Control of Breathing: Maturation and Associated Clinical Disorders
Nicole R. Dobson
Mark W. Thompson
Carl E. Hunt
The fetus makes breathing movements in utero that change in character and frequency throughout gestation. In addition to being important for lung development, the maturation of breathing control is essential for ensuring a successful transition from episodic fetal breathing to continuous postnatal breathing. Control of breathing is immature in infants born preterm and is progressively less mature, the younger the gestational age at birth. As a consequence of this immaturity, clinical symptoms related to apnea, bradycardia, and intermittent hypoxia are common problems in the early weeks of life and may continue beyond term-equivalent age in infants born extremely preterm. In this chapter, fetal breathing, initiation of breathing at birth, and immaturity of control of breathing in infants born preterm are first reviewed. We then describe the clinical manifestations of immature breathing, including respiratory pauses and periodic breathing, apnea, apnea of prematurity (AOP), and its potential adverse clinical consequences. Finally, we also review three clinical disorders for which preterm infants are at increased risk after neonatal intensive care unit (NICU) discharge: sudden infant death syndrome (SIDS), apparent life-threatening events (ALTEs), and sleep-disordered breathing (SDB) (sleep apnea).
▪ MATURATION OF AUTONOMIC CONTROL OF BREATHING
Fetal Breathing
Studies in animal models and human fetuses have demonstrated a maturational progression in fetal breathing movements during gestation that can be altered by a variety of pharmacologic and physiologic inputs. In humans, fetal breathing movements have been characterized in response to maternal condition and as a potential indicator of overall fetal condition. Regardless of gestational age, fetal breathing is not a continuous process; significant periods of apnea lasting as long as 2 hours occur even in near-term fetuses and are generally more frequent and of longer duration at younger gestational ages (1). During periods of frequent respiratory motion, patterns of both regular and irregular breathing are documented by chest/abdominal wall movements and by Doppler sonography assessing tracheal fluid flow (2). Fetal breathing movements exhibit a circadian rhythmicity, with well-documented increases during certain periods of the day. Maternal condition, particularly maternal glucose status, can have significant effects on fetal breathing frequency, with well-documented increases in fetal breathing frequency after maternal glucose loading. This response to maternal glucose loading is most pronounced when the mother is fasting (3).
Fetal breathing has some clinical utility when assessing fetal well-being. Several studies have documented diminished fetal breathing activity in association with poor fetal health, and this decreased activity, along with other measures of fetal well-being, can be helpful in guiding obstetric management (4). The fetal breathing pattern responds to a variety of pharmacologic and physiologic manipulations. Fetal breathing increases if the mother inhales CO2 (5). Maternal hyperoxia does not alter fetal breathing movements or pattern in near-term normally grown fetuses, but growth-restricted fetuses exhibit an increase in respiratory rate with maternal hyperoxia (6). Tocolytics, indomethacin, and terbutaline increase fetal breathing movements when administered during preterm labor (7).
Animal studies augment the human ultrasound data and provide a clearer picture of the maturational development of breathing control. Fetal breathing activity in sheep starts early in gestation, arises from centrally mediated stimuli, and occurs primarily during periods of low-voltage electrocortical activity (REM sleep) (8). REM sleep comprises about 40% of fetal life during the last trimester in sheep. Breathing also occurs during periods of high-voltage electrocortical activity (quiet sleep), but it is only episodic and generally associated with muscular discharges (9). Animal data have also confirmed that the fetal breathing pattern changes in response to physiologic derangements (i.e., hypercarbia, hypoxia, hyperoxia) (10,11). In response to hypercapnia, the fetus increases respiratory rate and tidal volume, suggesting intact central chemoreception. The fetal response to hypoxia appears to be centrally mediated and results in diminished neuronal activity and diminished or absent fetal breathing movements, but the peripheral chemoreceptors may also contribute to absence of the “adult” response to hypoxia of an increase in respiratory rate and tidal volume.
Initiation of Breathing at Birth
Despite the enhanced understanding of fetal maturation of breathing control, our understanding remains incomplete regarding factors responsible for initiating and maintaining a regular pattern at birth (12). Development and maintenance of respiration in the newborn are likely due to a complex interaction of sensory stimuli and both central and peripheral chemoreceptor inputs (Fig. 25.1). The basal level of fetal chemoreceptor discharge adapts to the fetal PaO2, and the several-fold increase in PaO2 at birth silences the chemoreceptors (13). During the fetal-to-neonatal transition, however, peripheral chemoreceptors may not be completely silenced, as evidenced by the fact that supplemental O2 compared to room air at birth may delay onset of the first cry and of sustained ventilation thereafter. The degree of maturation in the central respiratory centers also appears to be important since the responses to respiratory stimuli in the term infant are more developed than in the preterm infant.
