sign in sign up
<<
Home , Apnea, Apnea of prematurity, Central chemoreceptors, Hyperventilation

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 of prematurity: pathogenesis and management strategies

OP Mathew Section of Neonatology, Department of , Medical College of Georgia, Augusta, GA, USA

respiratory group are believed to be responsible for rhythmogenisis. (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 , 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 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. 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 and 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 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 and animal neonates. Any transient 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 is the main peripheral . 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, and , 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 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 , reflex bronco- chemoreceptors undergo a resetting phenomenon postnatally. Once constriction and rapid .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 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 observed during laryngeal infants to apnea. afferent stimulation. Similar types of endings have been documented in glossopharyngeal and trigeminal nerves.

Airway afferents and enhanced inhibitory response Enhanced inhibitory responses Lower airway afferents Reflex effects of laryngeal afferent stimulation have been The vagus nerve is the primary afferent source of the lower airway. investigated extensively in neonatal animal models. These studies Unmyelinated fibers (C-fibers) constitute >90% of the respiratory show that apnea and inhibition of breathing commonly ensue.29,31 afferents from the and have been implicated in the Apnea can be induced in tracheostomized animals by applying bronchoconstrictive and bradycardic responses (associated with negative pressure or airflow to the isolated upper airway31 or apnea or rapid shallow breathing) to right heart injection of instillation of water into the larynx,29 indicating that laryngeal capsaicin, a C-fiber stimulant. Pulmonary C-fibers are also afferent input into the brainstem is a potent source of inhibition. stimulated by . Apnea precipitated by patent The classic definition of laryngeal chemoreflex is the triad of

Journal of Perinatology Apnea of prematurity OP Mathew 304

A detailed discussion of this reflex is beyond the scope of this review and the reader is referred elsewhere.36 Whether this reflex is mediated by cold receptors or mechanoreceptors has not been established.

Sleep Sleep states influence breathing profoundly. Changes in neuromodulatory inputs originating from the catecholaminergic and serotonergic arousal systems of the brainstem are linked to alterations in respiratory function during the sleep–wake cycle. Activity of serotonin-containing neurons decreases by nearly half during slow-wave sleep and become nearly silent during rapid eye movement sleep via activation of GABAergic inputs.37 Figure 1 Role of laryngeal afferent in apnea and bradycardia. Some of the superior laryngeal nerve (SLN) afferents are monosynaptically connected to is typically irregular in active sleep, whereas it can cardiac vagal neurons (CVN) in nucleus ambiguus, whereas most afferents be regular or irregular in quiet sleep. Generalized inhibition of terminate in the nucleus of the solitary tract (NTS). Inhibition of phrenic and activity seen during active sleep is not observed in cardiac motoneurons results in immediate apnea and bradycardia. the phasic diaphragmatic activity. On the contrary, loss of phasic PVN, postganglionic vagal neuron. and tonic activity of pharyngeal muscles such as the genioglossus makes the upper airway uniquely vulnerable for collapse, especially in preterm infants.38 Furthermore, the overall gain of the apnea, bradycardia and hypertension elicited by instillation of is decreased during sleep as reflected in the liquids into the larynx. This airway protective response is typically decreased slope of the ventilatory response to CO2. associated with laryngeal closure and swallowing as well. These reflex effects can be eliminated by nerve section and decreases with increasing postnatal age.29 Greater reflex effects in the neonatal Insights from transgenic models animals cannot be explained on the basis of greater discharge Genetic and environmental factors may lead to severe respiratory frequencies of the endings in the newborn; instead, it can only be problems including apnea. The genetic cause of Congenital Central explained on the basis of greater inhibition on the respiratory Syndrome, defined by the lack of CO2 neurons in the brainstem. responsiveness during sleep, is the mutation of the developmental Evidence supporting a role for upper airway afferents in transcription factor Phox2B.39 Severe depletion of neurons of the neonatal apnea in humans has emerged slowly over the years. retrotrapezoı¨d nucleus/parafacial respiratory group was observed in 32 Johnson and Salisbury provided the early evidence in human these mice; no other neuronal loss was identified.40 The Rett neonates. Additional evidence for the laryngeal chemoreflex was syndrome, a neurodevelopmental disorder, is caused by mutations 33 provided by Perkett and Vaughan. These investigators in the transcriptional repressor methyl-CpG-binding protein 2 and documented the occurrence of apnea with water infusion but not is accompanied by complex symptoms, including erratic breathing following saline infusion. Indirect evidence for the existence of an and life-threatening .41 Prader–Willi syndrome is caused by inhibitory response induced by upper airway negative pressure in the loss of paternal expression of genes in the 15q11-q13 region. 34 human neonates was provided by Milner et al. These Breathing disorders such as apnea, hypoventilation and blunted investigators documented the development of central apnea during response to changes in CO2 or O2 may be observed from birth. airway occlusions in 10 preterm infants, where as none of the term Respiratory defects similar to those seen in Pradder–Willi infants exhibited this response. Direct evidence supporting the syndrome have been shown in vivo and in vitro in Necdin- inhibitory effect of upper airway negative pressure on inspiration deficient mice.42 These defects are central and are associated with 35 was provided by Thach et al. in tracheostomized human biochemical and anatomical abnormalities of the respiratory neonates. The above observations clearly indicate that stimulation control systems. of laryngeal afferents can induce apnea in human neonates. However, their role in spontaneously occurring AOP is not clear. In newborns of many species including humans, apnea can Neonatal apnea be elicited by irritants, odors and water applied to the face or into Definition and classification the nose. This apneic reflex is mediated by the trigeminal nerves American Academy of Pediatrics43 defined AOP as ‘cessation of and is typically associated with bradycardia and laryngeal closure. breathing that lasts for at least 20 seconds y.’ However, all apneic

