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Respiratory physiology
Among many physiologic adaptations for the survival of humans at birth, cardiorespiratory adaptation is by far the most crucial. The respiratory and circulatory systems must be developed sufficiently in utero for the newborn infant to withstand drastic changes at birth—from the fetal circulatory pattern with liquid-filled lungs to air breathing with transitional circulatory adaptation in a matter of a few minutes. The newborn infant must exercise an effective neuronal drive and respiratory muscles to displace the liquid filling the airway system and to introduce sufficient air against the surface force in order to establish sufficient alveolar surface for gas exchange. At the same time, pulmonary blood vessels must dilate rapidly to increase pulmonary blood flow and to establish adequate regional alveolar ventilation/pulmonary perfusion ( 
a /Q) balance for sufficient pulmonary gas exchange. The neonatal adaptation of lung mechanics and respiratory control takes several weeks to complete. Beyond this immediate neonatal period, the infant’s lungs continue to mature at a rapid pace, and postnatal development of the lungs and the thorax surrounding the lungs continues well beyond the first year of life. Respiratory function in infants and toddlers, especially during the first several months of life, as with cardiovascular system and hepatic function, is both qualitatively and quantitatively different from that in older children and adults, and so is their response to pharmacologic agents, especially anesthetics.
This chapter reviews clinically relevant aspects of the development of the respiratory system and function in infants and children and their application to pediatric anesthesia. Such knowledge is indispensable for the proper care of infants and children during the perianesthetic period and for the care of those with respiratory insufficiency.
The respiratory system consists of the respiratory centers in the brainstem; the central and peripheral chemoreceptors; the phrenic, intercostal, hypoglossal (efferent), and vagal (afferent) nerves; the thorax (including the thoracic cage and the muscles of the chest, abdomen, and the diaphragm); the upper (extrathoracic) and lower (intrathoracic) airways; alveoli and lung parenchyma; and the pulmonary vascular system. The principal function of the respiratory system is to maintain the oxygen and carbon dioxide (CO 2 ) equilibrium in the body. The lungs also make an important contribution to the regulation of acid-base (pH) balance. The maintenance of body temperature (via loss of water through the lungs) is an additional but secondary function of the lungs. The lungs are also an important organ of metabolism.
Development of the respiratory system
Prenatal development of the lungs
The morphologic development of the human lung is seen as early as several weeks into the embryonic period and continues well into the first decade of postnatal life and beyond ( Fig. 3.1 ). The fetal lungs begin to form within the first several weeks of the embryonic period, when the fetus is merely 3 mm in length. A groove appears in the ventral aspect of the foregut, creating a small pouch. The outgrowth of the endodermal cavity, with a mass of surrounding mesenchymal tissue, projects into the pleuroperitoneal cavity and forms lung buds. The future alveolar membranes and mucous glands are derived from the endoderm, whereas the cartilage, muscle, elastic tissue, and lymph vessels originate from the mesenchymal elements surrounding the lung buds ( ).
During the pseudoglandular period, which extends until 17 weeks’ gestation, the budding of the bronchi and lung growth rapidly takes place, forming a loose mass of connective tissue. The morphologic development of the human lung is illustrated in Fig. 3.2 . By 16 weeks’ gestation, preacinar branching of the airways (down to the terminal bronchiole) is complete ( ). A disturbance of the free expansion of the developing lung during this stage, as occurs with diaphragmatic hernia, results in hypoplasia of the airways and lung tissue ( ). During the canalicular period, in midgestation, the future respiratory bronchioli develop as the relative amount of connective tissue diminishes. Capillaries grow adjacent to the respiratory bronchioli, and the whole lung becomes more vascular ( ).
At about 24 weeks’ gestation, the lung enters the terminal sac period, which is characterized by the appearance of clusters of terminal air sacs, termed saccules, with flattened epithelium ( ). These saccules are large and irregular with thick septa and have few capillaries in comparison with the adult alveoli ( ). At about 26 to 28 weeks’ gestation, proliferation of the capillary network surrounding the terminal air spaces becomes sufficient for pulmonary gas exchange ( ). These morphologic developments may occur earlier in some premature infants (born at 24 to 25 weeks’ gestation) who have survived through neonatal intensive care. Starting at 28 weeks’ gestation, air space wall thickness decreases rapidly. From this period onward toward term, there is further lengthening of saccules with possible growth of additional generations of air spaces. Some mammalian species, such as the rat, have no mature alveoli at birth ( ). In contrast, alveolar development from saccules begins in some human fetuses as early as 32 weeks’ gestation, but alveoli are not uniformly present until 36 weeks’ gestation ( ). Most alveolar formation in humans takes place postnatally during the first 12 to 18 months of postnatal life. Development of respiratory bronchioles by transformation of preexisting terminal airways does not take place until after birth ( ).
The fetal lung produces a large quantity of liquid, which expands the airways while the larynx is closed. This expansion of airways per se stimulates and produces growth factors, such as human bombesin (also known as gastrin-releasing peptide) from pulmonary endocrine cells, which stimulates airway branching and accelerates lung growth and development ( ; ). The fetal larynx is periodically relaxed and lung fluid is expelled into the uterine cavity and contributes about one-third of the total amniotic fluid; the remaining two-thirds comes from fetal urinary outputs. Congenital diaphragmatic hernia is characterized by unilateral pulmonary hypoplasia secondary to ipsilateral herniation of abdominal viscera displaced into the thoracic cavity. Prenatal ligation or occlusion of the trachea was tried in the 1990s with some success for the treatment of the fetus with congenital diaphragmatic hernia ( ). This treatment causes the expansion of the fetal airways with accumulating lung fluid and results in an accelerated growth of the otherwise hypoplastic lung ( ).
The lung fluid contains components of surfactant from the osmiophilic lamellar bodies produced in and expelled from the cuboidal type II alveolar pneumocytes during the last trimester of pregnancy. The type II pneumocytes containing lamellar bodies appear at about 24 to 26 weeks’ gestation but occasionally as early as 20 weeks ( ; ). In mature lungs, lamellar bodies, containing pulmonary surfactant, are expelled from the type II pneumocytes onto the alveolar surface, spread and form a thin alveolar lining layer, and reduce surface tension at the air-liquid interface and stabilize air spaces. The presence of functioning pulmonary surfactant is essential to keep pulmonary alveoli open during the respiratory cycle (see Surface Activity and Pulmonary Surfactant). Idiopathic (or infantile) respiratory distress syndrome (IRDS), also known as hyaline membrane disease (HMD), which occurs in premature infants, is caused by the immaturity of the lungs with insufficient pulmonary surfactant production and their inactivation by plasma proteins exudating onto the alveolar surface.
Experimental evidence from animals indicates that certain pharmacologic agents such as cortisol and thyroxin administered to the mother or directly to the fetus accelerate the maturation of the lungs, resulting in the early appearance of type II pneumocytes and surfactant ( ; ; ; ; ). reported accelerated maturation of human fetal lungs after the administration of corticosteroids to mothers to prevent premature contractions 24 to 48 hours before the delivery of premature babies. Despite initial concern that steroids might potentially be toxic to other organs of the fetus, particularly to central nervous system development, prenatal glucocorticoid therapy has been used widely since the 1980s to induce lung maturation and surfactant synthesis in mothers at risk of premature delivery. This has resulted in improved survival of prematurely born infants ( ; ).
