Apnea of prematurity – Perfect storm

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/237003414 Apnea of Prematurity - Perfect Storm. ARTICLE in RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY · MAY 2013 Impact Factor: 1.97 · DOI: 10.1016/j.resp.2013.05.026 · Source: PubMed CITATIONS READS 16 99 3 AUTHORS, INCLUDING: Juliann M Di Fiore Estelle B Gauda 73 PUBLICATIONS 1,298 CITATIONS 83 PUBLICATIONS 1,693 CITATIONS Case Western Reserve University SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. Johns Hopkins Medicine SEE PROFILE Available from: Juliann M Di Fiore Retrieved on: 04 February 2016 ARTICLE IN PRESS G Model RESPNB 2099 1–10 Respiratory Physiology & Neurobiology xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol 1 Review 2 Apnea of prematurity – Perfect storm夽 3 4 5 6 7 Q1 Juliann M. Di Fiore a,∗ , Richard J. Martin a , Estelle B. Gauda b,∗∗ a Department of Pediatrics, Division of Neonatology, Rainbow Babies & Children’s Hospital, Room 3100, 11100 Euclid Avenue, Cleveland, OH 44106, United States b Department of Pediatrics, Division of Neonatology, Neonatology Research Laboratories, Johns Hopkins Medical Institutions, CMSC 6-104, 600 N. Wolfe Q2 Street, Baltimore, MD 21287, United States 8 9 a r t i c l e i n f o a b s t r a c t 10 11 12 Article history: Accepted 21 May 2013 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Keywords: Apnea of prematurity Chronic intermittent hypoxemia Preterm infant Hypoxia Lung inflammation Chronic lung disease Peripheral arterial chemoreceptors Q4 Pulse oximetry With increased survival of preterm infants as young as 23 weeks gestation, maintaining adequate respiration and corresponding oxygenation represents a clinical challenge in this unique patient cohort. Respiratory instability characterized by apnea and periodic breathing occurs in premature infants because of immature development of the respiratory network. While short respiratory pauses and apnea may be of minimal consequence if oxygenation is maintained, they can be problematic if accompanied by chronic intermittent hypoxemia. Underdevelopment of the lung and the resultant lung injury that occurs in this population concurrent with respiratory instability creates the perfect storm leading to frequent episodes of profound and recurrent hypoxemia. Chronic intermittent hypoxemia contributes to the immediate and long term co-morbidities that occur in this population. In this review we discuss the pathophysiology leading to the perfect storm, diagnostic assessment of breathing instability in this unique population and therapeutic interventions that aim to stabilize breathing without contributing to tissue injury. © 2013 Published by Elsevier B.V. 1. Introduction Breathing is an essential, involuntary and dynamic process that is modulated by a multitude of central and peripheral inputs such that oxygen and metabolic demands of cells and tissues can be met. Since the fetus does not rely on ventilation to oxygenate tissues, it is not necessary for breathing to be sustained even though it can be modulated by arterial oxygen tension and blood glucose levels. The primary function of fetal breathing is to provide intermittent stretch for structural development of the lung (Kitterman, 1996; Sanchez-Esteban et al., 2001). For the infant who is born prematurely, central and peripheral mechanisms that control breathing are still “set” for intra-uterine life and breathing is both unsustained and punctuated by frequent respiratory pauses. These respiratory pauses are of minimal consequence to the fetus but can be problematic for the premature infant for which breathing is a prerequisite for life. Apnea of prematurity, therefore, is a developmental disorder that occurs in infants born before 34 weeks gestational age and usually resolves by term 夽 This paper is part of a special issue entitled “Clinical Challenges to Ventilatory Control”, guest-edited by Dr. Gordon Mitchell, Dr. Jan-Marino Ramirez, Dr. Tracy Baker-Herman and Dr. Dr. David Paydarfar. ∗ Corresponding author. Q3 ∗∗ Corresponding author. Tel.: +1 410 614 7232. E-mail addresses: jmd3@case.edu (J.M. Di Fiore), rxm6@case.edu (R.J. Martin), egauda@jhmi.edu (E.B. Gauda). gestation (Henderson-Smart, 1981). However, for infants born less than 28 weeks gestation, apnea can often persist past term gestation (Eichenwald et al., 1997; Hofstetter et al., 2008). While short respiratory pauses should be of little consequence provided that adequate oxygenation is maintained, these apneic pauses can be problematic if associated with intermittent hypoxemia. Chronic intermittent hypoxia (CIH) increases free radical production and contributes to the pathogenesis of adverse outcomes associated with obstructive apnea in adults (Sunderram and Androulakis, 2012) and children (Bass et al., 2004). As we have reported, CIH frequently occurs in premature infants (Di Fiore et al., 2010a,b). Infants with a high frequency of apnea associated with CIH need prolonged respiratory support, take longer to achieve oral feeds, have a greater incidence of retinopathy of prematurity (Di Fiore et al., 2010a,b), and have greater risk of adverse neurodevelopmental outcomes (Martin et al., 2011; Pillekamp et al., 2007). Thus, it is not the apnea per se that is of concern but the associated hypoxemia and/or bradycardia that often accompanies the apnea and compromises oxygenation and perfusion to vital organs and tissues. Paradoxically, the frequency and severity of apnea of prematurity (Miller et al., 1959) and associated CIH often progressively increases during the first weeks of life (Di Fiore et al., 2010a,b). Thus, the most significant clinical challenge is to understand the physiological basis for this paradox – why hypoxemia occurs – and develop therapeutic strategies to prevent CIH associated with apnea of prematurity. Premature infants are also born with underdeveloped lungs that are vulnerable to injury. The concurrent occurrence of an 1569-9048/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.resp.2013.05.026 Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. (2013), http://dx.doi.org/10.1016/j.resp.2013.05.026 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 G Model RESPNB 2099 1–10 2 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 ARTICLE IN PRESS J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology xxx (2013) xxx–xxx “immature respiratory network” and immature lung development creates the perfect storm for apnea of prematurity associated with CIH. In fact, infants with the most severe apnea often have worse lung disease (Eichenwald et al., 1997). While providing supplemental oxygen to premature infants reduces the severity and frequency of apnea and CIH (Weintraub et al., 1992), determining the optimal level of arterial oxygen that prevents CIH without increasing the risk of retinopathy of prematurity remains a clinical challenge. In order to begin to address these challenges, here we review the (1) current understanding of the unique physiology of the developing premature infant that creates the perfect storm, (2) techniques that most accurately assess CIH and its temporal relationship with cardiorespiratory events (apnea and bradycardia), and (3) lastly, the current therapies that target this unique physiology to reduce apnea and associated CIH. 85 2. Pathophysiology–apnea