Neonatal Breathing
Studies in human and animal neonates have provided important insights into the understanding of respiratory rhythm generation (14). The control and maintenance of normal breathing largely reside within the respiratory control centers of the bulbopontine
region of the brainstem. Neurons within this area respond to multiple afferent inputs to modulate their own inherent rhythmicity and provide efferent output to the respiratory control muscles. Multiple afferent inputs induce modulation of the central respiratory center efferent outputs to the lungs and respiratory and airway muscles. These afferent inputs are “categorized” by the respiratory control center; some inputs cause an instantaneous response in the control center output, while others only act to “shape” the respiratory response, resulting in small changes in muscular output, tidal volume, and airway tone (15). Among these inputs are signals from central and peripheral chemoreceptors, pulmonary stretch receptors, and cortical and reticuloactivating system neurons. These afferent inputs and resultant efferent outputs of the central respiratory center are summarized in Figure 25.1. Sleep state can also have a profound effect on respiratory pattern, although sleep state is often difficult to classify in preterm infants.
region of the brainstem. Neurons within this area respond to multiple afferent inputs to modulate their own inherent rhythmicity and provide efferent output to the respiratory control muscles. Multiple afferent inputs induce modulation of the central respiratory center efferent outputs to the lungs and respiratory and airway muscles. These afferent inputs are “categorized” by the respiratory control center; some inputs cause an instantaneous response in the control center output, while others only act to “shape” the respiratory response, resulting in small changes in muscular output, tidal volume, and airway tone (15). Among these inputs are signals from central and peripheral chemoreceptors, pulmonary stretch receptors, and cortical and reticuloactivating system neurons. These afferent inputs and resultant efferent outputs of the central respiratory center are summarized in Figure 25.1. Sleep state can also have a profound effect on respiratory pattern, although sleep state is often difficult to classify in preterm infants.
 FIGURE 25.1 Major factors influencing respiratory control. PCO2, carbon dioxide partial pressure; PO2, oxygen pressure. Reprinted from Martin RJ, Miller MJ, Carlo WA. Pathogenesis of apnea in preterm infants. J Pediatr 1986;109:733-741, with permission. |
In the adult, these multiple afferent inputs act upon the neurons within the respiratory control center and provide a well-integrated response to perturbations in the system and characteristic respiratory patterns. For example, increased respiratory rate and depth will characteristically result from activation of central chemoreceptors in response to hypercarbia. In the newborn infant and especially in the preterm infant, however, these responses are less well organized and of lesser magnitude, and apnea with associated desaturation and/or bradycardia is a common result of this disorganized or immature response to multiple afferent inputs.
The central chemosensitivity to hypercarbia is diminished in infants born preterm and is unrelated to any mechanical limitations of ventilation (16). The slope of the CO2 response curve (Fig. 25.2) increases significantly between 29 to 32 and 33 to 36 weeks of gestation, especially in infants without clinically evident apnea. The cause of this decreased sensitivity of central respiratory centers to CO2 in preterm infants is related to central nervous system immaturity as indicated by decreased synaptic connections and incomplete dendritic arborization.
 FIGURE 25.2 CO2 response curves for preterm infants with and without AOP. PaCO2, arterial carbon dioxide pressure. Reprinted from Gerhardt T, Bancalari E. Apnea of prematurity: I. Lung function and regulation of breathing. Pediatrics 1984;74:58-62, with permission. |
Preterm infants and full-term infants up to approximately 3 weeks’ postnatal age have a characteristic biphasic response to hypoxia that is quite different than in older infants. In contrast to the sustained hyperventilation in older infants, preterm infants have only a transient hyperventilation lasting 30 seconds to a minute, followed by progressive ventilatory depression despite continued low inspired oxygen concentrations. The initial hyperventilatory response may be completely blunted in extremely premature infants. This initial transient hyperventilation is likely in response to peripheral chemoreceptor input, and the subsequent hypoxic depression appears to be at least primarily due to centrally mediated decreased peripheral chemoreceptor activity secondary to descending inhibition from the upper brainstem, midbrain, or higher structures (16).
