Neonatal Apnea and the Foundation of Respiratory Control

Neonatal Breathing Pattern

Neonatal respiratory activity is irregular with spontaneous changes alternating between eupnea, apnea, periodic breathing, and tachypnea. Respiratory frequency, often inversely proportional to body weight, may be quite variable in the preterm infant. Periods of slow respiratory rates are secondary to prolongation of expiratory time (T _E ), whereas inspiratory time (T _I ) remains relatively unchanged during development. Extreme prolongation of T _E results in respiratory pauses and apnea, which occur frequently in preterm and, to a lesser extent, in healthy term neonates. Paradoxical inward movement of the rib cage during inspiration is especially common in preterm infants. The mechanism behind this paradoxical movement is related to a combination of a highly compliant rib cage and diminished intercostal muscle tone opposed by diaphragmatic contraction. The effort required to produce a tidal volume during these paradoxical movements is substantially greater than during “normal” breathing, which further hinders an already immature respiratory system. Because of chest wall instability and immature lung development, the preterm infant often compensates with a shortened expiratory time and expiratory breaking to maintain expiratory lung volume. Occasional sigh breaths re-open areas of atelectasis. Apnea often leads to a loss in lung volume, decrease in functional residual capacity (FRC), and reduction in oxygen stores. The incidence of central apnea decreases with advancing gestational age and is present in almost all infants with a birth weight less than 1000 g or gestational age less than 28 weeks. At 43-44 weeks’ corrected gestational age, the incidence of apnea is comparable to that of a term neonate. Apnea is not exclusively confined to preterm babies. Healthy term infants may also have apnea exceeding 20 seconds on home monitoring.

Hypercapnia and Acidosis

Small increases in arterial P co ₂ resulting in central acidosis increase ventilation dramatically. The ventilatory response to CO ₂ is the net result of activation of both peripheral and central chemoreceptors. The contribution of the peripheral chemoreceptors, mainly through the carotid body, is 10%-40% of the total hypercapneic response. Central chemoreceptors originally thought to be confined to the ventrolateral medulla have been found to be widespread in the brainstem, including the retrotrapezoid nucleus, the region of the nucleus tractus solitarius, the region of the locus coeruleus, the rostral aspect of the ventral respiratory group, and the medullary raphe. Other sites of chemoreception include the fastigial nucleus of the cerebellum and the pre-Botzinger complex. The ventilatory response to CO ₂ is impaired in preterm infants relative to term newborns and adults; however, it increases with advancing postnatal and gestational age. It has been demonstrated that, unlike adults, preterm infants and newborn animals are less able to increase their respiratory rate in response to CO ₂ , but tidal volume increases appropriately. Possible mechanisms for this impaired response to CO ₂ include changes in the mechanical properties of the lung, maturation in the peripheral or central chemoreceptors, or changes in the central integration of chemoreceptor or other neuronal signals. Multiple studies have indicated a central origin for the attenuated CO ₂ response in preterm babies, in particular those with apnea. However, a cause-and-effect relationship between apnea of prematurity and the attenuated response to CO ₂ has not been clearly established, and both might simply represent facets of a decreased respiratory drive.

Hypoxia

Unlike adults who express a sustained response to hypoxia, the neonatal hypoxic ventilatory response is biphasic, with an initial increase in ventilation that lasts 1-2 minutes, followed by a decline that falls below baseline ventilation in preterm infants ( Fig. 67.1 ). This late decline has been traditionally termed hypoxic ventilatory depression . Although the increase in tidal volume is sustained, breathing frequency decreases during hypoxic exposure, hence the biphasic response. The increase in ventilation occurs through activation of peripheral chemoreceptors located primarily in the carotid body and is eliminated by carotid body denervation. During development, the initial rise increases, while the late depression decreases with advancing postnatal age; however, in one study, hypoxic ventilatory depression persisted in convalescing preterm neonates at 4-6 weeks of age. Several mechanisms have been postulated to explain the pathogenesis of late respiratory depression, including a time-dependent decrease in carotid body stimulation, hypocapnea secondary to the initial hyperventilation, and a decrease in metabolism. Increasing evidence, however, suggests a central origin for hypoxic ventilatory depression, probably through interaction of multiple neurotransmitters, including adenosine, GABA, and endorphins, or through descending inhibitory pontine tracts. Consistent with these findings is the observation that a progressive decrease in inspired oxygen concentration causes a significant flattening of carbon dioxide responsiveness in preterm infants ( Fig. 67.2 ).

Laryngeal and Pulmonary Afferent Reflexes

Stimulation of the laryngeal mucosa, either chemically (water, ammonium chloride, or acidic solutions) or mechanically, causes inhibition of breathing and apnea in neonates and newborn animals. This reflex-induced apnea, known as the laryngeal chemoreflex (LCR), is usually associated with glottic closure, swallowing, bradycardia, and hypotension, and has been shown to undergo maturational changes with age. Although it may serve a protective function, preterm infants express an exaggerated LCR as evidenced by prolonged apnea response to instilling saline in the oropharynx. The mechanisms underlying such maturational change in reflex-induced apnea are not known but seem to be related to a decrease in central neural output or a dominance of inhibitory pathways. The inhibitory neurotransmitters adenosine and GABA have both been implicated where blockade of GABA _A receptors prevented, and activation of adenosine A _2A exaggerated, the LCR.