Prenatal development of breathing
Respiratory rhythmogenesis occurs long before parturition. were the first to demonstrate “breathing” activities with rhythmic diaphragmatic contractions in the fetal lamb. They found it to be episodic and highly variable in frequency. recorded movement of the human fetal thorax with an ultrasound device and interpreted this as evidence of fetal breathing. Later studies have shown that during the last 10 weeks of full-term pregnancy, fetal breathing is present approximately 30% of the time ( ). The breathing rate in the fetus at 30 to 31 weeks’ gestation is higher (58 breaths/min) than that in the near-term fetus (47 breaths/min). A significant increase in fetal breathing movements occurs 2 to 3 hours after a maternal meal and is correlated with the increase in the maternal blood sugar level ( ).
Spontaneous breathing movements in the fetus occur only during active, or rapid eye movement (REM), sleep and with low-voltage electrocortical activity, and they appear to be independent of the usual chemical and nonchemical stimuli of postnatal breathing ( ; ). Later studies, however, have clearly shown that the fetus can respond to chemical stimuli known to modify breathing patterns postnatally ( ; ; ). In contrast, hypoxemia in the fetus abolishes, rather than stimulates, breathing movements. This may be related to the fact that hypoxemia diminishes the incidence of REM sleep ( ). It appears that normally low arterial oxygen tension, or PaO 2 (19 to 23 mm Hg), in the fetus is a normal mechanism inhibiting breathing activities in utero ( ). Severe hypoxia induces gasping, which is independent of the peripheral chemoreceptors and apparently independent of rhythmic fetal breathing ( ).
The near-term fetus is relatively insensitive to PaCO 2 changes. Extreme hypercapnia (PaCO 2 >60 mm Hg) in the fetal lamb, however, can induce rhythmic breathing movement that is preceded by a sudden activation of inspiratory muscle tone with expansion of the thorax and inward movement (inspiration) of amniotic fluid, as much as 30 to 40 mL/kg (an apparent increase in functional residual capacity [FRC]) (Motoyama, unpublished observation). When PaO 2 was reduced, breathing activities ceased, and there was a reversal of the sequence of events noted above (i.e., relaxation of the thorax, decreased FRC as evidenced by outward flow of amniotic fluid) ( ).
The Hering–Breuer (inflation) reflex is present in the fetus. Distention of the lungs by saline infusion slows the frequency of breathing ( ). Transection of the vagi, however, does not change the breathing pattern ( ).
Maternal ingestion of alcoholic beverages abolishes human fetal breathing for up to 1 hour. Fetal breathing movement is also abolished by maternal cigarette smoking. These effects may be related to fetal hypoxemia resulting from changes in placental circulation ( ). It is not clear why the fetus must “breathe” in utero, when gas exchange is handled by the placental circulation. suggested that fetal breathing might represent “prenatal practice” to ensure that the respiratory system is well developed and ready at the moment of birth. Another reason may be that the stretching of the airways and lung parenchyma is an important stimulus for lung development; bilateral phrenic nerve sectioning in the fetal lamb results in hypoplasia of the lungs ( ).
Prenatal fetal gas exchange takes place between the maternal (uterine arterial) capillary blood and cotyledonary vasculatures in the fetal side of the placenta. Arteriolized umbilical venous blood returns to the right side of the fetal heart via the ductus venosus and inferior vena cava (also see Chapter 5 : Cardiovascular Physiology). The mean value of umbilical venous P o 2 (functionally somewhat analogous to arteriolized pulmonary venous blood in normal adult circulation) in the near-term eucapneic gravida is reported to be 29 mm Hg (range, 25 to 33), whereas preductal (carotid) P o 2 ranged between 20 to 25 mm Hg; the average postductal umbilical arterial P o 2 (analogous to desaturated pulmonary arterial blood) is 22 mm Hg in eucapneic gravida at elective caesarian section ( ). reported the median umbilical arterial (postductal) P o 2 of 17 mm Hg and P co 2 of 52 mm Hg.
Neonatal respiratory adaptation
During normal labor and vaginal delivery, the human fetus goes through a period of transient hypoxia, hypercapnia, and acidemia. The traditional view of the mechanism of the onset of breathing at birth until the 1980s was that the transient fetal asphyxia stimulates the chemoreceptors and produces gasping, which is followed by rhythmic breathing at birth that is aided by thermal, tactile, and other sensory stimuli. Subsequent studies have challenged this concept ( ; ; ). Indeed, the clamping of the umbilical cord and increasing arterial oxygen tensions with air breathing and resultant relative “hyperoxia” from the normally low fetal PO 2 (but not transient hypoxia during labor and delivery) initiate and maintain rhythmic breathing at birth. The current concept regarding the mechanism of continuous neonatal breathing is summarized in Box 3.1 .
BOX 3.1
Mechanism of Continuous Neonatal Breathing
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The onset of breathing activities occurs not at birth but in utero, as a part of normal fetal development.
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The clamping of the umbilical cord initiates rhythmic breathing.
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Relative hyperoxia with air breathing, compared with low fetal PaO 2 , augments and maintains continuous and rhythmic breathing.
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Continuous breathing is independent of the level of PaCO 2 .
-
Breathing is unaffected by carotid denervation.
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Hypoxia depresses or abolishes continuous breathing.
To introduce air into the fluid-filled lungs at birth, the newborn infant must overcome large surface force with the first few breaths. Usually a negative pressure of 30 cm H 2 O is necessary to introduce air into the fluid-filled lungs. In some normal full-term infants, even with sufficient surfactant, a force of as much as −70 cm H 2 O or more must be exerted to overcome the surface force ( ) ( Fig. 3.3 ). Usually, fluid is rapidly expelled via the upper airways. The residual fluid leaves the lungs through the pulmonary capillaries and lymphatic channels over the first few days of life, and changes in compliance parallel this time course. All changes are delayed in the premature infant.
As the lungs expand with air, pulmonary vascular resistance decreases dramatically and pulmonary blood flow ( 
p or simply Q) increases markedly, thus allowing gas exchange between alveolar air and pulmonary capillaries to increase. Changes in P o 2 , P co 2 , and pH are largely responsible for the dramatic decrease in pulmonary vascular resistance ( ). The resultant large increases in pulmonary blood flow and the increase in left atrial pressure with a decrease in right atrial pressure reverse the pressure gradient across the atria and close (initially functionally and eventually anatomically) the foramen ovale, a right-to-left one-way valve. With these adjustments, the cardiopulmonary system approaches adult levels of alveolar ventilation/pulmonary perfusion ( a / p , 
a / 
or simply V/Q) balance within a few days ( ). The process of expansion of the lungs during the first few hours of life and the resultant circulatory adaptation for establishing pulmonary gas exchange are greatly influenced by the adequate supply of pulmonary surfactant.
Once the newborn has begun rhythmic breathing, ventilation is adjusted to achieve a lower PaCO 2 than is found in older children and adults ( Table 3.1 ). The reason for this difference is not clear but most likely is related to a poor buffering capacity in the neonate and a ventilatory compensation for metabolic acidosis. The Pa O 2 of the infant approximates the adult level within a few weeks of birth ( ).