In addition to maturation of central chemoreception, peripheral chemoreceptors progressively mature over the first weeks of life in both full-term and preterm infants, as manifested by the decrease in ventilation with hyperoxia and the hypoxic ventilatory response (13). The magnitude of the ventilatory depression occurring with acute hyperoxia is relatively blunted in infants born preterm, and the magnitude of the hypoxic ventilatory depression is greater in preterm infants with symptomatic AOP. However, it is still unclear to what extent, if any, immature or mature peripheral chemoreception is associated with apnea symptoms. Peripheral chemoreceptor activation plays a role in apnea termination, but excessive peripheral chemoreceptor activation may destabilize the respiratory pattern in AOP and exacerbate the extent of apnea and associated bradycardia and intermittent hypoxia. Carotid chemoreceptors may thus be important not only in stimulating arousal from apnea-associated desaturation, and hence apnea termination, but also potentiating the risk of occurrence. The extent of apnea does seem to correlate with maturation of the ventilatory response to acute hypoxia, with less apnea and intermittent hypoxia present in the early weeks of life and increased apnea-related symptoms in the later weeks with maturation of carotid chemoreceptivity and greater sensitivity to acute hypoxia (13).
Both central and peripheral inputs are thus likely important in the onset and termination of apnea (16). The coordination of phasic and tonic inputs to determine breathing rhythms is not yet fully understood, but stable autonomic control of breathing appears to involve multiple phasic, random, and descending inputs. Upper airway reflexes also may play a role in inhibiting respiration, particularly in preterm infants. Multiple sensory afferent fibers exist within the upper airways, and stimulation of these fibers by various mechanisms can result in abnormal respiratory responses. Responses to upper airway afferent fiber stimulation can change markedly with maturation. Negative pressure in the upper airways in human infants results in depressed ventilation. This inhibition may contribute to the central apnea that often follows obstructed breaths (Fig. 25.3). As upper airway obstruction occurs, the infant makes respiratory efforts against this obstruction, and the resulting increased negative pressure in the upper airway may result in reflex inhibition of diaphragmatic contraction. Due to a blunted response to hypercarbia and hypoxic ventilatory depression, less mature preterm infants with apnea may be unable to recover spontaneously and hence be more likely to require active intervention.
Activation of laryngeal mucosal receptors can elicit strong airway protective reflexes in both full-term and preterm infants. This laryngeal chemoreflex can result in autonomic responses including apnea, bradycardia, hypotension, upper airway closure, and swallowing (16). Although this chemoreflex is an important contributor to aspiration-related apnea and bradycardia, there is no clear relationship to AOP.
 FIGURE 25.3 Examples of mixed, obstructive, and central apnea episodes occurring in AOP. A: Mixed apnea. Obstructed breaths precede and follow a central respiratory pause. B: Obstructive apnea. Breathing efforts continue, although no nasal airflow occurs. C: Central apnea. Both nasal airflow and breathing efforts are absent. BPM, beats per minute. Reprinted from Miller MJ, Martin RJ, Carlo WA. Diagnostic methods and clinical disorders in children. In: Edelman NH, Santiago TV, eds. Breathing disorders of sleep. New York: Churchill Livingstone, 1986:157-180, with permission. |
Genetics of Control of Breathing
Recent genetic studies related to brainstem autonomic regulation have enhanced our understanding of normal development of respiratory regulation (17). Targeted gene inactivation studies in animals have identified multiple genes involved with prenatal brainstem development of respiratory control including arousal responsiveness. During embryogenesis, the survival of specific cellular populations composing the respiratory neuronal network is regulated by neurotrophins, a multigene family of growth factors and receptors. Brain-derived neurotrophic factor (BDNF) is required for development of normal breathing behavior in mice, and newborn mice lacking functional BDNF exhibit ventilatory depression associated with apparent loss of peripheral chemoafferent input. Ventilation is depressed, and hypoxic ventilatory drive is deficient or absent.
Krox-20, a homeobox gene, appears to be required for normal development of the respiratory central pattern generator (18). Krox-20 null mutants exhibit an abnormally slow respiratory rhythm and increased incidence of respiratory pauses, and this respiratory depression can be further modulated by endogenous enkephalins. Absence of Krox-20 may result in the absence of a rhythm-promoting reticular neuron group localized in the caudal pons and could thus be a cause of life-threatening apnea.
