Chronic Lung Disease of Childhood: Control of Breathing During Wake and Sleep

Abstract

Control of breathing in infants during wake and sleep is immature at birth and undergoes rapid maturation over the first year of life. Infants with chronic lung disease (CLD) have multiple control of breathing impairments leaving them particularly vulnerable to hypoxic and asphyxic events. These impairments in the control of breathing are thought to contribute significantly to increased morbidity and the increased incidence of sudden infant death in infants with CLD. This review provides an overview of factors integral to the control of breathing during wake and sleep and factors that influence the development of control of breathing with a focus on the impact of CLD.

Introduction

Postnatal maturation of the respiratory system is often thought of as lung, airway, and respiratory pump development. However, ventilatory control is also immature at the time of birth and takes time to reach a mature state of stability and function. The mechanisms controlling minute ventilation (V_E), breathing pattern, ventilatory responses to abnormal blood levels of O₂ and CO₂, upper airway function, and other aspects of respiratory control are all immature in premature infants and may contribute to adverse clinical outcomes. In addition to immaturity, infants with chronic lung disease (CLD) may exhibit more severe abnormalities of respiratory control, which can have practical implications for their medical care by pediatric pulmonologists, pediatricians, and other care providers. The purpose of this review is to provide a brief overview of factors integral to the control of breathing during wake and sleep, factors that influence their development, and the impact of CLD on ventilatory control and its maturation.

Bronchopulmonary dysplasia (BPD) remains a common complication of premature birth, although the characteristics of CLD associated with premature birth have evolved over the last several decades, mainly due to the introduction of surfactant replacement therapy. Although some of the research assessing the impact of CLD on ventilatory control spanned the era from the old BPD through the transition to the new BPD and other forms of infant CLD, it remains highly relevant today. In spite of extensive research on the mechanisms responsible for the control of breathing and its postnatal maturation, a great deal remains poorly understood.

Overview of Respiratory Control

Maintenance of O₂ and CO₂ levels within a narrow range is paramount to homeostasis at the cellular level and, thus, to life itself. This delicate balance has led to the development of a complex system that senses changes in O₂ and CO₂ levels and pH, in arterial blood, and in the brain and uses these data to make precise adjustments to maintain these chemical parameters within a narrow range by altering breathing. Oxygen levels are primarily sensed by the peripheral chemoreceptors, the carotid bodies and aortic bodies, which transduce changes in arterial O₂ into neural inputs to the brainstem. CO₂ is sensed mainly by central chemoreceptors that are widely distributed in the brainstem and also input to the brainstem respiratory controller. Perturbations in levels of O₂, CO₂, and pH will prompt precise changes in the depth of respiration (tidal volume), respiratory rate, and/or the breathing pattern.

The basal respiratory rhythm is produced by a central pattern generator, a group of neuronal circuits, located within the brainstem, capable of producing a rhythmic pattern without input from other neuronal circuits or from sensory feedback.¹ Within the central pattern generator there are multiple discrete groups of neurons with phase-related functions (ie, inspiratory, expiratory), spatially distributed in specific areas of the pons and medulla.^2,3 Central and peripheral chemoreceptor, pulmonary and upper airway receptor, and other inputs are integrated at the level of the brainstem to modulate the respiratory pattern and maintain homeostasis during widely varying activities, from quiet sleep to vigorous exercise, and environmental conditions such as high altitude. The respiratory control system does not function in isolation, but it is tightly integrated with control of cardiovascular function and complex motor activities such as swallowing.

Outside of the perinatal period, sudden infant death syndrome (SIDS) is the most common cause of death in the first year of life. SIDS is defined as the sudden death of an infant, unexpected by clinical history that remains unexplained after a thorough postmortem examination and death scene investigation.⁴ Infants born prematurely have an increased risk of SIDS,⁴ which is increased, to a greater degree, in infants with CLD.^5–7 Although the specific underlying mechanisms of SIDS are not known, abnormalities of ventilatory control are thought to play an important role.^8–10

Chemoreceptor Development in CLD

The strength and timing of chemoreceptors responses has been a focus of study in children with CLD. Surgical denervation of the carotid bodies in immature piglets leads to severe abnormalities of respiratory control and increased mortality^11,12 highlighting their importance in ventilatory control. Chemoreceptor responses are impaired in premature infants¹³ and, to greater degrees, in infants with CLD.¹⁴ When exposed to 100% inspired O₂, V_E decreases within seconds, due to sudden removal of peripheral chemoreceptor input. Thus, the transient 100% O₂ test can be used to assess the contribution of the peripheral chemoreceptors to overall V_E drive in human infants.¹⁵ When transiently exposed to 100% FiO₂, preterm infants exhibit larger decreases in V_E compared with term infants, and the decrease in both groups of infants is greater than in adults, thus indicating greater contribution of peripheral chemoreceptors to respiratory drive compared with adults.¹⁶ Infants with CLD, however, exhibit impaired peripheral chemoreceptor responses to the transient hyperoxia test at birth and a marked delay in the development of age appropriate responses,¹⁴ which may persist as long as 6–8 months spanning the peak ages of incident SIDS.¹⁴

