Snoring and Obstructive Sleep Apnea in Children: An Evidence-Based, Multidisciplinary Approach

Snoring and Obstructive Sleep Apnea in Children: An Evidence-Based, Multidisciplinary Approach provides researchers and practitioners with a complete and comprehensive source of information on the epidemiology, pathophysiology, diagnosis, management and controversies concerning sleep disordered breathing in infants. Written by an interdisciplinary team of authors, chapters consolidate information on the evaluation and management of pediatric sleep disordered breathing (SDB) currently fragmented across different specialties.

Principles of surgery for SDB as well as non-medical approaches, such as continuous positive airway pressure (CPAP) are covered, and a section dedicated to controversies in pediatric SDB discusses clinical cases and future trends for the treatment of snoring and obstructive sleep apnea in children.

• Consolidates information on pediatric sleep disordered breathing (SDB) across disciplines
• Covers common diagnostic modalities and adverse outcomes related to snoring and sleep apnea in infants and children
• Includes flowcharts and clinical guidelines for evaluation and management of pediatric SDB

• Language: English
• Publisher: Academic Press
• Release date: Nov 11, 2023
• ISBN: 9780323996549

Book preview

Preface

Amal Isaiah and Ron B. Mitchell

As pediatric otolaryngologists, we have encountered numerous children with symptoms of common yet frequently overlooked conditions—pediatric snoring and obstructive sleep apnea (OSA). In this book, our objective is to disseminate our knowledge and experiences in the field, while empowering fellow clinicians, researchers, as well as parents and caregivers with the necessary tools to understand, diagnose, and effectively manage pediatric OSA. Our intention is to bridge the divide among clinical communities, such as pediatricians, otolaryngologists, sleep physicians, and pulmonologists, fostering a collaborative approach that optimizes the care and outcomes for children affected by snoring and OSA.

This book commences by describing the fundamental aspects of upper airway anatomy and development. It subsequently delves into more intricate aspects of pediatric OSA, encompassing the underlying pathophysiology, risk-based phenotypes, and clinical presentations. Drawing upon cutting-edge research and clinical experiences, we describe unique diagnostic challenges within this domain. We emphasize the significance of a multidisciplinary evaluation while incorporating the latest technological and surgical advancements. A paramount focus of this book is in the comprehensive discussion of surgical interventions for pediatric OSA, as well as the controversies and future directions of this field.

We would like to express our profound gratitude to the contributors whose collective expertise will serve as a valuable resource for all those dedicated to the welfare of children with OSA. In addition, this project would not have been complete without the hard work of the editorial and production teams at Elsevier. Finally, we thank our respective families for their support and understanding that made this book possible.

Section 1

Epidemiology and pathophysiology

Outline

Chapter 1 Anatomy of the upper airway

Chapter 2 Regulation of the upper airway during sleep

Chapter 3 Socioeconomic disparities in pediatric sleep disordered breathing

Chapter 4 Cerebral oxygenation in pediatric obstructive sleep apnea

Chapter 5 Genetics of pediatric obstructive sleep apnea

Chapter 6 Neurobehavioral outcomes of pediatric obstructive sleep apnea

Chapter 7 Quality of life outcomes of pediatric obstructive sleep apnea

Chapter 8 Cardiovascular complications of pediatric obstructive sleep apnea

Chapter 9 Pediatric obstructive sleep apnea: high-risk groups

Chapter 10 Growth and development in pediatric obstructive sleep apnea

Chapter 1

Anatomy of the upper airway

Derek J. Lam,    Department of Otolaryngology—Head and Neck Surgery, Oregon Health and Science University, Portland, OR, United States

Abstract

The anatomy of the upper airway in children can be divided into five distinct regions: the nasal airway, the nasopharynx, the oral cavity, the oropharynx, and the hypopharynx. Each of these regions comprises structures that can impact the patency of the airway during sleep. These include relatively fixed structures like the inferior turbinates or pharyngeal lymphoid tissue that can potentially be obstructive and structures prone to dynamic collapse like the soft palate, tongue base, and supraglottis. Knowledge of these structures is essential in understanding therapeutic modalities to treat snoring and obstructive sleep apnea in children.