Journal of Perinatology Apnea of prematurity OP Mathew 305 episodes are not associated with cessation of breathing; some almost always was preceded by short apneic pauses such as occur in the presence of breathing efforts but are associated observed during periodic breathing. with airway obstruction and cessation of airflow. On the basis of respiratory efforts and airflow apnea has been classified as Relationship to bradycardia central, obstructive or mixed. Mixed apnea constitutes the majority The triad of apnea, bradycardia and oxygen desaturation occurs of apneic episodes.44 frequently in neonatal intensive care units. Air flow is not routinely The primary site of airway obstruction appears to be the monitored clinically. Impedance technique utilized for monitoring pharynx,45 which is the most collapsible portion of the upper breathing does not allow the identification of obstructive and airway. A neuromuscular mechanism is necessary to maintain mixed apnea. The relationship between apnea, bradycardia and airway patency during life.46,47 In the absence of muscle activity, oxygen desaturation has been the focus of numerous clinical pharyngeal airway in the neonate (with the head in the neutral studies. Arterial oxygen tension in preterm infants is typically position) becomes occluded at transmural pressures seen during maintained in the 50 to 80 mm Hg range. Given the slope of the tidal breathing.48 This finding is consistent with the observation oxygen dissociation curve in this range, any significant decrease in made by Safar et al.49 several decades ago. These investigators ventilation because of apnea quickly results in oxygen desaturation noted that the pharyngeal airway can become obstructed during and subsequent bradycardia (Figure 2). It is also clear that during induction of anesthesia when pharyngeal muscle activity is some of apnea and bradycardia episodes, especially in very depressed. Neck flexion can also precipitate airway obstruction in immature infants, bradycardia precedes oxygen desaturation. the neonates.50 Mechanism of development of bradycardia has been subject of 56–58 59 Apnea occurs predominantly during active sleep.51 Activities of debate among various investigators. Carbone et al. reported upper airway muscles are reduced markedly during sleep that apnea and drop in heart rate began simultaneously in 14% of predisposing the upper airway to collapse, especially during medium and 25% of short apneas. Simultaneous development of inspiration when the upper airway is subjected to airway collapsing apnea and bradycardia can be attributed to enhanced inhibitory forces. Milner et al.,52 utilizing the cardiac oscillation normally responses to airway afferent stimulation. Anatomical and present on airflow channel, documented that the airway can become physiological basis for this hypothesis has been compelling in occluded even during central apnea. Further evidence confirming studies utilizing the animal model. Potential relationships between that inspiratory efforts are not essential in the development of upper apnea, bradycardia and oxygen desaturation is schematically airway obstruction was provided by Rigatto et al.53 Lack of upper shown in Figure 2. airway muscle tone during the cessation of central respiratory drive is Along with others, we have documented the sudden onset of 60,61 presumably responsible for this phenomenon. bradyarrhythmias in very low birth weight infants and most of these bradyarrhythmias develop before decreases Relationship to periodic breathing significantly.61 Non-sinus atrial rhythm (atrial escape) was the Periodic breathing occurs predominantly during active sleep. most frequent bradyarrhythmia; this was followed by junctional Although relatively infrequent during the first few days of life, it escape and very rarely ventricular escape.60 This hierarchical becomes more prominent during the first month. Its prevalence response is consistent with increasing vagal tone. approaches 100% in preterm infants weighing <1000 g.54 In very low birth weight infants, periodic breathing is associated with a Relationship to gastroesophageal reflux (GER) significant decrease in minute ventilation and is accompanied by a Both GER and apnea are common in very low birth weight marked decrease in oxygen saturation.54 In fact, periodic breathing infants. GER has been implicated as a cause of apnea in premature is a marker for AOP. Rigatto et al.55 showed that prolonged apnea infants for decades. Yet, there has been no compelling evidence

Figure 2 Probable mechanisms involved in the pathogenesis of apnea of prematurity. Potential relationships between apnea, bradycardia and oxygen desaturation are schematically shown. The most common sequence is shown with filled arrows (modified from reference Mathew56).