Paramount to chemoreceptor response maturation is environmental exposure. Alterations of oxygen levels in utero and perinatally have potent effects on chemoreceptor response development. Infants with CLD may experience both chronic and intermittent hypoxia during wake and sleep¹⁷ that can be severe^17,18 and persist as long as 3–5 years of age.¹⁹ Chronic hypoxia profoundly blunts carotid body responses in animal models.^20–23 In preterm infants,²⁴ exposure to chronic hypoxia may delay carotid body functional development, although evidence of this remains circumstantial, as it is difficult to establish definitively in human infants.²⁵ Intermittent hypoxia also diminishes carotid chemoreceptor O₂ responses.²⁶ Studies assessing the effect of hypoxia on carotid body development have also been limited, however, by their ability to distinguish between diminished carotid body output and respiratory control center responses, thus leaving investigators to question whether one or both systems are affected.

Exposure to hyperoxia also has a detrimental effect on carotid body development. Rats reared during the first month of life in hyperoxia exhibit dramatically attenuated carotid body responses when challenged acutely with hypoxia.²⁷ The impairment in carotid body development has been associated with carotid body hypoplasia,^28–30 carotid sinus nerve axon loss, and reduced axonal myelination.²⁹ Timing of exposure to hyperoxia is important. Although exposure to hyperoxia shortly after birth causes long-term impairment of chemoreceptor responses to hypoxia,^23,31,32 these effects are minimal or only transient when adults are exposed to hyperoxia, thus suggesting a critical window of time when the respiratory control system is more susceptible to environmental influences.

Specifically, the time periods in utero and shortly after birth represent a critical time for structural and functional development of the neural systems that comprise respiratory control. During this period, environmental influences can alter the developmental process to greater degrees than similar environmental exposures later in life, which has been termed developmental plasticity.²¹ Wong-Riley et al. assessed maturation of the pre-Botzinger complex, an important site in the respiratory control center that dictates the underlying respiratory rhythm, and found an overall increase in cytochrome oxidase activity (a marker of neuronal functional activity) in rats between 0 and 21 days of age, with a transient decrease in cytochrome oxidase activity at postnatal days 11–13, suggesting a period of developmental reorganization or synaptic adjustment.³⁰ Although neurotransmission in the respiratory control centers is, in general, increasingly excitatory during postnatal maturation, there is a transient period of inhibitory neurotransmitter dominance at about days 11–13, which is associated developmental changes or “switches” in neurotransmitter receptor function. These and other similar changes in respiratory center maturation may render the system vulnerable to failure if stressed during this sensitive period.³⁰ During this period of life, development of respiratory control might also be vulnerable to environmental influences such as exposure to hypoxia or hyperoxia. Thus, the timing of exposure to varied levels of oxygen might be as important as the presence of hypoxia or hyperoxia; this area has not yet been adequately assessed in human infants.

In addition to hypoxia and hyperoxia, nicotine profoundly effects development of cardiorespiratory control. Pre- and postnatal tobacco smoke exposure has been strongly linked to SIDS risk.^33,34 Richardson et al. demonstrated a dose-dependent response of urine cotinine levels and cortical arousal in response to an air jet stimulus in 12 full-term infants, and the depressed cortical arousal persisted through 6 months of age.³⁵ Animal studies have demonstrated altered development of nicotinic binding in brain stem nuclei related to arousal or cardiorespiratory control.³⁶ Additionally, in infants exposed to nicotine abnormalities in autoresuscitation,³⁷ development of hypoxic ventilatory responses³⁸ and arousal responses³⁵ have been identified. Avoidance of nicotine exposure in infants with CLD should be an aspect of parental education for parents of children with CLD.