TABLE 3.1
Normal Blood Gas Values
Control of breathing in the neonate evolves gradually during the first month of extrauterine life and beyond and is different from that in older children and adults, especially in the response to hypoxemia and hyperoxia. The neonates’ breathing patterns and responses to chemical stimuli are detailed after a general overview of the control of breathing.
Postnatal development of the lungs and thorax
The development and growth of the lungs and surrounding thorax continue with amazing speed during the first year of life. Although the formation of the airway system all the way to the terminal bronchioles is complete by 16 weeks’ gestation, alveolar formation begins only at about 36 weeks’ gestation. At birth the number of terminal air sacs (most of which are saccules) is between 20 and 50 million, and is only one-tenth that of fully grown lungs of the child. Most postnatal development of alveoli from primitive saccules occurs during the first year and is essentially completed by 18 months of age ( ). The morphologic and physiologic development of the lungs, however, continues throughout the first decade of life ( ).
During the early postnatal period, the lung volume of infants is disproportionately small in relation to body size ( Table 3.2 ). In addition, because of higher metabolic rates in infants (oxygen consumption per unit body weight is twice as high as that of adults), the ventilatory requirement per unit of lung volume in infants is markedly increased. Therefore infants have much less reserve of lung volume and surface area for gas exchange. This is the primary reason why infants and young children become rapidly desaturated with hypoventilation or apnea of relatively short duration.
In the neonate, static (elastic) recoil pressure of the lungs is very low (i.e., compliance, normalized for volume, is unusually high) because the elastic fibers do not develop until the postnatal period ( ; ; ). In addition, the elastic recoil pressure of the infant’s thorax (chest wall) is extremely low because of its compliant cartilaginous rib cage with poorly developed thoracic muscle mass, which does not add rigidity. These unique characteristics make infants more prone to lung collapse, especially under general anesthesia when inspiratory muscles are markedly relaxed (see Maintenance of FRC in Infants below). Throughout infancy and childhood, static recoil pressure of the lungs and thorax steadily increases (compliance, normalized for volume, decreases) toward normal values for young adults ( ; ).
The actual size of the airway from the larynx to the bronchioles in infants and children, of course, is much smaller than in adolescents and adults, and flow resistance in absolute terms is extremely high. When normalized for lung volume or body size, however, infants’ airway size is relatively much larger; airway resistance is much lower than that in adults ( ; ; ). Infants and toddlers, however, are more prone to severe obstruction of the upper and lower airways because their absolute (not relative) airway diameters are much smaller than those in adults. As a consequence, relatively mild airway inflammation, edema, or secretions can lead to far greater degrees of airway obstruction than in adults, such as laryngotracheobronchitis (subglottic croup) and acute supraglottitis (epiglottitis).
Further description on the development of the lungs and thorax and their effects on lung function, especially under general anesthesia, is given later in the chapter. Perinatal and postnatal adaptations of respiratory control are included in the following section on the control of breathing.
Control of breathing
The mechanism that regulates and maintains pulmonary gas exchange is remarkably efficient. In a normal person the level of Paco 2 is maintained within a very narrow range, whereas oxygen demand and carbon dioxide production vary greatly during rest and exercise. This control is achieved by a precise matching of the level of ventilation to the output of carbon dioxide. Breathing is produced by the coordinated action of a number of inspiratory and expiratory muscles. Inspiration is produced principally by the contraction of the diaphragm, which creates negative intrathoracic pressure that draws air into the lungs. Expiration, on the other hand, is normally produced passively by the elastic recoil of the lungs and thorax. It may be increased actively by the contraction of abdominal and thoracic expiratory muscles during exercise. During the early phase of expiration, sustained contraction of the diaphragm with decreasing intensity (braking action) and the upper airway muscles’ activities and narrowing of the glottic aperture impede and smoothen the rate of expiratory flow.
Rhythmic contraction of the respiratory muscles is governed by the respiratory centers in the brainstem and tightly regulated by feedback systems so as to match the level of ventilation to metabolic needs ( ) ( Fig. 3.4 ). These feedback mechanisms include central and peripheral chemoreceptors, stretch receptors in the airways and lung parenchyma via the vagal afferent nerves, and segmental reflexes in the spinal cord provided by muscle spindles ( ). The control of breathing comprises neural and chemical controls that are closely interrelated.
Neural control of breathing
Respiratory neurons in the medulla have inherent rhythmicity even when they are separated from the higher levels of the brainstem. In the cat, respiratory neurons are concentrated in two bilaterally symmetric areas in the medulla near the level of the obex. The dorsal respiratory group of neurons (DRG) is located in the dorsomedial medulla just ventrolateral to the nucleus tractus solitarius and contains predominantly inspiratory neurons. The ventral respiratory group of neurons (VRG), located in the ventrolateral medulla, consists of both inspiratory and expiratory neurons ( ; ; ) ( Fig. 3.5 ).
Dorsal respiratory group of neurons
The DRG is spatially associated with the tractus solitarius, which is the principal tract for the ninth and tenth cranial (glossopharyngeal and vagus) nerves. These nerves carry afferent fibers from the airways and lungs, heart, and peripheral arterial chemoreceptors. The DRG may constitute the initial intracranial site for processing some of these visceral sensory afferent inputs into a respiratory motor response ( ).
On the basis of lung inflation, three types of neurons have been recognized in the DRG: type Iα ( I stands for inspiratory ), type Iβ, and pump (P) cells. Type Iα is inhibited by lung inflation ( ). The axons of these neurons project to both the phrenic and the external (inspiratory) intercostal motoneurons of the spinal cord. Some type Iα neurons have medullary collaterals that terminate among the inspiratory and expiratory neurons of the ipsilateral VRG ( ).
The second type, Iβ, is excited by lung inflation and receives synaptic inputs from pulmonary stretch receptors. There is controversy as to whether Iβ axons project into the spinal cord respiratory neurons; the possible functional significance of such spinal projections is unknown. Both Iα and Iβ neurons receive excitatory inputs from the central pattern generator (or central inspiratory activity) for breathing, so that when lung inflation is terminated or the vagi in the neck are cut, the rhythmic firing activity of these neurons continues ( ; ).
The third type of neurons in the DRG receives no input from the central pattern generator. The impulse of these neurons, the P cells, closely follows lung inflation during either spontaneous or controlled ventilation ( ). The P cells are assumed to be relay neurons for visceral afferent inputs ( ).
The excitation of Iβ neurons by lung inflation is associated with the shortening of inspiratory duration. The Iβ neurons appear to promote inspiration-to-expiration phase-switching by inhibiting Iα neurons. This network seems to be responsible for the Hering–Breuer reflex inhibition of inspiration by lung inflation ( ; ).
The DRG thus functions as an important primary and possibly secondary relay site for visceral sensory inputs via glossopharyngeal and vagal afferent fibers. Because many of the inspiratory neurons in the DRG project to the contralateral spinal cord and make excitatory connections with phrenic motoneurons, the DRG serves as a source of inspiratory drive to phrenic and possibly to external intercostal motoneurons ( ).