Journal of Perinatology Apnea of prematurity OP Mathew 306 supporting a causal relationship between the two. On the contrary, be based on modulating this unstable respiratory rhythm into a some well-designed studies have shown no temporal relationship more stable one. Methylxanthines have become the mainstay in the between GER and apnea.62 A decrease in lower esophageal treatment of AOP. A number of non-pharmacological therapies sphincter tone and increased GER following apnea has been have been attempted over the last few decades. Continuous positive documented.63 It is important to remember that airway protective airway pressure (CPAP) has achieved the most success in this reflexes are elicited when refluxate reaches the laryngeal/ arena of non-pharmacological therapies. For a comprehensive epilaryngeal area and this response includes apnea, laryngeal review of this topic, the reader is referred elsewhere.68 closure and swallowing. Fortunately, this is a rare event in most infants with GER. Results of a masked trial comparing Methyl xanthines and central stimulation metoclopramide and ranitidine with saline placebo in a group of Methyl xanthines have remained as the primary treatment choice preterm infants (each infant serving as his/her own control) in for AOP for three decades69 (see for a review). They are central whom the incidence of bradycardia attributed to clinically stimulants and increase respiratory output. Their effect is not suspected GER were reported recently.64 These results have again mediated through sleep state changes, at least in neurologically reaffirmed the available evidence that anti-reflux medications do normal and clinically stable preterm infants.70 Multiple clinical not reduce bradycardia episodes in preterm infants with GER. trials have shown that both caffeine and are effective treatment for AOP.71–74 Initially theophylline was the standard Apnea termination therapy and it required close monitoring of serum levels. Since Arousal is an integral part of termination of in adults. Food and Drug Administration approval of caffeine, theophylline Peripheral chemoreceptors are presumed to mediate this response. has been largely replaced by caffeine as the first line of We evaluated the role of behavioral arousal in preterm infants with management. Methylxanthines increase minute ventilation, 65 apnea. Behavioral arousal was observed in only a minority of improve CO2 sensitivity, decrease hypoxic depression, enhance episodes (<10%). However, it was more common in prolonged diaphragmatic activity and decrease periodic breathing. The apnea (>15 s) compared with short apnea and during mixed apnea common side effects include , feeding intolerance, compared with central apnea. Also, it was more common during emesis, jitteriness, restlessness and irritability. Toxic levels may apneic episodes with oxygen desaturation <80%. These findings are produce cardiac dysrhythmias and seizures. Methyl xanthines in agreement with the observations in animal models that several increase metabolic rate and oxygen consumption. They also have a factors such as hypoxia, sleep states and airway afferents have a role mild diuretic effect. Caffeine has much less side effects, is better in arousal responses. As electroencephalogram (EEG) recordings tolerated and has a higher therapeutic index compared with were not performed as a part of this study, EEG arousal could not be theophylline. Its long half-life translates into convenient once excluded. The relationship between apnea termination and EEG a day dosing regimen and its large margin of safety means arousal in preterm infants was investigated in a subsequent study by monitoring of caffeine levels at the recommended dosing is 66 Wulbrand et al. These investigators studied 10 preterm infants seldom necessary. longitudinally and observed no EEG changes at apnea termination. Methylxanthines also increase cerebral metabolic rate75 and 67 McNamara et al. observed EEG changes indicative of cortical decrease cerebral flow.76–78 As a result of these findings arousal in only <10% of apneic events among term infants studied there were concerns about the long-term effects of caffeine at a mean age of 9.5 weeks. The lack of correlation between oxygen on brain development. However, results of placebo-controlled saturation and arousal indicates that peripheral chemoreceptor multicenter trials showed that caffeine therapy for AOP reduces input does not have a critical role in terminating apnea in these the incidence of bronchopulmonary dysplasia79 and improves infants. The relative insensitivity of surface EEG to detect sub- survival without neurodevelopmental disability in very low birth cortical arousal in infants is one explanation. A likely explanation, weight infants.80 In this regard, the finding of Back et al.81 that at least for obstructive apnea, is an increase in neuromuscular drive caffeine has a protective effect on chronic hypoxia-induced white 67 overcoming airway closure before the onset of arousal. Local matter is intriguing. neural reflexes that augment the activity of upper airway muscle How methyl xanthines stabilize the respiratory rhythm and may have a role in this. Finally, the apneic event could be the result decrease apnea is not entirely clear. Enhancing the CO2 sensitivity of central respiratory control instability and as such the duration of may be an important component of its effectiveness. Animal studies each event may be predetermined. show that adenosine protects brain cells during experimental hypoxic ischemic episodes.82,83 Methylxanthines are inhibitors of adenosine receptors. Although both A1 and A2 receptors are Treatment strategies involved, a greater role for A2A receptors has recently emerged. Periodic breathing with episodic apnea in premature infants is the Mechanism of action of methylxanthines in reducing apnea may 84 epitome of unstable rhythm. Treatment strategies for AOP should be through blockade of A2A receptors on GABAergic neurons.