Keywords

Anatomy; obstructive sleep apnea; upper airway; tonsils and sleep disordered breathing

1.1 Introduction

Knowledge of the anatomy of the upper airway is essential to understand the various causes of airway obstruction that can result in sleep disordered breathing (SDB) or obstructive sleep apnea (OSA). The upper airway in children is analogous to the adult airway, but with important age-related differences that can impact airway patency during sleep. Infants and younger children have proportionally smaller airways that increase the resistance to airflow and the possibility of obstruction or collapse (Xi et al., 2014). In addition, the larynx sits in a higher position so the pharynx is shorter in craniocaudal length with a closer relationship between the soft palate and the tongue base and epiglottis. Beginning at approximately 18 months, the larynx descends to the level of the fifth cervical vertebrae. The relatively short oropharynx in young children can predispose them to more pharyngeal crowding and potential for obstruction, especially in children with adenotonsillar hypertrophy. As children grow into adolescents, the pharynx lengthens, and the sources and patterns of obstruction become more similar to adults. The upper airway from the nostrils to the larynx can be divided into five anatomic regions: the nasal airway, the nasopharynx, the oral cavity, the oropharynx, and the hypopharynx.

1.2 Nasal airway

The anterior nasal airway encompasses the external nasal valve, internal nasal valve, and nasal cavity. The external nasal valve is defined as the caudal septum, medial crura of the alar cartilages, alar rim, and nasal sill. The internal nasal valve is the narrowest part of the nasal airway. It sits slightly posterior to the external valve, bounded medially by the caudal septum, laterally by the caudal margin of the upper lateral cartilage, and inferiorly by the head of the inferior turbinate (Fig. 1.1).

Figure 1.1 Nasal anatomy showing the relationship between the cartilaginous framework and the nasal valve area.

The nasal cavity is bounded by the cribriform plate and sphenoid rostrum superiorly, the maxilla and palatine bones inferiorly, and the superior, middle, and inferior nasal conchae forming the corresponding turbinates laterally. Within the nasal cavity, the most common causes of obstruction are inferior turbinate hypertrophy and septal deviation, frequently exacerbated by mucosal edema or inflammation due to allergic rhinitis or rhinosinusitis. Other conditions that can cause nasal obstruction include nasal polyposis, intranasal dermoid cysts, encephaloceles, and skull base tumors. Unlike adults, external nasal valve collapse is uncommon in young children due to the shorter and more rounded nasal dorsum and alar cartilage. However, congenital anomalies such as piriform aperture stenosis or choanal atresia can cause significant nasal obstruction in neonates.

Historically the nasal airway has been underappreciated as a potential contributor to OSA in children. This is partly because nasal obstruction in younger children is often a chronic problem attributed to frequent upper respiratory infections, allergic rhinitis, or adenoid hypertrophy. Surgical interventions for the anterior nasal passage, such as septoplasty and inferior turbinate reduction, are typically only offered to older children and adolescents. However, evidence demonstrates that treating the anterior nasal passage through inferior turbinate reduction or septoplasty is safe and effective in improving nasal airflow and OSA (Arganbright et al., 2015; Cheng et al., 2012).

1.3 Nasopharynx

The nasopharynx is bounded anteriorly by the choanae, laterally by the medial pterygoid plates and superior constrictor muscles, superiorly by the sphenoid rostrum, posteriorly by the adenoid pad and posterior pharyngeal wall, and inferiorly by the soft palate. In children, adenoid hypertrophy is the most common cause of obstruction in this location and has an estimated prevalence between 34% and 70% among children and adolescents (Fig. 1.2).

Figure 1.2 Adenoid hypertrophy.

Chronic nasopharyngeal obstruction due to adenoid hypertrophy, sometimes in combination with anterior nasal obstruction due to allergic rhinitis or septal deviation, predisposes to chronic mouth-breathing and open-mouth posture. This has been associated with adenoid facies, characterized by a retrusive mandible, narrow, high-arched palate, short upper lip, and long midface (Agostinho et al., 2015; Lione et al., 2014).

1.4 Oral cavity

The oral cavity comprises the oral commissure, maxillary and mandibular alveoli and teeth, the floor of the mouth and anterior tongue floor, the hard palate, and the soft palate and uvula. With the mouth at the maximum opening, the degree to which the soft palate, uvula, and posterior pharynx can be visualized has been used as a proxy for oral cavity crowding. The severity of oral crowding can be graded according to the Mallampati classification (Mallampati et al., 1985), where the tongue is protruded maximally (Fig. 1.3). This classification is independently associated with OSA severity in adults (Friedman et al., 2013; Nuckton et al., 2006). A related classification is the Friedman tongue position (FTP), based on a similar grading with the tongue resting on the floor of the mouth, and a staging system, as shown in Fig. 1.4 based on the FTP, tonsil size, and BMI is predictive of the outcome of uvulopalatopharyngoplasty in adults (Friedman et al., 2004). Unfortunately, applying a similar staging system was not associated with the outcome for adenotonsillectomy (AT) in children (Smith et al., 2013).

Figure 1.3 Mallampati classification.

Figure 1.4 Friedman classification. Source: From Gil, H., & Fougeront, N. (2015). Tongue dysfunction screening: assessment protocol for prescribers. Journal of Dentofacial Anomalies and Orthodontics, 18(4), 408.