Ventral respiratory group of neurons
The VRG extends from the rostral to the caudal end of the medulla and has three subdivisions ( Fig. 3.5 ). The Bötzinger complex, located in the most rostral part of the medulla in the vicinity of the retrofacial nucleus, contains mostly expiratory neurons ( ; ). These neurons send inhibitory signals to DRG and VRG neurons and project into the phrenic motoneurons of the spinal cord, causing its inhibition ( ; ). The physiologic significance of these connections may be to ensure inspiratory neuronal silence during expiration (reciprocal inhibition) and to contribute to the “inspiratory off-switch” mechanism.
The nucleus ambiguus (NA) and nucleus paraambigualis (NPA), lying side by side, occupy the middle portion of the VRG. Axons of the respiratory motoneurons originating from the NA project along with other vagal efferent fibers and innervate the laryngeal abductor (inspiratory) and adductor (expiratory) muscles via the recurrent laryngeal nerve ( ; ). The NPA contains mainly inspiratory (Iγ) neurons, which respond to lung inflation in a manner similar to that of Iα neurons. The axons of these neurons project both to phrenic and external (inspiratory) intercostal motoneuron pools in the spinal cord. The nucleus retroambigualis (NRA) occupies the caudal part of the VRG and contains expiratory neurons whose axons project into the spinal motoneuron pools for the internal (expiratory) intercostal and abdominal muscles ( ; ).
The inspiratory neurons of the DRG send collateral fibers to the inspiratory neurons of the NPA in the VRG. These connections may provide the means for ipsilateral synchronization of the inspiratory activity between the neurons in the DRG and those in the VRG ( ; ). Furthermore, axon collaterals of the inspiratory neurons of the NPA on one side project to the inspiratory neurons of the contralateral NPA and vice versa. These connections may be responsible for the bilateral synchronization of the medullary inspiratory motoneuron output, as evidenced by synchronous bilateral phrenic nerve activity ( ; ).
Pontine respiratory group of neurons
In the dorsolateral portion of the rostral pons, both inspiratory and expiratory neurons have been found. Inspiratory neuronal activity is concentrated ventrolaterally in the region of the nucleus parabrachialis lateralis (NPBL). The expiratory activity is centered more medially in the vicinity of the nucleus parabrachialis medialis (NPBM) ( ; ) ( Fig. 3.5 ). The respiratory neurons of these nuclei are referred to as the pontine respiratory group (PRG), which was, and sometimes still is, called the pneumotaxic center, although the term is generally considered obsolete ( ). There are reciprocal projections between the PRG neurons and the DRG and VRG neurons in the medulla. Electrical stimulation of the PRG produces rapid breathing with premature switching of respiratory phases, whereas transaction of the brainstem at a level caudal to the PRG prolongs inspiratory time ( ; ). Bilateral cervical vagotomies produce a similar pattern of slow breathing with prolonged inspiratory time; a combination of PRG lesions and bilateral vagotomy in the cat results in apneusis (apnea with sustained inspiration) or apneustic breathing (slow rhythmic respiration with marked increase end inspiratory hold) ( ; ). The PRG probably plays a secondary role in modifying the inspiratory off-switch mechanism ( ; ).
Respiratory rhythm generation
Rhythmic breathing in mammals can occur in the absence of feedback from peripheral receptors. Because transection of the brain rostral to the pons or high spinal transection has little effect on the respiratory pattern, respiratory rhythmogenesis apparently takes place in the brainstem. The PRG, DRG, and VRG have all been considered as possible sites of the central pattern generator, although its exact location is still unknown ( ; ). A study with an in vitro brainstem preparation of neonatal rats has indicated that respiratory rhythm is generated in the small area in the ventrolateral medulla just rostral to the Bötzinger complex (pre-Bötzinger complex), which contains pacemaker neurons ( ).
The pre-Bötzinger complex contains a group of neurons that is responsible for respiratory rhythmogenesis ( ; ; ). Although the specific cellular mechanism responsible for rhythmogenesis is not known, two possible mechanisms have been proposed ( ; ). One hypothesis is that the pacemaker neurons possess intrinsic properties associated with various voltage- and time-dependent ion channels that are responsible for rhythm generation. Rhythmic activity in these neurons may depend on the presence of an input system that may be necessary to maintain the neuron’s membrane potential in a range in which the voltage-dependent properties of the cell’s ion channels result in rhythmic behavior. The network hypothesis is the alternative model in which the interaction between the neurons produces respiratory rhythmicity, such as reciprocal inhibition between inhibitory and excitatory neurons and recurrent excitation within any population of neurons ( ). The output of this central pattern generator is influenced by various inputs from chemoreceptors (central and peripheral), mechanoreceptors (e.g., pulmonary receptors and muscle and joint receptors), thermoreceptors (central and peripheral), nociceptors, and higher central structures (such as the PRG). The function of these inputs is to modify the breathing pattern to meet and adjust to ever-changing metabolic and behavioral needs ( ).
Airway and pulmonary receptors
The upper airways, trachea and bronchi, lungs, and chest wall have a number of sensory receptors sensitive to mechanical and chemical stimulation. These receptors affect ventilation as well as circulatory and other nonrespiratory functions.
Upper airway receptors
Stimulation of receptors in the nose can produce sneezing, apnea, changes in bronchomotor tone, and the diving reflex, which involves both the respiratory and the cardiovascular systems. Stimulation of the epipharynx causes the sniffing reflex, a short, strong inspiration to bring material (mucus, foreign body) in the epipharynx into the pharynx to be swallowed or expelled. The major role of receptors in the pharynx is associated with swallowing. It involves the inhibition of breathing, closure of the larynx, and coordinated contractions of pharyngeal muscles ( ; ; ).
The larynx has a rich innervation of receptors. The activation of these receptors can cause apnea, coughing, and changes in the ventilatory pattern ( ). These reflexes, which influence both the patency of the upper airway and the breathing pattern, are related to transmural pressure and airflow. Based on single-fiber action potential recordings from the superior laryngeal nerve in the spontaneously breathing dog preparation in which the upper airway is isolated from the lower airways, three types of receptors have been identified: pressure receptors (most common, about 65%), “drive” (or irritant) receptors (stimulated by upper airway muscle activities), and flow or cold receptors ( ; ). The laryngeal flow receptors show inspiratory modulation with room air breathing but become silent when inspired air temperature is raised to body temperature and 100% humidity or saturation ( ). The activity of pressure receptors increases markedly with upper airway obstruction ( ).
Tracheobronchial and pulmonary receptors
Three major types of tracheobronchial and pulmonary receptors have been recognized: slowly adapting (pulmonary stretch) receptors and rapidly adapting (irritant or deflation) receptors, both of which lead to myelinated vagal afferent fibers and unmyelinated C-fiber endings (J-receptors). Excellent reviews on pulmonary receptors have been published ( ; ; ; ).
Slowly adapting (pulmonary stretch) receptors
Slowly adapting (pulmonary stretch) receptors (SARs) are mechanoreceptors that lie within the submucosal smooth muscles in the membranous posterior wall of the trachea and central airways ( ). A small proportion of the receptors are located in the extrathoracic upper trachea ( ). SARs are activated by the distention of the airways during lung inflation and inhibit inspiratory activity (Hering-Breuer inflation reflex), whereas they show little response to steady levels of lung inflation. The Hering–Breuer reflex also produces dilation of the upper airways from the larynx to the bronchi. Although SARs are predominantly mechanoreceptors, hypocapnia stimulates their discharge, and hypercapnia inhibits it ( ). In addition, SARs are thought to be responsible for the accelerated heart rate and systemic vasoconstriction observed with moderate lung inflation ( ). These effects are abolished by bilateral vagotomy.