of prematurity and associated chronic intermittent hypoxia 86 2.1. Integrated respiratory network 84 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 The structure and function of all components (sensors, controls and effectors) of the integrated respiratory network are undergoing significant modification during early development such that ventilation progresses from sporadic fetal breathing to more sustained breathing seen in infants born at term gestation (Givan, 2003). The current hypothesis states that respiratory rhythm is generated from the central pattern generator within the ventral brainstem. Inspiration is driven by the pre-Bötzinger complex (PBC) an endogenously bursting group of interneurons that project to premotor inspiratory neurons carrying inspiratory drive throughout the ventral respiratory column and then project to the diaphragm, external intercostals and upper airway muscles (pharyngeal and laryngeal) (Feldman et al., 2012). The retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) generates active expiration to premotor neurons that project to muscles that are involved in active expiration (Feldman et al., 2012). The intrinsic properties and neurotransmitter profiles of respiratory-related neurons in the brainstem may modify peripheral mechano and chemoreceptors that mono or polysynaptically synapse on to respiratory-related neurons. Thus, a stable respiratory pattern that is also dynamic and responsive to metabolic needs depends on the correct balance of excitatory and inhibitory inputs from (1) higher brain centers (frontal and insular cortex, hypothalamus, reticular activating system and amygdala), (2) mechanoreceptors in the lungs and upper airways, (3) peripheral chemoreceptors in the carotid body, and (4) central chemoreceptors on the ventral medullary surface. Lastly, the integrated respiratory output is also dependent on the strength of the synapse between the premotor respiratory neurons and the respiratory motoneurons innervating the diaphragm, chest wall and muscles of the upper airway. Afferent activity originating from mechanoreceptors in the lung and peripheral chemoreceptors have a greater modulatory role on breathing behavior during early postnatal development than later in life (Gauda and Martin, 2012). 2.2. Classification of apnea and its relationship to chronic intermittent hypoxia Apnea of prematurity results from a number of influences (intrinsic and extrinsic) affecting the central respiratory network, peripheral and central chemoreceptors and mechanoreceptors, and ultimately leads to a reduction in output to the muscles of respiration. The chest wall and soft tissues of the upper airway, both of which are quite compliant in premature infants, predispose to upper and lower airway collapse and obstruction. Apnea is categorized as either central, obstructive or mixed. Central apnea is the total cessation of inspiratory efforts with no evidence of obstruction. Obstructive apnea is absence of airflow associated with respiratory movements against a closed larynx or pharynx (Milner et al., 1980). Mixed apnea consists of obstructed respiratory efforts, usually following central pauses. During mixed apnea there is an initial loss of central respiratory drive during the central component, followed by a delayed recovery with activation of upper airway muscles superimposed upon a closed upper airway (Gauda et al., 1987). In preterm infants, mixed apnea is the most frequent, typically accounting for 50% of long apneic episodes, followed by central apnea (Barrington and Finer, 1990). Purely obstructive spontaneous apnea in the absence of positional or fixed anatomical problems is uncommon in infants. While this classification of apnea implies different mechanisms, it is more likely all types are part of a continuum with the speculation that all apnea are a result of low central drive from the integrated respiratory network (Idiong et al., 1998; Waggener et al., 1989). Periodic breathing is a well described oscillatory pattern of breathing that is quite common in premature infants. It is characterized by ventilatory cycles of 10–15 s with pauses of 5–10 s and is thought to be the result of increased peripheral arterial chemoreceptor influence on breathing stability (Al-Matary et al., 2004). Short respiratory pauses during periodic breathing can be associated with desaturations in premature infants, and upper airway obstruction may occur at the onset of the respiratory cycle (Miller et al., 1988). Improvements in oxygen saturation monitoring to reduce false alarms and respiratory monitoring to detect both central and obstructive apnea have allowed for a more careful assessment of the relationship between hypoxemia, bradycardia and apnea. Using respiratory inductance plethysmography, Adams et al. (1997), studied 30 premature infants at a postmenstrual age of 32 ± 2.3 weeks who were born between 24 and 32 weeks to determine the respiratory characteristics associated with severe hypoxemia, defined as <80% saturation for ≥4 s. They found that 25% of hypoxic events were associated with apnea of 15 s, (of which 80% had an obstructive component), 58% were associated with apneic pauses between 4 and 14 s with no change in end-expiratory lung volume,14% were associated with a decrease in end-expiratory lung volume, and 3% of events were not associated with an apnea. Of note, many of the severe hypoxic events were preceded by hypoventilation or arterial oxygen saturations of ≤90% associated with a short apneic pause or periodic breathing (Adams et al., 1997). These early reports are quite similar to our recent observation that premature infants with the lower baseline saturations have a higher number of CIH episodes (Di Fiore et al., 2012b). 2.3. The state of the lung and its contribution to chronic intermittent hypoxia during apnea 2.3.1. End expiratory volumes Adequate lung volumes at the end of expiration (functional residual capacity, FRC), normal pulmonary vascular resistance, normal hypoxic pulmonary vasoconstriction (HPV), and rapid recovery of ventilation mediated by peripheral and central chemoreceptors are all operative in preventing rapid desaturations from occurring and persisting during apnea. Premature infants are particularly prone to inadequate end expiratory lung volumes due to excessive chest wall compliance leading to distal airway closure (Poets et al., 1997; Poets, 2010). Activation of chest wall muscles substantially contributes to chest wall stability and maintaining FRC (Lopes et al., 1981) which is problematic as premature infants spend >80% of their sleep in indeterminant and active sleep, a state associated with tonic inhibition of chest wall muscles (Lopes et al., 1981). Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. (2013), http://dx.doi.org/10.1016/j.resp.2013.05.026 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 G Model RESPNB 2099 1–10 ARTICLE IN PRESS J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology xxx (2013) xxx–xxx 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 Prone sleeping position stabilizes the chest wall and increases FRC and oxygen saturation in infants with and without BPD (Kassim et al., 2007; Saiki et al., 2009). In fact, prone sleeping position may improve arterial oxygen saturation to a greater extent in infants with chronic lung disease (Kassim et al., 2007) by also optimizing VA/Q. Vagally mediated reflexes, specifically the Breuer–Hering (B–H) deflation and inflation reflex, modify inspiratory and expiratory time in infants (Widdicombe, 2006). Specifically, the deflation reflex shortens expiration and prolongs inspiration during lung deflation. However, the deflation reflex is less active in premature than it is term infants (Hannam et al., 1998). To compensate for these challenges, preterm infants have a high respiratory rate and activate rapidly adapting receptors (RARs) during lung deflation. Stimulating RARs in the lung induces an augmented breath (sigh) of which premature infants have greater frequency than term infants. These augmented breaths are frequently followed by apnea in premature infants (Alvarez et al., 1993; Poets et al., 1997). It is important to maintain adequate FRC since it serves as an oxygen buffer that prevents the fall in oxygen saturation during a respiratory pause. This has been shown in premature infants of 36 wks PCA with a reduction in FRC during apnea that was inversely correlated with the speed of hemoglobin desaturation (Poets et al., 1997). In younger premature infants, of 32 ± 2 weeks PCA, Adams et al. (1997) found that 14% of apneas were accompanied by severe hypoxemia (<80% for at least 4 s) and lower expiratory lung volumes. Although neither group of infants received respiratory support at the time of study, intubation has been shown to be only partially successful at stabilizing oxygen saturation and expiratory lung volume (Bolivar et al., 1995). Infants at 24–28 weeks gestation have a progressive increase in CIH during the first 3 weeks of postnatal development, followed by a plateau and slow decline by 8 weeks of postnatal life (Di Fiore et al., 2010a,b). Taken together, these data suggest that premature infants are prone to low expiratory lung volumes predisposing them to a profound and rapid fall in arterial saturation during apnea. 2.3.2. Baseline oxygen saturation In an attempt to prevent the injurious effects of oxygen exposure on the developing lung and retina, it is common practice in some neonatal intensive care units to titrate oxygen levels to maintain oxygen saturation between 85 and 92%. However, a lower baseline saturation of ≤90%, initiated by hypoventilation (Adams et al., 1997), or maintained because of current clinical practice (Bashambu et al., 2012; Kassim et al., 2007) can destabilize breathing and induce CIH in premature infants (Rigatto and Brady, 1972). Recent multicenter trials have shown a reduction in the incidence of severe ROP with an oxygen saturation target of 85–89% versus 91–95%. Unexpectedly, the lower saturation target was associated with an as yet unexplained increase in mortality. (Stenson et al., 2011; SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, 2010). The current challenge is identifying the optimal oxygen concentration that prevents CIH, minimizes abnormal development of retinal vessels and avoids death. We address some potential strategies to accomplish this goal in section 4.0 of this review. 2.3.3. Lung development It is easy to understand why premature infants are prone to hypoxemia if the stage of lung development at the time of birth is taken into account. This is especially true for infants born between 23 and 27 weeks of gestation. At this gestational age, lung development is at the canalicular stage where cellular differentiation gives rise to surfactant producing Type II pneumocytes but the respiratory units are still quite immature (Hislop, 2005) (Fig. 1). At this time, a more direct interaction and cross-talk between 3 endothelial and epithelial cells drives the differentiation of each cell type via growth factor signaling pathways (Hislop, 2005; Jakkula et al., 2000). For example, VEGF binding to its receptor Flk-1 is essential for angiogenesis of the pulmonary vasculature and the continued differentiation of the canalicula into alveoli. Inhibitors of Flk-1 receptor reduces the number of arteries and alveoli (Le Cras et al., 2002). Hyperoxia reduces VEGF transcription by inhibiting hypoxia inducible factor, HIF-1␣ production which is associated with altered lung development. Thus, inhibition of VEGF signaling either by reducing VEGF levels or blocking the receptor causes a reduced number and simplification of alveoli, reduced number of small pulmonary arteries, persistence of smooth muscle in distal pulmonary arteries, and an altered pattern of vascular distribution (Abman, 2010; Hislop et al., 1987; Mourani et al., 2009). At birth, premature infants have reduced alveoli-capillary surface area and, therefore, an increased diffusion barrier for gas exchange due to an unformed 2 cell layer endothelial/epithelial unit needed for gas exchange. Thus, regardless of the level of surfactant deficiency, the architecture of the lung in premature infants predisposes to impaired gas exchange at birth (Backstrom et al., 2011). 2.3.4. Lung Inflammation Ex-utero exposure to higher oxygen tensions (breathing 21% oxygen can be toxic to developing lungs), increases the production of free radicals that can initiate an inflammatory cascade causing cellular injury and disruption of normal maturation of tissues and organs. Furthermore, premature infants are often exposed to infection and inflammatory agents prior to birth and thereafter. Some premature infants born to mothers with chorioamnionitis have minimal respiratory distress syndrome and oxygen requirements at birth but then progress to significant chronic lung disease (Shimoya et al., 2000; Watterberg et al., 1996). Thus, the progressive inflammation that occurs in the lung of premature infants is temporally related to a progressive increase in chronic intermittent hypoxia that is observed during the first 2 week of postnatal life: perhaps there is a cause and effect. While local inflammation injures tissues and cells within a given organ, studies in older animals show that local inflammation can activate brain circuits via vagally-mediated process (Gakis et al., 2009; Hale et al., 2012). We have shown that LPS (0.1 mg/kg) instilled into the trachea of newborn rat pups at day of life (10–12) increases inflammatory cytokine gene expression in the medulla oblongata and attenuates both the immediate and late hypoxic ventilatory response when animals were tested within 3 h of treatment (Balan et al., 2011). It is not known whether lung inflammation in particular or inflammation in general modifies vagally mediated reflexes that affect lung volume, such as pulmonary stretch and rapidly adapting receptors in premature infants. Clinically, apnea increases in frequency and severity during acute infections in premature infants (Hofstetter et al., 2008). Although, inflammatory cytokines do not directly cross the blood brain barrier, systemic infection does up regulate inflammatory cytokines in the brain and other modulators such as prostaglandins via a IL-1␤ mechanisms that inhibits respiration in newborns (Olsson et al., 2003). Direct application of IL-1␤ into the nucleus tractus solitarii of the isolated brainstem–spinal cord preparation removed from rat pups between 0 and 4 days postnatal age significantly slows fictive breathing (Gresham et al., 2011). The maturation of the respiratory network in rat pups at birth is comparable to that of a 32 week infant (Darnall, 2010). 