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Apnea of prematurity (AOP) remains a major clinical problem in present day neonatology that warrants frequent evaluations and imposes challenges in therapeutic strategies. Although the pathogenesis of AOP is poorly understood, it is probably a manifestation of physiologic immaturity of breathing control rather than a pathologic disorder. Immature breathing responses to hypoxia, hypercapnia and exaggerated inhibitory pulmonary reflexes in preterm infants might also contribute to the occurrence or severity of AOP. Recent data suggest a role for genetic predisposition. Although typically resolve with maturation, the role of bradycardia and desaturation episodes associated with AOP in the development of sleep disorder breathing and neurodevelopmental delay needs further clarification. Pharmacological treatment with methylxanthines and CPAP remain the mainstay for treatment of AOP. However, recent studies have implicated central inhibitory neuromodulators including prostaglandins, GABA and adenosine in its pathogenesis, the fact that might provide future specific targets for treatment. This review will summarize new insights involving these issues as well as others involving the pathogenesis, treatment strategies and consequences of apnea in premature infants.

GABA and adenosine contribute to respiratory inhibition in early postnatal life. In this study the adenosine A2A receptor agonist CGS21680 was used to evaluate adenosine receptor specificity and the interrelation of adenosine and GABA in the inhibition of inspiratory drive. In neonatal piglets (n = 10), CGS21680 was injected into the fourth ventricle resulting in apnea and/or decreased burst area and frequency of phrenic discharge. Phrenic burst area decreased to 58.9 +/- 8.6% (S.E.M.) after CGS21680 injection (control = 91.8 +/- 1.0%). Expiratory time increased 261.0 +/- 59.9% after CGS21680 from control (87.7 +/- 2.7%). When bicuculline was injected locally within the rostral ventrolateral medulla (n = 5), or into the fourth ventricle (n = 5), the CGS21680 induced inhibition of phrenic was abolished. To define expression of A2A receptor at the message level (mRNA), we employed in situ hybridization with a digoxigenin-coupled oligonucleotide. Adenosine A2A receptor mRNA was expressed in regions of the medulla oblongata known to contain GABAergic neurons. We conclude that GABAergic inputs affecting respiratory timing and inspiratory drive are modulated by activation of A2A receptors. These findings offer new insight into the mechanism whereby xanthine therapy diminishes apnea of prematurity.

Respiratory control in the fetus and neonate is quite immature when compared to that of adults. This immaturity involves all facets of respiration including respiratory responses to hypoxia, hypercapnia, an exaggerated apnoeic response to laryngeal stimulation and immature responses to activation of pulmonary afferents. The net result of this immaturity of breathing responses is the vulnerability of neonates and especially preterm infants to apnoea and respiratory pauses. The mechanisms behind immature control of breathing are not fully understood, but seem to originate from a predominance of inhibitory input early in life on respiratory centres. The relative contribution of up-regulation of inhibitory pathways versus down-regulation of excitatory ones is not clear. Multiple neurotransmitters have been implicated in the regulation of breathing in mammals and some of them are discussed in this chapter.

We have previously documented anatomic and functional relationships between ventilatory and autonomic neural output. Therefore, we hypothesized in this study that hypoxia-induced changes in respiratory neural output are associated with changes in autonomic regulation of lower esophageal sphincter (LES) pressure. Respiratory neural output, heart rate, and LES pressure were measured before and during a 3-min exposure to 8% oxygen (balance nitrogen) in 12 3- to 7-d-old piglets. Respiratory neural output was determined from diaphragmatic electromyogram and LES pressure from an esophageal catheter. Studies were repeated after atropine administration in eight animals. Hypoxic exposure resulted in significant increases in diaphragmatic amplitude, respiratory rate, and minute diaphragmatic activity as well as heart rate. The biphasic response of diaphragm amplitude peaked at 1 min, whereas the responses of respiratory frequency and heart rate were sustained. Hypoxia caused a 50% increase in LES pressure (p < 0.05), which was eliminated by i.v. atropine administration. Development of apnea during subsequent hyperoxic exposure was always followed by a decline in LES pressure. Hypoxia-induced increase in respiratory neural output and accompanying increase in heart rate are associated with enhanced constrictive output to the LES. Blockade by atropine implicates a peripheral cholinergic mechanism for this LES response. We speculate that whereas hypoxia in the presence of enhanced respiratory neural output seems to be protective against reflux, decreased respiratory drive and accompanying apnea may be associated with a decline in LES tone and predispose to gastroesophageal reflux.

