Apnea of Prematurity – Perfect Storm

Home , Apnea of prematurity, Hypoxemia

Respiratory Physiology & Neurobiology 189 (2013) 213–222

Contents lists available at ScienceDirect

Respiratory Physiology & Neurobiology

j ournal homepage: www.elsevier.com/locate/resphysiol

Review

ଝ

Apnea of prematurity – Perfect storm

a,∗ a b,∗∗

Juliann M. Di Fiore , Richard J. Martin , Estelle B. Gauda

Department of Pediatrics, Division of Neonatology, Rainbow Babies & Children’s Hospital, Room 3100, 11100 Euclid Avenue, Cleveland, OH 44106, United States

Department of Pediatrics, Division of Neonatology, Neonatology Research Laboratories, Johns Hopkins Medical Institutions, CMSC 6-104, 600 N. Wolfe

Street, Baltimore, MD 21287, United States

a r t i c l e i n f o a b s t r a c t

Article history: With increased survival of preterm infants as young as 23 weeks gestation, maintaining adequate res-

Accepted 21 May 2013

piration 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

Keywords:

of immature development of the respiratory network. While short respiratory pauses and apnea may be

Preterm infant

of minimal consequence if oxygenation is maintained, they can be problematic if accompanied by chronic

Hypoxia

intermittent hypoxemia. Underdevelopment of the lung and the resultant lung injury that occurs in this

Lung inﬂammation

population concurrent with respiratory instability creates the perfect storm leading to frequent episodes

Chronic lung disease

of profound and recurrent hypoxemia. Chronic intermittent hypoxemia contributes to the immediate and

Peripheral arterial chemoreceptors

long term co-morbidities that occur in this population. In this review we discuss the pathophysiology

Pulse oximetry

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.

1. Introduction gestation (Henderson-Smart, 1981). However, for infants born

less than 28 weeks gestation, apnea can often persist past term

Breathing is an essential, involuntary and dynamic process gestation (Eichenwald et al., 1997; Hofstetter et al., 2008). While

that is modulated by a multitude of central and peripheral inputs short respiratory pauses should be of little consequence provided

such that oxygen and metabolic demands of cells and tissues can that adequate oxygenation is maintained, these apneic pauses can

be met. Since the fetus does not rely on ventilation to oxygenate be problematic if associated with intermittent hypoxemia.

tissues, it is not necessary for breathing to be sustained even Chronic intermittent hypoxia (CIH) increases free radical pro-

though it can be modulated by arterial oxygen tension and blood duction and contributes to the pathogenesis of adverse outcomes

glucose levels. The primary function of fetal breathing is to pro- associated with obstructive apnea in adults (Sunderram and

vide intermittent stretch for structural development of the lung Androulakis, 2012) and children (Bass et al., 2004). As we have

(Kitterman, 1996; Sanchez-Esteban et al., 2001). For the infant reported, CIH frequently occurs in premature infants (Di Fiore et al.,

who is born prematurely, central and peripheral mechanisms that 2010a,b). Infants with a high frequency of apnea associated with

control breathing are still “set” for intra-uterine life and breathing CIH need prolonged respiratory support, take longer to achieve oral

is both unsustained and punctuated by frequent respiratory feeds, have a greater incidence of retinopathy of prematurity (Di

pauses. These respiratory pauses are of minimal consequence Fiore et al., 2010a,b), and have greater risk of adverse neurodevel-

to the fetus but can be problematic for the premature infant for opmental outcomes (Martin et al., 2011; Pillekamp et al., 2007).

which breathing is a prerequisite for life. Apnea of prematurity, Thus, it is not the apnea per se that is of concern but the associated

therefore, is a developmental disorder that occurs in infants born hypoxemia and/or bradycardia that often accompanies the apnea

before 34 weeks gestational age and usually resolves by term and compromises oxygenation and perfusion to vital organs and

tissues. Paradoxically, the frequency and severity of apnea of pre-

maturity (Miller et al., 1959) and associated CIH often progressively

increases during the ﬁrst weeks of life (Di Fiore et al., 2010a,b).

ଝ

This paper is part of a special issue entitled “Clinical Challenges to Ventilatory Thus, the most signiﬁcant clinical challenge is to understand the

Control”, guest-edited by Dr. Gordon Mitchell, Dr. Jan-Marino Ramirez, Dr. Tracy physiological basis for this paradox – why hypoxemia occurs –

Baker-Herman and Dr. Dr. David Paydarfar.

∗ and develop therapeutic strategies to prevent CIH associated with

Corresponding author.

∗∗ apnea of prematurity.

Corresponding author. Tel.: +1 410 614 7232.

Premature infants are also born with underdeveloped lungs

E-mail addresses: [email protected] (J.M. Di Fiore), [email protected] (R.J. Martin),

[email protected] (E.B. Gauda). that are vulnerable to injury. The concurrent occurrence of an

214 J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222

“immature respiratory network” and immature lung development of which are quite compliant in premature infants, predispose to

creates the perfect storm for apnea of prematurity associated with upper and lower airway collapse and obstruction.

CIH. In fact, infants with the most severe apnea often have worse Apnea is categorized as either central, obstructive or mixed.

lung disease (Eichenwald et al., 1997). While providing supple- Central apnea is the total cessation of inspiratory efforts with no

mental oxygen to premature infants reduces the severity and evidence of obstruction. Obstructive apnea is absence of airﬂow

frequency of apnea and CIH (Weintraub et al., 1992), determining associated with respiratory movements against a closed larynx or

the optimal level of arterial oxygen that prevents CIH without pharynx (Milner et al., 1980). Mixed apnea consists of obstructed

increasing the risk of retinopathy of prematurity remains a clinical respiratory efforts, usually following central pauses. During mixed

challenge. In order to begin to address these challenges, here we apnea there is an initial loss of central respiratory drive during the

review the (1) current understanding of the unique physiology of central component, followed by a delayed recovery with activa-

the developing premature infant that creates the perfect storm, tion of upper airway muscles superimposed upon a closed upper

(2) techniques that most accurately assess CIH and its temporal airway (Gauda et al., 1987). In preterm infants, mixed apnea is the

relationship with cardiorespiratory events (apnea and bradycar- most frequent, typically accounting for 50% of long apneic episodes,

dia), and (3) lastly, the current therapies that target this unique followed by central apnea (Barrington and Finer, 1990). Purely

physiology to reduce apnea and associated CIH. obstructive spontaneous apnea in the absence of positional or ﬁxed

anatomical problems is uncommon in infants. While this classiﬁ-

cation of apnea implies different mechanisms, it is more likely all

2. Pathophysiology–apnea of prematurity and associated types are part of a continuum with the speculation that all apnea

chronic intermittent hypoxia are a result of low central drive from the integrated respiratory net-

work (Idiong et al., 1998; Waggener et al., 1989). Periodic breathing

2.1. Integrated respiratory network is a well described oscillatory pattern of breathing that is quite com-

mon in premature infants. It is characterized by ventilatory cycles

The structure and function of all components (sensors, controls of 10–15 s with pauses of 5–10 s and is thought to be the result of

and effectors) of the integrated respiratory network are undergoing increased peripheral arterial chemoreceptor inﬂuence on breathing

signiﬁcant modiﬁcation during early development such that venti- stability (Al-Matary et al., 2004). Short respiratory pauses during

lation progresses from sporadic fetal breathing to more sustained periodic breathing can be associated with desaturations in prema-

breathing seen in infants born at term gestation (Givan, 2003). The ture infants, and upper airway obstruction may occur at the onset

current hypothesis states that respiratory rhythm is generated from of the respiratory cycle (Miller et al., 1988).

the central pattern generator within the ventral brainstem. Inspira- Improvements in oxygen saturation monitoring to reduce false

tion is driven by the pre-Bötzinger complex (PBC) an endogenously alarms and respiratory monitoring to detect both central and

bursting group of interneurons that project to premotor inspi- obstructive apnea have allowed for a more careful assessment of

ratory neurons carrying inspiratory drive throughout the ventral the relationship between hypoxemia, bradycardia and apnea. Using

respiratory column and then project to the diaphragm, external respiratory inductance plethysmography, Adams et al. (1997),

intercostals and upper airway muscles (pharyngeal and laryngeal) studied 30 premature infants at a postmenstrual age of 32 2.3

(Feldman et al., 2013). The retrotrapezoid nucleus/parafacial respi- weeks who were born between 24 and 32 weeks to determine

ratory group (RTN/pFRG) generates active expiration to premotor the respiratory characteristics associated with severe hypoxemia,

≥

neurons that project to muscles that are involved in active expira- deﬁned as <80% saturation for 4 s. They found that 25% of hypoxic

tion (Feldman et al., 2013). events were associated with apnea of 15 s, (of which 80% had an

The intrinsic properties and neurotransmitter proﬁles of obstructive component), 58% were associated with apneic pauses

respiratory-related neurons in the brainstem may modify periph- between 4 and 14 s with no change in end-expiratory lung vol-

eral mechano and chemoreceptors that mono or polysynaptically ume,14% were associated with a decrease in end-expiratory lung

synapse on to respiratory-related neurons. Thus, a stable respi- volume, and 3% of events were not associated with an apnea.