Journal of Perinatology Apnea of prematurity OP Mathew 307

Co-localization of A2A receptors on GABAergic neurons in the low flow. A neural mechanism is likely. The nose and the larynx medulla85 has strengthened this argument. are densely innervated and contain both mechanoreceptors and cold receptors. The cold receptors are rapidly adapting and are not Doxapram and peripheral chemoreceptors stimulated by warm humidified air. Therefore, mechanoreceptors Doxapram acts as a nonspecific stimulant on the central nervous are more likely to mediate this response. The site of origin of this system. It has a direct effect on medullary respiratory neuron in response could be nasal or laryngeal. One could test these large doses. However, much smaller doses are used in the treatment hypotheses in well designed studies using local anesthesia. of apnea in preterm infants. In these smaller doses doxapram Conventional has been the backup increases tidal volume and minute ventilation in the newborn.86 option for infants who have significant apnea and bradycardia on These effects are mediated through stimulation of peripheral methylxanthines and nasal CPAP. In recent years, other less chemoreceptors because denervation of peripheral chemoreceptors invasive therapies, such as high flow nasal cannula, and nasal eliminated the increase in ventilation by doxapram at doses intermittent positive pressure ventilation (both synchronized and <6 mg kg–1 (Mitchell and Herbert87). Several studies have shown non-synchronized) have been attempted to avoid endotracheal the effectiveness of doxapram in reducing apnea refractory to intubation and mechanical ventilation in these infants to reduce methylxanthines.86,88 In a blinded, placebo-controlled trial Peliowski the incidence of bronchopulmonary dysplasia. These therapies have et al.89 found no significant difference between theophylline and been successful in some infants. Given the high doxapram. As a result of its poor absorption, it is typically used as a and short inspiratory time as well as the sensitivity and response continuous intravenous infusion. A number of side effects have been time of the triggers used, it is difficult to achieve optimal reported with its use. These include increase in blood pressure, synchronization in the preterm neonate. There is insufficient abdominal distension, irritability, jitteriness, increased gastric residuals evidence to suggest that synchronized nasal ventilation is superior and emesis. Concern about benzyl alcohol, a preservative used in to non-synchronized nasal ventilation. On the basis of evidence doxapram, has limited its use in the United States. from the animal model one could make an argument that synchronized phasic afferent input from the upper airway would CPAP and airway patency have a stabilizing influence on respiratory rhythm. Nasal CPAP is effective in reducing apnea in preterm infants.90 This is especially true when these episodes have an element of Novel/intriguing therapies airway obstruction but it is not effective in central apnea.91 This is Olfactory stimulation. A novel therapy in the form of olfactory the basis to suggest that the primary effect of CPAP is on airway stimulation in premature infants with apnea and bradycardia was 97 patency or its splinting effect. However, CPAP has other effects as reported by Marlier et al. They investigated the effects of a pleasant well. For example, it has an effect on functional residual capacity. odor in preterm infants with apnea and bradycardia that were During active sleep, functional residual capacity decreases because refractory to caffeine and doxapram. Introduction of a pleasant odor of a reduction in tonic and post-inspiratory activity of the into the incubator reduced the incidence of apnea and bradycardia diaphragm.92,93 CPAP can have a beneficial effect on apnea by significantly in this group of preterm infants. It is worth remembering increasing the function residual capacity resulting in better that only a small group of infants were evaluated and that oxygenation. By improving oxygenation, CPAP can decrease the treatment effects were evaluated only for 24 h. Apparent periodic breathing and apnea. Another potential mechanism is lack of side effects is encouraging. A large trial investigating through laryngeal mechanoreceptors. During upper airway positive the effectiveness for a longer period of treatment is warranted. pressure application, inhibitory feedback from mechanoreceptors in 94 98 the upper airway is reduced. This decrease in inhibitory influence Inhaled CO2. Al-Saif et al. evaluated the treatment with low may translate into more stable respiratory rhythm and less apnea. inhaled CO2 in preterm infants with apnea compared with methylxanthines. These investigators concluded that these two Other therapies treatment modalities were similarly effective. Inhaled CO2 reduces Flow through the nasal cannula (both high and low) can be a apnea largely by regularizing breathing. It decreases the amount of useful adjunctive therapy in some infants with apnea who are periodic breathing. Furthermore, inhaled CO2 treatment was not already receiving methylxanthines. High flow produces a associated with any apparent adverse side effects. This is an distending pressure, especially in the very low birth weight infants. intriguing observation from a physiological perspective but is not The magnitude of this distending pressure depends on factors such ready for clinical use. as the flow rate, nasal leak and mouth closure.95 We do not often monitor the airway pressure while using high flow. Benefits Exogenous stochastic stimulation. Low-level exogenous comparable to CPAP have been reported with this form of stochastic stimulation in stabilizing breathing pattern of preterm therapy.96 It is more intriguing to explain the effects of room air infants was tested in a recent study.99 Mechanosensory stimulation