After completing this article, readers should be able to: 1. Identify common neonatal problems that may present with apnea. 2. Describe the role of pharmacologic and nonpharmacologic treatment of apnea. 3. Characterize the findings of long-term follow-up of infants who have apnea. Although apnea typically results from immaturity of the respiratory control system (see accompanying article in this issue), it also may be the presenting sign of other diseases or pathophysiologic states that frequently affect preterm infants. A thorough consideration of possible causes is always warranted, especially when there is an unexpected increase in the frequency of episodes of apnea or bradycardia (Fig. 1). Figure 1. Multiple etiologic factors that may contribute to apnea in preterm infants. IVH=intraventricular hemorrhage. Central nervous system problems, particularly intracranial hemorrhage, can precipitate apnea in the preterm infant. Asphyxia, including transient birth depression, may cause either episodic or prolonged apnea. Malformations of the brain or less likely, the spinal cord, should be considered in an otherwise healthy infant who presents with apnea at birth. Infections (bacteremia possibly accompanied by meningitis) may cause unstable breathing patterns and should prompt the appropriate evaluation and possibly antibiotic therapy. In the older infant, the onset of a viral illness such as respiratory syncytial virus (RSV) infection sometimes is heralded by apnea, although the precise mechanism whereby RSV presents with apnea is unclear. Anemia, another frequent problem in preterm infants, whether iatrogenic or due to bleeding, is a potential precipitating factor. Blood transfusions have been demonstrated to improve irregular breathing patterns in preterm infants, although the risk of blood transfusion has limited its use as treatment for apnea. It has been assumed, although unproven, that enhanced oxygen-carrying capacity, as with red blood cell transfusion, may decrease the likelihood of hypoxia-induced respiratory depression. Other disease states that may precipitate apnea include metabolic disorders such as …

After completing this article, readers should be able to: 1. Characterize the unique features of neonatal respiratory control mechanisms. 2. Clarify how immature respiratory control contributes to neonatal apnea. 3. Identify the contribution of upper airway obstruction to episodes of mixed apnea. Idiopathic apnea of prematurity is a common disorder that requires therapeutic intervention to avoid potential morbidity in preterm infants who require neonatal intensive care. Severe, recurrent apneic episodes may lead to multiple investigations to rule out secondary disorders leading to apnea (see accompanying article in this issue). Although the incidence of neonatal apnea is inversely related to gestational age and is probably as high as 100% in the most immature preterm infants, the onset may be delayed by the presence of lung disease in the first days of life. Apnea of prematurity, especially if severe or persistent, has been associated with poor developmental outcome in school-age children, although a cause-and-effect relationship is difficult to establish. The definition of apnea varies among studies. Apnea of prematurity has been defined most widely as cessation of breathing in excess of 15 seconds’ duration, typically accompanied by desaturation and bradycardia. However, shorter episodes of apnea, and even periodic breathing, may be accompanied by bradycardia or hypoxemia. Prolonged desaturation episodes also have been reported in the absence of apnea or bradycardia, both in healthy preterm infants and in infants who have chronic lung disease. These episodes might represent obstructive apnea, hypoventilation, or possibly intrapulmonary right-to-left shunting, although episodes of desaturation and bradycardia almost always are preceded by apnea or hypoventilation. Apnea is classified traditionally into three categories based on the presence or absence of upper airway obstruction: central, obstructive, and mixed apneas. Central apnea is characterized by total cessation of inspiratory efforts with no evidence of obstruction. In obstructed apnea, the infant tries to breathe against …

Hypercapnia induces prolongation of expiratory time (T e ) during early development. In the present study, we determined the response to steady state hypercapnia of three neural phases of the total respiratory cycle, inspiration (T i ), stage 1 or passive expiration, T e -1 and stage 2 or active expiration, T e -2. Experiments were performed in decerebrate, vagotomized, spontaneously breathing piglets aged 5–10 days. Neural phases of the respiratory cycle were based on electrical activities of the thyroarytenoid (TA, laryngeal adductor) and triangularis sternii (TS, chest wall expiratory muscle) in relation to diaphragm (D) activity. We observed that hypercapnia induced prolongation of both expiratory phases. The greater prolongation of T e -1 was associated with an increase in TA activity and an increase in laryngeal resistance, which peaked early in T e -1, and then progressively decreased. These findings demonstrate that, in early postnatal life, a hypercapnia induced increase in respiratory drive is associated with centrally mediated prolongation of both phases of expiration, a greater prolongation of T e -1, and an increase in laryngeal resistance during post-inspiration. We speculate that the latter serves to optimize gas exchange by reducing large fluctuations in functional residual capacity.

