural lesions, solid or cystic parenchymal lesions, pulmonary embolisms, and bronchiectasis. Intravenous contrast material can be infused during the scan to enhance vascular structures, thereby allowing distinction of vessels from other soft tissue densities. MRI can be useful for the same disease entities as CT. MRI is an excellent procedure to delineate hilar and vascular anatomy associated with vascular rings or slings.
FLUOROSCOPY.

Fluoroscopy is especially useful for evaluating stridor and abnormal movement of the diaphragm or mediastinum. Many procedures, such as needle aspiration or biopsy of a peripheral lesion, are also best accomplished with the aid of fluoroscopy, CT, or ultrasonography. Videotape recording, which does not increase radiation exposure, may allow detailed study through replay capability during a brief exposure to fluoroscopy.
BARIUM SWALLOW.

This study, performed with fluoroscopy and spot films, is indicated in the evaluation of patients with recur rent pneumonia, persistent cough of undetermined cause, stridor, or persistent wheezing. The technique can be modified by using barium of different textures and thicknesses, ranging from thin liquid to solids, to evaluate swallowing mechanics, the presence of vascular rings, and tracheoesophageal fistulas, especially when aspiration is suspected. A contrast esophagram has been used in the evaluation of newborns with suggested esophageal atresia, but this procedure entails a high risk of pulmonary aspiration and is not usually recommended. Barium swallows are useful in the evaluation of suggested gastroesophageal reflux, but because of the high incidence of asymptomatic reflux in infants, the applicability of the findings to the clinical problem may be complicated.
BRONCHOGRAPHY.

The details of smaller bronchi that cannot be easily evaluated by plain films or even bronchoscopy can be delineated by instilling contrast material directly into the airway. This technique has been used in the past to diagnose suspected bronchiectasis or airway anomalies that may need surgery; CT and MRI have largely replaced bronchography, which requires sedation and topical or general anesthesia.
PULMONARY ARTERIOGRAPHY AND AORTOGRAMS.

Pulmonary arteriography has been used to allow detailed evaluation of the pulmonary vasculature; has been helpful in assessing pulmonary blood flow and in diagnosing congenital anomalies, such as lobar agenesis, unilateral hyperlucent lung, vascular rings, and arteriovenous malformations; and is sometimes useful in evaluating solid or cystic lesions. Thoracic aortograms demonstrate the aortic arch, its major vessels, and the systemic (bronchial) pulmonary circulation. They are useful in evaluating vascular rings and suspected pulmonary sequestration. Although most hemoptysis is from the bronchial arteries, bronchial arteriography is seldom helpful in diagnosing or treating intrapulmonary bleeding in children. Real-time and Doppler echocardiography and thoracic CT with contrast are noninvasive

methods that often reveal similar information and should be performed before arteriography is considered.
RADIONUCLIDE LUNG SCANS.

The usual scan uses intravenous injection of material (macroaggregated human serum albumin labeled with 99mTc) that will be trapped in the pulmonary capillary bed. The distribution of radioactivity, proportional to pulmonary capillary blood flow, is useful in evaluating pulmonary embolism and congenital cardiovascular and pulmonary defects. Acute changes in the distribution of pulmonary perfusion may reflect alterations of pulmonary ventilation. The distribution of pulmonary ventilation can also be determined by scanning after the patient inhales a radioactive gas such as xenon-133. After the intravenous injection of xenon-133 dissolved in saline, both pulmonary perfusion and ventilation can be evaluated by continuous recording of the rate of appearance and disappearance of the xenon over the lung. Appearance of xenon early after injection is a measure of perfusion, whereas the rate of washout during breathing is a measure of ventilation in the pediatric population. The most important indication for this test is to demonstrate defects in the pulmonary arterial distribution that can occur with congenital malformations or pulmonary embolism. Spiral reconstruction CT with contrast medium enhancement is being increasingly used in the evaluation of pulmonary thrombi and emboli. Abnormalities in regional ventilation are also easily demonstrable in congenital lobar emphysema, cystic fibrosis, and asthma.
PULMONARY FUNCTION TESTING

The measurement of respiratory function in infants and young children can be difficult because of the lack of cooperation. Attempts have been made to overcome this limitation by creating standard tests that do not require the patient's active participation. Respiratory function tests still provide only a partial insight into the mechanisms of respiratory disease at early ages. Whether restrictive or obstructive, most forms of respiratory disease cause alterations in lung volume and its subdivisions (see Chapter 370 ). Restrictive diseases typically decrease total lung capacity (TLC). TLC includes residual volume, which is not accessible to direct determinations. It must therefore be measured indirectly by gas dilution methods or, preferably, by plethysmography. Restrictive disease also decreases vital capacity (VC). VC can be measured by spirometry (see Fig. 370-1 ) and is commonly used at the bedside to assess the progression of neuromuscular disorders. Obstructive diseases produce gas trapping and thus increase residual volume and FRC, particularly when these measurements are considered with respect to TLC. Airway obstruction is most frequently evaluated from determinations of gas flow in the course of a forced expiratory maneuver. The peak expiratory flow is reduced in advanced obstructive disease. The wide availability of simple devices that perform this measurement at the bedside makes it useful for assessing children with airway obstruction. Evaluation of peak flows requires a voluntary effort, and peak flows may not be altered when the obstruction is moderate or mild. Other gas flow measurements require that the child inhale to TLC and then exhale as far and as fast as possible for several seconds. Cooperation and good muscle strength are therefore necessary for the measurements to be reproducible. The forced

expiratory volume in 1 sec (FEV1 ) correlates well with the severity of obstructive diseases. The maximal midexpiratory flow rate, the average flow during the middle 50% of the forced vital capacity, is a more reliable indicator of mild airway obstruction. Its sensitivity to changes in residual volume and vital capacity, however, limits its use in children with more severe disease. The construction of flow-volume relationships during the forced vital capacity maneuvers overcomes some of these limitations by expressing the expiratory flows as a function of lung volume (see Chapter 370 ). A spirometer is used to measure VC and its subdivisions and expiratory (or inspiratory) flow rates (see Fig. 370-1 ). A simple manometer can measure the maximal inspiratory and expiratory force a subject generates, normally at least 30 cm H2 O, which is useful in evaluating the neuromuscular component of ventilation. Expected normal values for VC, FRC, TLC, and residual volume are obtained from prediction equations based on body height. Flow rates measured by spirometry usually include the FEV1 and the maximal midexpiratory flow rate. More information results from a maximal expiratory flow-volume curve, in which expiratory flow rate is plotted against expired lung volume (expressed in terms of either VC or TLC). Flow rates at lung volumes less than about 75% VC are relatively independent of effort. Expiratory flow rates at low lung volumes (<50% VC) are influenced much more by small airways than are flow rates at high lung volumes (FEV1 ). The flow rate at 25% VC (V25) is a useful index of small airway function. Low flow rates at high lung volumes associated with normal flow at low lung volumes suggest upper airway obstruction (see Chapter 370 ). Airway resistance (RAW) is measured in a plethysmograph, or, alternatively, the reciprocal of RAW, airway conductance (GAW), may be used. Because airway resistance measurements vary with the lung volume at which they are taken, it is convenient to use specific airway resistance, SRAW (SRAW = R AW/lung volume), which is nearly constant in subjects older than 6 yr (normally <7 sec/cm H2 O). The diffusing capacity for carbon monoxide (DLCO) is related to oxygen diffusion and is measured by rebreathing from a container having a known initial concentration of carbon monoxide or by using a single breath technique. Decreases in diffusing capacity for carbon monoxide reflect decreases in effective alveolar capillary surface area or decreases in diffusibility of the gas across the alveolar-capillary membrane. Primary diffusion abnor malities are unusual in children; therefore, this test is most frequently employed in children exposed to toxic drugs to the lungs (e.g., oncology patients) or chest wall radiation. Regional gas exchange can be conveniently estimated with the perfusion-ventilation xenon scan. Determining arterial blood gas levels also discloses the effectiveness of alveolar gas exchange. Pulmonary function testing, although rarely resulting in a diagnosis, is helpful in defining the type of process (obstruction, restriction) and the degree of functional impairment, in following the course and treatment of disease, and in estimating the prognosis. It is also useful in preoperative evaluation and in confirmation of functional impairment in patients having subjective complaints but a normal physical examination. In most patients with obstructive disease, a repeat test after administering a bronchodilator is warranted. Most tests require some cooperation and understanding by the patient, and interpretation is greatly facilitated if the test conditions and the patient's behavior during the test are known.

