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William Janes, OTR/L, MSCI, OTD is Assistant Research Professor and Academic Fieldwork Coordinator in Occupational Therapy at the University of Missouri. Dr. Janes serves as Chair of the American Occupational Therapy Association Academic Fieldwork Coordinators Academic Leadership Council Research Advancement Ad Hoc Committee and President of the Gateway Occupational Therapy Education Council.

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This narrative review provides a broad perspective on immature control of breathing, which is universal in infants born premature. The degree of immaturity and severity of clinical symptoms are inversely correlated with gestational age. This immaturity presents as prolonged apneas with associated bradycardia or desaturation, or brief respiratory pauses, periodic breathing, and intermittent hypoxia. These manifestations are encompassed within the clinical diagnosis of apnea of prematurity, but there is no consensus on minimum criteria required for diagnosis. Common treatment strategies include caffeine and noninvasive respiratory support, but other therapies have also been advocated with varying effectiveness. There is considerable variability in when and how to initiate and discontinue treatment. There are significant knowledge gaps regarding effective strategies to quantify the severity of clinical manifestations of immature breathing, which prevent us from better understanding the long-term potential adverse outcomes, including neurodevelopment and sudden unexpected infant death.

In this narrative review, we will address (1) the pathophysiology of immature control of breathing and its clinical manifestations; (2) pharmacological and nonpharmacological therapies for AOP; (3) resolution of clinical symptoms of AOP and readiness for discharge home; (4) post-discharge outcomes, including neurodevelopmental sequelae, brief resolved unexplained events (BRUE), sudden infant death syndrome (SIDS), and sleep disordered breathing (SDB); and (5) gaps in knowledge with future research directions. The methodology for this narrative review was based on a comprehensive summary of known studies published in English and supplemented by a PubMed search for additional relevant publications. Both sources were supplemented by a review of all relevant secondary references. Publications only as abstracts were not included.

Control of breathing is a complex process with neurons in the respiratory control centers of the bulbopontine region of the brainstem responsible for rhythmogenesis. Neurons within this region respond to multiple afferent inputs to modulate rhythmicity and provide efferent output to respiratory control muscles. The afferent inputs include signals from peripheral and central chemoreceptors, pulmonary stretch receptors, and cortical neurons. Preterm infants exhibit immature control of breathing, which includes aberrant activity of both central and peripheral chemoreceptors as well as poor neuromuscular control of upper airway patency (Fig. 1) [2]. Due to immaturity, central chemosensitivity to hypercarbia is diminished in infants born preterm, and when matched for gestational age, further reduced with AOP-related symptoms. Chemosensitivity to hypoxia is also impaired and is characterized by a biphasic response. The initial response is hyperventilatory and likely due to peripheral chemoreceptor input, but this initial hyperventilation may not occur in extremely preterm infants. The secondary depressive ventilatory response to hypoxia is due primarily to centrally mediated suppression of peripheral chemoreceptor activity [2, 8].

Brainstem respiratory centers demonstrate both immature central and peripheral chemoreceptor responses and diminished neuromuscular control of upper airway patency. In addition to prolonged apneas leading to bradycardia and desaturation, the immature respiratory centers also result in shorter respiratory pauses and periodic breathing. Peripheral chemoreceptors mature more rapidly postnatally than central chemoreceptors, which can result in the cyclic pattern of periodic breathing and intermittent hypoxia.

Additional clinical manifestations of immature control of breathing include shorter respiratory pauses that can be isolated or occur in clusters [12, 13]. Respiratory pauses occurring in clusters manifest as periodic breathing, which is an oscillatory breathing pattern due to hyperventilation followed by brief apneas or respiratory pauses [14,15,16]. Periodic breathing is primarily a consequence of immature brainstem control, but peripheral chemoreceptors are also of critical importance (Fig. 1) [9, 17]. Indeed, periodic breathing appears to be related at least in part to increased sensitivity or gain in peripheral chemoreceptors leading to overcompensation for small changes in PaO2 or PaCO2 and hence oscillations between brief episodes of tachypnea leading to relative hypocarbia that results in apnea in a cyclic pattern [15].