Studies by have demonstrated the importance of the inflation reflex in adjusting the pattern of ventilation in the cat and the human. In cats anesthetized with pentobarbital, inspiratory time decreases as tidal volume increases with hypercapnia, indicating the presence of the inflation reflex in the normal tidal volume range. Clark and von Euler demonstrated an inverse hyperbolic relationship between the tidal volume and inspiratory time. In the adult human, inspiratory time is independent of tidal volume until the latter increases to about twice the normal tidal volume, when the inflation reflex appears ( Fig. 3.6 ). In the newborn, particularly the premature newborn, the inflation reflex is present in the eupneic range for a few months ( ).
Apnea, commonly observed in adult patients at the end of surgery and anesthesia with the endotracheal tube cuff still inflated, may be related to the inflation reflex, because the trachea has a high concentration of stretch receptors ( ; ). Deflation of the cuff promptly restores rhythmic spontaneous ventilation.
Rapidly adapting (irritant) receptors
Rapidly adapting (irritant) receptors (RARs) are located superficially within the airway epithelial cells, mostly in the region of the carina and the large bronchi ( ; ). RARs respond to both mechanical and chemical stimuli. In contrast to SARs, RARs adapt rapidly to large lung inflation, distortion, or deflation, thus possessing marked dynamic sensitivity ( ). RARs are stimulated by cigarette smoke, ammonia, and other irritant gases including inhaled anesthetics, with significant interindividual variability ( ). RARs are stimulated more consistently by histamine and prostaglandins, suggesting their role in response to pathologic states ( ; ; ; ). The activation of RARs in the large airways may be responsible for various reflexes, including coughing, bronchoconstriction, and mucus secretion. Stimulation of RARs in the periphery of the lungs may produce hyperpnea. Because RARs are stimulated by deflation of the lungs to produce hyperpnea in animals, they are considered to play an important role in the Hering–Breuer deflation reflex ( ). This reflex, if it exists in humans, may partly account for increased respiratory drive when the lung volume is abnormally decreased, as in premature infants with IRDS and in pneumothorax.
When vagal conduction is partially blocked by cold, inflation of the lung produces prolonged contraction of the diaphragm and deep inspiration instead of inspiratory inhibition. This reflex, the paradoxical reflex of Head, is most likely mediated by RARs. It may be related to the complementary cycle of respiration, or the sigh mechanism, that functions to reinflate and reaerate parts of the lungs that have collapsed because of increased surface force during quiet, shallow breathing ( ). In the newborn, inflation of the lungs initiates gasping. This mechanism, which was considered to be analogous to the paradoxical reflex of Head, may help inflate unaerated portions of the newborn lung ( ).
C-fiber endings
Most afferent axons arising from the lungs, heart, and other abdominal viscera are slow-conducting (slower than 2.5 m/sec), unmyelinated vagal fibers (C-fibers). Extensive studies by have suggested the presence of receptors supposedly located near the pulmonary or capillary wall (juxtapulmonary capillary or J-receptors) innervated by such C-fibers. C-fiber endings are stimulated by pulmonary congestion, pulmonary edema, pulmonary microemboli, and irritant gases such as anesthetics. Such stimulation causes apnea followed by rapid, shallow breathing, hypotension, and bradycardia. Stimulation of J-receptors also produces bronchoconstriction and increases mucus secretion. All these responses are abolished by bilateral vagotomy. In addition, stimulation of C-fiber endings can provoke severe reflex contraction of the laryngeal muscles, which may be partly responsible for the laryngospasm observed during induction of anesthesia with isoflurane.
In addition to receptors within the lung parenchyma (pulmonary C-fiber endings), there appear to be similar nonmyelinated nerve endings in the bronchial wall (bronchial C-fiber endings) ( ). Both chemical and, to a lesser degree, mechanical stimuli excite these bronchial C-fiber endings. They are also stimulated by endogenous mediators of inflammation, including histamine, prostaglandins, serotonin, and bradykinin. Such stimulation may be a mechanism of C-fiber involvement in disease states such as pulmonary edema, pulmonary embolism, and asthma ( ).
The inhalation of irritant gases or particles causes a sensation of tightness or distress in the chest, probably caused by its activation of pulmonary receptors. The pulmonary receptors may contribute to the sensation of dyspnea in lung congestion, atelectasis, and pulmonary edema. Bilateral vagal blockade in patients with lung disease abolished dyspneic sensation and increased breath-holding time ( ).
Chest wall receptors
The chest wall muscles, including the diaphragm and the intercostal muscles, contain various types of receptors that can produce respiratory reflexes. This subject has been reviewed extensively ( ; ). The two types of receptors that have been most extensively studied are muscle spindles, which lie parallel to the extrafusal muscle fibers, and the Golgi tendon organs, which lie in series with the muscle fibers ( ).
Muscle spindles are a type of slowly adapting mechanoreceptors that detect muscle stretch. As in other skeletal muscles, the muscle spindles of respiratory muscles are innervated by γ-motoneurons that excite intrafusal fibers of the spindle.
Intercostal muscles have a density of muscle spindles comparable with those of other skeletal muscles. The arrangement of muscle spindles is appropriate for the respiratory muscle load compensation mechanism ( ). By comparison with the intercostal muscles, the diaphragm has a very low density of muscle spindles and is poorly innervated by the γ-motoneurons. Reflex excitation of the diaphragm, however, can be achieved via proprioceptive excitation within the intercostal system ( ).
Golgi tendon organs are located at the point of insertion of the muscle fiber into its tendon and, like muscle spindles, are a slowly adapting mechanoreceptor. Activation of the Golgi tendon organs inhibits the homonymous motoneurons, possibly preventing the muscle from being overloaded ( ). In the intercostal muscles, fewer Golgi tendon organs are present than muscle spindles, whereas the ratio is reversed in the diaphragm.
Chemical control of breathing
Regulation of alveolar ventilation and maintenance of normal arterial P co 2 , pH, and P o 2 are the principal functions of the medullary and peripheral chemoreceptors ( ).
Central chemoreceptors
The medullary, or central, chemoreceptors, located near the surface of the ventrolateral medulla, are anatomically separated from the medullary respiratory center ( Fig. 3.7 ). They respond to changes in hydrogen ion concentration in the adjacent cerebrospinal fluid rather than to changes in arterial P co 2 or pH ( ). Since CO 2 rapidly passes through the blood-brain barrier into the cerebrospinal fluid, which has poor buffering capacity, the medullary chemoreceptors are readily stimulated by respiratory acidemia. In contrast, ventilatory responses of the medullary chemoreceptors to acute metabolic acidemia and alkalemia are limited because changes in the hydrogen ion concentration in arterial blood are not rapidly transmitted to the cerebrospinal fluid. In chronic acid-base disturbances, the pH of cerebrospinal fluid (and presumably that of interstitial fluid) surrounding the medullary chemoreceptors is generally maintained close to the normal value of about 7.3 regardless of arterial pH ( ). Under these circumstances, ventilation becomes more dependent on the hypoxic response of peripheral chemoreceptors.
