This material is being provided in electronic format for the sole purpose of reference material for the creation

of slide sets as directed by the Sleep Research Society, and should not be used for reproduction or other purposes without the express written approval of the Sleep Research Society.

Chapter 10
Respiratory Physiology: Control of the Upper Airway
Richard L. Horner University of Toronto

Chapter 10: Respiratory Physiology: Control of the Upper Airway

91

This material is being provided in electronic format for the sole purpose of reference material for the creation of slide sets as directed by the Sleep Research Society, and should not be used for reproduction or other purposes without the express written approval of the Sleep Research Society.

Key Concepts
The pharynx is a collapsible tube vulnerable to closure during breathing. Tonic and respiratory-related pharyngeal muscle activity are important for airway patency. Respiratory activation of pharyngeal muscles precedes that of the diaphragm. Tonic activation of pharyngeal motoneurons is decreased in sleep. Upper airway size varies throughout the respiratory cycle. Mechanics of the upper airway influence airway collapsibility. Sub-atmospheric pressures in the upper airway cause reflex pharyngeal muscle activation. Chemoreceptor stimulation causes reflex pharyngeal muscle activation. The site of obstruction varies within and between patients with obstructive sleep apnea.

92

Chapter 10: Respiratory Physiology: Control of the Upper Airway

This material is being provided in electronic format for the sole purpose of reference material for the creation of slide sets as directed by the Sleep Research Society, and should not be used for reproduction or other purposes without the express written approval of the Sleep Research Society.

Introduction
This chapter addresses the respiratory function of the upper airway (UA) and the important effects of sleep on this function. The respiratory activation of the pharyngeal muscles awake and asleep is first addressed followed by the influence of this activation on the mechanical properties and collapsibility of the pharyngeal airspace. The reflex mechanisms maintaining an open airspace are also reviewed. Throughout this chapter these mechanisms are considered in the context of understanding the physiology and pathophysiology underlying the common clinical problems of obstructive sleep apnea (OSA) and snoring. Pharyngeal Muscles are Activated During Breathing The pharynx is a collapsible tube vulnerable to closure during breathing In contrast to the trachea and bronchi, the UA is the only region of the respiratory tract not surrounded by rigid cartilaginous support. Instead the UA is surrounded by a complex anatomical arrangement of skeletal muscles and soft tissues that support essential non-respiratory functions such as vocalization, suckling and swallowing, i.e. behaviors that require dynamic changes in airway size to move air, liquids and solids. Nevertheless, this property of a collapsible tube compromises the essential respiratory function of the UA, i.e., the airway must remain open during breathing, in all postures, to allow adequate pulmonary ventilation and gas exchange. Sleep, however, causes fundamental modifications of pharyngeal muscle tone and reflex responses that in normal individuals can lead to UA narrowing and increased resistance to breathing. This increased UA resistance contributes significantly to the hypoventilation and increased arterial PCO2 of 3-5 mmHg normally observed in sleeping humans, and its elimination reverses a large component of the sleep-induced hypoventilation. In individuals with an already anatomically narrow UA these effects of sleep on pharyngeal muscle tone can predispose to inspiratory flow limitation (hypopneas) and OSA. Tonic and respiratory-related pharyngeal muscle activity are important for UA patency During inspiration the UA experiences subatmospheric pressures transmitted from the thoracic cavity. The maintenance of an open airway depends on intrinsic collapsibility of the UA and the level of pharyngeal muscle activation which stiffens and enlarges the airway. To counteract the vulnerability of the UA during breathing, a number of pharyngeal muscles exhibit respiratoryrelated activity superimposed upon background tonic activity (Figure 1). There are several features distinguishing the control of cranial motoneurons innervating pharyngeal muscles from spinal motoneurons innervating respiratory pump muscles (Figure 1): (i) Respiratory activation of pharyngeal muscles precedes that of the diaphragm: Pre-activation by ~200 msec for a variety of pharyngeal muscles prepares for subsequent contraction of respiratory pump muscles and helps maintain airflow in the UA. Fast contractile properties of UA muscles also contribute to the maintenance of inspiratory airflow. (ii) Tonic activation of pharyngeal motoneurons: Unlike phrenic motoneurons innervating the diaphragm, hypoglossal motoneurons innervating the genioglossus muscle of the tongue, a major pharyngeal dilator, are not inhibited throughout expiration. Therefore, basal levels of pharyngeal muscle activity are a manifestation of prevailing tonic inputs which, importantly, contribute to resting airway size and stiffness. Accordingly, even though pharyngeal muscles conform to the classic concept of being respiratory muscles and show respiratory-related activity, the activity in expiration is simply the manifestation of prevailing tonic inputs of non-respiratory origin that are revealed when inspiratory activation is withdrawn. (iii) Tonic activation of pharyngeal motoneurons is decreased in sleep: Sleep reduces pharyngeal muscle tone, with decreases in tonic activity being especially prominent. Reduced tonic pharyngeal muscle activity in sleep, especially REM sleep, contributes to reductions in airway size and stiffness, thereby increasing vulnerability to collapse (Section 2). Some pharyngeal muscles exhibit more respiratory-related activity than others, while some are more tonically active, e.g., genioglossus vs. tensor