Lung afferents play an important role in regulating respiratory timing and may play a role in apnea of prematurity. Stimulation of pulmonary stretch receptors through increasing lung volume causes shortening of inspiratory time, prolongation of expiratory time, or both. This reflex is known as the Hering-Breuer reflex. The decrease in respiratory frequency and prolongation of expiratory time following institution of nasal continuous positive airway pressure (CPAP) is mediated through activation of this reflex. This probably serves to prevent lung overdistention on CPAP. The Hering-Breuer deflation reflex is activated on deflation of the lung and results in inspiratory augmentation. However, unlike term infants, preterm infants are less likely to initiate breathing and tend to have respiratory pauses on deflation of the lung, thus making them less likely to recover from an apnea event.

Neurotransmitters and Neuromodulators

There are limited data regarding the balance of excitatory and inhibitory neurotransmitters during development of respiratory control. Because invasive studies cannot be performed in newborn infants, most studies on the relationship of neurotransmitters to respiratory control are based on the effect of these substances or their inhibitors on the breathing responses to hypoxia, hypercapnia, and reflex apnea in animal models. The most widely studied neurotransmitters in relation to disturbances in control of breathing include adenosine, GABA, prostaglandins, endorphins, and serotonin.

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). It has been implicated in the attenuated ventilatory responses to hypoxia, hypercapnia, and LCR. Blocking GABA _A receptors prevented hypoxic ventilatory depression and the decrease in breathing frequency in response to CO ₂ and attenuated the LCR. Both structural and functional differences in GABA _A receptors have been observed during development. GABA _A receptors are hetero-oligomers assembled from five subunits. During embryonic and early postnatal development, the brainstem has a much higher GABA _A receptor density than does the adult brainstem, and the “mix” of GABA _A receptor subunits differs from that in adults. Therefore, GABA has the potential to play a key role in the vulnerability of preterm infants to disturbed breathing, including apnea of prematurity. Of interest is the observation that GABA may switch from an excitatory to inhibitory neurotransmitter during the transition from fetal to neonatal life.

Adenosine is a product of ATP that is ubiquitous to most brain tissue as well as the cerebrospinal fluid (CSF). Adenosine is known to depress neural function and respiration, and its level has been shown to increase during hypoxia in brain tissue, CSF, and plasma. Furthermore, adenosine antagonists reversed hypoxic depression in anesthetized newborn piglets. The role of adenosine in apnea of prematurity is suggested by the ability of the methylxanthines, theophylline, and caffeine, which are nonspecific adenosine receptor inhibitors, to decrease the incidence of apnea of prematurity. However, the exact mechanism and location of action of adenosine, as well as the interaction of adenosine with other neurotransmitters, remain to be identified. Adenosine receptors may be inhibitory (A ₁ ) or excitatory (A _2B ). An interaction between adenosine and GABA in the regulation of breathing has been documented. Blockade of GABA _A receptors abolished the inhibition of phrenic activity and the exaggerated LCR induced by adenosine A _2A agonist. Furthermore, A _2A receptors were found to co-localize on GABAergic neurons in the medulla oblongata of both piglets and rats. These data suggest that the mechanism of action of methylxanthines in the prevention of apnea of prematurity is through central blockade of either inhibitory A ₁ receptors or excitatory A ₂ adenosine receptors on GABAergic neurons. In either case, respiratory inhibition is diminished.

Exogenous endorphin and enkephalin analogues have been shown to produce a consistent decrease in respiration in fetal and neonatal animals. Endorphin levels are elevated in the human neonate at birth, and endogenous opioids were found to modulate the hypoxic ventilatory response in newborn infants and animals. Furthermore, the opioid antagonist naloxone produced an improvement in apnea and periodic breathing in infants in whom β-endorphin–like immunoreactivity in the CSF was elevated. Although these data support a role for opioids in respiratory control in neonates, the effect of anesthesia in such studies and the interaction of opioids with other inhibitory neurotransmitters need to be clarified. Infusion of prostaglandin E ₁ (PGE ₁ ) may produce respiratory depression in infants during treatment for critical congenital heart disease. Prostaglandin E ₁ has been shown to decrease, and indomethacin has been shown to enhance, phrenic activity in newborn piglets.

The involvement of serotonin in respiratory control is well established; however, the nature of this involvement is complex. Both activation and inhibition of breathing have been described with different doses and routes of administration. The different responses may owe, in part, to the effect on different subtypes of serotonin receptors preferentially expressed on respiratory neurons. Serotonin has been implicated as a regulatory factor in the production of apneusis. Blocking 5-HT _1A receptors has been shown to reverse apneustic breathing, which might result during hypoxia or ischemia. There is increasing evidence to suggest an important role for serotonergic neurons in the raphe nuclei in maturation of central chemoreception. This has been highlighted by findings in cohorts of sudden infant death syndrome (SIDS) victims (Japanese, African-American, and white) in whom there was a significant positive association with the presence of a homozygous gene that encodes for the long allele of the 5-HT transporter promoter (5-HTT), as well as the long allele itself. In both studies, SIDS victims were more likely than control subjects to express the long allele of 5-HTT, as well as to miss the short allele of 5-HTT. Therefore, it is possible that a delay in maturation of serotonergic neurons or overexpression of the long allele for 5-HTT in the arcuate nucleus, as well as in other respiratory groups, might contribute to a failure of arousal and inadequate respiratory response to a life-threatening event. There is increasing evidence that this may be the underlying mechanism in the pathogenesis of SIDS.