Journal of Perinatology (2011) 31, 302–310 r 2011 Nature America, Inc. All rights reserved. 0743-8346/11 www.nature.com/jp STATE-OF-THE-ART Apnea of prematurity: pathogenesis and management strategies OP Mathew Section of Neonatology, Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA respiratory group are believed to be responsible for rhythmogenisis. Apnea of prematurity (AOP) is a significant clinical problem manifested by This rhythm is modulated by afferent inputs and is the result of an unstable respiratory rhythm reflecting the immaturity of respiratory integration of inputs from peripheral and central chemoreceptors, control systems. This review will address the pathogenesis of and treatment airway afferents and state-dependent controls. Integration of strategies for AOP. Although the neuronal mechanisms leading to apnea are overlapping, opposing synaptic inputs to respiratory motoneurons still not well understood, recent decades have provided better insight into the is important in controlling motor outflow. These key variables generation of the respiratory rhythm and its modulation in the neonate. and their relevance to the pathogenesis of AOP are discussed Ventilatory responses to hypoxia and hypercarbia are impaired and below. inhibitory reflexes are exaggerated in the neonate. These unique vulnerabilities predispose the neonate to the development of apnea. Central chemoreceptors and impaired hypercapnic Treatment strategies attempt to stabilize the respiratory rhythm. Caffeine ventilatory response remains the primary pharmacological treatment modality and is presumed In response to increasing CO2, both adults and term neonates to work through blockade of adenosine receptors A1 and A2. Recent increase their ventilation by increasing tidal volume and breathing evidences suggest that A2A receptors may have a greater role than previously frequency, whereas no increase in breathing frequency is seen in thought. AOP typically resolves with maturation suggesting increased 2–4 myelination of the brainstem. preterm infants. Hypercapnic ventilatory response is primarily Journal of Perinatology (2011) 31, 302–310; doi:10.1038/jp.2010.126; mediated by central chemoreceptors. Serotonergic (5-HT) neurons, published online 2 December 2010 located in the rostral ventrolateral medulla, are putative central chemoreceptors. There is compelling evidence now that there are Keywords: apnea; prematurity; caffeine; airway receptors; chemoreceptors multiple additional sites of central chemoreception5 (see for a review). Ventilatory response to CO2 is significantly reduced in preterm infants but increases with advancing postnatal age.6,7 There is even greater impairment of ventilatory response in preterm Apnea of prematurity (AOP) is a manifestation of an unstable infants with apnea. Slope of the CO2 response curve is shifted to the respiratory rhythm, reflecting the immaturity of the respiratory 8 right in infants with apnea (that is, at the same level of CO2, control system. Anatomically the immaturity is manifested as minute ventilation is lower in apneic infants when compared with decreased synaptic connections, decreased dendritic arborization their counterparts without apnea). There are no differences in and poor myelination. As AOP resolves with maturation, it should pulmonary mechanics between these two groups, suggesting a be considered a developmental disorder rather than a disease state. central origin for the observed difference. Unlike adults, CO2 apneic Significant advances in our understanding of neonatal 9 threshold is close to the baseline PCO2 in preterm infants. Hypoxia respiratory rhythm generation have been made during the last few can narrow this difference further through reduced metabolism. 1 decades from studies in human and animal neonates. Any transient hyperventilation event can easily precipitate apnea in Intracellular recordings and brain slice preparations under reduced these premature infants by decreasing the PCO2 below the apneic experimental conditions have provided important insights. During threshold. the late gestational and early neonatal stages, the medullary compartments in the pre-Bo¨tzinger complex and parafacial Peripheral chemoreceptors and impaired hypoxic Correspondence: Dr OP Mathew, Department of Pediatrics, Medical College of Georgia, 1120 ventilatory response 15th Street, BIW 6033, Augusta, GA 30912-3740, USA. The carotid body is the main peripheral chemoreceptor. The E-mail: [email protected] Received 28 March 2010; revised 4 August 2010; accepted 26 August 2010; published online 2 glomus cells, the primary receptors, release transmitters in response December 2010 to hypoxia, hypercapnia and acidosis, increasing the afferent Apnea of prematurity OP Mathew 303 discharge of