2.4. The contribution of the carotid body to unstable breathing The carotid body, located in the bifurcation of the carotid artery, has specialized cells that rapidly depolarize during hypoxia, hypercarbia and acidosis. In fact, these chemoreceptors are responsible Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. (2013), http://dx.doi.org/10.1016/j.resp.2013.05.026 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 G Model RESPNB 2099 1–10 4 ARTICLE IN PRESS J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology xxx (2013) xxx–xxx Fig. 1. Schematic depicting the stages of fetal lung development. The lung is at the canalicular stage of fetal lung development in premature infants who are born at 23–27 weeks gestational age. At the canalicular stage, respiratory bronchioles, alveolar ducts and primitive alveoli are starting to develop; epithelial cells are differentiating into type I and type II pneumocytes with type II pneumocytes producing surfactant. Lastly, the alveolar duct arteries are giving rise to the alveolar capillaries. However, the distance between the developing air sacs and capillary is much greater than that of the alveolar stage of lung development which occurs at 36 wks gestation. At the alveolar stage, terminal airways are differentiating into alveolar air sacs, microvasculature matures and the capillaries fuse. The epithelial cells flatten with marked reduction in the alveoli-capillary diffusion barrier exchange unit which becomes 2 cells thick as represented in the schematic. Adapted from Hislop (2005) permission from Elsevier. for initiating the reflex that causes an immediate (within seconds) and rapid rise in ventilation in response to hypoxia (Gonzalez 321 et al., 1994; Kumar and Prabhakar, 2012). In contrast, during hyper322 oxia or hypocapnia, output from the carotid body immediately 323 decreases associated with an immediate and rapid fall in ventila324 tion sometimes leading to short apneas (Dejours, 1962). However, 325 during sustained (min) exposure to hypoxia, the rise in ventila326 tion initiated by the carotid body is followed by a decline (Martin 327 et al., 1998), known as hypoxic ventilatory decline (HVD). Dur328 ing HVD, the carotid sinus nerve activity remains elevated, as 329 shown in experiments performed in animals (Vizek et al., 1987). 330 HVD is centrally mediated with major inhibitory projections orig331 inating in the pons and involving inhibitory neuromodulators, a 332 major one of which is adenosine (Easton and Anthonisen, 1988; 333 Koos et al., 2005; Walker, 1984; Yan et al., 1995). This may con334 tribute to the improved central respiratory drive after adenosine 335 receptors are blocked with caffeine or aminophylline in prema336 ture infants (Henderson-Smart and De Paoli, 2010). Alternatively, 337 adenosine 2A receptors have been shown to constrain expression 338 of serotonin-dependent phrenic and hypoglossal long term facili339 Q5 tation following acute intermittent hypoxia (Hoffman et al., 2010). 340 Therefore, caffeine may stabilize breathing through adenosine 2A 341 inhibition increasing intermittent hypoxia induced plasticity. 342 A functioning carotid body is not necessary for the initiation 343 of breathing after birth because the higher oxygen tension that 344 occurs in the transition from fetal to ex utero life inhibits its activity. 345 Chemosensitive cells within the carotid body then reset to a higher 346 oxygen tension within a few days after birth. Thereafter, chemosen347 sitivity of the carotid chemoreceptors increases with postnatal 348 maturation (Gauda et al., 2009; Gauda and Lawson, 2000). Although 349 central chemoreceptors, located in the brainstem are considered 319 320 the main chemoreceptors that modulate breathing in response to changes in pCO2 or H+ , carotid chemoreceptors also respond to changes in arterial pCO2 (Khan et al., 2005). Thus, rapid changes in arterial oxygen and carbon dioxide tension will have a significant effect on ventilation in premature infants. High sensitivity of the carotid chemoreceptors has been associated with periodic breathing, a prominent and frequent breathing pattern observed in premature infants that decreases with postnatal maturation (Al-Matary et al., 2004; Wilkinson et al., 2007). Periodic breathing and significant apnea occur infrequently during the first week after birth (Barrington and Finer, 1990; Edwards et al., 2013; Miller et al., 1959), as does CIH (Di Fiore et al., 2010a,b). Decreased peripheral chemoreceptor activity at this time may contribute to the low incidence of periodic breathing in the early postnatal period. The subsequent development of periodic breathing appears to be associated with the combination of high peripheral chemosensitivity to hypoxia and an apneic pCO2 threshold that is only within 1–2 Torr of the eupneic pCO2 level. Despite the prominent role of peripheral chemoreceptors in initiating periodic breathing, it is becoming increasingly clear that the peripheral chemoreceptors modulate central chemoreceptor responses to pCO2 (Blain et al., 2010). In addition, sighs (augmented breaths) stimulated by low lung volumes, markedly reduce arterial pCO2 , and increase arterial pO2 , and are often immediately followed by an apneic pause in premature infants (Alvarez et al., 1993). Decreased peripheral chemosensitivity may delay resolution of apnea and onset of spontaneous respiration during the transition from fetal to neonatal life or under hyperoxic conditions. In contrast, increased peripheral chemosenstivity may contribute to initiation of periodic breathing and apnea as discussed above. An area of considerable interest is the role of altered neonatal Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. (2013), http://dx.doi.org/10.1016/j.resp.2013.05.026 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 G Model RESPNB 2099 1–10 ARTICLE IN PRESS J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology xxx (2013) xxx–xxx 393 peripheral chemoreceptor function on respiratory control on later life. Animal data from neonatal rodent models suggest that CIH exposure has long lasting effects on respiratory control mediated via alterations in sensitization (Prabhakar et al., 2006). Other data in neonatal CIH exposed rodents have demonstrated increased normoxic ventilation, decreased acute hypoxic response and decreased phrenic long term facilitation following acute intermittent hypoxia compared to normoxic exposed rats (Reeves et al., 2006). The results of these studies are clearly influenced by the timing, duration and age at the time of IH exposure. This plasticity in respiratory neural output induced by IH may also be modulated by inflammatory mechanisms to which neonates may be exposed both pre and postnatally (Huxtable et al., 2011). 