A short lingual frenulum has been associated with a high-arched narrow hard palate and chronic mouth-breathing and may be associated with a greater risk of SDB (Guilleminault et al., 2016; Villa et al., 2020). Though it has been suggested that malocclusion and other craniofacial dysmorphology may similarly be independent risk factors for SDB in children, evidence supporting this hypothesis is limited by poor quality studies with a significant risk of bias, and with inconsistent definitions of SDB. A recent metaanalysis of studies assessing the association between SDB and malocclusion found no clear association between molar relationship and crowding and SDB symptoms in children (Hansen et al., 2022).

1.4.1 The anterior tongue

The tongue musculature is complex, with numerous interwoven individual muscles allowing the complex and intricate tongue movements that contribute to speech and swallowing. They fall into three general categories: protrusors that extending the tongue anteriorly (genioglossus, geniohyoid, and mylohyoid), retrusors that pull the tongue posteriorly (styloglossus, hyoglossus, and palatoglossus), and intrinsic muscles that stiffen and stabilize the tongue (transverse, verticalis, superior, and inferior longitudinal). The genioglossus is worth highlighting as the triangular or fan-shaped muscle with its apex attached anteriorly to the genial tubercle of the mandible and its base attached posteriorly to the body of the hyoid, and the tongue dorsum. The genioglossus is the most important tongue protrusor and has been identified as the key muscle in widening and stabilizing the retrolingual airway through upper airway stimulation (Oliven et al., 2003).

1.4.2 Soft palate

The soft palate makes up the posterior third of the palate and is continuous with the bony hard palate and the palatine aponeurosis. Its function is to elevate superiorly and posteriorly to seal off the nasopharynx from the oropharynx during speech and swallowing. It comprises five muscles the palatoglossus, palatopharyngeus, the tensor veli palatini, levator veli palatini, and musculus uvulae. The tensor veli palatini and levator veli palatini are attached to the palatine aponeurosis caudally and cranially to the medial pterygoid plate and the eustachian tube orifice, respectively. Together they serve to elevate the palate during speech and swallowing. The palatoglossus and palatopharyngeus insert into the palatine aponeurosis cranially and caudally attach to the lateral border of the tongue base and the thyroid cartilage, respectively. They form the anterior and posterior tonsillar pillars and function to tense the soft palate and elevate the larynx during swallowing. The musculus uvulae originate from the posterior nasal spine and are an extension of the palatine aponeurosis forming the uvula (Fig. 1.5).

Figure 1.5 Muscles of the soft palate. Source: From Olszewska, E., & Woodson, B.T. (2019). Palatal anatomy for sleep apnea surgery. Laryngoscope Investigative Otolaryngology, 4(1), 181–187.

The soft palate and uvula are the most commonly noted source of obstruction in adult OSA, observed to affect 84%–92% of patients undergoing drug-induced sleep endoscopy (DISE) (Lee & Cho, 2019). A long or pendulous uvula is a frequent observation in adults with sleep apnea, presumably due to the negative pressure and repeated vibratory trauma from chronic snoring. While the soft palate is a less common source of obstruction in children, it has been observed during DISE to be a contributor in 15%–59% of children with persistent OSA after AT (Coutras et al., 2018; Durr et al., 2012; Esteller et al., 2019).

1.5 Oropharynx

The oropharynx is bounded anteriorly by the posterior aspect of the soft palate, anterior tonsillar pillars, and circumvallate papillae. It extends superiorly from the superior aspect of the soft palate to the vallecula and hyoid inferiorly. It is bounded posteriorly by the posterior pharyngeal wall and laterally by the lateral pharyngeal wall and palatine tonsils.

1.5.1 Tonsillar region

In addition to the palatine tonsils, the tonsillar region includes the palatoglossus and palatopharyngeus, forming the anterior and posterior tonsillar pillars, respectively. Hypertrophy of the palatine tonsils is the most common cause of obstruction and snoring in children, and SDB is the most common indication for AT. Tonsil size observed during routine clinical examination has been described as a percentage of the transverse distance from the lateral sidewall to the midline (Brodsky scoring) (Brodsky, 1989), or by the transverse degree of pharyngeal obstruction relative to surrounding structures (Friedman scoring, Fig. 1.1) (Friedman et al., 1999).

Though the documentation of tonsil size is a routine part of a head-and-neck examination in the clinic and is frequently used as a determinant for candidacy for tonsillectomy, clinic-based awake assessments of tonsil size have not consistently correlated with OSA severity or with outcome after tonsillectomy (Howard & Brietzke, 2009; Hwang et al., 2013; Nolan & Brietzke, 2011; Pierce & Brietzke, 2019). This may reflect that true tonsil volume can often be obscured by relative positioning within the tonsillar fossae, with recessed tonsils appearing relatively small based on the above scoring methods, but having significant volume and potential for obstruction. Indeed, objective measurements of tonsil volume or weight after excision have both been shown to correlate better with OSA severity than clinic tonsil scoring (Howard & Brietzke, 2009). In addition, awake upright tonsil scoring does not account for the dynamic collapse that can occur during sleep, something better captured by DISE, which has also been shown to correlate better with both OSA severity and the outcome of tonsillectomy (Lam et al., 2019).