In these studies, we determined the contribution of central mechanisms and the role of GABA A -receptor signal transduction pathways in mediating hypercapnia-induced slowing of breathing frequency. Experiments were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated piglets of 3–5 days and 2–3 weeks of age ( n =19). Repeated exposure to progressive hyperoxic hypercapnia induced a reproducible increase in phrenic nerve activity, accompanied by a CO 2 concentration-dependent increase in expiratory duration. No differences were observed in piglets with intact or cut carotid sinus nerves. Intravenous administration of bicuculline (2 mg/kg; n =7), a γ-aminobutyric acid (GABA A ) receptor antagonist, significantly reduced the CO 2 -induced prolongation of Te . These data demonstrate for the first time that in early postnatal life, hypercapnia induced increase in phrenic activity is associated with centrally mediated prolongation of expiratory duration. Furthermore, the results suggest that brainstem GABAergic mechanisms play an important role in CO 2 -induced prolongation of expiratory time during early development.

Premature infants respond to hypercapnia by an attenuated ventilatory response that is characterized by a decrease in respiratory frequency. We hypothesized that this impaired hypercapnic ventilatory response is of central origin and is mediated via γ-aminobutyric acid-ergic (GABAergic) pathways. We therefore studied two groups of maturing Sprague-Dawley rats: unrestrained rats in a whole body plethysmograph at four postnatal ages (5, 16–17, 22–23, and 41–42 days); and ventilated, decerebrate, vagotomized, paralyzed rats in which phrenic nerve responses to hypercapnia were measured at 4–6 and 37–39 days of age. In the unrestrained group, the increase in minute ventilation induced by hypercapnia was significantly lower at 5 days vs. beyond 16 days. Although there was an increase in tidal volume at all ages, frequency decreased significantly from baseline at 5 days, whereas it increased significantly at 16–17, 22–23, and 41–42 days. The decrease in frequency at 5 days of age was mainly due to a significant prolongation in expiratory duration (Te). In the ventilated group, hypercapnia also caused prolongation in Te at 4–6 days but not at 37–39 days of age. Intravenous administration of bicuculline (GABAA-receptor blocker) abolished the prolongation of Te in response to hypercapnia in the newborn rats. We conclude that newborn rat pups exhibit a characteristic ventilatory response to CO2expressed as a centrally mediated prolongation of Te that appears to be mediated by GABAergic mechanisms.

Activation of the laryngeal mucosa results in apnea that is mediated through, and can be elicited via electrical stimulation of, the superior laryngeal nerve (SLN). This potent inhibitory reflex has been suggested to play a role in the pathogenesis of apnea of prematurity and sudden infant death syndrome, and it is attenuated by theophylline and blockade of GABAAreceptors. However, the interaction between GABA and adenosine in the production of SLN stimulation-induced apnea has not been previously examined. We hypothesized that activation of adenosine A2Areceptors will enhance apnea induced by SLN stimulation while subsequent blockade of GABAAreceptors will reverse the effect of A2Areceptor activation. The phrenic nerve responses to increasing levels of SLN stimulation were measured before and after sequential intracisternal administration of the adenosine A2Areceptor agonist CGS ( n = 10) and GABAAreceptor blocker bicuculline ( n = 7) in ventilated, vagotomized, decerebrate, and paralyzed newborn piglets. Increasing levels of SLN stimulation caused progressive inhibition of phrenic activity and lead to apnea during higher levels of stimulation. CGS caused inhibition of baseline phrenic activity, hypotension, and enhancement of apnea induced by SLN stimulation. Subsequent bicuculline administration reversed the effects of CGS and prevented the production of apnea compared with control at higher SLN stimulation levels. We conclude that activation of adenosine A2Areceptors enhances SLN stimulation-induced apnea probably via a GABAergic pathway. We speculate that SLN stimulation causes endogenous release of adenosine that activates A2Areceptors on GABAergic neurons, resulting in the release of GABA at inspiratory neurons and subsequent respiratory inhibition.