Infants and young children who cannot or will not cooperate with test procedures can be studied in a limited number of ways, which often require sedation. Flow rates and pressures during tidal breathing, with or without transient interruption of the flow, may be useful to assess some aspects of airway resistance or obstruction and to measure compliance of the lungs and thorax. Expiratory flow rates can be studied in sedated infants with passive compression of the chest and abdomen with a rapidly inflatable jacket. Gas dilution or plethysmographic methods can also be used in sedated infants to measure FRC and RAW.
MICROBIOLOGY: EXAMINATION OF LUNG SECRETIONS

The specific diagnosis of infection in the lower respiratory tract depends on the proper handling of an adequate specimen obtained in an appropriate fashion. Nasopharyngeal or throat cultures are often used but may not correlate with cultures obtained by more direct techniques from the lower airways. Sputum specimens are preferred and are often obtained from patients who do not expectorate by deep throat swab immediately after coughing or by saline nebulization. Specimens can also be obtained directly from the tracheobronchial tree by nasotracheal aspiration (usually heavily contaminated), by transtracheal aspiration through the cricothyroid membrane (useful in adults and adolescents but hazardous in children), and in infants and children by a sterile catheter inserted into the trachea either during direct laryngoscopy or through an endotracheal tube. A specimen can also be obtained at bronchoscopy. A percutaneous lung tap or an open biopsy is the only way to obtain a specimen absolutely free of oral flora. A specimen obtained by direct expectoration is usually assumed to be of tracheobronchial origin, but often, especially in children, it is not from this source. The presence of alveolar macrophages (large, mononuclear cells) is the hallmark of tracheobronchial secretions. Both nasopharyngeal and tracheobronchial secretions may contain ciliated epithelial cells, which are more commonly found in sputum. Nasopharyngeal and oral secretions often contain large numbers of squamous epithelial cells. Sputum may contain both ciliated and squamous epithelial cells. During sleep, mucociliary transport continually brings tracheobronchial secretions to the pharynx, where they are swallowed. An early morning fasting gastric aspirate often contains material from the tracheobronchial tract that is suitable for culture for acid-fast bacilli. The absence of polymorphonuclear leukocytes in a Wright-stained smear of sputum or bronchoalveolar lavage (BAL) fluid containing adequate numbers of macrophages may be significant evidence against a bacterial infectious process in the lower respiratory tract, assuming that the patient has normal neutrophil counts and function. Eosinophils suggest allergic disease. Iron stains may reveal hemosiderin granules within macrophages, suggesting pulmonary hemosiderosis. Specimens should also be examined by Gram stain. Bacteria within or near macrophages and neutrophils can be significant. Viral pneumonia may be accompanied by intranuclear or cytoplasmic inclusion bodies visible on Wright-stained smears, and fungal forms may be identifiable on Gram or silver stains.
EXERCISE TESTING

Exercise testing (see Chapter 423.5 ) is a more direct approach for detecting diffusion impairment as well as other forms of respiratory disease. Measurements of heart and respiratory rate, minute ventilation, oxygen consumption, carbon dioxide production, and

arterial blood gases during incremental exercise loads often provide invaluable information about the functional nature of the disease. Often a simple assessment of the patient's exercise tolerance in conjunction with other, more static forms of respiratory function testing can allow a distinction between respiratory and nonrespiratory disease in children.
SLEEP STUDIES

The sleep state has an important influence on respiratory function, particularly in the newborn and young infant (see Chapter 18 ). Polysomnographic studies are often helpful when abnormalities of central respiratory control, muscular disorders, or respiratory complications from gastroesophageal reflux (GER) are suspected. Polysomnography is now considered to be the gold standard test for obstructive sleep apnea or hypoventilation during sleep. pH probe studies are indicated and are added to such sleep studies when GER is suspected. In these studies, a pH probe is placed in the esophagus and prolonged (usually over several hours) monitoring is undertaken (see Chapter 320 ). These studies, which usually include the simultaneous assessment of ventilatory effort, airway gas flow, gas exchange, and sleep state, are also useful in the diagnosis and management of disorders of respiratory control and nocturnal hypoxemia and hypercapnia in children with chronic respiratory disease (see Chapter 370 ).
LUNG VISUALIZATION AND LUNG SPECIMEN BASED DIAGNOSTIC TESTS LARYNGOSCOPY.

The evaluation of stridor, problems with vocalization, and other upper airway abnormalities usually require direct inspection. Although indirect (mirror) laryngoscopy may be reasonable in older children and adults, it is rarely feasible in infants and small children. Direct laryngoscopy can be performed with either a rigid or a flexible instrument. The safe use of the rigid scope for examination of the upper airway requires topical anesthesia and either sedation or general anesthesia, whereas the flexible laryngoscope can often be used in the office setting with or without sedation. Further advantages to the flexible scope include the ability to assess the airway without the distortion that may be introduced by the use of the rigid scope and the ability to assess airway dynamics more accurately. Because there is a relatively high incidence of concomitant lesions in the upper and lower airways, it is often prudent to examine the airways above and below the glottis, even when the primary indication is in the upper airway (stridor).
BRONCHOSCOPY AND BRONCHEOALVEOLAR LAV AGE (BAL).