Peripheral chemoreceptors
The carotid bodies, located near the bifurcation of the common carotid artery, react rapidly to changes in PaO 2 and pH. Their contribution to the respiratory drive amounts to about 15% of resting ventilation ( ). The carotid body has three types of neural components: type I (glomus) cells, presumably the primary site of chemotransduction; type II (sheath) cells; and sensory nerve fibers ( ). Sensory nerve fibers originate from terminals in apposition to the glomus cells, travel via the carotid sinus nerve to join the glossopharyngeal nerve, and then enter the brainstem. The sheath cells envelop both the glomus cells and the sensory nerve terminals. A variety of neurochemicals have been found in the carotid body, including acetylcholine, dopamine, substance P, enkephalins, and vasoactive intestinal peptide. The exact functions of these cell types and the mechanisms of chemotransduction and the specific roles of these neurochemicals have not been well established ( ).
The carotid bodies are perfused with extremely high levels of blood flow and respond rapidly to an oscillating PaO 2 rather than a constant PaO 2 at the same mean values ( ; ). This mechanism may be partly responsible for hyperventilation during exercise.
The primary role of peripheral chemoreceptors is their response to changes in arterial PO 2 . Moderate to severe hypoxemia (PaO 2 <60 mm Hg) results in a significant increase in ventilation in all age groups except for newborn, particularly premature, infants, whose ventilation is decreased by hypoxemia ( ; ). Peripheral chemoreceptors are also partly responsible for hyperventilation in hypotensive patients. Respiratory stimulation is absent in certain states of tissue hypoxia, such as moderate to severe anemia and carbon monoxide poisoning; despite a decrease in oxygen content, PaO 2 in the carotid bodies is maintained near normal levels, so that the chemoreceptors are not stimulated.
In acute hypoxemia, the ventilatory response via the peripheral chemoreceptors is partially opposed by hypocapnia, which depresses the medullary chemoreceptors. When a hypoxemic environment persists for a few days—for example, during an ascent to high altitude—ventilation increases further as cerebrospinal fluid bicarbonate decreases and pH returns toward normal ( ). However, later studies demonstrated that the return of cerebrospinal fluid pH toward normal is incomplete and a secondary increase in ventilation precedes the decrease in pH, indicating that some other mechanisms are involved ( ; ). In chronic hypoxemia that lasts for a number of years, the carotid bodies initially exhibit some adaptation to hypoxemia and then gradually lose their hypoxic response. In people native to high altitudes, the blunted response of carotid chemoreceptors to hypoxemia takes 10 to 15 years to develop and is sustained thereafter ( ; ). In cyanotic heart diseases the hypoxic response is lost much sooner but returns after surgical correction of the right-to-left shunts ( ).
In patients who have chronic respiratory insufficiency with hypercapnia, hypoxemic stimulation of the peripheral chemoreceptors provides the primary impulse to the respiratory center. If these patients are given excessive levels of oxygen, the stimulus of hypoxemia is removed and ventilation decreases or ceases. P co 2 further increases, patients become comatose (CO 2 narcosis), and death may follow unless ventilation is supported. Rather than oxygen therapy, such patients need their effective ventilation increased artificially with or without added inspired oxygen.
Response to carbon dioxide
The graphic demonstration of relations between the alveolar or arterial P co 2 and the minute ventilation ( e /P co 2 ) is commonly known as the CO 2 response curve ( Fig. 3.8 ). This curve normally reflects the response of the chemoreceptors and respiratory center to carbon dioxide. The CO 2 response curve is a useful means for evaluation of the chemical control of breathing, provided that the mechanical properties of the respiratory system, including the neuromuscular transmission, respiratory muscles, thorax, and lungs, are intact. In normal persons, ventilation increases more or less linearly as the inspired concentration of carbon dioxide increases up to 9% to 10%, above which ventilation starts to decrease ( ). Under hypoxemic conditions the CO 2 response is potentiated, primarily via carotid body stimulation, resulting in a shift to the left of the CO 2 response curve ( ) (see Fig. 3.8 ). On the other hand, anesthetics, opioids, and barbiturates in general depress the medullary chemoreceptors and, by decreasing the slope, shift the CO 2 response curve progressively to the right as the anesthetic concentration increases ( ) ( Fig. 3.9 ).
A shift to the right of the CO 2 response curve in an awake human may be caused by decreased chemoreceptor sensitivity to CO 2 , as seen in patients whose carotid bodies had been destroyed ( ). It may also be caused by lung disease and resultant mechanical failure to increase ventilation despite intact neuronal response to carbon dioxide. In patients with various central nervous system dysfunctions, the CO 2 response may be partially or completely lost (central congenital hypoventilation syndrome) ( ). In the awake state, these patients have chronic hypoventilation but can breathe on command. During sleep, they further hypoventilate or become apneic to the point of CO 2 narcosis and death unless mechanically ventilated or implanted with a phrenic pacemaker ( ).
It has been difficult to separate the neuronal component from the mechanical failure of the lungs and thorax, because the two factors often coexist in patients with chronic lung diseases ( ). demonstrated that occlusion pressure at 0.1 second (P 0.1 , or the negative mouth pressure generated by inspiratory effort against airway occlusion at FRC) correlates well with neuronal (phrenic) discharges but is uninfluenced by mechanical properties of the lungs and thorax. The occlusion pressure is a useful means for the clinical evaluation of the ventilatory drive.
As mentioned previously, hypoxemia potentiates the chemical drive and increases the slope of the CO 2 response curve ( e /P co 2 ). Such a change has been interpreted as “a synergistic (or multiplicative) effect” of the stimulus, whereas a parallel shift of the curve has been considered as “an additive effect.” This analysis may be useful for descriptive purposes, but it is misleading. Because ventilation is the product of tidal volume and frequency ( 
e = V t × f ), an additive effect on its components could result in a change in the slope of the CO 2 response curve. Obviously, the responses of tidal volume and frequency to CO 2 should be examined separately to understand the effect of various respiratory stimulants and depressants.
proposed that ventilatory response to CO 2 be analyzed in terms of the mean inspiratory flow (V t /T i , where V t is tidal volume and T i is the inspiratory time) and in terms of the ratio of inspiratory time to total ventilatory cycle duration or respiratory duty cycle (T i /T tot ) ( Fig. 3.10 ). Because the tidal volume is equal to V t /T i × T i and respiratory frequency ( f ) is 1/T tot , ventilation can be expressed as follows:
e 
The advantage of analyzing the ventilatory response in this fashion is that V t /T i is an index of inspiratory drive, which is independent of the timing element. The tidal volume, on the other hand, is time dependent, because it is (V t /T i ) × T i . The second parameter, T i /T tot , is a dimensionless index of effective respiratory timing (respiratory duty cycle) that is determined by the vagal afferent or central inspiratory off-switch mechanism or by both ( ). From this equation, it is apparent that in respiratory disease or under anesthesia, changes in pulmonary ventilation may result from a change in V t /T i , T i /T tot , or both. A reduction in T i /T tot indicates that the relative duration of inspiration decreased or that expiration increased. Such a reduction in the T i /T tot ratio may result from changes in central or peripheral mechanisms. In contrast, a reduction in V t /T i may indicate a decrease in the medullary inspiratory drive or neuromuscular transmission or an increase in inspiratory impedance (i.e., increased flow resistance, decreased compliance, or both). By relating the mouth occlusion pressure to V t /T i , it becomes clinically possible to determine whether changes in the mechanics of the respiratory system contribute to the reduction in V t /T i ( ).