Great strides have been made in our understanding of developmental respiratory neurobiology. A clear picture is, therefore, emerging of the physiological mechanisms that underlie apnea of prematurity. The ventral surface of the medulla and adjacent areas play a key integrative function for central CO2 chemosensitivity and modulation of afferent inputs from peripheral chemoreceptors and laryngeal afferents. Maturational change in medullary neurotransmitter function appears to contribute to the physiological events that characterize apnea of prematurity. Despite this greater scientific insight, therapeutic strategies for neonatal apnea have changed little in 30 years. Xanthine therapy and continuous positive airway pressure remain the mainstay of therapy while other therapeutic approaches have been inadequately studied. Our understanding of a possible relationship between the triad of apnea, bradycardia and desaturation, and impaired neurodevelopmental outcome is also limited. These are all issues that need our attention if optimal therapy and outcome are to be provided for preterm infants with immature respiratory control.

Apnea of prematurity remains a troublesome clinical problem in the care of low birth weight infants. It may significantly impact the neonatal course of such patients by necessitating the use of assisted ventilation, prolonging their hospitalization, and resulting in a need for xanthine or other pharmacologic intervention. To better understand the physiologic basis for neonatal apnea, the response of respiratory neural output to hypercapnia, hypoxia, and stimulation of laryngeal and other mechanoreceptor-mediated afferents has been extensively studied in both human infants and various animal models. However, maturation of the role of neurotransmitters that mediate these neural pathways at the brainstem is poorly understood. As fetal and early neonatal life are characterized by greater inhibition of respiratory output than in later life, it is tempting to speculate that this period is associated with greater expression of inhibitory versus excitatory neurotransmitters and neuromodulators in respiratory-related neurons. A variety of such substances have been implicated in neonatal respiratory control and some, such as serotonin and adenosine, may have excitatory or inhibitory effects depending on the receptor subtypes activated (Fig 1). Although prostaglandins and endorphins have both been studied for their role as inhibitory neurotransmitters in relation to neonatal respiratory control, 1 the focus of this review will be on gamma aminobutyric acid (GABA), adenosine, and their potential interaction as the major modulators of respiratory neural output in early life.

Idiopathic apnoea of prematurity is a common and troublesome disorder which requires therapeutic intervention to avoid potential morbidity in premature infants who require neonatal intensive care. Although the definition of apnoea is inconsistent, this condition has been defined most widely as cessation of breathing in excess of 15 seconds duration, typically accompanied by desaturation and bradycardia. Shorter episodes of apnoea, and even periodic breathing, may be accompanied by bradycardia or hypoxemia, with an incidence approaching 100% in the most immature preterm infants.1 Resolution of apnoea of prematurity runs a very variable time course, and the persistence of such episodes is of uncertain pathophysiologic consequence. Apnoea is traditionally classified into three categories based on the presence or absence of obstruction of the upper airways. Central apnoea is characterised by total cessation of inspiratory efforts with no evidence of obstruction. In obstructed apnoea, the infant tries to breathe against an obstructed upper airway resulting in chest wall motion without airflow throughout the entire apnoea. Mixed apnoea consists of obstructed respiratory efforts usually following central pauses, and is probably the most common type of apnoea.2,3 The site of obstruction in the upper airways is mostly in the pharynx, however, it may also occur at the larynx, and possibly both sites. Mixed apnoea typically accounts for more than half of all long apnoeic episodes, followed in decreasing frequency by

Reflexes from the larynx induce cessation of breathing in newborn animals. The magnitude of respiratory inhibition is inversely related to the level of central chemical input. Recent studies indicate that selective inhibition of Na+/H+ exchanger type 3 (NHE3) activates CO2/H+-sensitive neurons, resembling the responses evoked by hypercapnic stimuli. Hence, the use of NHE3 inhibitors may reduce reflexly mediated respiratory depression and duration of apnea in the neonatal period. This possibility was examined in decerebrate, vagotomized, ventilated, and paralyzed piglets by testing the effects of i.v. administration of NHE3 blocker S8218 on the response of phrenic nerve amplitude, frequency, and duration of apnea induced by graded electrical stimulation of the superior laryngeal nerve. Superior laryngeal nerve stimulation caused a significant decrease in phrenic nerve amplitude, frequency, minute phrenic activity, and inspiratory time (all p < 0.01) that was proportional to the level of electrical stimulation. Increased levels of stimulation were more likely to induce apnea both during and after cessation of stimulation. NHE3 blocker S8218 reduced the superior laryngeal nerve stimulation–induced decrease in phrenic nerve amplitude, minute phrenic activity, and phrenic nerve frequency (all p < 0.05) and reduced superior laryngeal nerve stimulation-induced apnea and duration of poststimulation apnea (p < 0.05). In six other pigs the brain concentrations of S8218 were measured at different intervals after i.v. administration of the drug and were found to be higher in the brain tissue than plasma at all intervals. These findings suggest that the use of NHE3 blockers may decrease the duration of apnea and possibly reduce the pathophysiologic consequences of potentially life-threatening apnea in infants.