Bronchoscopy is the inspection of the airways. BAL is a method used to obtain a representative specimen of fluid and secretions from the lower respiratory tract, which is useful for the cytologic and microbiologic diagnosis of lung diseases, especially in those who are unable to expectorate sputum. BAL is performed after the general inspection of the airways and before tissue sampling with a brush or biopsy forceps. BAL is accomplished by gently wedging the scope into a lobar, segmental, or subsegmental bronchus and sequentially instilling and withdrawing sterile nonbacteriostatic saline in a volume sufficient to ensure that some of the aspirated fluid contains material that originated from the alveolar space. Nonbronchoscopic BAL can be performed, although with less accuracy and, therefore, less reliable results, in intubated patients by instilling and withdrawing saline through a catheter passed though the artificial airway and blindly wedged into a distal airway. In either case, the presence of alveolar macrophages documents that an alveolar sample has been obtained. Because the methods used to perform BAL involve passage of the equipment through the

upper airway, there is a risk of contamination of the specimen by upper airway secretions. Careful cytologic examination and quantitative microbiologic cultures are important for correct interpretation of the data. BAL can often obviate the need for more invasive procedures such as open lung biopsy, especially in immunocompromised individuals. Indications for diagnostic bronchoscopy and BAL include recurrent or persistent pneumonia or atelectasis, unexplained or localized and persistent wheeze, the suspected presence of a foreign body, hemoptysis, suspected congenital anomalies, mass lesions, interstitial disease, and pneumonia in the immunocompromised host. Indications for therapeutic bronchoscopy and BAL include bronchial obstruction by mass lesions, foreign bodies or mucous plugs, and general bronchial toilet and bronchopulmonary lavage. The individual undergoing bronchoscopy ventilates around the flexible scope, whereas, with the rigid scope, ventilation is accomplished through the scope. Rigid bronchoscopy is preferentially indicated for the extraction of foreign bodies, for the removal of tissue masses, and in patients with massive hemoptysis. In other cases, the flexible scope offers the advantages that it can be passed through endotracheal or tracheostomy tubes, can be introduced into bronchi that come off the airway at acute angles, and can be safely and effectively inserted with topical anesthesia and conscious sedation. Regardless of the instrument used, the procedure performed, or its indications, the most common complications are related to sedation. The relatively more common complications include transient hypoxemia, laryngospasm, bronchospasm, and cardiac arrhythmias. Iatrogenic infection, bleeding, pneumothorax, and pneumomediastinum are rare but reported complications of bronchoscopy or BAL. Bronchoscopy in the setting of possible pulmonary abcess or hemoptysis must be undertaken with advance preparations for definitive airway control, mindful of the possibility that pus or blood might flood the airway. Subglottic edema is a more common complication of rigid bronchoscopy than of flexible procedures, in which the scopes are smaller and less likely to traumatize the mucosa. Postbronchoscopy croup is treated with oxygen, mist, vasoconstrictor aerosols, and corticosteroids as necessary.
THORACOSCOPY.

The pleural cavity can be examined through a thoracoscope, which is similar to a rigid bronchoscope. The thoracoscope is inserted through an intercostal space and the lung is partially deflated, thus allowing the operator to view the surface of the lung, the pleural surface of the mediastinum and diaphragm, and the parietal pleura. Multiple thoracoscopic instruments can be inserted, allowing endoscopic lung or pleural biopsy, bleb resection, pleural abrasion, and ligation of vascular rings.
THORACENTESIS.

For diagnostic or therapeutic purposes, fluid can be removed from the pleural space by needle. Generally, as much fluid as possible should be withdrawn, and an upright chest roentgenogram should be obtained after the procedure. Complications of thoracentesis include infection, pneumothorax, and bleeding. Thoracentesis on the right may be complicated by puncture or laceration of the capsule of the liver and, on the left, by puncture or laceration of the capsule of the spleen. Specimens obtained should always be cultured, examined microscopically for evidence of bacterial infection, and evaluated for total protein and total differential cell counts. Lactic acid dehydrogenase, glucose, cholesterol, triglyceride

(chylous), and amylase determinations may also be useful. If malignancy is suspected, cytologic examination is imperative. Transudates result from mechanical factors influencing the rate of formation or reabsorption of pleural fluid and generally require no further diagnostic evaluation. Exudates result from inflammation or other disease of the pleural surface and underlying lung and require a more complete diagnostic evaluation. In general, transudates have a total protein of <3 g/dL or a ratio of pleural protein to serum protein <0.5, a total leukocyte count of fewer than 2,000/mm3 with a predominance of mononuclear cells, and low lactate dehydrogenase levels. Exudates have high protein levels and a predominance of polymorphonuclear cells (although malignant or tuberculous effusions may have a higher percentage of mononuclear cells). Complicated exudates often require continuous chest tube drainage and have a pH < 7.2. Tuberculous effusions may have low glucose and high cholesterol content.
LUNG TAP.

Using a technique similar to that used for thoracentesis, a percutaneous lung tap is the most direct method of obtaining bacteriologic specimens from the pulmonary parenchyma and is the only technique other than open lung biopsy not associated with at least some risk of contamination by oral flora. After local anesthesia, a needle attached to a syringe containing nonbacteriostatic sterile saline is inserted using aseptic technique through the inferior aspect of an intercostal space in the area of interest. The needle is rapidly advanced into the lung; the saline is injected and reaspirated, and the needle is withdrawn. These actions are performed as quickly as possible. This procedure usually yields a few drops of fluid from the lung, which should be cultured and examined microscopically. Major indications for a lung tap are roentgenographic infiltrates of undetermined cause, especially those unresponsive to therapy in immunosuppressed patients who are susceptible to unusual organisms. Complications are the same as for thoracentesis, but the incidence of pneumothorax is higher and somewhat dependent on the nature of the underlying disease process. In patients with poor pulmonary compliance, such as children with Pneumocystis pneumonia, the rate may approach 30%, with 5% requiring chest tubes. Bronchopulmonary lavage has replaced lung taps for most purposes.
LUNG BIOPSY.

Lung biopsy may be the only way to establish a diagnosis, especially in protracted, noninfectious disease. In infants and small children, thoracoscopic or open surgical biopsies are the procedures of choice, and in expert hands, there is low morbidity. Biopsy through the 3.5 mm diameter pediatric bronchoscopes limits the sample size and diagnostic abilities. As well as ensuring that an adequate specimen is obtained, the surgeon can inspect the lung surface and choose the site of biopsy. In older children, transbronchial biopsies can be performed using flexible forceps through a bronchoscope, an endotracheal tube, a rigid bronchoscope, or an endotracheal tube, usually with fluoroscopic guidance. This technique is most appropriately used when the disease is diffuse, as in the case of Pneumocystis pneumonia, or after rejection of a transplanted lung. The diagnostic limitations related to the small size of the biopsy specimens can be mitigated by the ability to obtain several samples. The risk of pneumothorax related to bronchoscopy is increased when trans bronchial biopsies are part of the procedure; however, the ability to obtain biopsy specimens in a procedure

performed with topical anesthesia and conscious sedation offers advantages to the select population for whom this procedure offers a reasonable diagnostic yield.
SWEAT TESTING.

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Kliegman: Nelson Textbook of Pediatrics, 18th ed.

Copyright 2007 Saunders, An Imprint of Elsevier Chapter 372 Sudden Infant Death Syndrome Carl E. Hunt Fern R. Hauck Sudden infant death syndrome (SIDS) is defined as the sudden death of an infant that is unexpected by history and unexplained by a thorough postmortem examination, which includes a complete autopsy, investigation of the scene of death, and review of the medical history. An autopsy is essential to identify natural causes of sudden, unexpected death such as congenital anomalies or infection and to diagnosis traumatic child abuse (Tables 372-1, 3722, 372-3 [1] [2] [3]). The autopsy cannot reliably distinguish between SIDS and intentional suffocation, but the scene investigation and medical history may be of help if inconsistencies are evident.