Perturbations in cardiorespiratory control have been suggested as possible SIDS pathophysiologic mechanisms.³⁹ Studies assessing the development of baroreceptors in children with CLD have taken our understanding of cardiorespiratory control in new directions. Vestibular nuclei influence variability of heart rate and blood pressure (BP) and control of BP in response to postural changes,⁴⁰ and vestibular damage has been identified in a substantial number of SIDS victims.⁴¹ Viskari et al. examined BP and heart rate responses in infants with and without BPD in response to tilt table and side swinging stimulation and found that HR and BP responses were impaired in infants with BPD.⁴² Vestibular nuclei are susceptible to damage from hypoxia, and all infants in this study exhibited varying degrees of hypoxia. Regardless of the underlying mechanism, this study establishes an important link between CLD and cardiovascular instability shortly after birth.

Effect of Sleep

The transition from wake to sleep is associated with changes in ventilatory patterns and the elimination of voluntary control of respiration. During nonrapid eye movement (non-REM) sleep, the respiratory rate slows, tidal volumes increase, the respiratory pattern is regular, and there is a decline in V_E. In contrast, during rapid eye movement (REM) sleep, the respiratory pattern becomes irregular, the metabolic rate and, subsequently, CO₂ production and V_E all increase. Chemosensitivity to hypoxia and hypercapnia fall during non-REM sleep compared with wakefulness and to greater degrees during REM sleep, thereby leading to decreases in PaO₂ and increases in PaCO₂.³⁶ Alterations in pharyngeal neuromuscular responses and the control of breathing during sleep result in the occurrence of obstructive and central sleep-disordered breathing.

Infants with CLD have an increased prevalence of obstructive⁴³ and central sleep-disordered breathing.⁴⁴ Central sleep apnea is due to a decrease in ventilatory drive exhibited as a cessation of airflow without evidence of respiratory effort, thus resulting in impairment in gas exchange. Infants with BPD have an increased incidence of central apnea compared with infants of similar weight without BPD.⁴⁴ All premature infants exhibit some degree of periodic breathing and frequent central apnea that decreases over time.⁴⁵ Fajardo et al. assessed sleep-disordered breathing event frequency in 12 infants with and 12 infants without BPD matched for postconceptional age and weight at the time of the study. Infants with BPD exhibited a higher incidence of obstructive apnea events.⁴³ The underlying mechanisms responsible for the increased risk for OSA in infants with CLD, however, are not fully understood.

Infants with CLD also exhibit hypoxia during sleep that is often not clinically suspected¹⁷ and not predicted by assessment of waking SpO₂ over a short period (20 min).¹⁹ Studies suggest that even mild degrees of hypoxia during sleep in infants with CLD are detrimental to sleep quality and growth. Harris and Sullivan assessed sleep structure with polysomnography in 7 infants (6 with BPD) at baseline either on room air or on supplemental O₂ (if prescribed) in mildly hypoxic infants (baseline SpO₂>90%), and a second night on an additional ¼ liter per minute of supplemental O₂. They found that increasing SpO₂ levels resulted in greater overall sleep duration and duration of REM sleep and decreased arousal frequency during REM.⁴⁶ Fitzgerald et al. performed a similar study in 14 infants with CLD with higher baseline SpO₂ levels (>93%), and found that increasing SpO₂ further with supplemental oxygen (SpO₂>97%) might have actually worsened sleep quality by shortening sleep duration and sleep efficiency.⁴⁷ These data suggest that although treatment of mild hypoxia improved sleep quality, use of supplemental oxygen to increase SpO₂ levels above normal thresholds had no additional beneficial effect.

Mild hypoxia can also impair growth in infants with CLD. Moyer-Mileur et al. stratified a group of infants with BPD on supplemental O₂ based on minimal sustained SpO₂ levels during sleep on room air (88%–92% versus >92%) and followed their growth trajectory. After supplemental oxygen was removed, infants with BPD (n=11, 26.7±2.2 weeks gestation) with mild hypoxia (sustained SpO₂ nadir >88% and <92%) had a reduction in growth velocity that was not seen in infants (n=34, 28.6±2.7 weeks gestation) with higher oxygen levels (sustained SpO₂ nadir >92%).¹⁹

In addition to exposure to hypoxia, infants with CLD have abnormal responses to hypoxia during sleep. Garg et al. challenged infants with CLD (n=12, 41±1 weeks postconceptional age) with hypoxia (O₂ tension of 80 mm Hg) for 3 min or until arousal occurred and found that although they aroused normally, after arousal these infants exhibited prolonged apnea, bradycardia, and often required resuscitation.^19,48 Taken together, infants with CLD are at increased risk for sleep disordered breathing and hypoxia during sleep, and are unable to adequately defend themselves during these events because of abnormal cardiorespriatory responses. Incorporation of assessment of apnea and hypoxia during sleep into the routine care of these children might have implications for growth and development and might decrease the risk of hypoxic or asphyxic events.