The prevalence of periodic breathing may approach 100% at very low gestational ages, and progressively decreases with increasing postnatal and postmenstrual age (PMA), reaching a nadir by about 44 weeks PMA [15, 18]. The respiratory pauses in periodic breathing are generally not of sufficient duration to cause bradycardia or desaturation that trigger monitor alarms or to be evident clinically unless occurring in prolonged clusters. Intermittent hypoxia (IH) is perhaps the most important consequence of periodic breathing, but requires continuous respiratory recording for documentation. In preterm infants

In summary, AOP and periodic breathing with IH are manifestations of immature control of breathing due to central and peripheral chemoreceptor immaturity. The severity of immature control of breathing and its clinical manifestations are inversely associated with gestational age at birth. Clusters of periodic breathing and associated IH may be as important as prolonged apneas in determining risk for long-term morbidities. The extent to which genotype affects the phenotype of AOP is unknown, but an important focus for future research.

There is no consensus on when to initiate therapy for AOP. Generally, treatment is indicated when episodes are recurrent, do not resolve spontaneously or with minimal stimulation, and are associated with bradycardia or hypoxemia. Various nonpharmacological therapies have been advocated for AOP, but the first line of therapy is usually a methylxanthine, specifically caffeine.

Methylxanthines have been used for >40 years to treat AOP. Early studies using aminophylline and theophylline showed they effectively reduced the incidence of apnea [24]. Caffeine, a trimethylxanthine, is the major metabolite of the dimethylxanthine theophylline and demonstrates more potent central activity and less peripheral effects. Caffeine has become the preferred methylxanthine due to fewer side effects, a wider therapeutic index, and a longer half-life that allows once-daily dosing [25, 26].

Methylxanthines act both centrally and peripherally to stimulate respiration through antagonism of adenosine A1 and A2A receptors They activate the medullary respiratory centers and increase CO2 sensitivity, induce bronchodilation, and enhance diaphragmatic function, all of which lead to increased minute ventilation, improved respiratory pattern, and reduced hypoxic respiratory depression [24]. Studies suggest that the primary mechanism by which methylxanthines reduce apnea is antagonism of excitatory A2A receptors on GABAergic neurons and blockade of inhibitory A1 receptors, with resultant stimulation of central respiratory neural output [27, 28].

Adenosine receptors are present throughout the brain as well as in the heart, blood vessels, respiratory system, gastrointestinal system, and kidneys. Since methylxanthines are nonspecific adenosine antagonists, their use can lead to secondary effects in organ systems outside the brain. The side effects of methylxanthine therapy result from increased metabolic rate and catecholamine stimulation, leading potentially to transient tachycardia, irritability, and slowing of growth. In the Caffeine for Apnea of Prematurity (CAP) trial, caffeine-treated infants gained less weight during the first 3 weeks after randomization but by 4 weeks there was no difference in weight gain, and there were no long-term adverse effects on growth [35,36,37]. Animal studies and small clinical trials show that caffeine delays gastric emptying time, decreases lower esophageal sphincter tone, and transiently reduces splanchnic oxygenation but the clinical significance of these findings is uncertain [38,39,40]. Importantly, the CAP trial observed no differences in the rate of NEC between caffeine and placebo groups [35].

In addition to reducing apnea-related symptoms, methylxanthines facilitate extubation and reduce the need for mechanical ventilation [46]. The CAP trial revealed many other benefits of caffeine therapy for extremely preterm infants born

In the CAP Trial, the benefits of caffeine were most significant when treatment was initiated within 3 days after birth [48]. Several retrospective cohort studies have associated earlier initiation of caffeine therapy with improved outcomes, but the evidence is generally of low quality and has to be interpreted with caution [24, 49]. The only randomized, controlled trial investigating early caffeine administration in extremely preterm ventilated infants was terminated early due to concern for higher mortality in the early caffeine group without any clinical benefit; however, baseline demographic differences between the groups and small sample size limit the ability to draw definitive conclusions [50]. Nevertheless, clinical practice has evolved and early initiation of caffeine treatment has become very common in extremely preterm infants, with 62% of international neonatologists reporting prophylactic use [51]. 2b1af7f3a8