Journal of Perinatology Apnea of prematurity OP Mathew 308 was achieved using actuators embedded within the infant’s 2 Noble LM, Carlo WA, Miller MJ, DiFiore JM, Martin RJ. Transient changes in mattress. The stimulus intensities were subthreshold for causing expiratory time during hypercapnia in premature infants. J Appl Physiol 1987; 62: behavioral arousal or for causing shifts in the power spectrum of 1010–1013. EEG activities. An improvement in breathing stability associated 3 Eichenwald EC, Ungarelli RA, Stark AR. Hypercapnia increases expiratory braking in preterm infants. J Appl Physiol 1993; 75: 2665–2670. with decreased incidence of apneic pauses and a reduction in 4 Martin RJ, Carlo WA, Robertson SS, Day WR, Bruce EN. Biphasic response of O2 destauration was observed. The investigators speculate that the respiratory frequency to hypercapnea in preterm infants. Pediatr Res 1985; 19: effective stimulus was predominantly somatic mechanoreceptors. 791–796. This report should be viewed in the historical context in which 5 Corcoran AE, Hodges MR, Wu Y, Wang W, Wylie CJ, Deneris ES et al. Medullary several attempts at nonspecific afferent stimulation (cutaneous/ serotonin neurons and central CO2 chemoreception. Respir Physiol Neurobiol 2009; 168: 49–58. muscle/joint/vestibular receptors) have resulted in only transient 6 Frantz III ID, Adler SM, Thach BT, Taeusch Jr HW. Maturational effects on 68 beneficial effects. A larger study evaluating the long-term benefits respiratory responses to in premature infants. J Appl Physiol 1976; is indeed needed. 41: 41–45. 7 Rigatto H, Brady JP, de la Torre Verduzco R. Chemoreceptor reflexes in preterm Maturational effects infants: II. The effect of gestational and postnatal age on the ventilatory response to AOP resolves with maturation. In the vast majority of infants, this inhaled carbon dioxide. Pediatrics 1975; 55: 614–620. occurs around 36 weeks postmenstrual age and are symptom free at 8 Gerhardt T, Bancalari E. Apnea of prematurity. 1. function and regulation of breathing. Pediatrics 1984; 74: 58–62. discharge. This often coincides with other signs of brainstem 9 Khan A, Qurashi M, Kwiatkowski K, Cates D, Rigatto H. Measurement of the CO2 maturation, such as suck-swallow co-ordination associated with nipple apneic threshold in newborn infants: possible relevance for periodic breathing and feeding. In the Collaborative Home Infant Monitoring Evaluation apnea. J Appl Physiol 2005; 98: 1171–1176. (CHIME) study, the symptomatic group of preterm infants at 42 to 10 Cross KW, Oppe TE. The effect of of high and low concentration of 45 weeks postconceptional age and thereafter had events similar to oxygen on the respiration of the premature infant. J Physiol 1952; 117: 38. 100 11 Rigatto H, Kalapesi Z, Leahy FN, Durand M, MacCallum M, Cates D. Ventilatory term controls. Physiological basis for the resolution of apnea is response to 100% and 15% O2 during wakefulness and sleep in preterm infants. believed to be myelination of the brainstem. Evidence supporting this Early Hum Dev 1982; 7: 1–10. 101 notionwasprovidedbyanelegantstudybyHenderson-Smartet al. 12 Ang RC, Hoop B, Kazemi H. Role of glutamate as the central neurotransmitter in Utilizing auditory evoked responses, these investigators studied a group the hypoxic ventilatory response. J Appl Physiol 1992; 72: 1480–1487. of babies with and without apnea and showed that brainstem 13 Rigatto H, Brady JP, de la Torre Verduzco R. Chemoreceptor reflexes in preterm conduction time was shorter in infants without apnea when compared infants: I. The effect of gestational and postnatal age on the ventilatory response to inhalation of 100% and 15% oxygen. Pediatrics 1975; 55: 604–613. to preterm infants with apnea. Furthermore, when infants with apnea 14 Alvaro R, Alvarez J, Kwiatkowski K, Cates D, Rigatto H. Small preterm infants (less were longitudinally followed, the time of resolution apnea coincided than or equal to 1500 g) have only a sustained decrease in ventilation in response to with shortening of conduction time, suggesting the onset of hypoxia. Pediatr Res 1992; 32: 403–406. myelination of this pathway. Further indirect supporting evidence was 15 Martin RJ, DiFiore JM, Jana L, Davis RL, Miller MJ, Coles SK et al. Persistence provided by the observation by Eichenwald et al.102 that AOP persists of the biphasic ventilatory response to hypoxia in preterm infants. J Pediatr 1998; well beyond term gestation in the most immature preterm infants 132: 960–964. 16 Eden GJ, Hanson MA. Effects of chronic hypoxia from birth on the ventilatory (24to28weeks).Delayedpostnatalmyelination of these extremely response to acute hypoxia in the newborn rat. J Physiol 1987; 392: 11–19. premature infants is likely to be responsible for this observation. 17 Ling L, Olson Jr EB, Vidruk EH, Mitchell GS. Attenuation of the hypoxic ventilatory Cortical maturation appear to be preserved after moderate response in adult rats following one month of perinatal hyperoxia. J Physiol 1996; prematurity,103 whereas high incidence of white mater injury was seen 495: 561–571. in extremely premature infants at term equivalent age104 and was 18 Katz-Salamon M, Jonsson B, Lagercrantz H. Blunted peripheral chemoreceptor response to hyperoxia in a group of infants with bronchopulmonary dysplasia. associated with neurodevelopmental delay. and Pediatr Pulmonol 1995; 20: 101–106. developmental delay are associated with delay in myelination of 19 Cardot V, Chardon K, Tourneux P, Micallef S, Ste´phan E, Le´ke´ A et al. Ventilatory cerebral white mater. response to a hyperoxic test is related to the frequency of short apneic episodes in late preterm neonates. Pediatr Res 2007; 62: 591–596. 20 Nock ML, Difiore JM, Arko MK, Martin RJ. Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants. J Pediatr 2004; 144: 291–295. Conflict of interest 21 Peng YJ, Rennison J, Prabhakar NR. Intermittent hypoxia augments carotid body The author declares no conflict of interest. and ventilatory response to hypoxia in neonatal rat pups. J Appl Physiol 2004; 97: 2020–2025. 22 Nault MA, Vincent SG, Fisher JT. Mechanisms of capsaicin- and lactic acid-induced in the newborn dog. J Physiol 1999; 515: 567–578. References 23 Sant’Ambrogio G, Widdicombe J. Reflexes from airway rapidly adapting receptors. Respir Physiol 2001; 125: 33–45. 1 Bianchi AL, Gestreau C. The brainstem respiratory network: an overview of a half 24 Fleming PJ, Bryan AC, Bryan MH. Functional immaturity of pulmonary irritant century of research. Respir Physiol Neurobiol 2009; 168: 4–12. receptors and apnea in newborn preterm infants. Pediatrics 1978; 61: 515–518.