ratory pattern that is also dynamic and responsive to metabolic Of note, many of the severe hypoxic events were preceded by

≤

needs depends on the correct balance of excitatory and inhibitory hypoventilation or arterial oxygen saturations of 90% associated

inputs from (1) higher brain centers (frontal and insular cor- with a short apneic pause or periodic breathing (Adams et al., 1997).

tex, hypothalamus, reticular activating system and amygdala), (2) These early reports are quite similar to our recent observation that

mechanoreceptors in the lungs and upper airways, (3) peripheral premature infants with the lower baseline saturations have a higher

chemoreceptors in the carotid body, and (4) central chemore- number of CIH episodes (Di Fiore et al., 2012b).

ceptors on the ventral medullary surface. Lastly, the integrated

respiratory output is also dependent on the strength of the synapse 2.3. The state of the lung and its contribution to chronic

between the premotor respiratory neurons and the respiratory intermittent hypoxia during apnea

motoneurons innervating the diaphragm, chest wall and muscles

of the upper airway. Afferent activity originating from mechanore- 2.3.1. End expiratory volumes

ceptors in the lung and peripheral chemoreceptors have a greater Adequate lung volumes at the end of expiration (functional

modulatory role on breathing behavior during early postnatal residual capacity, FRC), normal pulmonary vascular resistance, nor-

development than later in life (Gauda and Martin, 2012). mal hypoxic pulmonary vasoconstriction (HPV), and rapid recovery

of ventilation mediated by peripheral and central chemoreceptors

are all operative in preventing rapid desaturations from occurring

2.2. Classiﬁcation of apnea and its relationship to chronic and persisting during apnea. Premature infants are particularly

intermittent hypoxia prone to inadequate end expiratory lung volumes due to exces-

sive chest wall compliance leading to distal airway closure (Poets

Apnea of prematurity results from a number of inﬂuences et al., 1997; Poets, 2010). Activation of chest wall muscles substan-

(intrinsic and extrinsic) affecting the central respiratory network, tially contributes to chest wall stability and maintaining FRC (Lopes

peripheral and central chemoreceptors and mechanoreceptors, and et al., 1981) which is problematic as premature infants spend >80%

ultimately leads to a reduction in output to the muscles of respi- of their sleep in indeterminant and active sleep, a state associated

ration. The chest wall and soft tissues of the upper airway, both with tonic inhibition of chest wall muscles (Lopes et al., 1981).

J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222 215

Prone sleeping position stabilizes the chest wall and increases FRC endothelial and epithelial cells drives the differentiation of each cell

and oxygen saturation in infants with and without BPD (Kassim type via growth factor signaling pathways (Hislop, 2005; Jakkula

et al., 2007; Saiki et al., 2009). In fact, prone sleeping position may et al., 2000). For example, VEGF binding to its receptor Flk-1 is

improve arterial oxygen saturation to a greater extent in infants essential for angiogenesis of the pulmonary vasculature and the

with chronic lung disease (Kassim et al., 2007) by also optimizing continued differentiation of the canalicula into alveoli. Inhibitors of

VA/Q. Flk-1 receptor reduces the number of arteries and alveoli (Le Cras

Vagally mediated reﬂexes, speciﬁcally the Breuer–Hering (B–H) et al., 2002). Hyperoxia reduces VEGF transcription by inhibiting

deflation and inflation reflex, modify inspiratory and expiratory hypoxia inducible factor, HIF-1␣ production which is associated

time in infants (Widdicombe, 2006). Speciﬁcally, the deﬂation with altered lung development. Thus, inhibition of VEGF signaling

reﬂex shortens expiration and prolongs inspiration during lung either by reducing VEGF levels or blocking the receptor causes a

deflation. However, the deflation reflex is less active in prema- reduced number and simplification of alveoli, reduced number of

ture than it is term infants (Hannam et al., 1998). To compensate small pulmonary arteries, persistence of smooth muscle in distal

for these challenges, preterm infants have a high respiratory rate pulmonary arteries, and an altered pattern of vascular distribu-

and activate rapidly adapting receptors (RARs) during lung deﬂa- tion (Abman, 2010; Hislop et al., 1987; Mourani et al., 2009). At

tion. Stimulating RARs in the lung induces an augmented breath birth, premature infants have reduced alveoli-capillary surface area

(sigh) of which premature infants have greater frequency than term and, therefore, an increased diffusion barrier for gas exchange due

infants. These augmented breaths are frequently followed by apnea to an unformed 2 cell layer endothelial/epithelial unit needed for

in premature infants (Alvarez et al., 1993; Poets et al., 1997). gas exchange. Thus, regardless of the level of surfactant deﬁciency,

It is important to maintain adequate FRC since it serves as an the architecture of the lung in premature infants predisposes to

oxygen buffer that prevents the fall in oxygen saturation during a impaired gas exchange at birth (Backstrom et al., 2011).

respiratory pause. This has been shown in premature infants of 36

wks PCA with a reduction in FRC during apnea that was inversely 2.3.4. Lung Inﬂammation

correlated with the speed of hemoglobin desaturation (Poets et al., Ex-utero exposure to higher oxygen tensions (breathing 21%

1997). In younger premature infants, of 32 ± 2 weeks PCA, Adams oxygen can be toxic to developing lungs), increases the production

et al. (1997) found that 14% of apneas were accompanied by of free radicals that can initiate an inﬂammatory cascade caus-

severe hypoxemia (<80% for at least 4 s) and lower expiratory lung ing cellular injury and disruption of normal maturation of tissues

volumes. Although neither group of infants received respiratory and organs. Furthermore, premature infants are often exposed to

support at the time of study, intubation has been shown to be only infection and inﬂammatory agents prior to birth and thereafter.

partially successful at stabilizing oxygen saturation and expiratory Some premature infants born to mothers with chorioamnionitis

lung volume (Bolivar et al., 1995). Infants at 24–28 weeks gesta- have minimal respiratory distress syndrome and oxygen require-

tion have a progressive increase in CIH during the ﬁrst 3 weeks of ments at birth but then progress to signiﬁcant chronic lung disease

postnatal development, followed by a plateau and slow decline by (Shimoya et al., 2000; Watterberg et al., 1996). Thus, the progres-

8 weeks of postnatal life (Di Fiore et al., 2010a,b). Taken together, sive inﬂammation that occurs in the lung of premature infants is

these data suggest that premature infants are prone to low expira- temporally related to a progressive increase in chronic intermittent

tory lung volumes predisposing them to a profound and rapid fall hypoxia that is observed during the ﬁrst 2 weeks of postnatal life:

in arterial saturation during apnea. perhaps there is a cause and effect.

While local inﬂammation injures tissues and cells within a given

2.3.2. Baseline oxygen saturation organ, studies in older animals show that local inﬂammation can

In an attempt to prevent the injurious effects of oxygen expo- activate brain circuits via vagally-mediated processes (Gakis et al.,

sure on the developing lung and retina, it is common practice in 2009; Hale et al., 2012). We have shown that LPS (0.1 mg/kg)

some neonatal intensive care units to titrate oxygen levels to main- instilled into the trachea of newborn rat pups at day of life (10–12)

tain oxygen saturation between 85 and 92%. However, a lower increases inﬂammatory cytokine gene expression in the medulla

baseline saturation of ≤90%, initiated by hypoventilation (Adams oblongata and attenuates both the immediate and late hypoxic ven-

et al., 1997), or maintained because of current clinical practice tilatory response when animals were tested within 3 h of treatment

(Bashambu et al., 2012; Kassim et al., 2007) can destabilize breath- (Balan et al., 2011). It is not known whether lung inﬂammation in

ing and induce CIH in premature infants (Rigatto and Brady, 1972). particular or inﬂammation in general modiﬁes vagally mediated

Recent multicenter trials have shown a reduction in the incidence reﬂexes that affect lung volume, such as pulmonary stretch and

of severe ROP with an oxygen saturation target of 85–89% versus rapidly adapting receptors in premature infants. Clinically, apnea

91–95%. Unexpectedly, the lower saturation target was associ- increases in frequency and severity during acute infections in pre-

ated with an as yet unexplained increase in mortality. (Stenson mature infants (Hofstetter et al., 2008). Although, inﬂammatory

et al., 2011; SUPPORT Study Group of the Eunice Kennedy Shriver cytokines do not directly cross the blood brain barrier, systemic

NICHD Neonatal Research Network, 2010). The current challenge infection does up regulate inﬂammatory cytokines in the brain and

␤

is identifying the optimal oxygen concentration that prevents CIH, other modulators such as prostaglandins via IL-1 mechanisms

minimizes abnormal development of retinal vessels and avoids that inhibits respiration in newborns (Olsson et al., 2003). Direct

␤

death. We address some potential strategies to accomplish this goal application of IL-1 into the nucleus tractus solitarii of the iso-

in section 4.0 of this review. lated brainstem–spinal cord preparation removed from rat pups

between 0 and 4 days postnatal age signiﬁcantly slows ﬁctive

2.3.3. Lung development breathing (Gresham et al., 2011). The maturation of the respira-

It is easy to understand why premature infants are prone to tory network in rat pups at birth is comparable to that of a 32 week

hypoxemia if the stage of lung development at the time of birth is infant (Darnall, 2010).