Analysis of inspiratory and expiratory durations provides useful information on the mechanism of anesthetic effects on ventilation. Fig. 3.11 illustrates the effect of pentobarbital, which depresses minute ventilation, and diethyl ether, which “stimulates” ventilation in newborn rabbits. With both anesthetics the mean inspiratory flow (V t /T i ) did not change but V t decreased because T i was shortened. With pentobarbital, however, T e was prolonged disproportionately and T i /T tot and frequency decreased; consequently, minute ventilation was decreased. With ether, on the other hand, ventilation increased as the result of disproportionate decrease in T e and consequent increases in T i /T tot and frequency ( ).
Control of breathing in neonates and infants
Response to hypoxemia in infants
During the first 2 to 3 weeks of age, both full-term and premature infants in a warm environment respond to hypoxemia (15% oxygen) with a transient increase in ventilation followed by sustained ventilatory depression ( ; ; ) ( Fig. 3.12 ). In infants born at 32 to 37 weeks’ gestation, the initial period of transient hyperpnea is abolished in a cool environment, indicating the importance of maintaining a neutral thermal environment ( ; ; ). When 100% oxygen is given, a transient decrease in ventilation is followed by sustained hyperventilation. This ventilatory response to oxygen is similar to that of the fetus and is different from that of the adult, in whom a sustained decrease in ventilation is followed by little or no increase in ventilation ( ). By 3 weeks after birth, hypoxemia induces sustained hyperventilation, as it does in older children and adults.
The biphasic depression in ventilation has been attributed to central depression rather than to depression of peripheral chemoreceptors ( ). In newborn monkeys, however, tracheal occlusion pressure, an index of central neural drive, and diaphragmatic electromyographic output were increased above the control level during both the hyperpneic and the hypopneic phases in response to hypoxic gas mixture ( ; ). These findings imply that the biphasic ventilatory response to hypoxemia results from changes in the mechanics of the respiratory system (thoracic stiffness or airway obstruction), rather than from neuronal depression, as has been assumed ( ). Premature infants continue to show a biphasic response to hypoxemia even at 25 days after birth ( ). Thus in terms of a proper response to hypoxemic challenge, maturation of the respiratory system may be related to postconceptional rather than postnatal age.
Response to carbon dioxide in infants
Newborn infants respond to hypercapnia by increasing ventilation but less so than do older infants. The slope of the CO 2 response curve increases appreciably with gestational age as well as with postnatal age, independent of postconceptional age ( ; ). This increase in slope may represent an increase in chemosensitivity, but it may also result from more effective mechanics of the respiratory system. In adults the CO 2 response curve both increases in slope and shifts to the left with the severity of hypoxemia ( Fig. 3.8 ). In contrast, in newborn infants breathing 15% oxygen, the CO 2 response curve decreases in slope and shifts to the right ( Fig. 3.13 ). Inversely, hyperoxemia increases the slope and shifts the curve to the left ( ).
Upper airway receptor responses in the neonatal period
Newborn animals are particularly sensitive to the stimulation of the superior laryngeal nerve either directly or through the receptors (such as water in the larynx), which results in ventilatory depression or apnea. In anesthetized newborn puppies and kittens, negative pressure or airflow through the larynx isolated from the lower airways produced apnea or significant prolongation of inspiratory and expiratory time and a decrease in tidal volume, whereas similar stimulation caused little or no effect in 4- to 5-week-old puppies or in adult dogs and cats ( ; ).
In a similar preparation using puppies anesthetized with pentobarbital, water in the laryngeal lumen produced apnea, whereas phosphate buffer with sodium chloride and neutral pH did not. The principal stimulus for the apneic reflex was the absence or reduced concentrations of chloride ions ( ). In awake newborn piglets, direct electric stimulation of the superior laryngeal nerve caused periodic breathing and apnea associated with marked decreases in respiratory frequency, hypoxemia, and hypercapnia with minimal cardiovascular effects. Breathing during superior laryngeal nerve stimulation was sustained by an arousal system ( ). The strong inhibitory responses elicited in newborn animals by various upper airway receptor stimulations have been attributed to the immaturity of the central nervous system ( ; ).
Active (REM) versus quiet (non-REM) sleep
During the early postnatal period, full-term infants spend 50% of their sleep time in active or REM sleep compared with 20% REM sleep in adults ( ; ). Wakefulness rarely occurs in neonates. Premature neonates stay in REM sleep most of the time, and quiet (non-REM) sleep is difficult to define before 32 weeks’ postconception ( ). Neonates, particularly prematurely born neonates, therefore breathe irregularly.
Neurologic and chemical control of breathing in infants is related to the state of sleep ( ). During quiet sleep, breathing is regulated primarily by the medullary respiratory centers, and breathing is regular with respect to timing as well as amplitude and is tightly linked to chemoreceptor input ( ). During REM sleep, however, breathing is controlled primarily by the behavioral system and is irregular with respect to timing and amplitude ( ).
Periodic breathing
Periodic breathing, in which breathing is interposed with repetitive short apneic spells lasting 5 to 10 seconds with minimal hemoglobin desaturation or cyanosis, occurs normally even in healthy neonates and young infants during wakefulness, REM sleep, and non-REM sleep ( ). Periodic breathing tends to be more regular in quiet sleep than in active sleep and has been observed more often during active sleep ( ) than during quiet sleep ( ). Minute ventilation increases during REM sleep due to increases in respiratory frequency with little change in tidal volume ( ).
An addition of 2% to 4% CO 2 to the inspired gas mixture abolishes periodic breathing, probably by causing respiratory stimulation ( ). Nevertheless, the ventilatory response to hypercapnia seems to be diminished during periodic breathing ( ). The decreased hypercapnic response appears to result from changes in respiratory mechanics rather than from a reduction in chemosensitivity, because respiratory center output as determined by airway occlusion pressure is greater during REM sleep than during non-REM sleep.
The incidence of periodic breathing was reported to be 78% in full-term neonates, whereas the incidence was much higher (93%) in preterm infants (mean postconceptional age of 37.5 weeks) ( ; ). The incidence of periodic breathing diminishes with increasing postconceptual age and decreases to 29% by 10 to 12 months of age ( ; ).
Apnea of prematurity and hypoxia
Central apnea of infancy is defined as cessation of breathing for 15 seconds or longer or a shorter respiratory pause associated with bradycardia (heart rate <100 beats/min, cyanosis, or pallor) ( ). Apnea is common in preterm infants and may be related to an immature respiratory control mechanism ( ). Most preterm infants with a birth weight of less than 2 kg have apneic spells at some time ( ). reported a 55% incidence of central apnea in preterm infants, whereas it was rarely found in full-term infants ( ). These studies, however, were based on a relatively small number of infants admitted to a single institution.