Figure 1: Pharyngeal muscle activity is determined by summation of tonic inputs with inspiratory drive, with the degree of respiratory-related activity differing between muscles (e.g. genioglossus verses tensor veli palatini). Respiratory activation of pharyngeal muscles precedes that of the respiratory pump. Decreases in tonic inputs occur in sleep. Abbreviations: Insp., Inspiration.

Chapter 10: Respiratory Physiology: Control of the Upper Airway

93

This material is being provided in electronic format for the sole purpose of reference material for the creation of slide sets as directed by the Sleep Research Society, and should not be used for reproduction or other purposes without the express written approval of the Sleep Research Society.

palatini (Figure 1). The tensor palatini displays mostly tonic activity and is thought to enhance stiffness in the rostral UA. Decreases in palatal muscle activity in sleep are associated with increased resistance in the airspace behind the soft palate, a consistent site of occlusion in OSA patients (Section 4). (iv) Mechanisms underlying decreased tonic activity in sleep: The neural mechanisms responsible for tonic sleep-state dependent inputs to pharyngeal motoneurons are being determined from animal studies. Brainstem serotonergic and noradrenergic neurons send excitatory projections to pharyngeal motoneurons with these neurons showing highest activity in wakefulness, reduced activity in non-REM sleep and minimal activity in REM sleep, i.e., a pattern that may contribute to reduced pharyngeal muscle activity in sleep via reduced excitation. Other neuronal systems, e.g. inhibitory neurotransmitters, may also contribute to suppression of pharyngeal muscle activity in sleep. Currently there is no effective pharmacotherapy for OSA. Mechanical Properties and Collapsibility of the UA UA size and variations throughout the respiratory cycle The retropalatal (behind the soft palate) and retroglossal (behind the tongue) airspaces are narrower in OSA patients than controls (Figure 2). Anatomical factors contributing to this narrowing include fat deposits around the pharynx, hypertrophied adenoids and tonsils, macroglossia, retrognathia and micrognathia. The weight of the tongue and neck (especially with obesity) can also narrow the airspace through gravitational forces when supine. Airway size also decreases with decreases in lung volume. Since decreases in functional residual capacity occur in sleep, especially REM sleep when the intercostal muscles are inhibited in parallel with other postural muscles, this will contribute to decreased UA size and increase collapsibility. The small UA at end expiration, particularly in OSA patients (Figure 2) increases the demand on UA muscles to maintain adequate airflow during inspiration. Increased genioglossus activity in awake OSA patients suggests a neural compensation to maintain adequate airflow but this compensation is lost in sleep. Figure 2 shows that significant enlargement of the UA does not occur in inspiration despite pharyngeal muscle activation, likely because the narrowing effects of inspiratory suction pressures offset the dilating effects of UA muscle activation. Caudal traction of the trachea during inspiration narrows but also stiffens the UA. The increases in UA size in expiration may be due to positive pressures acting on a compliant airway. Mechanics of the UA and influences on collapsibility The UA has been modeled as a collapsible tube (Figure 3a) with maximum flow (VMAX) determined by
94

Figure 2: The UA is (i) narrowest in the region posterior to the soft palate, (ii) narrower in OSA patients, and (iii) varies with the breathing cycle (Insp, Inspiration; Exp, Expiration). Modified from Schwab et al., 1993.

upstream nasal pressure (PN) and resistance (RN). Airflow ceases in the collapsible segment of the UA at a value of critical pressure (PCRIT). VMAX is determined by: VMAX = (PN - PCRIT) / RN Accordingly, increases in PN lead to increases in VMAX in the UA (the basis for nasal continuous positive airway pressure therapy in OSA), whereas decreases in PN decrease VMAX. This relationship is linear for the UA (Figure 3b). The PCRIT for airway closure is progressively more positive (i.e. indicating a more collapsible UA) from groups of normal sleeping subjects, to snorers, patients with hypopneas and OSA (Figure 3c). Subjects in whom the UA is closed, or nearly closed, at pressures near (or above) atmospheric are highly susceptible to OSA/hypopnea and require UA muscle activation to permit adequate airflow. Increased UA muscle activation (e.g. caused by reflexes, respiratory-related or tonic inputs) increases VMAX and decreases UA collapsibility, whereas decreased UA muscle activity (e.g. caused by sleep-related reductions

Figure 3: Mechanics of the UA and influences on collapsibility. Modified from Smith and Schwartz, 2002.