Journal of Perinatology Apnea of prematurity OP Mathew 309

25 Widdicombe JG, Sant’Ambrogio G, Mathew OP. Nervous receptors of the upper 50 Thach BT, Stark AR. Spontaneous neck flexion and airway obstruction during airway. In: Mathew OP, Sant’Ambrogio G (eds). Respiratory Function of the Upper apneic spells in preterm infants. J Pediatr 1979; 94: 275–281. Airway. Marcel Dekker: New York, 1988; 193–232. 51 Gabriel M, Albani M, Schulte FJ. Apneic spells and sleep states in preterm infants. 26 Sant’Ambrogio G, Mathew OP, Fisher JT, Sant’Ambrogio FB. Laryngeal Pediatrics 1976; 57: 142–147. mechanoreceptors responding to transmural pressure, airflow and local muscle 52 Milner AD, Boon AW, Saunders RA, Hopkin IE. Upper airways obstruction and activity. Respir Physiol 1983; 54: 317–330. apnoea in preterm babies. Arch Dis Child 1980; 55: 22–25. 27 Sant’Ambrogio G, Mathew OP, Sant’Ambrogio FB, Fisher JT. Laryngeal cold 53 Idiong N, Lemke RP, Lin YJ, Kwiatkowski K, Cates DB, Rigatto H. Airway closure receptors. Respir Physiol 1985; 59: 35–44. during mixed apneas in preterm infants: is respiratory effort necessary? J Pediatr 28 Mathew OP, Sant’Ambrogio G, Fisher JT, Sant’Ambrogio FB. Laryngeal pressure 1998; 133: 509–512. receptors. Respir Physiol 1984; 57: 113–122. 54 Rigatto H. Periodic breathing. In: Mathew OP (ed). Respiratory Control and its 29 Boggs DF, Bartlett Jr D. Chemical specificity of a laryngeal apneic reflex in puppies. Disorders in the Newborn. Marcel Dekker: New York, 2003, pp 237–272. J Appl Physiol 1982; 53: 455–462. 55 Al-Saif S, Alvaro R, Manfreda J, Kwiatkowski K, Cates D, Qurashi M et al. A 30 Mendelowitz D. Superior laryngeal neurons directly excite cardiac vagal neurons randomized controlled trial of theophylline versus CO2 inhalation for treating apnea within the nucleus ambiguus. Brain Res Bull 2000; 51: 135–138. of prematurity. J Pediatr 2008; 153: 513–518. 31 Fisher JT, Mathew OP, Sant’Ambrogio FB, Sant’Ambrogio G. Reflex effects and 56 Mathew OP. Apnea, bradycardia and desaturation: the clinical issues. In: Mathew OP receptor responses to upper airway pressure and flow stimuli in developing puppies. (ed). Respiratory Control and its Disorders in the Newborn. Marcel Dekker: J Appl Physiol 1985; 58: 258–264. New York, 2003, pp 273–293. 32 Johnson P, Salisbury DM. Sucking and breathing during artificial feeding in 57 Henderson-Smart DJ, Butcher-Puech MC, Edwards DA. Incidence and mechanism the human neonate. In: Bosma JF, Showacre J (eds). Development of Upper of bradycardia during apnoea in preterm infants. Arch Dis Child 1986; 61: Respiratory Anatomy and Function. NIH: Bethesda, MD, 1975; 206–211. 227–232. 33 Perkett EA, Vaughan RL. Evidence for a laryngeal chemoreflex in some human 58 Vyas H, Milner AD, Hopkin IE. Relationship between apnoea and bradycardia in preterm infants. Acta Paediatr Scand 1982; 71: 969–972. preterm infants. Acta Paediatr Scand 1981; 70: 785–790. 34 Milner AD, Saunders RA, Hopkin IE. Apnoea induced by airflow obstruction. Arch Dis 59 Carbone T, Marrero LC, Weiss J, Hiatt M, Hegyi T. Heart rate and oxygen saturation Child 1977; 52: 379–382. correlates of infant apnea. J Perinatol 1999; 19: 44–47. 35 Thach BT, Schefft GL, Pickens DL, Menon AP. Influence of upper airway negative 60 Mathew OP, Gamble YD, Zimowski K. Prevalence of bradyarrhythmias during pressure reflex on response to airway occlusion in sleeping infants. J Appl Physiol transient episodes of bradycardia among preterm Infants. J Neonatal-Perinatal 1989; 67: 749–755. Medicine 2008; 1: 43–47. 36 Widdicombe J. Nasal and pharyngeal reflexes. In: Mathew OP, Sant’Ambrogio G 61 Andriessen P, Koolen AM, Bastin FH, Lafeber HN, Meijler FL. Supraventricular escape (eds). Respiratory Function of the Upper Airway. Marcel Dekker: New York, 1988; rhythms during transient episodes of bradycardia in preterm infants. Cardiol Young 233–258. 2001; 11: 626–631. 