taken into account. This is especially true for infants born between

23 and 27 weeks of gestation. At this gestational age, lung devel- 2.4. The contribution of the carotid body to unstable breathing

opment is at the canalicular stage where cellular differentiation

gives rise to surfactant producing Type II pneumocytes but the The carotid body, located in the bifurcation of the carotid artery,

respiratory units are still quite immature (Hislop, 2005) (Fig. 1). has specialized cells that rapidly depolarize during hypoxia, hyper-

At this time, a more direct interaction and cross-talk between carbia and acidosis. In fact, these chemoreceptors are responsible

216 J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222

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) the main chemoreceptors that modulate breathing in response to

and rapid rise in ventilation in response to hypoxia (Gonzalez changes in pCO2 or H , carotid chemoreceptors also respond to

et al., 1994; Kumar and Prabhakar, 2012). In contrast, during hyper- changes in arterial pCO2 (Khan et al., 2005). Thus, rapid changes in

oxia or hypocapnia, output from the carotid body immediately arterial oxygen and carbon dioxide tension will have a signiﬁcant

decreases associated with an immediate and rapid fall in ventila- effect on ventilation in premature infants.

tion sometimes leading to short apneas (Dejours, 1962). However, High sensitivity of the carotid chemoreceptors has been associ-

during sustained (min) exposure to hypoxia, the rise in ventila- ated with periodic breathing, a prominent and frequent breathing

tion initiated by the carotid body is followed by a decline (Martin pattern observed in premature infants that decreases with post-

et al., 1998), known as hypoxic ventilatory decline (HVD). Dur- natal maturation (Al-Matary et al., 2004; Wilkinson et al., 2007).

ing HVD, the carotid sinus nerve activity remains elevated, as Periodic breathing and signiﬁcant apnea occur infrequently dur-

shown in experiments performed in animals (Vizek et al., 1987). ing the ﬁrst week after birth (Barrington and Finer, 1990; Edwards

HVD is centrally mediated with major inhibitory projections orig- et al., 2013; Miller et al., 1959), as does CIH (Di Fiore et al.,

inating in the pons and involving inhibitory neuromodulators, a 2010a,b). Decreased peripheral chemoreceptor activity at this time

major one of which is adenosine (Easton and Anthonisen, 1988; may contribute to the low incidence of periodic breathing in

Koos et al., 2005; Walker, 1984; Yan et al., 1995). This may con- the early postnatal period. The subsequent development of peri-

tribute to the improved central respiratory drive after adenosine odic breathing appears to be associated with the combination of

receptors are blocked with caffeine or aminophylline in prema- high peripheral chemosensitivity to hypoxia and an apneic pCO2

ture infants (Henderson-Smart and De Paoli, 2010). Alternatively, threshold that is only within 1–2 Torr of the eupneic pCO2 level.

adenosine 2A receptors have been shown to constrain expression Despite the prominent role of peripheral chemoreceptors in ini-

of serotonin-dependent phrenic and hypoglossal long term facili- tiating periodic breathing, it is becoming increasingly clear that

tation following acute intermittent hypoxia (Hoffman et al., 2010). the peripheral chemoreceptors modulate central chemoreceptor

Therefore, caffeine may stabilize breathing through adenosine 2A responses to pCO2 (Blain et al., 2010). In addition, sighs (augmented

inhibition increasing intermittent hypoxia induced plasticity. breaths) stimulated by low lung volumes, markedly reduce arterial

A functioning carotid body is not necessary for the initiation pCO2, and increase arterial pO2, and are often immediately followed

of breathing after birth because the higher oxygen tension that by an apneic pause in premature infants (Alvarez et al., 1993).

occurs in the transition from fetal to ex utero life inhibits its activity. Decreased peripheral chemosensitivity may delay resolution of

Chemosensitive cells within the carotid body then reset to a higher apnea and onset of spontaneous respiration during the transition

oxygen tension within a few days after birth. Thereafter, chemosen- from fetal to neonatal life or under hyperoxic conditions. In

sitivity of the carotid chemoreceptors increases with postnatal contrast, increased peripheral chemosenstivity may contribute

maturation (Gauda et al., 2009; Gauda and Lawson, 2000). Although to initiation of periodic breathing and apnea as discussed above.

central chemoreceptors, located in the brainstem are considered An area of considerable interest is the role of altered neonatal

J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222 217

peripheral chemoreceptor function on respiratory control in 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 intermit-

tent 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).

2.5. The perfect storm-incited by inﬂammation

As brieﬂy outlined above, systemic inﬂammation and infection

can have a profound inﬂuence on the frequency of apnea. Inﬂamma-

tion 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). Fig. 2. Schematic depicting the perfect storm: the consequences of the adverse

effects of prenatal or postnatal inﬂammation on the developing lung and respira-

Altered pulmonary vascular function may also contribute to the

tory network leading to the emergence of chronic intermittent hypoxia in premature

rapid hypoxemia that develops during apnea in infants with chronic

infants. See text, Section 2.5 for additional details.

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). the rib cage and maintain upper airway patency. Due to the highly

Over time, inﬂammatory processes causing metaplasticity within compliant chest wall of the preterm infant, any loss of accessory

peripheral and central circuits that control breathing are likely to muscle tone (i.e. intercostals stabilizing the rib cage or hypoglos-

occur (Huxtable et al., 2011). Furthermore, environmental expo- sal maintaining upper airway patency) may result in instability and

sures during maturation of central and peripheral mechanisms retraction of the rib cage in response to negative pressure generated

that control breathing may cause maldevelopment thereby pla- by the diaphragm during inspiration. As a result, asynchronous or

cing premature infants at greater risk for persistent ineffective paradoxical chest wall movements will occur with partial airway

reﬂex responses during cardiorespiratory challenges such as feed- obstruction – a common respiratory pattern in the preterm infant

ing, sleeping and infections that may persist after reaching term particularly during REM sleep. During extreme occasions total air-

gestation and being discharged to home (Gauda et al., 2007). There way obstruction may occur presenting as asynchronous chest wall

is considerable current interest in the role of inﬂammation as may and abdominal efforts and no corresponding airﬂow. Respiratory

occur both before and after birth on respiratory control via poten- pauses may also arise due to decreased central respiratory drive

tial effects at the carotid body or in the brainstem (Gauda et al., as can occur during periods of periodic breathing and spontaneous

2013). The adverse consequences of inﬂammation on the develop- central apnea. Therefore, ideal respiratory monitoring should have

ing respiratory network and lung create the perfect storm leading the ability to detect both central and obstructive apnea.

to CIH (Fig. 2) and its associated short and long term co-morbidities

in premature infants.

3.1.1. Flow sensors

The pneumotachometer is considered the gold standard for mea-

3. Diagnostic challenges

suring ﬂow and volume giving the most accurate measurements

needed for calculations of respiratory mechanics. Its use in the clin-

Cardiorespiratory monitoring is a vital component of clinical

ical setting has been limited to intubated patients or spontaneously

care of the neonate. Accurate measurements of respiration, oxy-

breathing patients if it is incorporated into a sealed nasal/oral

gen saturation and heart rate are imperative in detection of clinical

mask. To maintain precision all ﬂow must pass through the device

apnea during both spontaneous breathing and respiratory support.

which is problematic with the high occurrence of endotracheal tube

Continuous measurements of oxygen saturation are needed for

leaks. In addition, it adds a resistive load to the patient. With a

both detection of intermittent hypoxemia events and to maintain

high frequency-response, proven accuracy and minimal inspira-

infants within a safe oxygen saturation target range while unin-

tory and expiratory ﬂow resistance, many companies have replaced

terrupted ECG waveforms are necessary to document periods of

the pneumotachometer with the hot-wire anemometer for volume

cardiac instability.

measurements during mechanical ventilation.

End tidal CO and thermistor/thermocouple sensors have a mini-

3.1. Respiration 2

mal role in the measurement of respiration at the patient bedside.