TABLE 372-1 -- Differential Diagnosis of Sudden Unexpected Death in Infancy PRIMARY CAUSE OF DIAGNOSTIC CONFOUNDING FREQUENCY DEATH CRITERIA FACTOR(S) DISTRIBUTION EXPLAINED AT AUTOPSY Natural Infections Congenital anomaly Unintentional injury Traumatic child abuse Other natural History, autopsy, and cultures History and autopsy If minimal findings: SIDS If minimal findings: SIDS or intentional suffocation Traumatic child abuse Unintentional injury If minimal findings: 1820%[*] 3546%[] 1424%[]

History, scene investigation, autopsy Autopsy and scene investigation History and autopsy

15%[*] 1324%[*] 1217%[*]

CAUSE OF DEATH causes

PRIMARY DIAGNOSTIC CRITERIA

CONFOUNDING FACTOR(S) SIDS or intentional suffocation

FREQUENCY DISTRIBUTION

UNEXPLAINED AT AUTOPSY Sudden infant death syndrome (SIDS) History, scene Intentional suffocation investigation, absence of explainable cause at autopsy 8082%

Intentional Perpetrator confession, SIDS Unknown suffocation absence of explainable (filicide) cause at autopsy Adapted from Hunt CE: Sudden infant death syndrome and other causes of infant mortality: Diagnosis, mechanisms and risk for recurrence in siblings. Am J Respir Crit Care Med 2001;164:346357.
* As a percentage of all sudden unexpected infant deaths explained at autopsy. As a percentage of all natural causes of sudden unexpected infant deaths explained at autopsy.

TABLE 372-2 -- Condition That May Cause Apparent Life-threatening Events or Sudden Death CAUSE COMMENT CNS Arteriovenous malformation, seizures, congenital central hypoventilation, neuromuscular disorders (Werdnig-Hoffmann disease), Arnold-Chiari crisis, Leigh syndrome Subendocardial fibroelastosis, aortic stenosis, anomalous coronary artery, myocarditis, cardiomyopathy, arrhythmias (prolonged Q-T syndrome, Wolff-Parkinson-White syndrome, congenital heart block) Pulmonary hypertension, vocal cord paralysis, aspiration, laryngotrachael disease Congenital adrenal hyperplasia, malignant hyperpyrexia, long- or mediumchain acyl coenzyme A deficiency, hyperammonemias (urea cycle enzyme deficiencies), glutaricaciduria, carnitine deficiency (systemic or secondary), glycogen storage disease type I, maple syrup urine disease, congenital lactic acidosis, biotinidase deficiency Sepsis, meningitis, encephalitis, brain abscess, hepatitis, pyelonephritis, bronchiolitis (RSV), infant botulism, pertussis Child abuse, suffocation, physical trauma, Munchausen syndrome by proxy Boric acid, carbon monoxide, salicylates, barbiturates, ipecac, cocaine, insulin

Cardiac

Pulmonary

Gastrointestinal Pancreatitis, diarrhea and/or dehydration, gastroesophageal reflux, volvulus Endocrinemetabolic

Infection Trauma Poisoning

From Kliegman RM, Greenbaum LA, Lye PS: Practical Strategies in Pediatric Diagnosis and Therapy, 2nd ed. Philadelphia, Elsevier Saunders, 2004, p 98. CNS, central nervous system; RSV, respiratory syncytial virus.

TABLE 372-3 -- Differential Diagnosis of Recurrent Sudden Infant Death in a Sibship Idiopathic Recurrent true sudden infant death syndrome CNS Cardiac Pulmonary Endocrinemetabolic Infection Congenital central hypoventilation, neuromuscular disorders, Leigh syndrome Endocardial fibroelastosis, Wolff-Parkinson-White syndrome, prolonged Q-T syndrome, congenital heart block Pulmonary hypertension See Table 372-2 Disorders of immune host defense

Child abuse Filicide, infanticide, Munchausen syndrome by proxy From Kliegman RM, Greenbaum LA, Lye PS:Practical Strategies in Pediatric Diagnosis and Therapy, 2nd ed. Philadelphia, Elsevier Saunders, 2004, p 101. CNS, central nervous system.

EPIDEMIOLOGY.

SIDS is the 3rd leading cause of infant mortality in the United States, accounting for 8% of all infant deaths. It is the most common cause of postneonatal infant mortality, accounting for 4050% of all deaths between 1 mo and 1 yr of age. The annual rate of SIDS in the United States was stable at 1.3-1.4/1,000 live births (about 7,000 infants/yr) before 1992, the year in which the American Academy of Pediatrics recommended that infants sleep non-prone as a way to reduce risk for SIDS. Since then, particularly after initiation of the national Back to Sleep campaign in 1994, the rate of SIDS progressively declined and then leveled off in 2002 at 0.57/1,000 live births (2,295 infants). The decline in the number of SIDS deaths in the United States and other countries around the world has been attributed to the increasing use of the supine position for sleep. Several other countries have decreased prone sleeping prevalence to 2%, but in the United States in 2004, 13% of infants were still being placed prone for sleeping.
PATHOLOGY.

There are no autopsy findings pathognomonic of SIDS and no findings required for the diagnosis, although there are some common findings. Petechial hemorrhages are found in 68 95% of cases and are more extensive than in explained causes of infant mortality. Pulmonary edema is often present and may be substantial. The reasons for these findings are unknown. SIDS victims have several identifiable changes in the lungs and other organs and in brainstem structure and function. Nearly of SIDS victims have structural evidence of pre-existing,

chronic low-grade asphyxia, while other studies have identified biochemical markers of asphyxia. SIDS victims have higher expression of vascular endothelial growth factor (VEGF) in the cerebrospinal fluid (CSF), which is upregulated by hypoxia, providing independent evidence of recent single or multiple hypoxemic events. Brainstem findings in SIDS victims include a persistent increase of dendritic spines and delayed maturation of synapses in the medullary respiratory centers, and decreased tyrosine hydroxylase immunoreactivity and catecholaminergic neurons. Decreases in 5-hydroxytryptamine (5-HT) 1A and 5-HT 2A receptor immunoreactivity have been observed in the dorsal nucleus of the vagus, solitary nucleus, and ventrolateral medulla, whereas increases are present in periaqueductal gray matter of the midbrain. The decreased immunoreactivity of receptors is accompanied by brainstem gliosis and it is therefore unclear whether the decreases are secondary to hypoxia or ischemia, or whether they reflect primary alterations in 5-HT metabolism or transport (see later discussion of 5-HT polymorphisms). The arcuate nucleus in the ventral medulla has been a particular focus for studies in SIDS victims. It is an integrative site for vital autonomic functions including breathing and arousal and is integrated with other regions that regulate arousal and autonomic chemosensory function. Quantitative 3-dimensional anatomic studies indicate that some SIDS victims have hypoplasia of the arcuate nucleus and up to 60% of SIDS victims have histopathologic evidence of less extensive bilateral or unilateral hypoplasia. Considering the apparent overlap between putative mechanisms for SIDS and for unexpected late fetal deaths, it is of interest that 30% of late unexpected and unexplained stillbirths also have hypoplasia of the arcuate nucleus. Neurotransmitter studies of the arcuate nucleus have also identified receptor abnormalities in some SIDS victims that involve several receptor types relevant to state-dependent autonomic control overall and to ventilatory and arousal responsiveness in particular. These deficits include significant decreases in binding to kainate, muscarinic cholinergic, and serotonergic (5-HT) receptors. High neuronal levels of interleukin 1 (IL-1 ) are present in the arcuate and dorsal vagal nuclei in SIDS victims compared to controls, perhaps contributing to molecular interactions affecting cardiorespiratory and arousal responses. The postmortem data summarized here do not establish any genetic risk factors for sudden unexpected deaths in infants (SUDI) to the exclusion of environmental risk factors. Recent genetic studies in SIDS victims, however, have identified several ways in which infants dying from SIDS differ genetically from both healthy infants and infants dying of other causes (see the Genetic Risk Factors section and Table 372-4 ).

