Treatment of Apnea of Prematurity

Introduction

Immaturity in respiratory control is of interest to scientists and clinicians alike. From a biologic perspective, it represents a unique link between the developing respiratory and central nervous systems. The resultant apnea precipitates repetitive oxygen desaturation and bradycardia, the longer-term consequences of which are uncertain. Nevertheless, the combination of immature respiratory control, an immature lung, and the resultant therapeutic ventilatory support predispose these infants to chronic respiratory morbidity. There is a need to optimize ventilatory support, both invasive and noninvasive, and provide safe pharmacotherapy that enhances respiratory neural output in this high-risk population of neonates. This is the primary focus of this chapter.

Pathophysiology

The multiple contributors to apnea of prematurity and resultant desaturation are summarized in Fig. 15.1 . They comprise upregulation of brainstem-mediated inhibitory pathways, altered peripheral chemosensitivity, decreased central chemosensitivity, enhanced inhibition from upper airway afferents, and an unstable upper airway. Apnea is clearly more likely to elicit desaturation with the low functional residual capacity (and other abnormalities of lung function) that characterizes bronchopulmonary dysplasia (BPD) (see Fig. 15.1 ).

The neural circuitry that generates respiratory rhythm and governs inspiratory and expiratory motor patterns is distributed throughout the pons and medulla. The medulla contains a specialized region known as the pre-Bötzinger complex, which contains neurons that exhibit intrinsic pacemaker activity capable of producing rhythmic respiratory motor output without sensory feedback. Although a fundamental feature of this network is that it enables breathing to occur automatically, this systematic central rhythmicity may fail in preterm infants.

Excitatory and inhibitory neurotransmitters and neuromodulators mediate the rhythmogenic synaptic communications between neurons of the medulla. Glutamate is the major neurotransmitter mediating excitatory synaptic input to brainstem respiratory neurons. Gamma-aminobutyric acid (GABA) and glycine are the two primary inhibitory neurotransmitters in the network. Interestingly, during late embryonic and early postnatal development, GABA can mediate excitatory neurotransmission secondary to changes in the chloride gradient across the membrane. It is unclear how this phenomenon relates to the inhibition of respiratory output and resultant apnea seen in preterm infants. Neonatal rodent data suggest that caffeine, which is a nonselective adenosine receptor inhibitor, may block excitatory A _2A receptors at GABAergic neurons and so inhibit GABA output and contribute to the ability of caffeine to enhance respiratory drive. Additionally, defects in the medullary serotonergic system likely contribute importantly to the pathogenesis of sudden infant death syndrome. For future advances in the pharmacotherapy of neonatal apnea, greater understanding of the maturation of these neurotransmitters/neuromodulators is imperative.

Responsiveness to CO ₂ is the major chemical driver of respiratory neural output. This is apparent in fetal life, where breathing movements increase under hypercapnic conditions in animal models. As in later life, CO ₂ /hydrogen ion (H ⁺ ) responsiveness is predominantly based in the brainstem, although peripheral chemoreceptors contribute to the ventilatory response and respond more rapidly. The reduced ventilatory response to CO ₂ in small preterm infants, especially those with apnea, is primarily the result of decreased central chemosensitivity; however, mechanical factors such as poor respiratory function and an unstable upper airway and/or chest wall may contribute. It is difficult to distinguish the neural from mechanical factors that contribute to respiratory failure in this population, as highlighted in Fig. 15.2 .

It has been known for many years that preterm infants respond to a decrease in inspired oxygen concentration with a transient increase in ventilation over approximately 1 minute, followed by a return to baseline or even depression of ventilation. The characteristic response to low oxygen in infants appears to result from initial peripheral chemoreceptor stimulation, followed by overriding depression of the respiratory center as a result of hypoxemia. Such hypoxic respiratory depression may be useful in the hypoxic intrauterine environment where respiratory activity is only intermittent and not contributing to gas exchange. The nonsustained response to low inspired oxygen concentration may, however, be a disadvantage postnatally. It may play an important role in the origin of neonatal apnea and offers a physiologic rationale for the decrease in incidence of apnea observed when a slightly increased concentration of inspired oxygen is administered to apneic infants who have a low baseline oxygen saturation. Decreased peripheral chemoreceptor responsiveness to oxygen or central hypoxic depression of respiratory neural output may impair recovery from apnea. In contrast, excessive peripheral chemosensitivity has also been shown to compromise ventilatory stability and predispose to periodic breathing and even apnea in preterm infants. ^, Finally, inhibitory sensory inputs from the upper airway (larynx and pharynx) may be prominent in early postnatal life and serve a protective function yet precipitate potential clinically significant apnea.

Clinical Features and Evaluations

Apnea can be classified into central, obstructive, or mixed. Central apnea occurs from central nervous system immaturity, which causes decreased respiratory effort and an exaggerated response to laryngeal stimulation (a normal reflex that closes the airway as a protective measure). Obstructive apnea in premature infants is mostly due to position (the infant's neck is hyperflexed or hyperextended) in combination with low pharyngeal muscle tone preventing air flow through the pharynx. Mixed apnea is the most common cause of clinically significant apnea of prematurity, accounting for over 50% of the episodes. Mixed apnea in premature infants consists of central pauses secondary to the immature state of respiratory control and obstructive respiratory efforts secondary to decreased pharyngeal or laryngeal muscle tone.

Apnea of prematurity presents as cessation of breathing for longer than 20 seconds or a shorter duration if accompanied by bradycardia, oxygen desaturation, or cyanosis ( Table 15.1 ). Incidence of apnea of prematurity is inversely related to gestational age. The incidence is nearly 100% for infants born at or before 28 weeks’ gestational age. At 30 weeks’ gestational age the incidence decreases to approximately 80% and at 34 weeks’ gestational age the incidence significantly decreases to 20%. Onset of apnea of prematurity is usually within the first week of life. The time period for resolution of apnea of prematurity is generally around 36 to 40 weeks’ postconceptual age. Apneic spells typically stop by 37 weeks’ postmenstrual age in 92% of infants and by 40 weeks’ postmenstrual age in 98% of infants. The time of resolution is also inversely related to gestational age. Infants born at <28 weeks’ gestation may have recurrent apnea and bradycardia events that persist to or beyond 38 weeks’ postconceptual age, whereas in infants born ≥28 weeks’ gestational age, the time to resolution for recurrent apnea and bradycardia events is generally around 36 to 37 weeks’ postmenstrual age.

Although apnea in a premature infant can be physiologic, it can be a sign of change in clinical status of the preterm infant. Other etiologies should be considered if there is escalation in respiratory support or if apnea is associated with other clinical findings such as feeding intolerance or lethargy. If this is the case, the infant should be further evaluated for infectious etiologies (such as sepsis or bacteremia), central nervous system abnormalities (such as intracranial hemorrhage), anemia, genetic disorders, or metabolic disorders because all of these can contribute to apnea in both preterm and term infants.