With poor correlation with quantitative measures of tidal volume

Respiratory instability in the preterm infant can be attributed to

their implementation is limited to the sleep lab where, used in con-

immaturity of the central nervous system and a highly compliant

junction with chest wall motion sensors (see below), they can be

chest wall resulting in both central and obstructive apnea. During

used to identify the presence or absence of ﬂow associated with

normal respiration the diaphragm contracts, expanding the thorax,

central and obstructive apnea.

in conjunction with activation of accessory muscles that stabilize

218 J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222

3.1.2. Chest wall motion sensors Common clinical practice has promoted the use of a long averaging

Impedance technology is the most widely used modality for time (16 s) to reduce false alarms. Recent data have shown that a

measuring respiration in the hospital setting. With two electrodes long averaging time will reduce the number of short (<20 s) desat-

placed on either side of the chest, above and below the inser- uration events while increasing the number and duration of events

tion of the diaphragm, impedance monitoring measures changes in >20 s. This is most likely due to short desaturation events being

electrical impedance across the thorax that occur during a breath. averaged into one prolonged event. In contrast, the averaging time

This modality is based on the principle that air has a much higher had no effect on the time spent in different SpO2 ranges (Vagedes

level of impedance when compared to tissue. During inspiration, et al., 2013).

there is a decrease in conductivity (and corresponding increase in The relationship between oxygen saturation and oxygen tension

impedance) due to both an increase in gas volume of the chest in is described by the oxygen dissociation curve. Although the oxygen

relation to the ﬂuid volume and increased length of the conduc- dissociation curve presents data in the total range of oxygen sat-

tance path with chest wall expansion. The advantage of impedance uration levels there is increased variability at greater and lower

monitoring is that it can be obtained from ECG electrodes allowing SpO2 levels with optimal accuracy limited to the range of 89–95%

for long term measurements of respiration in a non-invasive man- (Hay et al., 1989). Studies have reported median baseline oxygen

ner. However, as air moves from one compartment to the other saturation levels of 97–99% in healthy preterm infants in room air

during periods of obstruction, impedance monitoring cannot dis- (Ng et al., 1998; Poets et al., 1991). As the dissociation curve begins

tinguish obstructive efforts from normal respiration. to plateau with SpO2 levels >95%, a high monitor alarm above this

Respiratory inductance plethysmography (RIP) has been used threshold may result in hyperoxic exposure in infants requiring

extensively in both clinical research and pulmonary function lab supplemental oxygen (Bohnhorst et al., 2002). Surprisingly, with

settings. It is currently not utilized at the bedside but could be a a multitude of studies including recent multi center trials investi-

promising alternative choice for respiratory monitoring. As with gating oxygen saturation ranges in preterm infants (Stenson et al.,

impedance, it is a non-invasive method of measuring respiration 2011, SUPPORT Study Group of the Eunice Kennedy Shriver NICHD

with two bands wrapped around the chest wall and abdominal Neonatal Research Network, 2010) the optimal target range contin-

areas. As the chest wall and abdomen expand each band elon- ues to elude us. Regardless of the chosen oxygen saturation target

gates. This elongation causes an extension of the sinusoidal shaped range prevention of intermittent hypoxemia continues to be a chal-

wire in the band with a corresponding increase in inductance. The lenge in patient care as such events have been associated with

strength of this modality is the presentation of respiration as a two morbidity in preterm infants. Future care will most likely include

dimensional model. Thus obstructive apnea will present as asyn- automated feedback controllers that have been shown to increase

◦

chronous, 180 out of phase movements between the rib cage and time in target range (Claure et al., 2011) (see Section 3.3).

abdomen. With the addition of a software algorithm to calibrate In contrast to pulse oximetery which measures arterial oxygen

the rib cage and abdominal waveforms, a semi-quantitative vol- saturation, near-infrared spectroscopy (NIRS) uses a similar technol-

ume waveform van be acquired (Somnostar, Carefusion, San Diego, ogy of light wavelength (700–1000 nm) transmission to measure

CA) giving RIP the ability to identify obstructive apnea without the the difference between oxyhemoglobin and deoxyhemoglobin, a

need for a oral/nasal ﬂow sensor. Even with this advantage over reﬂection of oxygen uptake in the tissue bed (Martin et al., 2011).

impedance technology RIP has yet to make its way into clinical NIRS has been shown to provide an earlier warning of alterations

bedside monitoring. in oxygenation when compared to pulse oximetry (Tobias et al.,

2008) and has the ability to detect tissue perfusion in a range of

3.2. Blood gas status organ systems (Petrova and Mehta, 2006). A limitation of NIRS is

the lack of absolute normal values, whereby the patient must serve

Estimates of oxygen and carbon dioxide blood levels are rou- as their own baseline. Decreasing oxygenation is then deﬁned as a

tinely utilized in neonatal intensive care. Invasive arterial sampling change or percent of baseline as opposed to a drop below a given

via indwelling catheters is relied on for the most accurate and threshold.

direct measurements but limited to intermittent monitoring. In

addition, prolonged catheter placement can lead to infection and

other morbidities. Alternative technology allowing for continuous 3.2.2. Carbon dioxide

measurements of oxygen is widespread in preterm infants who are Maintaining normocarbia and avoiding hypo- or hypercarbia

notorious for having transient rapid ﬂuctuations in oxygenation. has been proposed to prevent a range of neonatal morbidities

(Erickson et al., 2002; Garland et al., 1995; McKee et al., 2009;

3.2.1. Oxygen Okumura et al., 2001). With risks associated with invasive periph-

Pulse oximetry is the most widely used method for continuous, eral or arterial catheters, continuous measurements of end tidal

non-invasive, monitoring of oxygenation using a small probe taped or transcutaneous CO2 monitoring may assist in minimizing mor-

around the infant’s foot that requires no calibration or heating of bidity. End tidal CO2 monitoring uses infrared absorption or mass

the skin. Pulse oximetry is based on the principle that oxygenated spectroscopy to estimate CO2 from samples acquired during exha-

hemoglobin absorbs light in the infrared (940 nm) light wavelength lation and has been shown to have good correlation with PaCO2

spectrum while deoxygenated hemoglobin absorbs light in the red in both term and healthy preterm infants (Molloy and Deakins,

(660 nm) wavelength spectrum. The amount of hemoglobin satu- 2006). However, with small tidal volumes and high respiratory

rated with oxygen can be calculated by measuring pulsatile changes rates PetCO2 may underestimate true alveolar gas values in preterm

in the transmission of light passing through the extremity in each of infants. For example, in ventilated very low birth weight infants

these wavelength spectrums. Factors affecting its accuracy include capnography has been shown to have a good correlation but poor

poor peripheral perfusion, medical dyes, hypothermia and sensitiv- agreement with PaCO2 especially in infants with severe pulmonary

ity to motion artifact resulting in loss of signal and a high incidence disease (Trevisanuto et al., 2012). Transcutaneous CO2 detectors

of false alarms. Advances in motion artifact reduction software are an alternative mode of non invasive CO2 monitoring which

algorithms have shown improvement in reducing false alarms (Hay have been shown to be superior to PetCO2 for infants on high fre-

et al., 2002) with the added cost of an increased incidence of missed quency oscillatory ventilation. However, heated electrodes require

events (Bohnhorst et al., 2002). Additional signal processing con- repeated repositioning of the sensor to avoid skin damage due to

cerns include the averaging time which can be modiﬁed by the user. burns.

J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222 219

Disposable colorimetric end tidal CO2 detectors are an efﬁcient records, large memory capacity of database servers and the con-

method of verifying correct endotracheal tube placement (Wyllie tinued progress in identifying at risk patterns of heart rate, oxygen

and Carlo, 2006). When placed between the ventilator and endotra- saturation and respiration, future improvements in diagnostic chal-

cheal tube, the pH sensitive chemical indicator (metacresol purple) lenges will most likely include the exploitation of these longer term

changes from purple to yellow when exposed to expired CO2. As recordings to improve patient care.

neonatal extubation failure can have devastating consequences

calorimetric detectors can play a signiﬁcant role in the intensive 4. Biologic basis for therapeutic interventions

care unit. However, this device cannot detect right main stem

bronchus intubation or oropharyngeal intubations in spontaneous The aggressiveness with which therapy is pursued in apneic

breathing patients. preterm infants must weigh the potential consequences of apnea

and resultant desaturation and bradycardia, with the natural his-

3.3. Heart rate tory which favors spontaneous resolution of these episodes with

advancing maturation. For the most widely used therapies, namely

Acquiring an acceptable EKG in the preterm infant can be continuous positive airway pressure (CPAP) and methyl xanthines,

challenging. Common causes of EKG artifact or poor waveform res- we are still gaining knowledge of their precise mechanisms of

olution include inadequate electrode adhesiveness, excessive gel action. While these two approaches are both effective and safe,

on the skin surface and improper position of electrodes. Baird et al. we need to explore other potential treatments which address the

(1992) have shown the optimal position for electrode placement mechanisms underlying immature respiratory control in preterm

is one electrode at the right mid-clavicle and one at the xyphoid. infants. We will focus this discussion on potential future, as well as

Additional care must be taken with the extremely low birth weight established, therapies.

infants as stripping of the stratum corneum layer of the skin can

occur during electrode removal. More sophisticated processing 4.1. Inhibition of proinﬂammatory responses

of the EKG waveform includes application of additional ﬁlters to

reduce noise and Holter monitoring for more extensive analysis This is an intriguing area of investigation (as already discussed),

including evaluation of abnormal cardiac rhythms. and is based on two fundamental clinical observations. The ﬁrst

is that neonatal sepsis typically presents with apnea; the second

3.4. Future diagnostic challenges is that maternal chorioamnionitis is associated with signiﬁcant

neurorespiratory morbidity in preterm infants. In rat pups sys-

Common clinical practice has included simpliﬁed summaries temic administration of the cytokine IL-1␤ inhibited respiratory

of cardiorespiratory waveforms such as mean oxygen saturation, activity, both at rest and in response to hypoxia, and this respira-

respiratory and heart rate recorded in the medical charts. More tory inhibition was diminished by prior blockade of prostaglandin

recently, with increases in memory storage and software capabili- synthesis with indomethacin (Olsson et al., 2003). The same inves-

ties of bedside monitors, this has expanded to include more detailed tigators demonstrated evidence for IL-1␤ binding to IL-1 receptors

information such as percent time in given oxygen saturation target on vascular endothelial cells of the blood brain barrier during a

ranges and the ability to review short term raw waveform trac- systemic immune response. Activation of the IL-1 receptor, in turn,

ings of clinical cardiorespiratory events. However, with continuous induces synthesis of prostaglandin E2 which is then released into

monitoring of respiration, heart rate and oxygen saturation there respiratory related regions of the brain stem, resulting in altered

is a tremendous amount of information that is never utilized. This respiratory rhythm; this may provide a substrate for the altered

is predominantly due to the lack of available memory to store long breathing patterns seen in neonates battling infection (Hofstetter

term waveforms and the inability to manage this massive amount et al., 2007). As noted earlier, subsequent data from our own group

of data in a way that can be useful for clinical practice. have demonstrated that intrapulmonary instillation of endotoxin