Effect of CLD on Pulmonary Mechanics

CLD results in pulmonary parenchymal changes that affect the respiratory pattern. Infants with CLD have decreased alveolarization, increased airway resistance, and less compliant lung fields Additionally, both term and preterm infants exhibit low resting lung volumes that decrease O₂ stores and can increase intrapulmonary shunting,⁴⁹ thus leading to more frequent, rapid, and larger oxygen desaturations. To compensate for changes in lung mechanics and lower resting lung volumes, infants with CLD increase their end-expiratory lung volume above the resting lung volume and exhibit higher respiratory rates.^50,51 The increased respiratory rate, however, is inefficient, because dead space ventilation increases, necessitating higher V_E to maintain SpO₂ and CO₂ levels. Taken together, these changes in respiratory mechanics may interact with respiratory control abnormalities and immaturity, impair gas exchange, increase caloric expenditure, and significantly impair weight and growth.

Swallowing and Feeding in Infants with CLD

In addition to controlling the rhythmic ventilatory pattern, the brainstem also controls swallowing and the integration breathing and feeding. Humans also have the ability to voluntarily control the breathing pattern, which enables activities including speaking, voluntary coughing, and swallowing. Precise coordination of the timing of breathing and swallowing is critical to avoid aspiration and maintain adequate gas exchange while feeding. Brainstem swallowing control centers interact with the central respiratory pattern generator in a highly complex manner that, similar to breathing control in general, is not fully mature at birth, especially in preterm infants.

Infants with CLD have difficulty with oral feeding beyond that due to preterm birth and immaturity. Suckling and swallowing were assessed by nipple and pharyngeal pressures. Infants with BPD were compared with a control group without BPD matched by postmenstrual age over the duration of their neonatal intensive care unit (NICU) stay. Infants with BPD compared with those without BPD did not develop normal patterns of suckling or swallowing.⁵² Gewolb et al. extended their study with an assessment of the variability of swallowing-breathing intervals and breathing intervals without swallowing in 34 infants (26–33 WGA, BPD=14), and found that infants with BPD had greater variability of both,⁵³ thus indicating lack of coordination of breathing with feeding. Mizuno and colleagues assessed suckling and swallowing function in 20 c with BPD and without BPD with nipple and pharyngeal pressure measurements. Infants with BPD exhibited lower sucking pressure, duration and frequency of swallows. However, infants with BPD exhibited longer deglutition apneas, the required period of cessation of breathing during swallowing.⁵⁴ Impairments in swallowing and sucking are predictive of abnormalities in neurocognitive development.⁵⁵ However, it remains unclear to what extent swallowing abnormalities in infants with BPD are due to neurological impairment versus pulmonary dysfunction and/or abnormal integration of breathing-swallowing control. Given the significant abnormalities during feeding identified in infants with CLD, swallowing evaluations and, if indicated, treatment including individualized feeding plans, such as appropriate volumes and feeding pace, and parental education, would be a beneficial and underappreciated aspect of care.

In addition to oro-pharyngeal dysfunction, hypoxia after feeding has also been identified in infants with CLD. Singer et al. assessed infants with BPD (43±2 weeks postconceptional age at the time of study) compared with very low birth weight infants without BPD (42±2 postconceptional age) of similar weight. Oxyhemoglobin saturation was similar in infants with and without BPD before and during feeding, but markedly decreased in infants with BPD after feeding.¹⁸ Similarly, Garg et al. assessed infants with BPD 42±2 postconceptional age compared to control infants with pulse oximetry during wake, sleep, and during and after feeding. Infants with BPD exhibited oxygen desaturations (<90%) in all states, including after feeding.¹⁷ Monitoring oxyhemoglobin levels during wake and sleep and particularly after feeding is indicated for infants with CLD. Goal oxyhemoglobin levels and duration of monitoring, however, are not well defined.

Conclusion

Humans have developed a complex respiratory control network to sense small changes in PCO₂, PO₂, and pH and are capable of generating precise responses in V_E to maintain these physiologic parameters within a narrow range. Infants with CLD have an increased risk of impairment of the respiratory control system at multiple levels, thus resulting in increased risk for hypoxic and asphyxic events as well as impaired feeding and growth. Research to date suggests that sleep disordered breathing, swallowing dysfunction, and mild degrees of hypoxia are more prevalent in these infants than clinically suspected and that incorporation of formal evaluations might have profound effects on comorbid and potentially mortal outcomes in this population.

Footnotes

Author Disclosure Statement

No conflicts of interest exist.

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