394 2.5. The perfect storm-incited by inflammation 381 382 383 384 385 386 387 388 389 390 391 392 424 As briefly outlined above, systemic inflammation and infection can have a profound influence on the frequency of apnea. Inflammation during early development also leads to arrested development of the airways and vasculature with associated changes in airway and vascular physiology. Arrested vascular development causes persistent pulmonary hypertension in human infants and blunted hypoxic pulmonary vasoconstriction as has been demonstrated in animal models of chronic lung disease (Rey-Parra et al., 2008). Altered pulmonary vascular function may also contribute to the rapid hypoxemia that develops during apnea in infants with chronic lung disease. We have recently reported, in a newborn rat model, that inflammation may also alter the structure and function of the carotid body, and increase frequency of apnea for at least 1 week after the acute inflammatory episode (Gauda et al., 2013). Over time, inflammatory processes causing metaplasticity within peripheral and central circuits that control breathing are likely to occur (Huxtable et al., 2011). Furthermore, environmental exposures during maturation of central and peripheral mechanisms that control breathing may cause maldevelopment thereby placing premature infants at greater risk for persistent ineffective reflex responses during cardiorespiratory challenges such as feeding, sleeping and infections that may persist after reaching term gestation and being discharged to home (Gauda et al., 2007). There is considerable current interest in the role of inflammation as may occur both before and after birth on respiratory control via potential effects at the carotid body or in the brainstem (Gauda et al., 2013). The adverse consequences of inflammation on the developing respiratory network and lung create the perfect storm leading to CIH (Fig. 2) and its associated short and long term co-morbidities in premature infants. 425 3. Diagnostic challenges 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 Cardiorespiratory monitoring is a vital component of clinical care of the neonate. Accurate measurements of respiration, oxygen saturation and heart rate are imperative in detection of clinical apnea during both spontaneous breathing and respiratory support. Continuous measurements of oxygen saturation are needed for both detection of intermittent hypoxemia events and to maintain infants within a safe oxygen saturation target range while uninterrupted ECG waveforms are necessary to document periods of cardiac instability. 3.1. Respiration Respiratory instability in the preterm infant can be attributed to immaturity of the central nervous system and a highly compliant chest wall resulting in both central and obstructive apnea. During normal respiration the diaphragm contracts, expanding the thorax, in conjunction with activation of accessory muscles that stabilize 5 Fig. 2. Schematic depicting the perfect storm: the consequences of the adverse effects of prenatal or postnatal inflammation on the developing lung and respiratory network leading to the emergence of chronic intermittent hypoxia in premature infants. See text, Section 2.5 for additional details. the rib cage and maintain upper airway patency. Due to the highly compliant chest wall of the preterm infant, any loss of accessory muscle tone (i.e. intercostals stabilizing the rib cage or hypoglossal maintaining upper airway patency) may result in instability and retraction of the rib cage in response to negative pressure generated by the diaphragm during inspiration. As a result asynchronous or paradoxical chest wall movements will occur with partial airway obstruction – a common respiratory pattern in the preterm infant particularly during REM sleep. During extreme occasions total airway obstruction may occur presenting as asynchronous chest wall and abdominal efforts and no corresponding airflow. Respiratory pauses may also arise due to decreased central respiratory drive as can occur during periods of periodic breathing and spontaneous central apnea. Therefore, ideal respiratory monitoring should have the ability to detect both central and obstructive apnea. 3.1.1. Flow sensors The pneumotachometer is considered the gold standard for measuring flow and volume giving the most accurate measurements needed for calculations of respiratory mechanics. Its use in the clinical setting has been limited to intubated patients or spontaneously breathing patients if it is incorporated into a sealed nasal/oral mask. To maintain precision all flow must pass through the device which is problematic with the high occurrence of endotracheal tube leaks. In addition, it adds a resistive load to the patient. With a high frequency-response, proven accuracy and minimal inspiratory and expiratory flow resistance, many companies have replaced the pneumotachometer with the hot-wire anemometer for volume measurements during mechanical ventilation. End tidal CO2 and thermistor/thermocouple sensors have a minimal role in the measurement of respiration at the patient bedside. With poor correlation with quantitative measures of tidal volume their implementation is limited to the sleep lab where, used in conjunction with chest wall motion sensors (see below), they can be used to identify the presence or absence of flow associated with central and obstructive apnea. Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. (2013), http://dx.doi.org/10.1016/j.resp.2013.05.026 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 G Model RESPNB 2099 1–10 6 ARTICLE IN PRESS J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology xxx (2013) xxx–xxx 511 3.1.2. Chest wall motion sensors Impedance technology is the most widely used modality for measuring respiration in the hospital setting. With two electrodes placed on either side of the chest, above and below the insertion of the diaphragm, impedance monitoring measures changes in electrical impedance across the thorax that occur during a breath. This modality is based on the principle that air has a much higher level of impedance when compared to tissue. During inspiration, there is a decrease in conductivity (and corresponding increase in impedance) due to both an increase in gas volume of the chest in relation to the fluid volume and increased length of the conductance path with chest wall expansion. The advantage of impedance monitoring is that it can be obtained from ECG electrodes allowing for long term measurements of respiration in a non-invasive manner. However, as air moves from one compartment to the other during periods of obstruction, impedance monitoring cannot distinguish obstructive efforts from normal respiration. Respiratory inductance plethysmography (RIP) has been used extensively in both clinical research and pulmonary function lab settings. It is currently not utilized at the bedside but could be a promising alternative choice for respiratory monitoring. As with impedance, it is a non-invasive method of measuring respiration with two bands wrapped around the chest wall and abdominal areas. As the chest wall and abdomen expand each band elongates. This elongation causes an extension of the sinusoidal shaped wire in the band with a corresponding increase in inductance. The strength of this modality is the presentation of respiration as a two dimensional model. Thus obstructive apnea will present as asynchronous, 180◦ out of phase movements between the rib cage and abdomen. With the addition of a software algorithm to calibrate the rib cage and abdominal waveforms, a semi-quantitative volume waveform van be acquired (Somnostar, Carefusion, San Diego, CA) giving RIP the ability to identify obstructive apnea without the need for a oral/nasal flow sensor. Even with this advantage over impedance technology RIP has yet to make its way into clinical bedside monitoring. 