The challenges of this area of research include collecting, stor- (LPS) in rat pups generates a rapid expression of the proinﬂam-

ing and processing raw waveform ﬁles of substantial size. Data can matory cytokine IL-1␤ in respiratory related brainstem regions

be downloaded from each bedside monitor manually or in mass by and accompanying enhancement of hypoxic respiratory depression

a centralized data acquisition system. Although less labor inten- (Balan et al., 2011; Gresham et al., 2011). These data suggest that

sive, the latter protocol has the additional challenge of dealing where feasible, prevention of a prenatal or postnatal inﬂammatory

with linking waveform ﬁles with the correct patient as they can milieu would beneﬁt neonatal respiratory control.

often move between patient rooms. Once data are collected, cor-

rected for missing data and ﬁltered to remove noise/artefact – an 4.2. Optimization of mechanosensory inputs

important component that can affect the ﬁnal analysis – appro-

priate signal processing models can be applied. These models may Care of preterm infants requires an optimal thermosensory

include simple statistical measures (i.e. mean, standard deviation) environment and maximal opportunity for parental interaction and

as well as more sophisticated linear and nonlinear models (ie, spec- physical contact (so-called Kangaroo care) with their infant. Unfor-

tral analysis, sample entropy). These models have the ability to tunately, the latter approach, while it should be encouraged, has

identify subtle transient changes in waveform patterns associated not been shown to enhance respiratory control. The respiratory

with morbidity that are not visually apparent. This concept has rhythm-generating circuitry within the central nervous system

been applied to EKG waveforms by Moorman et al. (2011) who (CNS) depends on intrinsic rhythmic activity and sensory affer-

developed a multivariable statistical predictive model of cardio- ent inputs to generate breathing movement. Bloch-Salisbury et al.

vascular oscillations and neonatal sepsis, known in the commercial (2009) have demonstrated that their novel technique of stochastic

market as HeRO (MPSC, Charlottesville, VA). Similar linear and non- mechanosensory stimulation, using a mattress with imbedded acu-

linear mathematical models including sample entropy and wavelet ators, is able to stabilize respiratory patterns in preterm infants as

analysis have identiﬁed oxygen saturation patterns associated with manifest by a decrease in apnea and an almost threefold decrease in

retinopathy of prematurity (ROP) with severe ROP being asso- percentage of time with oxygen saturations <85%. Interestingly, the

ciated with a higher incidence of intermittent hypoxia of more level of stimulation employed was below the minimum threshold

variable, longer and less severe duration (Di Fiore et al., 2012a). for behavioral arousal to wakefulness, thus inducing no apparent

With the development and implementation of electronic medical state change in the infants, and the effect could probably not be

220 J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222

attributed to the minimal increase in sound level associated with that provide relatively unregulated high ﬂow as a means of CPAP

stimulation. Such an approach is clearly worthy of future study. delivery.

4.5. Prevention of gastroesophageal reﬂux

4.3. Optimization of gas exchange and blood gas status

Preterm infants commonly exhibit not only apnea, bradycar-

It has long been suspected that targeting a lower baseline oxy-

dia, oxygen desaturation, but also gastroesophageal reﬂux (GER)

gen saturation in infants with bronchopulmonary dysplasia (BPD)

events. As all of these events occur during early postnatal life, often

results in more desaturation (McEvoy et al., 1993). Meanwhile,

a causal relationship is assumed, resulting in widespread use of

multiple large trials, some of which are ongoing, have randomized

anti-reﬂux medications to reduce the occurrence of cardiorespira-

infants to two different levels of baseline oxygen saturation in order

tory events. However, the evidence for an association between GER

to identify resultant morbidity. Based on a need for prolonged oxy-

and cardiorespiratory events remains controversial.

gen supplementation when levels of 95% are targeted, the current

There is ample evidence for potent and potentially protective

focus is on 85–89% versus 90–95% oxygen in preterm infants <28

respiratory inhibitory reﬂexes from laryngopharyngeal stimulation

weeks’ gestation. While the lower targeted range is associated with

in both infants and animal models. It is, therefore, likely that if acidic

less retinopathy of prematurity (ROP), there is a signiﬁcantly higher

or non-acidic reﬂuxate reaches this region apnea would result. It

mortality in this group (Stenson et al. 2011; SUPPORT Study Group

has been recently proposed that non-acid, rather than acid, reﬂux

of the Eunice Kennedy Shriver NICHD Neonatal Research Network,

is more likely to elicit a respiratory pause (Corvaglia et al., 2009).

2010). In a subgroup of infants from the latter trial, we have identi-

Despite the development of investigative tools to differentiate acid

ﬁed a higher incidence of intermittent hypoxic episodes in the low

versus non-acid reﬂuxate, it is difﬁcult to identify the small number

oxygen targeted group (Di Fiore et al., 2012b).

of infants whose apnea may be precipitated by GER. Our own data

Intermittent hypoxic episodes are almost always the result of

from a large cohort of preterm infants indicate that only approx-

respiratory pauses, apnea, or ineffective ventilation. It is unclear

imately 3% of apnea related events are preceded by GER (Di Fiore

whether targeting a lower baseline oxygen saturation increases

et al., 2010a,b). However, in a small case series in former preterm

the incidence of apnea with resultant hypoxemia, or whether the

infants at post term gestation, persistent cardiorespiratory events

incidence of apnea is comparable between oxygen targets, but the

temporally associated with GER were resolved after surgical treat-

lower oxygen saturation baseline predisposes to more frequent or

ment (Nunez et al., 2011).

profound intermittent hypoxemia. However, given the potential

oxidative stress associated with intermittent hypoxic episodes, the 4.6. Methylxanthine therapy

latter are probably best avoided (Martin et al., 2011; Prabhakar

et al., 2001). Xanthine therapy has been used to prevent and treat apnea of

Automated control of inspired oxygen is under study. This auto- prematurity since the 1970s. Its primary mechanism of action in the

mated technique has been compared to routine adjustments of perinatal period is thought to be blockade of inhibitory adenosine

inspired oxygen as performed by clinical personnel in infants of A1 receptors with resultant excitation of respiratory neural output

24–27 weeks gestation (Claure et al., 2011). During the automated (Herlenius et al., 2002). An alternative mechanism of caffeine action

period, time with oxygen saturation within the intended range of is blockade of excitatory adenosine A2A receptors at GABAergic neu-

87–93% increased signiﬁcantly, and times in the hyperoxic range rons and resultant decrease in GABA output, resulting in excitation

were signiﬁcantly reduced. This was not associated with a clear of respiratory neural output (Mayer et al., 2006).

beneﬁt for hypoxic episodes, nonetheless, future reﬁnement of this These complex neurotransmitter interactions elicited by caf-

technology may prove useful to minimize intermittent hypoxia. feine led to concerns regarding its safety and a large multicenter

Finally, a novel approach is supplementation of inspired air with trial was undertaken in the 1990s. The results of this study have

a very low concentration of supplemental CO2 to increase respira- demonstrated that caffeine treatment is effective in decreasing the

tory drive (Alvaro et al., 2012). While of interest from a physiologic rate of BPD and improving neurodevelopmental outcome at 18–21

perspective, and likely to be successful in decreasing apnea, it is months, especially in those receiving respiratory support (Davis

doubtful that this would gain widespread clinical acceptance as et al., 2010; Schmidt et al., 2007). It is possible that this bene-

most preterm infants have residual lung disease and are prone ﬁt is secondary to decrease in apnea and resultant intermittent

to baseline hypercapnia, which may make clinicians reluctant to hypoxic episodes; however, this is speculative. Clearly, improved

administer supplemental inspired CO2. 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

4.4. Continuous positive airway pressure (CPAP)

neuroinﬂammation in newborn animals (Brothers et al., 2010). In

adult models, blockade of excitatory adenosine A2A receptors aug-

CPAP, ranging from about 2 to 6 cm H2O has proven a rela-

ments instead of attenuates ventilator assisted lung injury (Chen

tively safe and effective therapy for 40 years. It has a dual function

et al., 2009). On the other hand, caffeine attenuates lung injury via

to stabilize lung volume and improve airway patency by limiting

an alternative pathway that does not involve adenosine receptors

upper airway closure. Because longer episodes of apnea frequently

which is dose dependent (Li et al., 2011). In premature infants, caf-

involve an obstructive component, CPAP appears to be effective by

feine is associated with either a pro- or anti-inﬂammatory cytokine

“splinting” the upper airway with positive pressure and decreasing

proﬁle depending on the serum level (Chavez et al., 2011). The clin-

the risk of pharyngeal or laryngeal obstruction. At the lower func-

ical beneﬁts of xanthine therapy in preterm infants should trigger

tional residual capacity which accompanies many preterm infants

interest in a ‘bedside-to-bench’ approach to enhance our under-

with residual lung disease, pulmonary oxygen stores are probably

standing of underlying mechanisms.

reduced and there is a very short time from cessation of breathing to

onset of desaturation and bradycardia. Nasal CPAP is well tolerated

References

in most preterm infants, however, high-ﬂow nasal cannula ther-

apy has been suggested as an equivalent treatment modality that

Abman, S.H., 2010. Impaired vascular endothelial growth factor signaling in the

may allow CPAP delivery while enhancing mobility of the infant.

pathogenesis of neonatal pulmonary vascular disease. Advances in Bladder

Some questions remain about the safety and efﬁcacy of devices Research 661, 323–335, http://dx.doi.org/10.1007/978-1-60761-500-2 21.