1.5.2 Tongue base

Crowding of the retrolingual airway in children can occur due to either lingual tonsil hypertrophy or glossoptosis in children with poor muscle tone or micrognathia. Lingual tonsil hypertrophy has been recognized as a common source of obstruction due to excess lymphoid tissue beginning from the circumvallate papillae and extending caudally toward the piriform sinuses laterally or the vallecula and epiglottis medially. In extreme cases, the vallecula and epiglottis can be entirely obscured when observed with flexible endoscopy from above (Friedman et al., 2016). Tongue base obstruction has been observed in 40%–85% of children with persistent OSA after AT (Coutras et al., 2018; Durr et al., 2012; Esteller et al., 2019).

Macroglossia, a common feature of Down syndrome and Beckwith–Wiedemann syndrome, is thought to be a key contributor to upper airway obstruction in both patient populations (Perkins, 2009). Relative macroglossia, as in the Pierre Robin sequence, characterized by severe micrognathia, glossoptosis, and airway compromise, also illustrates the importance of the tongue and its relationship to the surrounding oral cavity and oropharynx.

1.6 Hypopharynx

The hypopharynx is the inferior part of the pharynx, extending from the hyoid superiorly to the larynx and esophageal inlet inferiorly. It is bounded by the inferior constrictor muscles laterally and posteriorly and the vallecula and epiglottis anteriorly. The structures most relevant to obstruction during sleep are the epiglottis and the arytenoids. Supraglottic obstruction can occur during inspiration due to epiglottic retroflexion or lateral collapse, as seen when the epiglottis is omega shaped, and with anterior prolapse of the arytenoids (Fig. 1.6). These are features of laryngomalacia, the most common cause of infant stridor and airway obstruction. This type of supraglottic obstruction is much less common in older children but can occur primarily during sleep, when it is often referred to as occult or sleep-dependent laryngomalacia (Chan et al., 2012; Digoy et al., 2012; Mase et al., 2015). Though this has been described as a frequent contributor to OSA, the true prevalence is unknown. However, arytenoid prolapse has been reported to occur more frequently in children with Down syndrome than in the general pediatric population (Hyzer et al., 2021). In addition to this supraglottic obstruction, circumferential or lateral collapse of the pharyngeal walls can also occur throughout the oropharyngeal and hypopharyngeal airway (Boudewyns et al., 2018).

Figure 1.6 Arytenoids observed during drug-induced sleep endoscopy with anterior prolapse during inspiration.

1.7 Conclusion

Airway obstruction can occur at all levels of the upper airway in children, which often varies significantly with age. Understanding the anatomic sources and patterns of obstruction is important to design the best management strategy.

References

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Chapter 2

Regulation of the upper airway during sleep

Eliot S. Katz¹,²,    ¹Division of Respiratory Diseases, Department of Medicine, Boston Children’s Hospital, Boston, MA, United States,    ²Harvard Medical School, Boston, MA, United States

Abstract

The essential feature of obstructive sleep apnea in children is increased upper airway resistance during sleep. The upper airway size and compliance primarily depend upon the craniofacial skeleton, soft tissues, and nasopharyngeal muscle activity. Narrowing of the nose, maxilla, or mandible may contribute to airway collapse. Factors that influence the soft tissues include adiposity, fluid balance, lung volumes, inflammation, and genetics. Airway muscle tone is decreased during sleep onset and is further regulated by ventilatory control, sleep state, and afferent reflexes. Obstructive events during sleep are associated with paroxysmal decreases in pharyngeal muscle tone. Non rapid eye movement (NREM) sleep is associated with reduced pharyngeal muscle tone resulting in upper airway narrowing. Muscle activity is further attenuated during rapid eye movement (REM) sleep, especially phasic rapid eye movements. During wakefulness, upper airway muscles respond briskly to negative luminal pressure (mechanoreceptors) and carbon dioxide (chemoreceptors). This reflex activation of pharyngeal stabilizing muscles is greatly diminished during sleep, further increasing upper airway collapsibility. The responsiveness of upper airway muscles to reflex chemoreceptor and mechanoreceptor input is a variable physiological trait. This chapter describes the anatomical, physiological, and neuromuscular determinants of airway patency during sleep.