Brainstem muscarinic cholinergic pathways are important in ventilatory responsiveness to carbon dioxide (CO2). The muscarinic system develops from the neural crest, and the ret protooncogene is important for this development (17). Ret knockout mice have a depressed ventilatory response to hypercarbia, implicating absence of the ret gene as a cause of impaired hypercarbic responsiveness. Diminished ventilatory responsiveness to hypercarbia has also been demonstrated in male newborn mice heterozygous for Mash-1. There is a molecular link between ret and Mash-1, and the latter is expressed in embryonic neurons in vagal neural crest derivatives and in brainstem locus coeruleus neurons, an area involved with arousal responsiveness.
Serotonin (5-HT) is a widespread neurotransmitter that affects cardiovascular control and modulates activity of the circadian clock. Serotonergic receptors in the brainstem are critical components of respiratory drive. Multiple genes are involved in the control of serotonin synthesis, storage, membrane uptake, and metabolism (17). Polymorphisms have been identified in the promoter region of the 5-HT transporter protein gene located on chromosome 17, and variations in the promoter region of the gene appear to have a role in serotonin membrane uptake and regulation. Several transporter polymorphisms have been described that may occur in greater frequency in SIDS than in control infants, but no data are available related to maturation of breathing control in preterm infants in general or to AOP in particular. Thus, there are no data on the potential role of serotonin-related polymorphisms in determining the extent of clinical manifestations of AOP. However, the greater concordance for AOP among monozygotic twins than same-sex dizygotic twins suggests a genetic contribution (19).
These studies illustrate potentially important genetic foundations of neonatal control of breathing. Further work is needed, however, to better understand the developmental regulation of these targeted genes and their influence on maturation of the fetal/neonatal respiratory centers and peripheral chemoreceptors.
▪ CLINICAL MANIFESTATIONS OF IMMATURE BREATHING
Respiratory Pauses and Periodic Breathing
The clinical manifestations of immature autonomic regulation of respiration include brief respiratory pauses, apnea, bradycardia, and desaturation. Respiratory pauses occur commonly in both preterm and full-term infants and are typically manifested as periodic
breathing. Periodic breathing is a pattern of regular breathing alternating with respiratory pauses persisting through at least three cycles of breathing. The pauses are at least 3 seconds in duration and may last for 5 to 10 seconds or more (20). The prevalence of periodic breathing has been reported to be as high as 80% in term infants and may approach 100% in extremely low-birth-weight preterm infants (21,22). The prevalence diminishes with increasing postnatal and postmenstrual age (PMA) and appears to reach a nadir by about 44 weeks of PMA (23). Periodic breathing results primarily from immature central chemoreception, but the peripheral chemoreceptor response to intermittent hypoxia may also contribute to periodic breathing (16).
breathing. Periodic breathing is a pattern of regular breathing alternating with respiratory pauses persisting through at least three cycles of breathing. The pauses are at least 3 seconds in duration and may last for 5 to 10 seconds or more (20). The prevalence of periodic breathing has been reported to be as high as 80% in term infants and may approach 100% in extremely low-birth-weight preterm infants (21,22). The prevalence diminishes with increasing postnatal and postmenstrual age (PMA) and appears to reach a nadir by about 44 weeks of PMA (23). Periodic breathing results primarily from immature central chemoreception, but the peripheral chemoreceptor response to intermittent hypoxia may also contribute to periodic breathing (16).
Periodic breathing is common, especially in preterm infants, but this respiratory pattern is likely not benign when associated with longer respiratory pauses or apnea, intermittent hypoxia, and/or bradycardia. Particularly, in more immature preterm infants, minute ventilation can diminish significantly during episodes of periodic breathing, and oxygen saturation can decrease to hypoxemic levels in association with longer respiratory pauses and increased time spent in periodic breathing. The rate of decrease in oxygen saturation associated with respiratory pauses may also be related to baseline oxygenation, which in preterm infants may be adversely affected not only by reduced lung volumes but also by the extent of pulmonary disease. The intermittent respiratory pauses of periodic breathing are typically associated with intermittent hypoxia and heart rate decelerations or even bradycardia, and mounting evidence suggests that intermittent hypoxia may be associated with longer-term adverse consequences (discussed more in detail in later section) (24,25). The intermittent hypoxia and intermittent bradycardia associated with periodic breathing are typically not evident clinically and are documented only by review of continuous pulse oximeter recordings (26,27).