TABLE 372-4 -- Identified Genes for Which the Distribution of Polymorphisms Differs in SIDS Victims Compared to Control Infants Sodium and potassium cardiac ion channel genes (SCN5A) Serotonin (5-hydroxytrypamine) transporter protein promoter region (5-HTT) Genes pertinent to development of autonomic nervous system Paired-like homeobox 2a (PHOX2a) Rearranged during transfection factor (RET) Endothelin converting enzyme-1 (ECE1)

T-cell leukemia homeobox (TLX3) Engrailed-1 (EN1) Testis-specific Y-like (TSPYL) gene Complement C4A and C4B genes Interleukin 10 gene polymorphisms Adapted from Hunt CE: Gene-environment interations: Implications for sudden unexpected deaths in infancy. Arch Dis Child 2005;90:4853. SIDS, sudden infant death syndrome.

ENVIRONMENTAL RISK FACTORS.

Declines of 50% or more in rates of SIDS in the United States and around the world have occurred in the past decade, at least in part as a result of national education campaigns directed at reducing risk factors associated with SIDS. The reductions in risk appear to be related primarily to decreases in placing infants prone for sleep and increases in placing them supine. A number of other risk factors also have significant associations with SIDS ( Table 372-5 ); although many are nonmodifiable and most of the modifiable factors have not changed appreciably, self-reported maternal smoking prevalence during pregnancy has decreased by 25% in the past decade.

TABLE 372-5 -- Environmental Factors Associated with Increased Risk for SIDS MATERNAL AND ANTENATAL RISK FACTORS Elevated 2nd trimester serum -fetoprotein Smoking Alcohol use Drug use (cocaine, heroin) Nutritional deficiency Inadequate prenatal care Low socioeconomic status Younger age Lower education Single marital status Shorter interpregnancy interval Intrauterine hypoxia Fetal growth restriction INFANT RISK FACTORS: Age (peak 24 mo, but may be decreasing)

Male gender Race/ethnicity (African-American and Native American) Growth failure No pacifier (dummy) Prematurity Prone and side sleep position Recent febrile illness Smoking exposure (prenatal and postnatal) Soft sleeping surface, soft bedding Infant-mother or -parent bed sharing Thermal stress/overheating Colder season, no central heating SIDS, sudden infant death syndrome.

NONMODIFIABLE RISK FACTORS.

Although SIDS affects infants from all social strata, lower socioeconomic status is consistently associated with higher risk. In the United States, African-American, Native American, and Alaskan Native infants are 2 to 3 times more likely than white infants to die of SIDS, whereas Asian, Pacific Islander, and Hispanic infants have the lowest incidence. Some of this disparity may be related to the higher concentration of poverty and other adverse environmental factors found within the higher incidence communities. Infants are at greatest risk of SIDS at 24 mo of age, with most deaths having occurred by 6 mo. This characteristic age has decreased in some countries as the SIDS incidence has declined, with deaths occurring at earlier ages and with a flattening of the peak incidence. Similarly, the commonly found winter seasonal predominance of SIDS has declined or disappeared in some countries as prone prevalence has decreased, supporting prior findings of an interaction between sleep position and factors more common in colder months (overheating, infection). Male infants are 3050% more likely to be affected than females.
MODIFIABLE RISK FACTORS. Pregnancy-Related Factors.

An increased SIDS risk is associated with numerous obstetric factors, suggesting that the in utero environment of future SIDS victims is suboptimal. SIDS infants are more commonly of higher birth order, independent of maternal age, and of gestations after shorter interpregnancy intervals. Mothers of SIDS infants generally receive less prenatal care and initiate care later in pregnancy. Additionally, low birthweight, preterm birth, and slower intrauterine and postnatal growth rates are risk factors.
Cigarette Smoking.

There is a major association between intrauterine exposure to cigarette smoking and risk for SIDS. The incidence of SIDS is about 3 times greater among infants of mothers who smoke in studies conducted before SIDS risk reduction campaigns and 5 times higher after implementation of risk reduction campaigns. The risk of death is progressively greater as daily cigarette use increases. The effects of smoking by the father and other household members are more difficult to interpret because they are highly correlated with maternal smoking. There appears to be a small independent effect of paternal smoking, but data on other household members have been inconsistent. It is very difficult to assess the independent effect of infant exposure to environmental tobacco smoke (ETS) because parental smoking behaviors during and after pregnancy are also highly correlated. An increased risk of SIDS is also found for infants exposed to only postnatal maternal ETS. There is a dose response for the number of household smokers, number of people smoking in the same room as the infant, and the number of cigarettes smoked. Maternal smoking is currently the most important risk factor for SIDS.
Drug and Alcohol Use.

Overall, most studies do link maternal prenatal drug use with an increased risk of SIDS. Most studies have not found an association between maternal alcohol use prenatally or postnatally and SIDS. In one study of Northern Plains Indians, periconceptional alcohol use and binge drinking in the 1st trimester were associated with a sixfold and an eightfold increased risk of SIDS, respectively. Siblings of infants with fetal alcohol syndrome have a tenfold increased risk of SIDS compared to controls.
Infant Sleep Environment.