The report by the Collaborative Home Infant Monitoring Evaluation (CHIME) Study Group has shed a new light on the understanding of the incidence and extent of apnea in infancy ( ; ). The CHIME study was based on the recordings of respiratory inductive plethysmography, electrocardiography (ECG), and pulse oximetry in normal infants and those with increased risk of sudden infant death syndrome (SIDS), and it involved a total of 1079 infants during the first 6 months after birth ( ; ). This report has revealed evidence that the control of breathing and oxygenation during sleep in healthy term infants are not as precise as have been assumed. Normal infants, up to 2% to 3%, commonly have prolonged central, obstructive, or mixed apnea lasting up to 30 seconds, which is associated with oxygen desaturation ( ). With a simple upper respiratory infection, prolonged obstructive sleep apneas were recorded in a few normal full-term infants but were present in 15% to 30% of preterm infants. The risk of having such episodes was 20 to 30 times higher among preterm infants than in full-term infants before 43 weeks’ postconception ( ). Healthy term infants had an average baseline SpO 2 of 98% throughout the recorded period. However, hypoxemia (SpO 2 <90%, occasionally in the 70% to 80% range) occurred in 59% of these normal term infants ( ). Thus levels of hypoxemia or hypoxia previously considered pathologic are relatively common occurrences among normal infants.
An apparent life-threatening event (ALTE) is defined as an episode that is frightening to the observer. It is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, and gagging ( ). The incidence of ALTE is as high as 3% and may occur in previously healthy infants. Overnight polysomnography (PSG) may be helpful in the evaluation of infants with a history of unexplained apnea. Treatable pathologic conditions, however, were found only in about 30% of infants, and thus normal PSG results are not necessarily diagnostic for the purpose of ruling out ALTE ( ).
Postoperative apnea
Life-threatening apnea has been reported postoperatively in prematurely born infants earlier than 41 weeks’ postconception. It is frequently seen in those infants with a history of apneic spells after simple surgical procedures, such as inguinal herniorrhaphy, and can occur up to 12 hours postoperatively ( ; ). These reports resulted in a general consensus among the pediatric anesthesiologists that infants younger than 44 weeks’ postconception be admitted for overnight observation after inguinal hernia repair for safety. In a subsequent report, including various surgical procedures, apnea was reported in 4 of 18 prematurely born infants who were 49 to 55 weeks’ postconceptional age ( ). The authors of this report proposed that premature infants younger than 60 weeks’ postconception should be admitted for overnight observation, which raised controversy as to what postconceptional age is safe and appropriate for the same-day discharge from the hospital for the prematurely born infant ( ). analyzed the relationship between the incidence of postoperative apnea and maturation. They reported a high incidence of postoperative apnea (26%) in infants younger than 44 weeks’ postconception, whereas the incidence of apnea in those older than 44 weeks was only 3%.
Subsequently, performed a meta-analysis of the data from previously published studies of postoperative apnea in ex-premature infants after inguinal hernia repairs. They concluded that postoperative apnea was strongly and inversely correlated to both gestational age as well as postconceptual age and was associated with a previous history of apnea. The probability of postoperative apnea in those older than 44 weeks postconceptual age decreases significantly (to 5%) but still exists. Another important finding of this classic paper was that postoperative hypoxemia, hypothermia, and (most importantly) anemia (hematocrit value <30) are significant risk factors regardless of gestational or postconceptual age (see Chapter 21 : Induction, Maintenance, and Recovery; Chapter 27 : Neonatology for Anesthesiologists). Most of these studies occurred in the period when infants were predominantly anesthetized with halothane and without regional (caudal) block to maintain a lighter level of anesthesia with spontaneous breathing during surgery. Postoperative apnea still exists with newer anesthetic agents (e.g., sevoflurane or desflurane) but appears to occur much less often.
Both theophylline and caffeine have been effective in reducing apneic spells in preterm infants (Aranda and Trumen 1979). Caffeine is especially useful for premature infants during the postanesthetic period ( ). Xanthine derivatives are known to prevent muscle fatigue, and their respiratory stimulation in the premature infant may occur via both central and peripheral mechanisms ( ). The long-term effects of caffeine on brain development in the setting of prematurity is unknown ( ).
Maintenance of the upper airway and airway protective reflexes
Pharyngeal airway
The pharyngeal airway, unlike the laryngeal airway, is not supported by a rigid bony or cartilaginous structure. Its wall consists of soft tissues and is surrounded by muscles for breathing and for swallowing and is contained in a fixed bony structure (i.e., the maxilla, mandible, and spine) ( ). Anatomic imbalance between the bony structure (the container: micrognathia, facial anomalies) and the amount of the soft tissues (the content: macroglossia, adenotonsillar hypertrophy, obesity) would result in pharyngeal airway narrowing and obstruction ( ) ( Fig. 3.14 ).
Even the normal pharyngeal airway is easily obstructed by the relaxation of the velopharynx (soft palate), posterior displacement of the mandible (and the base of the tongue) in the supine position during sleep, flexion of the neck, or external compression over the hyoid bone. The pharyngeal airway also is easily collapsed by negative pressure within the pharyngeal lumen created by inspiratory effort, especially when airway-maintaining muscles are depressed or paralyzed ( ; ; ). In neonates, with a relatively hypoplastic mandible, the oropharynx and the entrance to the larynx at the level of the aryepiglottic folds are the areas most easily collapsed ( ).
Mechanical support to sustain the patency of the pharynx against the collapsing force of luminal negative pressure during inspiration is given by both the sustained muscle tension and cyclic contraction of the pharyngeal dilator muscles, acting synchronously with the contraction of the diaphragm. These include the genioglossus, geniohyoid, sternohyoid, sternothyroid, and thyrohyoid muscles ( Fig. 3.15 ) ( ; ; ). Similar phasic activities have been recorded in the scalene and sternomastoid muscles in humans ( ; ).
A neural balance model of pharyngeal airway maintenance proposed by and and further modified by is shown in Fig. 3.16 . In this model the suction (collapsing) force created in the pharyngeal lumen by the inspiratory pump muscles (primarily the diaphragm) must be well balanced by the activities of pharyngeal airway dilator muscles to maintain upper airway patency. Increased nasal and pharyngeal airway resistance (partial obstruction) exaggerates the suction force. In addition, once pharyngeal closure occurs, the mucosal adhesion force of the collapsed pharyngeal wall becomes an added force acting against the opening of pharyngeal air passages ( ).
Several reflex mechanisms are present to maintain the balance between the dilating and collapsing forces in the pharynx. Chemoreceptor stimuli such as hypercapnia and hypoxemia stimulate the airway dilators preferentially over the stimulation of the diaphragm so as to maintain airway patency ( ; ). Negative pressure in the nose, pharynx, or larynx activates the pharyngeal dilator muscles and simultaneously decreases the diaphragmatic activity ( Fig. 3.17 ) ( ; ; ). Such an airway pressure reflex is especially prominent in infants younger than 1 year of age ( ). Upper airway mechanoreceptors are located superficially in the airway mucosa and are easily blocked by topical anesthesia ( ). Sleep, sedatives, and anesthesia depress upper airway muscles more than they do the diaphragm ( ; ). The arousal from sleep shifts the balance toward pharyngeal dilation ( ).
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