512 3.2. Blood gas status 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 Estimates of oxygen and carbon dioxide blood levels are routinely utilized in neonatal intensive care. Invasive arterial sampling via indwelling catheters is relied on for the most accurate and direct measurements but limited to intermittent monitoring. In addition, prolonged catheter placement can lead to infection and other morbidities. Alternative technology allowing for continuous measurements of oxygen is widespread in preterm infants who are notorious for having transient rapid fluctuations in oxygenation. 3.2.1. Oxygen Pulse oximetry is the most widely used method for continuous, non-invasive, monitoring of oxygenation using a small probe taped around the infant’s foot that requires no calibration or heating of the skin. Pulse oximetry is based on the principle that oxygenated hemoglobin absorbs light in the infrared (940 nm) light wavelength spectrum while deoxygenated hemoglobin absorbs light in the red (660 nm) wavelength spectrum. The amount of hemoglobin saturated with oxygen can be calculated by measuring pulsatile changes in the transmission of light passing through the extremity in each of these wavelength spectrums. Factors affecting its accuracy include poor peripheral perfusion, medical dyes, hypothermia and sensitivity to motion artifact resulting in loss of signal and a high incidence of false alarms. Advances in motion artifact reduction software algorithms have shown improvement in reducing false alarms (Hay et al., 2002) with the added cost of an increased incidence of missed events (Bohnhorst et al., 2002). Additional signal processing concerns include the averaging time which can be modified by the user. Common clinical practice has promoted the use of a long averaging time (16 s) to reduce false alarms. Recent data have shown that a long averaging time will reduce the number of short (<20 s) desaturation events while increasing the number and duration of events >20 s. This is most likely due to short desaturation events being averaged into one prolonged event. In contrast, the averaging time had no effect on the time spent in different SpO2 ranges (Vagedes et al., 2012). The relationship between oxygen saturation and oxygen tension is described by the oxygen dissociation curve. Although the oxygen dissociation curve presents data in the total range of oxygen saturation levels there is increased variability at greater and lower SpO2 levels with optimal accuracy limited to the range of 89–95% (Hay et al., 1989). Studies have reported median baseline oxygen saturation levels of 97–99% in healthy preterm infants in room air (Ng et al., 1998; Poets et al., 1991). As the dissociation curve begins to plateau with SpO2 levels >95%, a high monitor alarm above this threshold may result in hyperoxic exposure in infants requiring supplemental oxygen (Bohnhorst et al., 2002). Surprisingly, with a multitude of studies including recent multi center trials investigating oxygen saturation ranges in preterm infants (Stenson et al., 2011, SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, 2010) the optimal target range continues to elude us. Regardless of the chosen oxygen saturation target range prevention of intermittent hypoxemia continues to be a challenge in patient care as such events have been associated with morbidity in preterm infants. Future care will most likely include automated feedback controllers that have been shown to increase time in target range (Claure et al., 2011) (see Section 3.3). In contrast to pulse oximetery which measures arterial oxygen saturation, near-infrared spectroscopy (NIRS) uses a similar technology of light wavelength (700–1000 nm) transmission to measure the difference between oxyhemoglobin and deoxyhemoglobin, a reflection of oxygen uptake in the tissue bed (Martin et al., 2011). NIRS has been shown to provide an earlier warning of alterations in oxygenation when compared to pulse oximetry (Tobias et al., 2008) and has the ability to detect tissue perfusion in a range of organ systems (Petrova and Mehta, 2006). A limitation of NIRS is the lack of absolute normal values, whereby the patient must serve as their own baseline. Decreasing oxygenation is then defined as a change or percent of baseline as opposed to a drop below a given threshold. 3.2.2. Carbon dioxide Maintaining normocarbia and avoiding hypo- or hypercarbia has been proposed to prevent a range of neonatal morbidities (Erickson et al., 2002; Garland et al., 1995; McKee et al., 2009; Okumura et al., 2001). With risks associated with invasive peripheral or arterial catheters, continuous measurements of end tidal or transcutaneous CO2 monitoring may assist in minimizing morbidity. End tidal CO2 monitoring uses infrared absorption or mass spectroscopy to estimate CO2 from samples acquired during exhalation and has been shown to have good correlation with PaCO2 in both term and healthy preterm infants (Molloy and Deakins, 2006). However, with small tidal volumes and high respiratory rates PetCO2 may underestimate true alveolar gas values in preterm infants. For example, in ventilated very low birth weight infants capnography has been shown to have a good correlation but poor agreement with PaCO2 especially in infants with severe pulmonary disease (Trevisanuto et al., 2012). Transcutaneous CO2 detectors are an alternative mode of non invasive CO2 monitoring which have been shown to be superior to PetCO2 for infants on high frequency oscillatory ventilation. However, heated electrodes require repeated repositioning of the sensor to avoid skin damage due to burns. Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. (2013), http://dx.doi.org/10.1016/j.resp.2013.05.026 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 G Model RESPNB 2099 1–10 ARTICLE IN PRESS J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology xxx (2013) xxx–xxx 612 Disposable colorimetric end tidal CO2 detectors are an efficient method of verifying correct endotracheal tube placement (Wyllie and Carlo, 2006). When placed between the ventilator and endotracheal tube, the pH sensitive chemical indicator (metacresol purple) changes from purple to yellow when exposed to expired CO2 . As neonatal extubation failure can have devastating consequences calorimetric detectors can play a significant role in the intensive care unit. However, this device cannot detect right main stem bronchus intubation or oropharyngeal intubations in spontaneous breathing patients. 613 3.3. Heart rate 603 604 605 606 607 608 609 610 611 625 Acquiring an acceptable EKG in the preterm infant can be challenging. Common causes of EKG artifact or poor waveform resolution include inadequate electrode adhesiveness, excessive gel on the skin surface and improper position of electrodes. Baird et al. (1992) have shown the optimal position for electrode placement is one electrode at the right mid-clavicle and one at the xyphoid. Additional care must be taken with the extremely low birth weight infants as stripping of the stratum corneum layer of the skin can occur during electrode removal. More sophisticated processing of the EKG waveform includes application of additional filters to reduce noise and Holter monitoring for more extensive analysis including evaluation of abnormal cardiac rhythms. 