Sleeping prone has consistently been shown to increase the risk of SIDS. As rates of prone positioning have decreased in the general population, the odds ratios for SIDS in infants still sleeping prone have increased. The highest risk of SIDS may occur in infants who are usually placed non-prone but placed prone for last sleep (unaccustomed prone) or found prone (secondary prone). The unaccustomed prone position is more likely to occur in daycare or other settings outside the home and highlights the need for all infant caretakers to be educated about appropriate sleep positioning. The initial SIDS risk reduction campaign recommendations considered side sleeping to be nearly equivalent to the supine position in reducing the risk of SIDS. Subsequent studies have indicated that, although safer than the prone position, side-sleeping infants are twice as likely to die of SIDS as infants sleeping supine. This increased risk may relate to the relative instability of the position, with some infants placed on the side rolling to the prone position. The current recommendations call for supine position for sleeping for all infants except those few with specific medical conditions for which recommending a different position may be justified. Many parents and health care providers were initially concerned that supine sleeping would be associated with an increase in adverse consequences, such as difficulty sleeping, vomiting, or aspiration. Evidence suggests that the risk of regurgitation and choking are highest for prone-sleeping infants. Some newborn nursery staff still tend to favor side positioning, which models inappropriate infant care practice to parents. Infants sleeping on their backs do not have more episodes of cyanosis or apnea; reports of apparent lifethreatening events decreased in Scandinavia after increased use of the supine position. Among infants in the United States who maintained the same sleep position at 1, 3, and 6 mo of age,

no clinical symptoms or reasons for outpatient visits (including fever, cough, wheezing, trouble breathing or sleeping, vomiting, diarrhea, or respiratory illness) are more common in infants sleeping supine or on their side compared with infants sleeping prone. Three symptoms are actually less common in infants sleeping supine or on their side: fever at 1 mo, stuffy nose at 6 mo, and trouble sleeping at 6 mo. Outpatient visits for ear infection are less common at 3 and 6 mo for infants sleeping supine and also less common at 3 mo for infants sleeping on their side. These results provide reassurance for parents and health care providers and will lead, it is hoped, to universal acceptance of supine as the safest and optimal sleep position for infants. Soft sleep surfaces or bedding, such as comforters, pillows, sheepskins, polystyrene bean pillows, and older or softer mattresses are associated with increased risk of SIDS. Head and face covering by loose bedding, particularly heavy comforters, is also associated with increased risk. Overheating has been associated with increased risk for SIDS based on indicators such as higher room temperature, high body temperature, sweating, and excessive clothing or bedding. Some studies have identified an interaction between overheating and prone sleeping, with overheating increasing the risk of SIDS only when infants were sleeping prone. Higher external environmental temperatures have not been associated with increased SIDS incidence in the United States. Several studies have implicated bed sharing as a risk factor for SIDS. Bed sharing is associated with increased risk of SIDS among infants up to 3 mo of age even if their mothers did not smoke. Bed sharing is particularly hazardous when other children are in the same bed, when the parent is sleeping with an infant on a couch or other soft or confining sleeping surface, and for infants <4 mo of age. Risk is also increased with longer duration of bed sharing during the night; returning the infant to his or her own crib is not associated with increased risk. There is increasing evidence that room sharing without bed sharing is associated with lower SIDS rates; the safest place for infants to sleep may be in their own crib in the parents' room.
Infant Feeding Care Practices and Exposures.

A number of studies have demonstrated a protective effect of breast-feeding that is not present after adjusting for potentially confounding factors. This suggests that breast-feeding is a marker for lifestyle or socioeconomic status rather than an independent factor. Although the benefits of breast-feeding are many, data are inadequate to recommend it as a strategy to reduce risk for SIDS. Pacifier (dummy) use lowers the risk of SIDS in the majority of studies when used for last/reference sleep. A meta-analysis found this reduced risk to be equal to an adjusted summary odds ratio of 0.39 (95% confidence intervals 0.310.50). Although it is not known if this is a direct effect of the pacifier itself or from associated infant or parental behaviors, there is increasing evidence that pacifier use and dislodgment may increase the arousability of infants during sleep. Concerns have been expressed about recommending pacifiers as a means of reducing the risk of SIDS for fear of creating adverse consequences, particularly interference with breast-feeding. In well-designed studies, however, no association between pacifiers and breast-feeding duration has been found. A small increased incidence of otitis media and of respiratory and gastrointestinal illness has been reported for pacifier users compared with non-users. The Netherlands (for bottle-fed babies) and Germany have recommended pacifier use as a potential way to reduce the risk of SIDS. The most recent

American Academy of Pediatrics guidelines recommend pacifier use once breast-feeding has been established. Upper respiratory tract infections have generally not been found to be an independent risk factor for SIDS. These and other minor infections, however, may play a role in the pathogenesis of SIDS. Risk for SIDS has been found to be increased after illness among prone sleepers, those who were heavily wrapped, and those whose heads were covered during sleep. No association between immunizations and SIDS has been found. SIDS infants are less likely to be immunized than control infants, and in immunized infants, no temporal relationship between vaccine administration and death has been identified. Parents should be reassured that immunizations do not present a risk for SIDS. SIDS rates remain higher among Native Americans, Alaskan Natives, and AfricanAmericans. This may be due, in part, to group differences in adopting supine sleeping or other risk-reduction behaviors. Greater efforts are needed to address this persistent disparity and to ensure that SIDS risk-reduction education reaches all parents. The messages must reach all care providers, including grandparents, other relatives, and personnel at daycare centers.
GENETIC RISK FACTORS.

Genetic studies have identified multiple ways in which SIDS victims differ from healthy infants and infants dying from other causes (see Table 372-4 ). Differences include sodium and potassium ion channel gene defects, serotonin (5-HT) transporter (5-HTT) gene, autonomic nervous system (ANS) development genes, complement C4, and IL-10. Long Q-T syndrome (LQTS) is associated with sodium channel gene (SCN5A) defects. SCN5A has emerged as the leading candidate ion channel gene having relevance for SIDS, with 2% of 93 SIDS cases in one study having a distinct SCN5A channel defect. These findings suggest that mutations in cardiac ion channels may provide a lethal arrhythmogenic substrate in some infants at risk for SIDS ( Fig. 372-1 ).

Figure 372-1 An arrhythmogenic pathogenetic pathway for sudden infant death syndrome (SIDS) from patient genotype to clinical phenotype, with environmental influences noted. The genetic abnormality, in this instance, a polymorphism in the car diac Na+ channel SCN5A, causes a molecular phenotype of increased late Na + current (I Na) under the influence of environmental factors such as acidosis. Interacting with other ion currents that may themselves be altered by genetic and environmental fac tors, the late Na+ current causes a cellular phenotype of prolonged action potential duration as well as early afterdepolarizations. Prolonged action potential in the cells of the ventricular myocardium and further interaction with environmental factors such as autonomic innervation, which, in turn, may be affected by genetic factors, produce a tissue/organ phenotype of a prolonged Q -T interval on the electrocardiogam (ECG) and torsades de pointes arrhythmia in the whole heart. If this is sustained or degener ates

to ventricular fibrillation, the clinical phenotype of SIDS results. Environmental and multiple genetic factors may interact at many different levels to produce the characteristic phenotypes at the molecular, cellular, tissue, organ, and clinical levels . (From Makielski JC: SIDS: Genetic and environmental influences may cause arrhythmia in this silent killer. J Clin Invest 2006;116:297299.)