Periodic breathing appears to occur predominantly during REM sleep, but it also occurs during quiet sleep (20). During quiet sleep, periodic breathing is “regular” with consistent durations of the apneic and breathing periods, while during REM sleep, periodic breathing tends to be irregular with inconsistent cycle durations. Since more immature infants generally spend more time in sleep and more of this sleep time is characterized by periodic breathing, these infants may be experiencing significant amounts of intermittent hypoxia (27).
Apnea
In contrast to the shorter respiratory pauses observed with periodic breathing, cessations in ventilation lasting longer than 15 to 20 seconds are generally labeled as apnea, especially if associated with bradycardia and/or desaturation. The mechanism for bradycardia associated with apnea in preterm infants has not been fully elucidated (16). Some evidence suggests that this bradycardia is a consequence of apnea-related hypoxic stimulation of carotid chemoreceptors, but in some instances, the bradycardia occurs coincident with the apnea, suggesting a brainstem mechanism (Fig. 25.4). Bradycardia occurs more frequently with longer durations of apnea and usually follows the oxygen desaturation (28). Occasionally, bradycardia may follow apnea without desaturation.
These events may be mediated by vagal nerve stimulation. Apneic episodes are subclassified as central, obstructive, or mixed (29). Figure 25.3 demonstrates the respiratory patterns during these events. Central apneas result from lack of respiratory effort. Obstructive apneas (obstructed breaths) are also central in origin but are related to absence of neuromuscular control of upper airway patency rather than absence of inspiratory diaphragmatic stimulation. Obstructive apneas are characterized by cessation of inspiratory air flow into the lungs despite persisting respiratory effort. Mixed apneas represent a combination of absent respiratory effort (central apnea) and obstructed breaths.
 FIGURE 25.4 Proposed physiologic mechanisms by which apnea results in reflex bradycardia. This can occur secondary to hypoxemia or by stimulation of upper airway afferents. Reprinted from Martin RJ, Wilson CG. Apnea of prematurity. Compr Physiol 2012;2:2923-2931, with permission. |
There are multiple possible etiologic factors leading to symptomatic apnea in the preterm and full-term infant (Tables 25.1 and 25.2). Clinical and laboratory assessments are needed to rule out conditions for which specific treatment is indicated. There are no systematic prevalence data for symptomatic apnea in full-term infants, but most occurrences will have an identifiable medical cause (Table 25.2). In preterm infants less than 1,500 g at birth, approximately 70% will have at least one clinically observed episode of symptomatic apnea while in the NICU, and about 20% of these infants will have a specific medical cause (Table 25.1). The other 80% of preterm infants with symptomatic apnea do not have a specific pathologic cause other than immaturity of control of breathing, and by exclusion are then considered to have AOP, the most important and prevalent manifestation of respiratory control immaturity in preterm infants.
TABLE 25.1 Etiology of Apnea in Preterm Infants | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||
TABLE 25.2 Etiology of Apnea in Full-Term Infants | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||
Apnea of Prematurity
Pathophysiology
The maturation of cardiorespiratory control and the clinical course of premature infants with AOP parallel each other. AOP is a direct consequence of immaturity of brainstem respiratory control centers, but numerous factors contribute to the development of apnea, including altered ventilatory responses to hypercapnia and hypoxia (see “Neonatal Breathing” section). In addition, diaphragmatic fatigue may contribute to the development of AOP (28). It is not possible as part of routine clinical care to quantify the degree of immaturity of brainstem autonomic cardiorespiratory control systems. However, brainstem auditory maturation can be quantified by serial measurements of brainstem conduction time from the auditory-evoked response (wave VI interval) (30), and the brainstem auditory nuclei are located in close proximity to the cardiorespiratory centers. Shortening of brainstem auditory conduction times occurs with advancing gestational age due to improved synaptic efficiency and myelination. Long brainstem conduction times for the auditory-evoked responses are strongly associated with clinical episodes of AOP. Since not all very-low-birth-weight (VLBW) preterm infants develop AOP and the severity varies among affected infants of the same gestational age, other genetic and/or environmental factors are also important. Twin modeling has been used to estimate the relative contributions of genetic and environmental influences in AOP (19). In this study, there was greater concordance for AOP among monozygotic twins than among same-sex dizygotic twins, suggesting a genetic contribution. Advanced model-fitting analysis revealed a strong genetic influence for AOP, and overall heritability was 87%. Genetic factors significantly contributed to susceptibility to AOP in males, but there was a combination of genetic and environmental factors in female infants. The importance of specific genetic risk factors and gene-environment interactions remain to be clarified.
Incidence and Diagnosis
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