Keywords

Obstructive sleep apnea; children; upper airway; pathophysiology; genioglossus; collapsibility and arousal

2.1 Introduction

Obstructive sleep apnea (OSA) is reported in 4%–6% of children and is associated with considerable neurocognitive, metabolic, and cardiovascular morbidity. The essential feature of OSA is increased upper airway collapsibility during sleep which derives from a combination of skeletal, soft tissue, and neuromuscular factors. In addition to ventilation, the upper airway facilitates swallowing and speech, during which it must naturally close. Airway collapse occurs when the airway wall pressure exceeds the luminal pressure. Besides anatomical factors, the primary determinants of airway patency are ventilatory control, arousal threshold, and pharyngeal dilator activity. The skeletal predisposition toward OSA includes nasal, maxillary, and mandibular narrowing. The airway soft tissues include the turbinates, adenoids, tonsils, palate, tongue, hypopharyngeal cartilages, and vocal cords, which may be susceptible to inflammation, fluid shifts, and lung volume changes. At sleep onset, the wakefulness stimulus to the upper airway musculature is lost, resulting in increased airway compliance and decreased size. During sleep, pharyngeal muscle tone is governed by ventilatory control considerations and airway reflexes. This chapter describes the physiological and neuromuscular regulation of the upper airway during sleep as it pertains to obstructive sleep-disordered breathing.

2.2 Central respiratory control of the upper airway

Neural networks produce the respiratory rhythm in medullary aggregations termed the dorsal respiratory group (DRG) and ventral respiratory group (VRG). The respiratory pattern generator contains neurons in the VRG called the preBotzinger complex. The DRG’s nucleus tractus solatarius receives projections from the preBotzinger complex and afferent modulation from the airway, lungs, and chemoreceptors. Following integration, signals project differentially to the upper airway and respiratory muscles (Ikeda et al., 2017). The primary innervation of the upper airway derives from the hypoglossal, trigeminal, and facial brainstem motor nuclei. Under normal circumstances, the hypoglossal nerve activates the pharyngeal dilator muscles and stiffens the upper airway prior to the intercostal muscle and diaphragm activation.

Central chemoreceptors on the ventral medulla are sensitive to cerebrospinal fluid (CSF) acidity. CSF and arterial blood are separated by the blood–brain barrier preventing H+ and bicarbonate equilibration but allowing CO2 diffusion. Ventilatory drive output is inversely related to pH. Peripheral chemoreceptors in the carotid artery and aortic arch are sensitive to PaCO2, PaO2, and H+ and provide afferents allowing for a breath-by-breath modulation of breathing and upper airway tone. Respiratory motoneurons receive excitatory and inhibitory inputs that vary as a function of sleep state, phase of the respiratory cycle, and behavioral actions. The balance of these inputs to the various respiratory motoneurons yields tonic (baseline) and phasic (respiratory-related) outputs. Phasic inputs are observed even in patients after a laryngectomy and are breathing through a tracheostomy, indicating a central phasic drive (Innes et al., 1995), which is augmented by mucosal afferents responding to negative luminal pressure (Horner et al., 1991).

During wakefulness, there are many inputs to respiratory drive besides chemical control, including voluntary control from the cerebral cortex, emotional control from the limbic system, proprioceptor feedback from muscles/joints, and the wakefulness stimulus from the ascending arousal system. The ascending arousal system promoting wakefulness includes nuclei input from the lateral dorsal and pedunculopontine tegmental (cholinergic), basal forebrain (cholinergic), dorsal raphae (serotonin), locus coeruleus (norepinephrine), tuberomammillary (histamine), perifornical region of the hypothalamus (orexin), and ventral periaqueductal gray (dopamine). Additionally, hypoglossal motor neurons are not actively inhibited during expiration, as observed in phrenic neurons. Instead, hypoglossal motoneurons maintain tonic activity during expiration, maintaining airway patency during wakefulness.

The primary determinant of respiratory drive and upper airway tone during sleep is carbon dioxide tension. At sleep onset, the ventrolateral preoptic neurons inhibit the arousal system through gamma-aminobutyric acid (GABA) and galanin-mediated mechanisms, thus removing the wakefulness stimulus to the upper airway in higher pharyngeal compliance that is susceptible to collapse. This pathway also explains the respiratory depression associated with GABAergic sedatives. There is also a withdrawal of endogenous noradrenergic and glutamatergic input to the hypoglossal motor nuclei. Glycine is the predominant inhibitory transmitter of spinal motoneurons, including the intercostal muscles, during rapid eye movement (REM) sleep. However, the chief inhibitory transmitter mediating the hypoglossal motor suppression and, therefore pharyngeal dilator activity during REM sleep is cholinergic (muscarinic). Given these excitatory and inhibitory inputs to the hypoglossal motor nuclei, there are preliminary reports of successful use of noradrenergic stimulants and cholinergic antagonists to increase pharyngeal dilator activity, therefore, treat OSA (Taranto-Montemurro et al., 2019).