J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222 221

Adams, J.A., Zabaleta, I.A., Sackner, M.A., 1997. Hypoxemic events in spontaneously and bronchopulmonary dysplasia. Journal of Paediatrics and Child Health 38,

breathing premature infants: etiologic basis. Pediatric Research 42, 463–471. 560–562.

Al-Matary, A., Kutbi, I., Qurashi, M., Khalil, M., Alvaro, R., Kwiatkowski, K., Cates, D., Feldman, J.L., Del Negro, C.A., Gray, P.A., 2013. Understanding the rhythm of breath-

Rigatto, H., 2004. Increased peripheral chemoreceptor activity may be critical in ing: so near, yet so far. Annual Review of Physiology 75, 423–452.

destabilizing breathing in neonates. Seminars in Perinatology 28, 264–272. Gakis, G., Mueller, M.H., Hahn, J., Glatzle, J., Grundy, D., Kreis, M.E., 2009. Neuronal

Alvarez, J.E., Bodani, J., Fajardo, C.A., Kwiatkowski, K., Cates, D.B., Rigatto, H., 1993. activation in the nucleus of the solitary tract following jejunal lipopolysaccha-

Sighs and their relationship to apnea in the newborn infant. Biology of the ride in the rat. Autonomous Neuroscience 148, 63–68.

Neonate 63, 139–146. Garland, J.S., Buck, R.K., Allred, E.N., Leviton, A., 1995. Hypocarbia before surfactant

Alvaro, R.E., Khalil, M., Qurashi, M., Al-Saif, S., Al-Matary, A., Chiu, A., Minski, J., therapy appears to increase bronchopulmonary dysplasia risk in infants with

Manfreda, J., Kwiatkowski, K., Cates, D., Rigatto, H., 2012. CO2 inhalation as a respiratory distress syndrome. Archives of Pediatrics and Adolescent Medicine

treatment for apnea of prematurity: a randomized double-blind controlled trial. 149, 617–622.

Journal of Pediatrics 160, 252–257. Gauda, E.B., Carroll, J.L., Donnelly, D.F., 2009. Developmental maturation of

Backstrom, E., Hogmalm, A., Lappalainen, U., Bry, K., 2011. Developmental stage is chemosensitivity to hypoxia of peripheral arterial chemoreceptors – invited

a major determinant of lung injury in a murine model of bronchopulmonary article. Advances in Experimental Medicine and Biology 648, 243–255.

dysplasia. Pediatric Research 69, 312–318. Gauda, E.B., Cristofalo, E., Nunez, J., 2007. Peripheral arterial chemoreceptors and

Baird, T.M., Goydos, J.M., Neuman, M.R., 1992. Optimal electrode locationa for mon- sudden infant death syndrome. Respiratory Physiology and Neurobiology 157,

itoring the ECG and breathing in neonates. Pediatric Pulmonology 12, 247. 162–170.

Balan, K.V., Kc, P., Hoxha, Z., Mayer, C.A., Wilson, C.G., Martin, R.J., 2011. Vagal affer- Gauda, E.B., Lawson, E.E., 2000. Developmental inﬂuences on carotid body responses

ents modulate cytokine-mediated respiratory control at the neonatal medulla to hypoxia. Respiration Physiology 121, 199–208.

oblongata. Respiratory Physiology and Neurobiology 178, 458–464. Gauda, E.B., Martin, R.J., 2012. In: Gleason, C.A., Devaskar, S. (Eds.), Avery’s Diseases

Barrington, K.J., Finer, N.N., 1990. Periodic breathing and apnea in preterm infants. of the Newborn. , 4th ed. Saunders, Philadelphia, pp. 584–589.

Pediatric Research 27, 118–121. Gauda, E.B., Miller, M.J., Carlo, W.A., DiFiore, J.M., Johnsen, D.C., Martin, R.J., 1987.

Bashambu, M.T., Bhola, M., Walsh, M., 2012. Evidence for oxygen use in preterm Genioglossus response to airway occlusion in apneic versus nonapneic infants.

infants. Acta Paediatrica 101, 29–33. Pediatric Research 22, 683–687.

Bass, J.L., Corwin, M., Gozal, D., Moore, C., Nishida, H., Parker, S., Schonwald, A., Gauda, E.B., Shirahata, M., Mason, A., Pichard, L.E., Kostuk, E.W., Chavez-Valdez, R.,

Wilker, R.E., Stehle, S., Kinane, T.B., 2004. The effect of chronic or intermittent 2013. Inﬂammation in the carotid body during development and its contribu-

hypoxia on cognition in childhood: a review of the evidence. Pediatrics 114, tion to apnea of prematurity. Respiratory Physiology and Neurobiology 185,

805–816. 120–131.

Blain, G.M., Smith, C.A., Henderson, K.S., Dempsey, J.A., 2010. Peripheral chemore- Givan, D.C., 2003. Physiology of breathing and related pathological processes in

ceptors determine the respiratory sensitivity of central chemoreceptors to CO2. infants. Seminars in Pediatric Neurology 10, 271–280.

Journal of Physiology 588, 2455–2471. Gonzalez, C., Almaraz, L., Obeso, A., Rigual, R., 1994. Carotid body chemoreceptors:

Bloch-Salisbury, E., Indic, P., Bednarek, F., Paydarfar, D., 2009. Stabilizing imma- from natural stimuli to sensory discharges. Physiological Reviews 74, 829–898.

ture breathing patterns of preterm infants using stochastic mechanosensory Gresham, K., Boyer, B., Mayer, C., Foglyano, R., Martin, R., Wilson, C.G., 2011. Airway

stimulation. Journal of Applied Physiology 107, 1017–1027. inﬂammation and central respiratory control: results from in vivo and in vitro

Bohnhorst, B., Peter, C.S., Poets, C.F., 2002. Detection of hyperoxaemia in neonates: neonatal rat. Respiratory Physiology and Neurobiology 178, 414–421.

data from three new pulse oximeters. Archives of Disease in Childhood. Fetal Hale, M.W., Rook, G.A., Lowry, C.A., 2012. Pathways underlying afferent signaling

and Neonatal Edition 87, F217–F219. of bronchopulmonary immune activation to the central nervous system. Chem.

Bolivar, J.M., Gerhardt, T., Gonzalez, A., Hummler, H., Claure, N., Everett, R., Bancalari, Immunol. Allergy 98, 118–141, http://dx.doi.org/10.1159/000336505.

E., 1995. Mechanisms for episodes of hypoxemia in preterm infants undergoing Hannam, S., Ingram, D.M., Milner, A.D., 1998. A possible role for the Hering–Breuer

mechanical ventilation. Journal of Pediatrics 127, 767–773. deﬂation reﬂex in apnea of prematurity. Journal of Pediatrics 132, 35–39.

Brothers, H.M., Marchalant, Y., Wenk, G.L., 2010. Caffeine attenuates Hay Jr., W.W., Brockway, J.M., Eyzaguirre, M., 1989. Neonatal pulse oximetry: accu-

lipopolysaccharide-induced neuroinﬂammation. Neuroscience Letters 480, racy and reliability. Pediatrics 83, 717–722.

97–100. Hay Jr., W.W., Rodden, D.J., Collins, S.M., Melara, D.L., Hale, K.A., Fashaw, L.M., 2002.

Chavez, V.R., Ahlawat, R., Wills-Karp, M., Nathan, A., Ezell, T., Gauda, E.B., 2011. Corre- Reliability of conventional and new pulse oximetry in neonatal patients. Journal

lation between serum caffeine levels and changes in cytokine proﬁle in a cohort of Perinatology 22, 360–366.

of preterm infants. Journal of Pediatrics 158 (57–64), 64. Henderson-Smart, D.J., 1981. The effect of gestational age on the incidence and dura-

Chen, C.M., Penuelas, O., Quinn, K., Cheng, K.C., Li, C.F., Zhang, H., Slutsky, A.S., 2009. tion of recurrent apnoea in newborn babies. Australian Paediatric Journal 17,

Protective effects of adenosine A2A receptor agonist in ventilator-induced lung 273–276.

injury in rats. Critical Care Medicine 37, 2235–2241. Henderson-Smart, D.J., De Paoli, A.G., 2010. Methylxanthine treatment for apnoea

Claure, N., Bancalari, E., D’Ugard, C., Nelin, L., Stein, M., Ramanathan, R., Hernandez, in preterm infants. CDS Review, CD000140.