37 Jacobs BL, Heym J, Trulson ME. Behavioral and physiological correlates of brain 62 Peter CS, Sprodowski N, Bohnhorst B, Silny J, Poets CF. Gastro esophageal reflux serotoninergic unit activity. J Physiol (Paris) 1981; 77: 431–436. and apnea of prematurity: no temporal relationship. Pediatrics 2002; 109: 8–11. 38 Cohen G, Henderson-Smart DJ. Upper airway stability and apnea during nasal 63 Omari TI. Apnea-associated reduction in lower esophageal sphincter tone in occlusion in newborn infants. J Appl Physiol 1986; 60: 1511–1517. premature infants. J Pediatr 2009; 154: 374–378. 39 Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B et al. 64 Wheatley E, Kennedy KA. Cross-over trial of treatment for bradycardia attributed to Polyalanine expansion and frameshift mutations of the paired-like homeobox gastroesophageal reflux in preterm infants. J Pediatr 2009; 155: 516–521. gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 2003; 65 Thoppil CK, Belan MA, Cowen CP, Mathew OP. Behavioral arousal in newborn infants 33: 459–461. and its association with termination of apnea. J Appl Physiol 1991; 70: 2479–2484. 40 Amiel J, Dubreuil V, Ramanantsoa N, Fortin G, Gallego J, Brunet JF et al. PHOX2B 66 Wulbrand H, Von Zezschwitz G, Bentele KHP. Submental and diaphragmatic muscle in respiratory control: lessons from congenital central hypoventilation syndrome and activity during and at resolution of mixed and obstructive apneas and its mouse models. Respir Physiol Neurobiol 2009; 168(1–2): 125–132. cardiorespiratory arousal in preterm infants. Pediatr Res 1995; 38: 298–305. 41 Menuet C, Dutschmann M, Hilaire G. Early breathing defects after moderate hypoxia 67 McNamara F, Issa FQ, Sullivan CE. Arousal pattern following central and obstructive or hypercapnia in a mouse model of Rett syndrome. Respir Physiol Neurobiol 2009; breathing abnormalities in infants and children. J Appl Physiol 1996; 81: 168: 109–118. 2651–2657. 42 Zanella S, Tauber M, Muscatelli F. Breathing deficits of the Prader-Willi syndrome. 68 Lawson EE. Nonpharmacological management of idiopathic apnea of the premature Respir Physiol Neurobiol 2009; 168: 119–124. infant. In: Mathew OP (ed). Respiratory Control and its Disorders in the Newborn. 43 American Academy of Pediatrics, Committee on Fetus and Newborn. Apnea, sudden Marcel Dekker: New York, 2003; 335–354. infant syndrome, and home monitoring. Pediatrics 2003; 111: 914–917. 69 Graham A, Finer NN. Pharmacotherapy of apnea of prematurity. In: Mathew OP (ed). 44 Dransfield DA, Spitzer AR, Fox WW. Episodic airway obstruction in premature Respiratory Control and its Disorders in the Newborn. Marcel Dekker: New York, infants. Am J Dis Child 1983; 137: 441–443. 2003; 317–333. 45 Mathew OP, Roberts JL, Thach BT. Pharyngeal airway obstruction in preterm 70 Curzi-Dascalova L, Aujard Y, Gaultier C, Rajguru M. Sleep organization is unaffected infants during mixed and obstructive apnea. J Pediatr 1982; 100: 964–968. by caffeine in premature infants. J Pediatr 2002; 140: 766–771. 46 Brouillette RT, Thach BT. A neuromuscular mechanism maintaining extrathoracic 71 Bairam A, Boutroy MJ, Badonnel Y, Vert P. Theophylline versus caffeine: comparative airway patency. J Appl Physiol 1979; 46: 772–779. effects in treatment of idiopathic apnea in the preterm infant. J Pediatr 1987; 110: 47 Mathew OP. Maintenance of upper airway patency. J Pediatr 1985; 106: 863–869. 636–639. 48 Wilson SL, Thach BT, Brouillette RT, Abu-Osba YK. Upper airway patency in the 72 Brouard C, Moriette G, Murat I, Flouvat B, Pajot N, Walti H et al. Comparative human infant: influence of airway pressure and posture. J Appl Physiol 1980; 48: efficacy of theophylline and caffeine in the treatment of idiopathic apnea in 500–504. premature infants. Am J Dis Child 1985; 139: 698–700. 49 Safar P, Escarraga LA, Chang F. Upper airway obstruction in the unconscious 73 Sims ME, Yau G, Rambhatla S, Cabal L, Wu PY. Limitations of theophylline in the patient. J Appl Physiol 1959; 14: 760–764. treatment of apnea of prematurity. Am J Dis Child 1985; 139: 567–570.