At sleep onset, there is a lowering of the ventilatory drive produced by CO2 and oxygen. Thus decreased pharyngeal dilator tone (Katz & White, 2003) and respiratory muscle activity reduce overall minute ventilation. In non rapid eye movement (NREM) sleep, ventilation is predominantly chemically controlled by CO2 tension. Thus at sleep onset, PaCO2 increases, and PaO2 decreases. At NREM sleep onset, there is a substantial decrease in the tone of pharyngeal dilator activity and the intercostal muscles. The resulting hypoventilation produces gas exchange abnormalities that augment airway muscle tone that may exceed the wakeful baseline. Other mechanisms recruiting pharyngeal dilators after sleep onset include the negative airway pressure reflex and arousal. By contrast, the diaphragm manifests minimal decrements in activity in NREM or REM sleep. In NREM, the emergence of an apneic threshold below eupneic PaCO2 predisposes to ventilatory instability. During apnea, CO2 accumulates, and oxygenation decreases, leading to chemoreceptor-induced ventilatory overshoot leading to a repetitive hypocapnia/hypercapnia obstructive cycling. An increase in PaCO2 above the apneic threshold is required to reinitiate breathing.

In REM sleep, breathing is irregular with frequent pauses, and significant motor suppression is ultimately mediated by glycinergic neurons lowering neuronal cell excitability. Further decreases in motoneuron excitability are observed during phasic REM resulting in marked reductions in pharyngeal dilator tone and decreased minute ventilation. Thus in REM sleep, a reduction in respiratory motoneuron activity is observed even in hypercapnia.

2.3 Anatomy of the upper airway

A comprehensive review of upper airway anatomy is provided in Chapter 1. Children with OSA have larger airway soft tissues and narrower pharyngeal airways compared to children without OSA (Arens et al., 2001; Isono et al., 1998; Monahan et al., 2002). Also, nasal resistance measured by anterior rhinometry is increased in children with OSA (Rizzi et al., 2002). The site of the increased upper airway resistance is variable, as is evident by OSA improvement in selected populations following adenotonsillectomy (Guilleminault et al., 2007; Tauman et al., 2006), turbinectomy (Guilleminault et al., 2004), septal repair (Guilleminault et al., 2004), intranasal corticosteroids (Brouillette et al., 2001), and rapid maxillary expansion (Pirelli et al., 2004). In addition, children with craniofacial dysmorphology involving hypoplasia or retro-positioning of the mandible or maxilla frequently have OSA. The contribution of skeletal abnormalities to the development of OSA in otherwise typically developing children is controversial.

2.3.1 Nose

Normal breathing during sleep is primarily by the nasal route, especially in infants (Miller et al., 1985). Some spontaneous mouth breathing is occasionally observed, but nasal occlusion challenges result in frequent arousal, oxygen desaturation, and audible grunting (Miller et al., 1985). Switching to mouth breathing is less effective during REM sleep and in younger infants (Purcell, 1976; Swift & Emery, 1973). Nasal resistance accounts for approximately 50% of the total upper airway resistance and is subject to increase considerably due to secretions, vascular engorgement in the supine position, and mucosal edema. Nasal obstruction may also be observed in choanal atresia, pyriform aperture stenosis, upper respiratory infection, septal deviation, or allergic rhinitis.

2.3.2 Pharynx

Pharyngeal compliance increases at sleep onset with a reduction in muscle tone resulting in airway narrowing, increased airflow resistance, and decreased tidal volume. There is an overall decrease in minute ventilation during NREM sleep despite a gradual increase in activity in the intercostal muscles and diaphragm (Tabachnik et al., 1981). During tidal breathing, the narrowest airway segment occurs at the site of overlap between the tonsil and adenoid in younger and older children (Arens et al., 2003; Fregosi et al., 2003). The location of airway narrowing during obstructive events in children with OSA may be the hypopharynx, soft palate, tonsil, and tongue. Thus airway narrowing likely necessitates increasingly negative airway pressures to sustain minute ventilation, which results in airway collapse at multiple sites.

2.3.3 Mandible

A small mandible displaces the tongue toward the posterior pharyngeal wall resulting in a narrow, more collapsible airway. The triad of micrognathia, glossoptosis, and cleft palate is termed the Pierre Robin sequence (PRS), which is frequently associated with OSA. About 80% of cases of PRS are syndromic, including Stickler, Velocardiofacial, Nagar, Treacher-Collins, and hemifacial microsomia (Shprintzen, 1992). Micrognathic infants have been documented to have increased airway collapsibility (Cohen & Henderson-Smart, 1986). Some infants with micrognathia can maintain airway patency with increased neuromuscular activation of the pharyngeal muscles (Roberts et al., 1986).