Polymorphisms in the 5-HTT gene are illustrative of the way in which alterations in individual genes could influence risk for SIDS. 5-HT is a widespread neurotransmitter affecting breathing, cardiovascular control, temperature, and mood. It modulates activity of the circadian clock and is the major neurotransmitter of nonrapid eye movement (NREM or quiet) sleep. Many genes are involved in the control of 5-HT synthesis, storage, membrane uptake, and metabolism. Several polymorphisms have been identified in the promoter region of the 5-HTT gene, which is located on chromosome 17. Variations in the promoter region of the 5-HTT gene appear to have a role in 5-HT membrane uptake and regulation. White, African-American, and Japanese SIDS victims are more likely than matched controls to have the L (long) allele. There is also a negative association between SIDS and the S/S genotype. An association has also been observed between SIDS and a 5-HTT intron 2 polymorphism that differentially regulates 5-HTT expression. These transporter polymorphisms would lead to reduced serotonin concentrations at nerve endings with the L allele in comparison to the short S allele. The L/L genotype is associated with increased serotonin transporters on neuroimaging and postmortem binding studies. Molecular genetic studies in SIDS victims have identified mutations pertinent to early embryologic development of the ANS. The relevant genes include mammalian achaete-scute homolog-1 (MASH1), bone morphogenic protein-2 (BMP2), paired-like homeobox 2a (PHOX2a), PHOX2b, rearranged during transfection factor (RET), endothelin converting enzyme-1 (ECE1), endothelin-1 (EDN1), T-cell leukemia homeobox (TLX3), and engrailed-1 (EN1). Genetic differences among SIDS infants have also been reported for the complement C4 gene, with SIDS victims who had mild upper respiratory infection before death more likely to have deletion of either the C4A or the C4B gene compared to SIDS victims without infection or to living controls. These data suggest that partial deletions of the C4 gene in combination with a mild upper respiratory infection place infants at increased risk for SIDS. SIDS victims have also been reported to have polymorphisms in the gene promoter region for IL-10, an anti-inflammatory cytokine. Sudden infant death was strongly associated with IL-10 genotype, both with the ATA haplotype and with presence of the -592*A and -592*C alleles. These IL-10 polymorphisms are associated with decreased IL-10 levels and hence could contribute to SIDS by delaying initiation of protective antibody production or reduced capacity to inhibit inflammatory cytokine production. An uncommon cause of SIDS is due to mutations in the testis-specific Y-like gene (TSPYL), which also demonstrates testicular dysgenesis.
GENE-ENVIRONMENT INTERACTIONS.

The actual risk for SIDS in individual infants is determined by complex interactions between genetic and environmental risk factors (see Fig. 372-1 ). There appears, for example, to be an

interaction between prone sleep position and impaired ventilatory and arousal responsiveness. Facedown or nearly facedown sleeping does occasionally occur in prone-sleeping infants and can result in episodes of airway obstruction and asphyxia in healthy full-term infants. Healthy infants arouse before such episodes become life-threatening, but infants with insufficient arousal responsiveness to asphyxia may be at risk for sudden death. There may also be links between modifiable risk factors such as soft bedding, prone sleep position, and thermal stress, and links between genetic risk factors such as ventilatory and arousal abnormalities and temperature or metabolic regulation deficits. Cardiorespiratory control deficits could be related to 5-HTT polymorphisms, for example, or to polymorphisms in genes pertinent to ANS development. Affected infants could be at increased risk for sleep-related hypoxemia and, hence, more susceptible to adverse effects associated with unsafe sleep position or bedding. Infants at increased risk for sleep-related hypoxemia could also be at greater risk for fatal arrhythmias in the presence of a sodium or potassium cardiac ion channel gene polymorphism. Recent febrile illness, often related to upper respiratory infection (see Table 372-5 ) has been observed in 50% or more of SIDS victims. Although historically not considered of primary etiologic significance, such otherwise benign infections could increase risk for SIDS if interacting with genetically determined impaired immune responses due, for example, to partial deletions in the complement C4 gene or interleukin polymorphisms (see Table 372-4 ), or other yet-to-be-identified polymorphisms. Interactions between upper respiratory infections or other minor illnesses and other factors such as prone sleeping may also play a role in the pathogenesis of SIDS. Deficient inflammatory responsiveness to infection has also been hypothesized to be a mechanism for SIDS, and mast cell degranulation has been reported in SIDS victims; this is consistent with an anaphylactic reaction to a bacterial toxin and some family members of SIDS victims also have mast cell hyperreleasability and degranulation, suggesting that increased susceptibility to an anaphylactic reaction is another genetic factor influencing fatal outcomes to otherwise minor infections in infants. The increased risk for SIDS associated with fetal and postnatal exposure to cigarette smoke also appears, at least in part, to depend on genetic factors affecting brainstem autonomic control. Maternal smoking can potentiate hyperplasia of pulmonary neuroendocrine cells and dysfunction of these cells may contribute to the pathophysiology of SIDS. Both animal and clinical studies indicate decreased ventilatory and arousal responsiveness to hypoxia after fetal exposure, including impaired autoresuscitation after apnea in association with postnatal nicotine exposure. Decreased brainstem immunoreactivity to selected protein kinase C and neuronal nitric oxide synthase isoforms has been observed in rats exposed to cigarette smoke prenatally, which could be associated with impaired ventilatory and arousal responsiveness to hypoxia. Hence, the age-specific attenuation of hypoxic defenses after nicotine exposure appears related, at least in part, to impaired brain catecholamine metabolism, but no genetic polymorphisms contributing to these smoking-related metabolic changes have yet been identified. In vitro studies also suggest that smoking increases risk for SIDS, due to greater susceptibility to viral and bacterial infections and enhanced bacterial binding after passive coating of mucosal surfaces with smoke components, hence suggesting interactions between smoking, cardiorespiratory control, and immune status.
INFANT GROUPS AT INCREASED RISK FOR SIDS UNEXPLAINED APPARENT LIFE -THREATENING EVENTS.

Infants with an unexplained apparent life-threatening event (ALTE) are at increased risk for SIDS. A history of an unexplained ALTE has been reported in 59% of SIDS victims, and the risk of SIDS appears to be higher with 2 or more unexplained events, but no definitive incidence rates are available. Compared with healthy control infants, the risk for SIDS may be as much as 3 to 5 times greater in infants having experienced an ALTE. Although most studies of ALTE have not specified gestational age, 30% of ALTE infants in the Collaborative Home Infant Monitoring Evaluation were 37 wk at birth.
SUBSEQUENT SIBLINGS OF A SIDS VICTIM.

The next-born siblings of first-born infants dying of any noninfectious natural cause are at significantly increased risk for infant death from the same cause, including SIDS. The relative risk is 9.1 for the same cause of recurrent death vs 1.6 for a different cause of death. The relative risk for recurrence of SIDS (range 5.45.8) is similar to the relative risk for non-SIDS causes of recurrent death (range 4.612.5). The risk for recurrent infant mortality from the same cause as in the index sibling thus appears to be increased to a similar degree in subsequent siblings for both explained causes and for SIDS. This increased risk in SIDS families is consistent with genetic risk factors interacting with environmental risk factors (see Table 372-2 ). The extent to which risk for SIDS may be increased in subsequent siblings has been a controversial subject due primarily to limited prior understanding of the role of genetic risk factors but also due to uncertainty about the frequency with which intentional suffocation is misclassified as SIDS. Clarification of the role of intentional suffocation has been impaired by the lack of objective criteria for diagnosis. Although some health professionals have in the past stated that only homicide runs in families and all subsequent cases of sudden unexpected infant deaths in a family should be investigated for possible homicide, there are substantial data in support of genetic as well as environmental factors leading to increased risk for recurrent SIDS in some families. In addition to genetic evidence consistent with increased risk for SIDS in subsequent siblings, epidemiologic data from the United Kingdom confirm that 2nd infant deaths in families are not rare and that at least 8090% are natural. The proportion of recurrent infant death from SIDS in subsequent siblings was 5.9 times greater than the proportion of probable homicides.
PREMATURITY.