626 3.4. Future diagnostic challenges 614 615 616 617 618 619 620 621 622 623 624 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 Common clinical practice has included simplified summaries of cardiorespiratory waveforms such as mean oxygen saturation, respiratory and heart rate recorded in the medical charts. More recently, with increases in memory storage and software capabilities of bedside monitors, this has expanded to include more detailed information such as percent time in given oxygen saturation target ranges and the ability to review short term raw waveform tracings of clinical cardiorespiratory events. However, with continuous monitoring of respiration, heart rate and oxygen saturation there is a tremendous amount of information that is never utilized. This is predominantly due to the lack of available memory to store long term waveforms and the inability to manage this massive amount of data in a way that can be useful for clinical practice. The challenges of this area of research include collecting, storing and processing raw waveform files of substantial size. Data can be downloaded from each bedside monitor manually or in mass by a centralized data acquisition system. Although less labor intensive, the latter protocol has the additional challenge of dealing with linking waveform files with the correct patient as they can often move between patient rooms. Once data are collected, corrected for missing data and filtered to remove noise/artefact – an important component that can affect the final analysis – appropriate signal processing models can be applied. These models may include simple statistical measures (i.e. mean, standard deviation) as well as more sophisticated linear and nonlinear models (ie, spectral analysis, sample entropy). These models have the ability to identify subtle transient changes in waveform patterns associated with morbidity that are not visually apparent. This concept has been applied to EKG waveforms by Moorman et al. (2011) who developed a multivariable statistical predictive model of cardiovascular oscillations and neonatal sepsis, known in the commercial market as HeRO (MPSC, Charlottesville, VA). Similar linear and nonlinear mathematical models including sample entropy and wavelet analysis have identified oxygen saturation patterns associated with retinopathy of prematurity (ROP) with severe ROP being associated with a higher incidence of intermittent hypoxia of more variable, longer and less severe duration (Di Fiore et al., 2012a). With the development and implementation of electronic medical 7 records, large memory capacity of database servers and the continued progress in identifying at risk patterns of heart rate, oxygen saturation and respiration, future improvements in diagnostic challenges will most likely include the exploitation of these longer term recordings to improve patient care. 4. Biologic basis for therapeutic interventions The aggressiveness with which therapy is pursued in apneic preterm infants must weigh the potential consequences of apnea and resultant desaturation and bradycardia, with the natural history which favors spontaneous resolution of these episodes with advancing maturation. For the most widely used therapies, namely continuous positive airway pressure (CPAP) and methyl xanthines, we are still gaining knowledge of their precise mechanisms of action. While these two approaches are both effective and safe, we need to explore other potential treatments which address the mechanisms underlying immature respiratory control in preterm infants. We will focus this discussion on potential future, as well as established, therapies. 4.1. Inhibition of proinflammatory responses This is an intriguing area of investigation (as already discussed), and is based on two fundamental clinical observations. The first is that neonatal sepsis typically presents with apnea; the second is that maternal chorioamnionitis is associated with significant neurorespiratory morbidity in preterm infants. In rat pups systemic administration of the cytokine IL-1␤ inhibited respiratory activity, both at rest and in response to hypoxia, and this respiratory inhibition was diminished by prior blockade of prostaglandin synthesis with indomethacin (Olsson et al., 2003). The same investigators demonstrated evidence for IL-1␤ binding to IL-1 receptors on vascular endothelial cells of the blood brain barrier during a systemic immune response. Activation of the IL-1 receptor, in turn, induces synthesis of prostaglandin E2 which is then released into respiratory related regions of the brain stem, resulting in altered respiratory rhythm; this may provide a substrate for the altered breathing patterns seen in neonates battling infection (Hofstetter et al., 2007). As noted earlier, subsequent data from our own group have demonstrated that intrapulmonary instillation of endotoxin (LPS) in rat pups generates a rapid expression of the proinflammatory cytokine IL-1␤ in respiratory related brainstem regions and accompanying enhancement of hypoxic respiratory depression (Balan et al., 2011; Gresham et al., 2011). These data suggest that where feasible, prevention of a prenatal or postnatal inflammatory milieu would benefit neonatal respiratory control. 4.2. Optimization of mechanosensory inputs Care of preterm infants requires an optimal thermosensory environment and maximal opportunity for parental interaction and physical contact (so-called Kangaroo care) with their infant. Unfortunately, the latter approach, while it should be encouraged, has not been shown to enhance respiratory control. The respiratory rhythm-generating circuitry within the central nervous system (CNS) depends on intrinsic rhythmic activity and sensory afferent inputs to generate breathing movement. Bloch-Salisbury et al. (2009) have demonstrated that their novel technique of stochastic mechanosensory stimulation, using a mattress with imbedded acuators, is able to stabilize respiratory patterns in preterm infants as manifest by a decrease in apnea and an almost threefold decrease in percentage of time with oxygen saturations <85%. Interestingly, the level of stimulation employed was below the minimum threshold for behavioral arousal to wakefulness, thus inducing no apparent state change in the infants, and the effect could probably not be Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. (2013), http://dx.doi.org/10.1016/j.resp.2013.05.026 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 G Model RESPNB 2099 1–10 8 ARTICLE IN PRESS J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology xxx (2013) xxx–xxx 726 attributed to the minimal increase in sound level associated with stimulation. Such an approach is clearly worthy of future study. 