R., Donn, S.M., Becker, M., Bachman, T., 2011. Multicenter crossover study of Herlenius, E., Aden, U., Tang, L.Q., Lagercrantz, H., 2002. Perinatal respiratory control

automated control of inspired oxygen in ventilated preterm infants. Pediatrics and its modulation by adenosine and caffeine in the rat. Pediatric Research 51,

127, e76–e83. 4–12.

Corvaglia, L., Zama, D., Gualdi, S., Ferlini, M., Aceti, A., Faldella, G., 2009. Gastro- Hislop, A., 2005. Developmental biology of the pulmonary circulation. Paediatric

oesophageal reﬂux increases the number of apnoeas in very preterm infants. Respiratory Reviews 6, 35–43.

Archives of Disease in Childhood. Fetal and Neonatal Edition 94, F188–F192. Hislop, A.A., Wigglesworth, J.S., Desai, R., Aber, V., 1987. The effects of preterm

Darnall, R.A., 2010. The role of CO2 and central chemoreception in the control of delivery and mechanical ventilation on human lung growth. Early Human Devel-

breathing in the fetus and the neonate. Respiratory Physiology and Neurobiology opment 15, 147–164.

173, 201–212. Hoffman, M.S., Golder, F.J., Mahamed, S., Mitchell GS, 2010. Spinal adenosine A2(A)

Davis, P.G., Schmidt, B., Roberts, R.S., Doyle, L.W., Asztalos, E., Haslam, R., Sinha, receptor inhibition enhances phrenic long term facilitation following acute

S., Tin, W., 2010. Caffeine for apnea of prematurity trial: beneﬁts may vary in intermittent hypoxia. The Journal of Physiology 588 (Pt 1), 255–266.

subgroups. Journal of Pediatrics 156, 382–387. Hofstetter, A.O., Legnevall, L., Herlenius, E., Katz-Salamon, M., 2008. Cardiorespi-

Dejours, P., 1962. Chemoreﬂexes in breathing. Physiological Reviews 42, 335–358. ratory development in extremely preterm infants: vulnerability to infection

Di Fiore, J., Arko, M., Herynk, B., Martin, R., Hibbs, A.M., 2010a. Characterization of and persistence of events beyond term-equivalent age. Acta Paediatrica 97,

cardiorespiratory events following gastroesophageal reﬂux in preterm infants. 285–292.

Journal of Perinatology 30, 683–687. Hofstetter, A.O., Saha, S., Siljehav, V., Jakobsson, P.J., Herlenius, E., 2007. The induced

Di Fiore, J.M., Bloom, J.N., Orge, F., Schutt, A., Schluchter, M., Cheruvu, V.K., Walsh, prostaglandin E2 pathway is a key regulator of the respiratory response to infec-

M., Finer, N., Martin, R.J., 2010b. A higher incidence of intermittent hypoxemic tion and hypoxia in neonates. Proceedings of the National Academy of Sciences

episodes is associated with severe retinopathy of prematurity. Journal of Pedi- of the United States of America 104, 9894–9899.

atrics 157, 69–73. Huxtable, A.G., Vinit, S., Windelborn, J.A., Crader, S.M., Guenther, C.H., Watters, J.J.,

Di Fiore, J.M., Kaffashi, F., Loparo, K., Sattar, A., Schluchter, M., Foglyano, R., Mar- Mitchell, G.S., 2011. Systemic inﬂammation impairs respiratory chemoreﬂexes

tin, R.J., Wilson, C.G., 2012a. The relationship between patterns of intermittent and plasticity. Respiratory Physiology and Neurobiology 178, 482–489.

hypoxia and retinopathy of prematurity in preterm infants. Pediatric Research Idiong, N., Lemke, R.P., Lin, Y.J., Kwiatkowski, K., Cates, D.B., Rigatto, H., 1998. Airway

72, 606–612. closure during mixed apneas in preterm infants: is respiratory effort necessary?

Di Fiore, J.M., Walsh, M., Wrage, L., Rich, W., Finer, N., Carlo, W.A., Martin, R.J., 2012b. Journal of Pediatrics 133, 509–512.

Low oxygen saturation target range is associated with increased incidence of Jakkula, M., Le Cras, T.D., Gebb, S., Hirth, K.P., Tuder, R.M., Voelkel, N.F., Abman, S.H.,

intermittent hypoxemia. Journal of Pediatrics 161, 1047–1052. 2000. Inhibition of angiogenesis decreases alveolarization in the developing rat

Easton, P.A., Anthonisen, N.R., 1988. Ventilatory response to sustained hypoxia after lung. American Journal of Physiology-Lung Cellular and Molecular Physiology

pretreatment with aminophylline. Journal of Applied Physiology 64, 1445–1450. 279, L600–L607.

Edwards, B.A., Sands, S.A., Berger, P.J., 2013. Postnatal maturation of breathing stabil- Kassim, Z., Donaldson, N., Khetriwal, B., Rao, H., Sylvester, K., Rafferty, G.F., Hannam,

ity and loop gain: the role of carotid chemoreceptor development. Respiratory S., Greenough, A., 2007. Sleeping position, oxygen saturation and lung volume in

Physiology and Neurobiology 185, 144–155. convalescent, prematurely born infants. Archives of Disease in Childhood. Fetal

Eichenwald, E.C., Aina, A., Stark, A.R., 1997. Apnea frequently persists beyond term and Neonatal Edition 92, F347–F350.

gestation in infants delivered at 24 to 28 weeks. Pediatrics 100, 354–359. Khan, A., Qurashi, M., Kwiatkowski, K., Cates, D., Rigatto, H., 2005. Measurement of

Erickson, S.J., Grauaug, A., Gurrin, L., Swaminathan, M., 2002. Hypocarbia in the CO2 apneic threshold in newborn infants: possible relevance for periodic

the ventilated preterm infant and its effect on intraventricular haemorrhage breathing and apnea. Journal of Applied Physiology 98, 1171–1176.

222 J.M. Di Fiore et al. / Respiratory Physiology & Neurobiology 189 (2013) 213–222

Kitterman, J.A., 1996. The effects of mechanical forces on fetal lung growth. Clinics infants at discharge from special care. Archives of Disease in Childhood 66,

in Perinatology 23, 727–740. 574–578.

Koos, B.J., Kawasaki, Y., Kim, Y.H., Bohorquez, F., 2005. Adenosine A2A-receptor Prabhakar, N.R., Fields, R.D., Baker, T., Fletcher, E.C., 2001. Intermittent hypoxia: cell

blockade abolishes the roll-off respiratory response to hypoxia in awake lambs. to system. American Journal of Physiology-Lung Cellular and Molecular Physi-

American Journal of Physiology-Regulatory Integrative and Comparative Phys- ology 281, L524–L528.

iology 288, R1185–R1194. Prabhakar, N.R., Peng, Y.J., Kumar, G.K., Pawar, A., 2006. Altered carotid body function

Kumar, P., Prabhakar, N.R., 2012. Peripheral chemoreceptors: function and plasticity by intermittent hypoxia in neonates and adults: relevance to recurrent apneas.

of the carotid body. Comprehensive Physiology 2, 141–129. Respiratory Physiology and Neurobiology 157, 148–153.

Le Cras, T.D., Markham, N.E., Tuder, R.M., Voelkel, N.F., Abman, S.H., 2002. Treatment Reeves, S.R., Mitchell, G.R., Gozal, D., 2006. Early postnatal chronic intermittent

of newborn rats with a VEGF receptor inhibitor causes pulmonary hyperten- hypoxia modiﬁes hypoxic respiratory responses and long-term phrenic facil-

sion and abnormal lung structure. Am. J. Physiol Lung Cell Mol. Physiol. 283, itation in adult rats. American Journal of Physiology-Regulatory Integrative and

L555–L562. Comparative Physiology 290, R1664–R1671.

Li, J., Li, G., Hu, J.L., Fu, X.H., Zeng, Y.J., Zhou, Y.G., Xiong, G., Yang, N., Dai, S.S., He, Rey-Parra, G.J., Archer, S.L., Bland, R.D., Albertine, K.H., Carlton, D.P., Cho, S.C., Kirby,

F.T., 2011. Chronic or high dose acute caffeine treatment protects mice against B., Haromy, A., Eaton, F., Wu, X., Thebaud, B., 2008. Blunted hypoxic pulmonary

oleic acid-induced acute lung injury via an adenosine A2A receptor-independent vasoconstriction in experimental neonatal chronic lung disease. American Jour-

mechanism. European Journal of Pharmacology 654, 295–303. nal of Respiratory and Critical Care Medicine 178, 399–406.

Lopes, J., Muller, N.L., Bryan, M.H., Bryan, A.C., 1981. Importance of inspiratory muscle Rigatto, H., Brady, J.P., 1972. Periodic breathing and apnea in preterm infants. II.

tone in maintenance of FRC in the newborn. Journal of Applied Physiology 51, Hypoxia as a primary event. Pediatrics 50, 219–228.