Journal of Perinatology Apnea of prematurity OP Mathew 310

74 Erenberg A, Leff RD, Haack DG, Mosdell KW, Hicks GM, Wynne BA. Caffeine citrate for 90 Kattwinkel J, Nearman HS, Fanaroff AA, Katona PG, Klaus MH. Apnea of prematurity. the treatment of apnea of prematurity: a double-blind, placebo-controlled study. Comparative therapeutic effects of cutaneous stimulation and nasal continuous Pharmacotherapy 2000; 20: 644–652. . J Pediatr 1975; 86: 588–592. 75 Thurston JH, Hauhard RE, Dirgo JA. Aminophylline increases cerebral metabolic rate 91 Miller MJ, Carlo WA, Martin RF. Continuous positive airway pressure and decreases anoxic survival in young mice. Science 1978; 201: 649–651. selectively reduces obstructive apnea in preterm infants. J Pediatr 1985; 76 McDonnell M, Ives NK, Hope PL. Intravenous aminophylline and cerebral blood flow 106: 91–94. in preterm infants. Arch Dis Child 1992; 67: 416–418. 92 Kosch PC, Stark AR. Dynamic maintenance of end-expiratory lung volume in 77 Hoecker C, Nelle M, Poeschl J, Beedgen B, Linderkamp O. Caffeine impairs cerebral full-term infants. J Appl Physiol 1984; 57: 1126–1133. and intestinal blood flow velocity in preterm infants. Pediatrics 2002; 109: 784–787. 93 Stark AR, Cohlan BA, Waggener TB, Frantz III ID, Kosch PC. Regulation of 78 Chang J, Gray PH. Aminophylline therapy and cerebral blood flow velocity in preterm end-expiratory lung volume during sleep in premature infants. J Appl Physiol 1987; infants. J Paediatr Child Health 1994; 30: 123–125. 62: 1117–1123. 79 Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Caffeine for 94 Mathew OP, Sant’Ambrogio G, Fisher JT, Sant’Ambrogio FB. Laryngeal pressure Apnea of Prematurity Trial Group et al. Long-term effects of caffeine therapy for receptors. Respir Physiol 1984; 57: 113–122. apnea of prematurity. N Engl J Med 2007; 357: 1893–1902. 95 Kubicka ZJ, Limauro J, Darnall RA. Heated, humidified high-flow nasal cannula 80 Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Caffeine for therapy: yet another way to deliver continuous positive airway pressure? Pediatrics Apnea of Prematurity Trial Group et al. Caffeine therapy for apnea of prematurity. 2008; 121: 82–88. N Engl J Med 2006; 354: 2112–2121. 96 Sreenan C, Lemke RP, Hudson-Mason A, Osiovich H. High-flow nasal cannulae in the 81 Back SA, Craig A, Luo NL, Ren J, Akundi RS, Ribeiro I et al. Protective effects of management of apnea of prematurity: a comparison with conventional nasal caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol 2006; continuous positive airway pressure. Pediatrics 2001; 107: 1081–1083. 60: 696–705. 97 Marlier L, Gaugler C, Messer J. Olfactory stimulation prevents apnea in premature 82 Boutilier RG. Mechanisms of cell survival in hypoxia and . J Exp Biol newborns. Pediatrics 2005; 115: 83–88. 2001; 204: 3171–3181. 98 Al-Saif S, Alvaro R, Manfreda J, Kwiatkowski K, Cates D, Qurashi M et al. 83 Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central A randomized controlled trial of theophylline versus CO2 inhalation for treating nervous system. Annu Rev Neurosci 2001; 24: 31–55. apnea of prematurity. J Pediatr 2008; 153: 513–518.

84 Mayer CA, Haxhiu MA, Martin RJ, Wilson CG. Adenosine A2A receptors mediate 99 Bloch-Salisbury E, Indic P, Bednarek F, Paydarfar D. Stabilizing immature breathing GABAergic inhibition of respiration in immature rats. J Appl Physiol 2006; 100: patterns of preterm infants using stochastic mechanosensory stimulation. J Appl 91–97. Physiol 2009; 107: 1017–1027. 85 Zaidi SI, Jafri A, Martin RJ, Haxhiu MA. Adenosine A2A receptors are expressed by 100 Ramanathan R, Corwin MJ, Hunt CE, Lister G, Tinsley LR, Baird T, Collaborative GABAergic neurons of in developing rat. Brain Res 2006; 1071: Home Infant Monitoring Evaluation (CHIME) Study Group et al. Cardiorespiratory 42–53. events recorded on home monitors: Comparison of healthy infants with those at 86 Barrington KJ, Finer NN, Peters KL, Barton J. Physiologic effects of doxapram in increased risk for SIDS. JAMA 2001; 285: 2199–2207. idiopathic apnea of prematurity. J Pediatr 1986; 108: 124–129. 101 Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea and brain-stem 87 Mitchell RA, Herbert DA. Potencies of doxapram and hypoxia in stimulating carotid- neural function in preterm infants. N Engl J Med 1983; 308: 353–357. body chemoreceptors and ventilation in anesthetized cats. Anesthesiology 1975; 42: 102 Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in 559–566. infants delivered at 24 to 28 weeks. Pediatrics 1997; 100: 354–359. 88 Brion LP, Vega-Rich C, Reinersman G, Roth P. Low-dose doxapram for apnea unresponsive 103 Zacharia A, Zimine S, Lovblad KO, Warfield S, Thoeny H, Ozdoba C et al. Early to aminophylline in very low birthweight infants. JPerinatol1991; 11: 359–364. assessment of brain maturation by MR imaging segmentation in neonates and 89 Peliowski A, Finer NN. A blinded, randomized, placebo-controlled trial to compare premature infants. Am J Neuroradiol 2006; 27: 972–977. theophylline and doxapram for the treatment of apnea of prematurity. Pediatr 1990; 104 Inder TE, Warfield SK, Wang H, Hu¨ppi PS, Volpe JJ. Abnormal cerebral structure is 116: 648–653. present at term in premature infants. Pediatrics 2005; 115: 286–294.

Journal of Perinatology