727 4.3. Optimization of gas exchange and blood gas status 725 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 It has long been suspected that targeting a lower baseline oxygen saturation in infants with bronchopulmonary dysplasia (BPD) results in more desaturation (McEvoy et al., 1993). Meanwhile, multiple large trials, some of which are ongoing, have randomized infants to two different levels of baseline oxygen saturation in order to identify resultant morbidity. Based on a need for prolonged oxygen supplementation when levels of 95% are targeted, the current focus is on 85–89% versus 90–95% oxygen in preterm infants <28 weeks’ gestation. While the lower targeted range is associated with less retinopathy of prematurity (ROP), there is a significantly higher mortality in this group (Stenson et al. 2011; SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, 2010). In a subgroup of infants from the latter trial, we have identified a higher incidence of intermittent hypoxic episodes in the low oxygen targeted group (Di Fiore et al., 2012b). Intermittent hypoxic episodes are almost always the result of respiratory pauses, apnea, or ineffective ventilation. It is unclear whether targeting a lower baseline oxygen saturation increases the incidence of apnea with resultant hypoxemia, or whether the incidence of apnea is comparable between oxygen targets, but the lower oxygen saturation baseline predisposes to more frequent or profound intermittent hypoxemia. However, given the potential oxidative stress associated with intermittent hypoxic episodes, the latter are probably best avoided (Martin et al., 2011; Prabhakar et al., 2001). Automated control of inspired oxygen is under study. This automated technique has been compared to routine adjustments of inspired oxygen as performed by clinical personnel in infants of 24–27 weeks’ gestation (Claure et al., 2011). During the automated period, time with oxygen saturation within the intended range of 87–93% increased significantly, and times in the hyperoxic range were significantly reduced. This was not associated with a clear benefit for hypoxic episodes, nonetheless, future refinement of this technology may prove useful to minimize intermittent hypoxia. Finally, a novel approach is supplementation of inspired air with a very low concentration of supplemental CO2 to increase respiratory drive (Alvaro et al., 2012). While of interest from a physiologic perspective, and likely to be successful in decreasing apnea, it is doubtful that this would gain widespread clinical acceptance as most preterm infants have residual lung disease and are prone to baseline hypercapnia, which may make clinicians reluctant to administer supplemental inspired CO2 . 4.4. Continuous positive airway pressure (CPAP) CPAP, ranging from about 2 to 6 cm H2 O has proven a relatively safe and effective therapy for 40 years. It has a dual function to stabilize lung volume and improve airway patency by limiting upper airway closure. Because longer episodes of apnea frequently involve an obstructive component, CPAP appears to be effective by “splinting” the upper airway with positive pressure and decreasing the risk of pharyngeal or laryngeal obstruction. At the lower functional residual capacity which accompanies many preterm infants with residual lung disease, pulmonary oxygen stores are probably reduced and there is a very short time from cessation of breathing to onset of desaturation and bradycardia. Nasal CPAP is well tolerated in most preterm infants, however, high-flow nasal cannula therapy has been suggested as an equivalent treatment modality that may allow CPAP delivery while enhancing mobility of the infant. Some questions remain about the safety and efficacy of devices that provide relatively unregulated high flow as a means of CPAP delivery. 4.5. Prevention of gastroesophageal reflux Preterm infants commonly exhibit not only apnea, bradycardia, oxygen desaturation, but also gastroesophageal reflux (GER) events. As all of these events occur during early postnatal life, often a causal relationship is assumed, resulting in widespread use of anti-reflux medications to reduce the occurrence of cardiorespiratory events. However, the evidence for an association between GER and cardiorespiratory events remains controversial. There is ample evidence for potent and potentially protective respiratory inhibitory reflexes from laryngopharyngeal stimulation in both infants and animal models. It is, therefore, likely that if acidic or non-acidic refluxate reaches this region apnea would result. It has been recently proposed that non-acid, rather than acid, reflux is more likely to elicit a respiratory pause (Corvaglia et al., 2009). Despite the development of investigative tools to differentiate acid versus non-acid refluxate, it is difficult to identify the small number of infants whose apnea may be precipitated by GER. Our own data from a large cohort of preterm infants indicate that only approximately 3% of apnea related events are preceded by GER (Di Fiore et al., 2010a,b). However, in a small case series in former preterm infants at post term gestation, persistent cardiorespiratory events temporally associated with GER were resolved after surgical treatment (Nunez et al., 2011). 4.6. Methylxanthine therapy Xanthine therapy has been used to prevent and treat apnea of prematurity since the 1970s. Its primary mechanism of action in the perinatal period is thought to be blockade of inhibitory adenosine A1 receptors with resultant excitation of respiratory neural output (Herlenius et al., 2002). An alternative mechanism of caffeine action is blockade of excitatory adenosine A2A receptors at GABAergic neurons and resultant decrease in GABA output, resulting in excitation of respiratory neural output (Mayer et al., 2006). These complex neurotransmitter interactions elicited by caffeine led to concerns regarding its safety and a large multicenter trial was undertaken in the 1990s. The results of this study have demonstrated that caffeine treatment is effective in decreasing the rate of BPD and improving neurodevelopmental outcome at 18–21 months, especially in those receiving respiratory support (Davis et al., 2010; Schmidt et al., 2007). It is possible that this benefit is secondary to decrease in apnea and resultant intermittent hypoxic episodes; however, this is speculative. Clearly, improved pulmonary outcomes in premature infants treated with caffeine suggest that development affords some unique properties as to how adenosine receptors may be affecting inflammation as it might for neuroinflammation in newborn animals (Brothers et al., 2010). In adult models, blockade of excitatory adenosine A2A receptors augments instead of attenuates ventilator assisted lung injury (Chen et al., 2009). On the other hand, caffeine attenuates lung injury via an alternative pathway that does not involve adenosine receptors which is dose dependent (Li et al., 2011). In premature infants, caffeine is associated with either a pro- or anti-inflammatory cytokine profile depending on the serum level (Chavez et al., 2011). The clinical benefits of xanthine therapy in preterm infants should trigger interest in a ‘bedside-to-bench’ approach to enhance our understanding of underlying mechanisms. References Abman, S.H., 2010. Impaired vascular endothelial growth factor signaling in the pathogenesis of neonatal pulmonary vascular disease. Advances in Bladder Research 661, 323–335, http://dx.doi.org/10.1007/978-1-60761-500-2 21. Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. 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Adenosine A2A-receptor blockade abolishes the roll-off respiratory response to hypoxia in awake lambs. Please cite this article in press as: Di Fiore, J.M., et al., Apnea of prematurity – Perfect storm. Respir. Physiol. Neurobiol. 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