Stimulation of the superior laryngeal nerve (SLN) results in apnea in animals of different species, the mechanism of which is not known. We studied the effect of the GABAAreceptor blocker bicuculline, given intravenously and intracisternally, on apnea induced by SLN stimulation. Eighteen 5- to 10-day-old piglets were studied: bicuculline was administered intravenously to nine animals and intracisternally to nine animals. The animals were anesthetized and then decerebrated, vagotomized, ventilated, and paralyzed. The phrenic nerve responses to four levels of electrical SLN stimulation were measured before and after bicuculline. SLN stimulation caused a significant decrease in phrenic nerve amplitude, phrenic nerve frequency, minute phrenic activity, and inspiratory time ( P < 0.01) that was proportional to the level of electrical stimulation. Increased levels of stimulation were more likely to induce apnea during stimulation that often persisted beyond cessation of the stimulus. Bicuculline, administered intravenously or intracisternally, decreased the SLN stimulation-induced decrease in phrenic nerve amplitude, minute phrenic activity, and phrenic nerve frequency ( P < 0.05). Bicuculline also reduced SLN-induced apnea and duration of poststimulation apnea ( P < 0.05). We conclude that centrally mediated GABAergic pathways are involved in laryngeal stimulation-induced apnea.

The respiratory network that generates rhythmic activity is continuously subjected to excitatory and inhibitory inputs which regulate tidal breathing and respiratory timing: inspiratory (Ti) and expiratory (Te) duration. Recently we have shown in unrestrained, 5 day (but not 3 wk old) rat pups, that hypercapnia induced increases in tidal volume are accompanied by reduction in frequency due to an increase in Te. To identify if this maturational change in timing response to CO2 is central or peripheral in origin, we examined the effect of graded increases in inhaled CO2 on phrenic activity in decerebrate, vagotomized, paralyzed, and mechanically ventilated rat pups at 4-6 (n=8), 12-17 (n=9), and 36-40 (n=8) days. Hypercapnia always induced an increase in peak phrenic activity, which was associated with a CO2 concentration-dependent increase in Te at 4-6 but not 12-17 or 36-39 days (Fig). Hypercapnia had no significant effect on Ti. These results indicate that in early postnatal life CO2 increases phrenic output in parallel with a prolongation of Te which is centrally mediated and not related to changes in vagal or upper airway reflexes. We postulate that in the youngest animals, prolongation of Te during hypercapnia provides sufficient time to empty the lungs, regulate functional residual capacity and optimize work of breathing. Excessive prolongation of Te during hypercapnia, however, might compromise the ventilatory response.

Respiratory center drive is most accurately reflected from the steepest rise of the diaphragmatic EMG (Edi) at inspiratory onset. This parameter equates to peak acceleration of diaphragmatic activation (PaEdi) and reflects diaphragmatic recruitment whereas further rise of Edi amplitude (EdiA) signifies continued neuronal discharge. Calibrated respiratory inductive plethysmography (RIP) provides rib cage (RC), abdominal (AB) and their sum(Vt) waveforms noninvasively. We therefore tested the hypothesis that RIP derived acceleration signals (PaRC, PaAB or PaVt) could be used as measures of respiratory drive by validation with PaEdi during unimpeded breathing and obstructed efforts. Five newborn piglets were lightly anesthetized and allowed to breathe spontaneously through cuffed endotracheal tubes. A wire electrode was inserted into the diaphragm using a percutaneous, subcostal approach and RIP transducers applied to the RC and AB compartments. Peak acceleration from RIP waveforms was measured as the highest value in a window range of±300 msec around the mechanical onset of inspiration. The same window was used for PaEdi. Data were displayed and stored on a Respitrace PT16 recorder (Nims, Miami Beach, FL) for subsequent analysis with RespiEvents software. Interventions included 7% CO2 rebreathing and end expiratory obstruction of the endotracheal tube over 2-4 efforts. For CO2 rebreathing, a correlation matrix was calculated for each animal and the means(SD) are listed below; *indicates r with p

Maturation of Ventilatory Responses to Hypoxia, Hypercapnia, and Combined Hypoxia and Hypercapnia in Rats. † 1446