830–834. Saiki, T., Rao, H., Landolfo, F., Smith, A.P., Hannam, S., Rafferty, G.F., Greenough, A.,

Martin, R.J., Di Fiore, J.M., Java, L., Davis, R.L., Miller, M.J., Coles, S.K., Dick, T.E., 1998. 2009. Sleeping position, oxygenation and lung function in prematurely born

Persistance of the biphasic ventilatory response to hypoxia in preterm infants. infants studied post term. Archives of Disease in Childhood. Fetal and Neonatal

Journal of Pediatrics 132, 960–964. Edition 94, F133–F137.

Martin, R.J., Wang, K., Koroglu, O., Di, F.J., Kc, P., 2011. Intermittent hypoxic episodes Sanchez-Esteban, J., Cicchiello, L.A., Wang, Y., Tsai, S.W., Williams, L.K., Torday, J.S.,

in preterm infants: do they matter? Neonatology 100, 303–310. Rubin, L.P., 2001. Mechanical stretch promotes alveolar epithelial type II cell

Mayer, C.A., Haxhiu, M.A., Martin, R.J., Wilson, C.G., 2006. Adenosine A2A receptors differentiation. Journal of Applied Physiology 91, 589–595.

mediate GABAergic inhibition of respiration in immature rats. Journal of Applied Schmidt, B., Roberts, R.S., Davis, P., Doyle, L.W., Barrington, K.J., Ohlsson, A., Solimano,

Physiology 100, 91–97. A., Tin, W., 2007. Long-term effects of caffeine therapy for apnea of prematurity.

McEvoy, C., Durand, M., Hewlett, V., 1993. Episodes of spontaneous desaturations in New England Journal of Medicine 357, 1893–1902.

infants with chronic lung disease at two different levels of oxygenation. Pediatric Shimoya, K., Taniguchi, T., Matsuzaki, N., Moriyama, A., Murata, Y., Kitajima, H.,

Pulmonology 15, 140–144. Fujimura, M., Nakayama, M., 2000. Chorioamnionitis decreased incidence of

McKee, L.A., Fabres, J., Howard, G., Peralta-Carcelen, M., Carlo, W.A., Ambalavanan, respiratory distress syndrome by elevating fetal interleukin-6 serum concen-

N., 2009. PaCO2 and neurodevelopment in extremely low birth weight infants. tration. Human Reproduction 15, 2234–2240.

Journal of Pediatrics 155, 217–221. Stenson, B., Brocklehurst, P., Tarnow-Mordi, W., 2011. Increased 36-week survival

Miller, H.C., Behrle, F.C., SMULL, N.W., 1959. Severe apnea and irregular respiratory with high oxygen saturation target in extremely preterm infants. New England

rhythms among premature infants; a clinical and laboratory study. Pediatrics Journal of Medicine 364, 1680–1682.

23, 676–685. Sunderram, J., Androulakis, I.P., 2012. Molecular mechanisms of chronic intermit-

Miller, M.J., Carlo, W.A., DiFiore, J.M., Martin, R.J., 1988. Airway obstruction dur- tent hypoxia and hypertension. Critical Reviews in Biomedical Engineering 40,

ing periodic breathing in premature infants. Journal of Applied Physiology 64, 265–278.

2496–2500. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research

Milner, A.D., Boon, A.W., Saunders, R.A., Hopkin, I.E., 1980. Upper airways obstruction Network, 2010. Target ranges of oxygen saturation in extremely preterm infants.

and apnoea in preterm babies. Archives of Disease in Childhood 55, 22–25. New England Journal of Medicine 362, 1959–1969.

Molloy, E.J., Deakins, K., 2006. Are carbon dioxide detectors useful in neonates? Tobias, J.D., Johnson, G.A., Rehman, S., Fisher, R., Caron, N., 2008. Cerebral oxygen-

Archives of Disease in Childhood. Fetal and Neonatal Edition 91, F295–F298. ation monitoring using near infrared spectroscopy during one-lung ventilation

Moorman, J.R., Delos, J.B., Flower, A.A., Cao, H., Kovatchev, B.P., Richman, J.S., Lake, in adults. Journal of Minimal Access Surgery 4, 104–107.

D.E., 2011. Cardiovascular oscillations at the bedside: early diagnosis of neonatal Trevisanuto, D., Giuliotto, S., Cavallin, F., Doglioni, N., Toniazzo, S., Zanardo, V., 2012.

sepsis using heart rate characteristics monitoring. Physiological Measurement End-tidal carbon dioxide monitoring in very low birth weight infants: corre-

32, 1821–1832. lation and agreement with arterial carbon dioxide. Pediatric Pulmonology 47,

Mourani, P.M., Mullen, M., Abman, S.H., 2009. Pulmonary hypertension in bron- 367–372.

chopulmonary dysplasia. Progress in Cardiology 27, 23–48. Vagedes, J., Poets, C.F., Dietz, K., 2013. Averaging time, desaturation level, duration

Ng, A., Subhedar, N., Primhak, R.A., Shaw, N.J., 1998. Arterial oxygen saturation pro- and extent. Archives of Disease in Childhood. Fetal and Neonatal Edition 98,

ﬁles in healthy preterm infants. Archives of Disease in Childhood. Fetal and F265–F266.

Neonatal Edition 79, F64–F66. Vizek, M., Pickett, C.K., Weil, J.V., 1987. Biphasic ventilatory response of adult

Nunez, J., Cristofalo, E., McGinley, B., Katz, R., Glen, D.R., Gauda, E., 2011. Temporal cats to sustained hypoxia has central origin. Journal of Applied Physiology 63,

association of polysomnographic cardiorespiratory events with GER detected 1658–1664.

by MII-pH probe in the premature infant at term. Journal of Pediatric Gastroen- Waggener, T.B., Frantz III, I.D., Cohlan, B.A., Stark, A.R., 1989. Mixed and obstructive

terology and Nutrition 52, 523–531. apneas are related to ventilatory oscillations in premature infants. Journal of

Okumura, A., Hayakawa, F., Kato, T., Itomi, K., Maruyama, K., Ishihara, N., Kubota, Applied Physiology 66, 2818–2826.

T., Suzuki, M., Sato, Y., Kuno, K., Watanabe, K., 2001. Hypocarbia in preterm Walker, D.W., 1984. Peripheral and central chemoreceptors in the fetus and new-

infants with periventricular leukomalacia: the relation between hypocarbia and born. Annual Review of Physiology 46, 687–703.

mechanical ventilation. Pediatrics 107, 469–475. Watterberg, K.L., Demers, L.M., Scott, S.M., Murphy, S., 1996. Chorioamnionitis and

Olsson, A., Kayhan, G., Lagercrantz, H., Herlenius, E., 2003. IL-1 beta depresses respi- early lung inﬂammation in infants in whom bronchopulmonary dysplasia devel-

ration and anoxic survival via a prostaglandin-dependent pathway in neonatal ops. Pediatrics 97, 210–215.

rats. Pediatric Research 54, 326–331. Weintraub, Z., Alvaro, R., Kwiatkowski, K., Cates, D., Rigatto, H., 1992. Effects of

Petrova, A., Mehta, R., 2006. Near-infrared spectroscopy in the detection of regional inhaled oxygen (up to 40%) on periodic breathing and apnea in preterm infants.

tissue oxygenation during hypoxic events in preterm infants undergoing critical Journal of Applied Physiology 72, 116–120.

care. Pediatric Critical Care Medicine 7, 449–454. Widdicombe, J., 2006. Reﬂexes from the lungs and airways: historical perspective.

Pillekamp, F., Hermann, C., Keller, T., von, G.A., Kribs, A., Roth, B., 2007. Factors Journal of Applied Physiology 101, 628–634.

inﬂuencing apnea and bradycardia of prematurity – implications for neurode- Wilkinson, M.H., Skuza, E.M., Rennie, G.C., Sands, S.A., Yiallourou, S.R., Horne, R.S.,

velopment. Neonatology 91, 155–161. Berger, P.J., 2007. Postnatal development of periodic breathing cycle duration in

Poets, C.F., 2010. Apnea of prematurity: what can observational studies tell us about term and preterm infants. Pediatric Research 62, 331–336.

pathophysiology? Sleep Medicine 11, 701–707. Wyllie, J., Carlo, W.A., 2006. The role of carbon dioxide detectors for conﬁrmation of

Poets, C.F., Rau, G.A., Neuber, K., Gappa, M., Seidenberg, J., 1997. Determinants of endotracheal tube position. Clinics in Perinatology 33, 111–119, vii.

lung volume in spontaneously breathing preterm infants. American Journal of Yan, S., Laferriere, A., Zhang, C., Moss, I.R., 1995. Microdialyzed adenosine in nucleus

Respiratory and Critical Care Medicine 155, 649–653. tractus solitarii and ventilatory response to hypoxia in piglets. Journal of Applied

Poets, C.F., Stebbens, V.A., Alexander, J.R., Arrowsmith, W.A., Salﬁeld, S.A., Southall, Physiology 79, 405–410.

D.P., 1991. Oxygen saturation and breathing patterns in infancy. 2: preterm