Chapter 10: Respiratory Physiology: Control of the Upper Airway

This material is being provided in electronic format for the sole purpose of reference material for the creation of slide sets as directed by the Sleep Research Society, and should not be used for reproduction or other purposes without the express written approval of the Sleep Research Society.

in tonic activity, anesthesia or alcohol) decreases VMAX and increases collapsibility (Figure 3d). Weight loss of ~15% can decrease PCRIT by ~6cmH2O which in individuals with a PCRIT close to atmospheric pressure may be sufficient to significantly improve OSA. In the absence of muscle tone the UA can narrow as intraluminal pressure decreases in inspiration. However, the degree of narrowing in the passive airway depends on the compliance which increases at smaller volumes indicating more collapsibility. Local narrowing in compliant airway segments also promotes further narrowing due to the Bernoulli effect. Acceleration of airflow at a site of narrowing implies a gain in kinetic energy and loss of potential energy; with the latter manifest as a fall in intraluminal pressure which will tend to narrow the airway further. Reflexes Maintaining an Open Airway and the Effects of Sleep Responses to sub-atmospheric intra-pharyngeal pressures Sub-atmospheric pressure in the UA causes reflex activation in a variety of pharyngeal muscles, e.g. in the nose and palate (alai nasi, palatoglossus, levator and tensor veli palatini), oral pharynx and hyoid muscles (genioglossus, geniohyoid, sternohyoid and sternothyroid) and larynx (posterior cricoarytenoid and cricothyroid). Sustained suction pressures increase both respiratoryrelated and tonic activity. This reflex is thought to help protect the UA from suction collapse. This protective reflex, however, is reduced in non-REM sleep and inhibited in REM. Trigeminal afferents from the nasal airspace mediate a significant component of the reflex response and are ideally placed to detect negative pressures caused, for example, by increased nasal resistance and congestion, and so produce compensatory pharyngeal muscle responses in more collapsible downstream segments of the UA. Afferents in the internal branches of the superior laryngeal nerve also mediate a significant component of the reflex responses and are ideally placed to respond to partial or complete UA occlusion, and may have a potential role in preventing OSA or re-opening the airway. There is a lesser contribution of glossopharyngeal afferents from the oropharynx to this protective reflex response. Sub-atmospheric pressures in the range encountered during normal breathing are sufficient to reflexly modulate pharyngeal muscle activity and contribute to pharyngeal muscle activation during breathing. Realistically, however, the larger intra-pharyngeal suction pressures encountered during sleep in snoring and OSA patients (at least -10 to -40 cmH2O) are sufficient to produce significant pharyngeal dilator muscle activation during sleep and may help keep the airway open in snorers. However, prolonged periods of heavy snoring (months or years) may ultimately damage those afferent pathways mediating this protective UA response. For example, the trauma associat-

ed with repeated vibration and closure of the UA walls leads to an edematous UA with impaired mechanical sensation that is reversed by treatment with nasal continuous airway pressure. The effects of repeated UA trauma may ultimately impair this protective reflex response to sub-atmospheric pressures and predispose to OSA. Responses to chemoreceptor stimulation Hypercapnia and hypoxia activate respiratory pump muscles during wakefulness and sleep causing increased ventilation. Chemoreceptor stimulation also activates a variety of UA dilator muscles but these responses are markedly suppressed in sleep, and can even be absent in REM sleep despite strong respiratory stimulation. The extrinsic tongue muscles include tongue protruders that dilate the UA (genioglossus and geniohyoid) and retractors that narrow the UA (hyoglossus and styloglossus). Animal and human data show that retractors are co-activated with protruders during respiratory stimulation with hypoxia and hypercapnia. Although such coactivation can result in net tongue retraction, the mechanical consequences are increased VMAX in the UA and reduced collapsibility showing that coordinated activation among pharyngeal muscles is most important to UA respiratory function. The basis for this common respiratory activation is that the medial and lateral branches of the hypoglossal nerves, innervating tongue protruder and retractor muscles respectively, receive activation from a common source, with the source of this inspiratory drive being different than phrenic motoneurons. Responses to baroreceptor inputs Increases in blood pressure inhibit genioglossus activity. This reflex may be relevant to the respiratory function of the UA since blood pressure increases occur during airway occlusions in OSA, with further increases accompanying arousal from sleep and relief of obstruction. Such changes may inhibit UA dilator muscle activity and predispose to subsequent apneas. Obstructive Sleep Apnea and Snoring The site of obstruction varies within and between patients with OSA OSA is characterized by cessation of oro-nasal airflow in the presence of attempted (but ineffective) respiratory efforts and is caused by UA occlusion in sleep (Figure 4). Hypopneas are caused by reductions in inspiratory flow due to elevated UA resistance. During hypopneas repetitive deteriorations in blood gases and arousals occur if airflow is too low for adequate pulmonary ventilation (~150 ml/sec), whereas at higher levels of airflow deteriorations in blood gases and arousals do not occur despite high sub-atmospheric inspiratory pressures. In non-REM sleep the UA obstruction occurs almost always at the level of the soft palate, i.e., the site of
95