the carotid sinus nerve terminals. Dopamine, ductus arteriosus in preterm infants may have a similar basis. acetylcholine and 50-adenosine-triphosphate have been proposed to Recent finding that the vannilloid receptor-1 antagonist, be the excitatory transmitters in the carotid body. The exact oxygen capsaizepine, blocks the bronchoconstrictive response to capsaicin þ sensor is not known. O2-sensitive K channel is a candidate. An has provided definitive evidence that C-fiber afferents mediate this alternative site may exist in the mitochondria. reflex response.22 Myelinated vagal afferents fall into two groups: Peripheral chemoreceptors are active only at very low oxygen slowly and rapidly adapting receptors. Slowly adapting receptors, levels in the fetal life and become essentially silent in the located in the smooth muscle, have a phasic discharge with immediate postnatal period because of the sudden increase in PaO2 inflation. Rapidly adapting (irritant) receptors ramify in the from <30 mm Hg to 50 to 70 mm Hg range or higher. Peripheral tracheo-bronchial epithelium and mediate cough, reflex bronco- chemoreceptors undergo a resetting phenomenon postnatally. Once constriction and rapid shallow breathing.23 Among intubated it is reset, carotid chemoreceptor drive is significant at relatively preterm infants, only 1 of 18 infants <35 weeks consistently hypoxic level of 50 to 70 mm Hg. These infants can become apneic showed a mature response to direct bronchial mucosal stimulation. when their inspired oxygen is increased sufficiently to produce a The majority of stimulations resulted in marked slowing of physiologic denervation of peripheral chemoreceptors.10,11 breathing or apnea.24 What role these vagal afferents have in Adults show a sustained increase in ventilation in response to AOP is yet to be determined. hypoxia. N-methyl D-aspartate glutamate receptors in the nucleus of the solitary tract have a pivotal role in the hypoxic ventilatory Upper airway afferents response.12 Preterm infants exhibit a biphasic ventilatory Afferent feedback originating in the upper airway can alter the response.13 There is an initial increase in ventilation for motor output on a breath by breath basis. Laryngeal afferents approximately 1 min. Following this period, ventilation decreases. responding to changes in respiratory stimuli such as airflow and In the group of preterm infants with birth weight <1500 g, there is transmural pressure have been studied extensively and are no initial period of hyperventilation.14 The decrease in ventilation classified as pressure, flow or drive receptors on the basis of their 25,26 is more pronounced in rapid eye movement sleep and is primarily primary response characteristics. Flow receptors respond to a because of a decrease in breathing frequency. The characteristic decrease in temperature; their phasic inspiratory discharge during biphasic ventilatory response to hypoxia persists for 4 to 6 weeks in room air breathing can be eliminated by breathing warm 27 preterm infants.15 The central respiratory depression because of humidified air. Pressure and drive receptors respond primarily to hypoxia is believed to prolong apnea and delay its recovery. transmural pressure changes and phasic respiratory muscle activity 28 Attenuation of the ventilatory responsiveness to hypoxia has (respiratory drive), respectively. These mechanoreceptors show been documented in humans and animal models exposed to some degree of chemosensitivity. On the other hand, some chronic hypoxia. Persistence of the biphasic response and delayed laryngeal afferents have no mechanosensitivity. Afferents mediating 29 emergence of adult response were seen in rat pups exposed to the laryngeal chemoreflex are stimulated by water and not saline. 29 chronic hypoxia from birth.16 It is also interesting to note that Elegant studies by Boggs and Bartlet showed that these endings hyperoxia results in blunting of peripheral chemoreceptor are indeed responding to the lack of small anions such as chloride. response.17 Katz-Salamon et al.18 have documented a reduced Sensory influences originating from the pulmonary and laryngeal peripheral chemoreceptor response in preterm infants with afferents are integrated in the nucleus of the solitary tract neurons bronchopulmonary dysplasia (BPD). There is also evidence linking and have inhibitory projections to phrenic motor neurons carotid chemoreceptor over stimulation to the persistence of (Figure 1). Some laryngeal fibers monosynaptically synapse on 30 AOP.19–21 Current evidence suggests that both increased and cardiac vagal neurons. This accounts for the simultaneous decreased carotid chemoreceptor activity can predispose the preterm development of apnea and bradycardia observed during laryngeal