2.3.4 Maxilla

Maxillary narrowing can be observed in the anteroposterior or mediolateral plane and may be congenital or acquired. Midfacial hypoplasia is observed in the craniosynostosis syndromes, Apert, Crouzon, and Pfeiffer, which may be associated with comorbid nasal anomalies, further increasing upper airway resistance. The prevalence of OSA with craniosynostosis in infancy is 40%, with many additional cases occurring later coincident with adenotonsillar growth (Moore, 1993). The neck position is an essential determinant of airway collapsibility in infants. Neck flexion of 15–30 degrees increases collapsibility by 4–5 cm H2O, whereas neck extension decreases collapsibility by 3–4 cm H2O (Wilson et al., 1980). These changes are sufficient to be an essential determinant of airway patency during tidal breathing.

2.4 Physiology of the upper airway during sleep

The upper airway has a highly compliant range over which a 2 cm H2O decrease in luminal pressure produces a 50% reduction in airway cross-sectional area. This has important implications in the pathophysiology of OSA, resulting in rapid airway closure and opening, making abrupt changes in minute ventilation and, therefore, in CO2 levels. In addition to neuromuscular factors, upper airway patency is influenced by lung volume and mouth breathing. Increasing lung volume stretches the soft tissues of the upper airway, decreasing airway compliance and reducing obstructive events (Heinzer et al., 2006). Conversely, the reduced lung volumes observed in obese patients increase airway collapsibility, predisposing them to OSA. Mouth breathing displaces the tongue toward the posterior pharyngeal wall increasing the likelihood of airway obstruction.

The viscoelastic properties of the airway vary with development. Under anesthesia and postmortem, infants have a mean airway closing pressure, which is −0.5 to −0.7 cm of H2O (Wilson et al., 1980). By 1 year, the infant’s airway under anesthesia becomes more stable with collapsibility of −6 cm H2O (Isono, 2006). Pharyngeal dilator activity modulates the cross-sectional area and compliance of the upper airway. During sleep, muscle activation results in the infant’s airway closing pressure being less than −25 cm H2O, indicating adequate neuromuscular compensation to maintain airway patency (Marcus et al., 2004). Infants respond to increased airway resistance or occlusion with abrupt increases in genioglossal electromyography (EMG) (Carlo et al., 1985; Gauda et al., 1987), though an immediate and sustained decrease in minute ventilation is observed (Abbasi et al., 1984; Purcell, 1976). This compensatory mechanism may be absent in hypotonic infants.

2.5 Neuromuscular compensation

Twenty-four pairs of skeletal muscles comprise the upper airway from the nose to the larynx. Some pharyngeal dilator muscles (genioglossus, levator palatini) are phasically activated during inspiration, increasing the luminal size and stiffness of the airway. Phasic activity of the upper airway muscles precedes diaphragmatic and intercostal contraction resulting in a stiffened airway less prone to collapse. Other airway muscles are tonically active (tensor palatini) independent of the respiratory cycle.

In normal children, the collapsing pressure of the airway (Pcrit) under paralysis is −7.4 cm H2O and during sleep is −25 cm H2O. This indicates the considerable activity of the upper airway musculature during sleep (Isono et al., 1998; Marcus et al., 2005). By contrast, in children with OSA, the Pcrit under paralysis is −2 cm H2O and during sleep is −5 cm H2O, indicating less adequate neuromuscular compensation. Children with OSA have more collapsible airways during sleep at baseline and impaired airflow responses to negative pressure and hypercapnia compared to normal children (Marcus et al., 2005). Whether the impaired responses to negative pressure in children with OSA are related to neural processing or a phenomenon secondary to damaged afferent receptors due to mucosal swelling/inflammation remains to be determined.

The collapse of the upper airway reduces minute ventilation and induces a compensatory increase in respiratory effort and elevated negative luminal pressure. The negative pressure reflex consists of airway mucosal mechanoreceptor-induced activation of pharyngeal dilator muscles, stabilizing the airway. Children who successfully augment airflow early during airway collapse may be spared the progression to apneas or hypopneas, which would be more likely to result in sleep disruption. It is plausible that mucosal inflammation or edema could impair the afferent limb of this reflex. Blunted respiratory perception in children with OSA has been reported by measuring respiratory-related evoked potentials (Huang et al., 2013). Direct evidence for inflammatory changes to the upper airway includes the increased expression of leukotriene receptors in tonsillar tissue from children with OSA (Goldbart et al., 2004) and successful treatment studies using antiinflammatory agents (Brouillette et al., 2001; Kheirandish et al., 2006).