Many studies have identified an inverse relationship between risk for SIDS and birthweight/gestational age. The environmental risk factors associated with SIDS in preterm infants are not substantially different from those observed in full-term infants, including prone and side sleeping. The postnatal age of preterm infants dying of SIDS is 57 wk older than that of full-term infants, and the postconceptional age is 46 wk younger than that of full-term infants. Compared with infants with birthweight >2,500 g, infants with birthweights of 1,000 1,499 g and 1,5002,499 g are approximately 4 and 3 times more likely to die of SIDS, respectively.
PHYSIOLOGIC STUDIES.

Physiologic studies have been performed on healthy infants in early infancy, a few of whom later died of SIDS. Physiologic studies have also been performed on infant groups at increased risk for SIDS, especially infants having experienced an unexplained ALTE and subsequent siblings of SIDS victims. In the aggregate, these studies are indicative of a

brainstem abnormality related to neuroregulation of cardiorespiratory control or other autonomic functions and are consistent with the autopsy findings including genetic studies in SIDS victims (see the Pathology and Genetic Risk Factors sections). The observed physiologic abnormalities affect respiratory patterns, chemoreceptor sensitivity, control of heart and respiratory rate or variability, and asphyxic arousal responsiveness. A deficit in arousal responsiveness may be a necessary prerequisite for SIDS to occur but may be insufficient to cause SIDS in the absence of other genetic or environmental risk factors. Autoresuscitation (gasping) is a critical component of the asphyxic arousal response, and a failure of autoresuscitation in victims of SIDS may be the final and most devastating physiologic failure. Most full-term infants <9 wk of age arouse in response to mild hypoxia, but only 1015% of normal infants >9 wk of age arouse. These data thus suggest that as infants mature, their ability to arouse to mild-moderate hypoxic stimuli diminishes as they reach the age range of greatest risk for SIDS. The ability to shorten the Q-T interval as heart rate increases appears to be impaired in some SIDS victims, suggesting that such infants may be predisposed to ventricular arrhythmia. This is consistent with the observations of cardiac ion channel gene polymorphisms in other SIDS victims (see Table 372-4 ), but there are no ante mortem Q-T interval data in the SIDS infants having postmortem genetic data. Infants studied physiologically and later dying of SIDS have higher heart rates in all sleep-waking states, diminished heart rate variability during wakefulness, and significantly lower heart rate variability at the respiratory frequency across all sleep-waking cycles. Part of the decreased heart rate variability and increased heart rate observed in infants who later die of SIDS may be related to decreased vagal tone. This decreased tone appears, at least in part, to be related to vagal neuropathy or to brainstem damage in areas responsible for parasympathetic cardiac control. In a comparison of heart rate power spectra before and after obstructive apneas in infants, future SIDS victims do not have the decreases in low-frequency to high-frequency power ratios observed in control infants. Some future SIDS victims thus have different autonomic responsiveness to obstructive apnea, perhaps indicating impaired ANS control associated with higher vulnerability to external or endogenous stress factors and hence to reduced electrical stability of the heart. Sweating during sleep has been observed in some infants who have had an idiopathic ALTE or have died of SIDS. Although overheating may be the cause of this sweating, it may also be caused by alveolar hypoventilation and secondary asphyxia or by autonomic dysfunction as part of a more generalized deficiency in brainstem function. Although home cardiorespiratory monitors with memory capability have recorded the terminal events in some SIDS victims, these recordings have not included pulse oximetry and do not permit identification of obstructed breaths due to reliance on transthoracic impedance for breath detection. In most instances, there has been sudden and rapid progression of severe bradycardia that is either unassociated with central apnea or appears to occur too soon to be explained by the central apnea. These observations are consistent with an abnormality in autonomic control of heart rate variability, or with obstructed breaths and associated bradycardia or hypoxemia.
CLINICAL STRATEGIES MONITORING.

SIDS cannot currently be prevented in individual infants because it is not, at this time, possible to identify prospective SIDS victims and no effective intervention has been established even if victims could be prospectively identified. Studies of cardiorespiratory pattern or other autonomic abnormalities do not have sufficient sensitivity and specificity to be clinically useful as a screening test. Home electronic surveillance using existing technology has not been shown to reduce the risk of SIDS. Although prolonged Q-T interval in an infant may be treated if diagnosed, neither the role of routine postnatal electrocardiographic (ECG) screening nor the safety of treatment has been established (see Chapter 435.5 ). Parental ECG screening is not likely to be helpful because spontaneous mutations are common.
REDUCING THE RISK OF SIDS.

The American Academy of Pediatrics guidelines to reduce the risk of SIDS in individual infants are appropriate for most infants, but physicians and other health care providers may, on occasion, need to consider alternative approaches. The major components are as follows: 1. Full-term and premature infants should be placed for sleep in the supine position. There are no adverse health outcomes from supine sleeping. Side sleeping is not recommended. It is recommended that infants sleep in the same room as their parents, but in their own crib or bassinette that conforms to the safety standards of the Consumer Product Safety Commission. Placing the crib or bassinette near the mother's bed facilitates nursing and contact. Infants should be put to sleep on a firm mattress. Waterbeds, sofas, soft mattresses, or other soft surfaces should not be used. Soft materials in the infant's sleep environmentover, under, or near the infant should be avoided. These include pillows, comforters, quilts, sheepskins, cushion-like bumper pads, and stuffed toys. Because loose bedding may be hazardous, blankets, if used, should be tucked in around the crib mattress. Sleeping clothing, such as a sleep sack, can be used in place of blankets. Avoid overheating and overbundling. The infant should be lightly clothed for sleep and the thermostat set at a comfortable temperature. Infants should have some time in the prone position (tummy time) while awake and observed. Alternating the placement of the infant's head as well as his or her orientation in the crib can also minimize the risk of head flattening from supine sleeping (positional plagiocephaly). Devices advertised to maintain sleep position, protect a bed-sharing infant, or reduce the risk of rebreathing are not recommended. Home respiratory, cardiac, and O2 saturation monitoring may be of value for selected infants who have extreme instability, but there is no evidence that monitoring decreases the incidence of SIDS and it is, therefore, not recommended for this purpose. Consider offering a pacifier at bedtime and naptime. The pacifier should be used when placing the infant down for sleep and not be reinserted once it falls out. For breast-fed infants, delay introduction of the pacifier until breast-feeding is well established.

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10. Mothers should not smoke during pregnancy and infants should not be exposed to secondhand smoke. 11. The national Back to Sleep campaign should continue and be expanded to emphasize the multiple characteristics of a safe sleeping environment and to focus on the groups who continue to have higher rates of SIDS. Educational strategies must be tailored to each racial-ethnic group to ensure acceptance within that cultural context. Secondary care providers need to be targeted to receive these educational messages, including daycare providers, grandparents, foster parents, and babysitters. Health care professionals in intensive care and normal newborn nurseries should implement these recommendations well before anticipated discharge. Email to ColleaguePrint Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com