2.6 Ventilatory control

The highest density of obstructive events in children is observed in REM sleep, where chemical ventilatory control is the least important. Nevertheless, the pharyngeal dilator activity variability is highest in REM, intermediate in stage 2 sleep, and lowest in slow-wave sleep. Paroxysmal reductions in the respiratory drive to the upper airway underlie the variability in REM sleep. By contrast, during NREM sleep, the ventilatory response to CO2 is robust, and hyperpnea may lead to a ventilatory overshoot. Consequently, CO2 levels may drop below an apneic threshold, a unique property of NREM sleep. This apneic threshold may be 1–3 Torr below eupneic breathing in infants, which predisposes them toward periodic breathing, whereas the apneic threshold is 2–6 Torr in adults resulting in more stable ventilatory control.

Ventilatory cycling in OSA patients is facilitated by significant changes in tidal volume occurring as the airway opens and closes. If the obstructive event is associated with an arousal, the ventilatory overshoot is magnified, and ventilation is more destabilized. Ventilatory control stability may be modeled as the ratio of the ventilator response to a ventilator disturbance, termed loop gain. Patients with high loop gain are at risk for CO2 fluctuations and pharyngeal muscle tone fluctuations. Central, mixed, and obstructive apneas in infants and children occur at the nadir of oscillations in ventilation (Waggener et al., 1989) and airway muscle activity (Katz & White, 2004). Loop gain is reduced with supplemental oxygen (Wellman et al., 2008) and acetazolamide (Edwards et al., 2012), thus decreasing ventilatory instability.

2.7 Sleep state effect

During wakefulness, children with OSA have increased pharyngeal dilator activity compared to children without OSA (Katz & White, 2003). This represents reflex activation by mucosal mechanoreceptors sensing negative airway pressure. Further, applying topical anesthesia during wakefulness to the airway results in a more significant decline in airway size in OSA patients (Gozal & Burnside, 2004). Thus mucosal mechanoreceptor-induced pharyngeal dilator activity is more active in OSA patients during wakefulness.

During the sleep onset period, the airway muscle activity decreases in both OSA and non OSA patients, but more so in the former (Katz & White, 2003). The reduction in muscle activity is associated with increased airway resistance and collapsibility. As stable NREM sleep is established over several minutes, most children with severe OSA have a rebound increase in pharyngeal dilator activity during stage 2 sleep, consistent with a reflex driven by mechano- and chemoreceptors (Katz & White, 2004). The highest density of obstructive events in children is observed during REM, followed by stage 2, and is very rare in slow-wave sleep (Goh et al., 2000). Overall in REM sleep, the pharyngeal dilator activity is reduced, and the variability increases. Sudden decrements in airway muscle activity during REM sleep lasting a few seconds are observed coincident with apneic and hypopneic events (Katz & White, 2004).

The minute ventilation declines by about 15% during NREM sleep resulting in a reduction in the PaO2 of 4–8 Torr and an increase in the PaCO2 by 2–4 Torr. In REM sleep, there is a further reduction in the hypercapnic and hypoxemic ventilatory drives and a variable alternating marked activation/suppression of the airway, respiratory pump, and nonrespiratory muscles (REM processes) independent of carbon dioxide or oxygen levels. During phasic REM sleep, there is an additional reduction in airway muscle tone and minute ventilation. During NREM sleep in normal subjects, the cross-sectional airway at the retroglossal level decreases by 33%, with additional narrowing during REM sleep (Rowley et al., 2001).

Lung volume decreases in the supine position and further during sleep, especially during REM sleep (Henderson-Smart & Read, 1979). The supine position also results in a redistribution of fluid into the upper airway, further predisposing toward airway collapsibility (White & Bradley, 2013). Lower lung volumes lessen the caudal tension on the pharyngeal muscles increasing airway collapsibility (Stanchina et al., 2003; Van de Graaff, 1988), adversely affecting ventilation–perfusion matching, resulting in more rapid gas exchange abnormalities.

2.8 Arousal

Arousal from sleep is a hierarchical phenomenon resulting in the activation of pharyngeal dilator muscles and increased ventilation. The principal stimulus for arousal appears to be respiratory effort and hypercapnia, whereas hypoxemia is a poor arousal stimulus. Arousal is a critical safety mechanism to restore airway patency after collapsing during sleep. However, arousal also results in an abrupt surge in minute ventilation resulting in a decrease in CO2 that may promote subsequent airway hypotonia. Individuals with low arousal indexes or high ventilatory responses to arousal are prone to ventilatory control instability and obstructive cycling. Airway opening mechanisms may utilize brainstem reflexes alone or extend to include cortical arousal. In adults, over 85% of obstructive events are accompanied by electrocortical arousal, compared to only about 50% of events in childhood and 12%–18% in infants (Mcnamara et al.,