Chapter 10: Respiratory Physiology: Control of the Upper Airway

This material is being provided in electronic format for the sole purpose of reference material for the creation of slide sets as directed by the Sleep Research Society, and should not be used for reproduction or other purposes without the express written approval of the Sleep Research Society.

Selected Bibliography
Original Articles Gleadhill, I. C., A. R. Schwartz, N. Schubert, R. A. Wise, S. Permutt, and P. L. Smith. 1991. Upper airway collapsibility in snorers and in patients with obstructive hypopnea and apnea. Am Rev Respir Dis 143(6):1300-3 Horner, R. L., J. A. Innes, H. B. Holden, and A. Guz. 1991. Afferent pathway(s) for pharyngeal dilator reflex to negative pressure in man: a study using upper airway anaesthesia. Journal of Physiology 436:31-44. Kimoff, R. J., E. Sforza, V. Champagne, L. Ofiara, and D. Gendron. 2001. Upper airway sensation in snoring and obstructive sleep apnea. American Journal of Respiratory and Critical Care Medicine 164:250-5. Mateika, J. H., D. L. Millrood, J. Kim, H. P. Rodriguez, and G. J. Samara. 1999. Response of human tongue protrudor and retractors to hypoxia and hypercapnia. American Journal of Respiratory and Critical Care Medicine 160:1976-82. Mezzanotte, W. S., D. J. Tangel, and D. P. White. 1992. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). Journal of Clinical Investigation 89:1571-9. Schwab, R. J., W. B. Gefter, E. A. Hoffman, K. B. Gupta, and A. I. Pack. 1993. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. American Review of Respiratory Disease 148:1385-400. Shepard, J. W., Jr., and S. E. Thawley. 1990. Localization of upper airway collapse during sleep in patients with obstructive sleep apnea. American Review of Respiratory Disease 141:1350-5. Stanchina, M. L., A. Malhotra, R. B. Fogel, N. Ayas, J. K. Edwards, K. Schory, and D. P. White. 2002. Genioglossus muscle responsiveness to chemical and mechanical stimuli during non-rapid eye movement sleep. American Journal of Respiratory and Critical Care Medicine 165:945-9. Thompson, S. R., U. Ackermann, and R. L. Horner. 2001. Sleep as a teaching tool for integrating respiratory physiology and motor control. Advances in Physiology Education 25:29-44. Wheatley, J. R., W. S. Mezzanotte, D. J. Tangel, and D. P. White. 1993. Influence of sleep on genioglossus muscle activation by negative pressure in normal men. American Review of Respiratory Disease 148:597-605 Younes, M. 2003. Contributions of upper airway mechanics and control mechanisms to severity of obstructive apnea. American Journal of Respiratory and Critical Care Medicine 168:645-58. Review Articles and Book Chapters Fogel, R. B., A. Malhotra, and D. P. White. 2004. Sleep. 2: pathophysiology of obstructive sleep apnoea/hypopnoea syndrome. Thorax 59:159-63. 96 Chapter 10: Respiratory Physiology: Control of the Upper Airway

Figure 4: Polysomnographic tracings in obstructive sleep apnea. Modified from Thompson et al., 2001.

minimal UA cross-sectional area when awake (Figure 2). The obstruction also extends caudally to regions behind the tongue in about half the patients with OSA (Figure 5). In REM sleep, the lower level of the obstruction extends to even more caudal levels compared to non-REM likely due to greater suppression of pharyngeal muscle activity. Therefore, an individual with obstruction only at the level of the soft palate in nonREM sleep may extend into the region caudal to the soft palate and posterior to the tongue in REM, whereas an individual already obstructing at these levels in nonREM sleep may have a longer obstructed segment in REM. Variations in the sites of obstruction within and between patients is likely responsible for variable responses to surgical interventions such as uvulopalatopharyngoplasty (UPPP) which enlarges the oropharyngeal airspace at the level of the soft palate but not behind the tongue. In contrast nasal continuous airway pressure relieves airway obstruction in all OSA patients since the efficacy of this treatment is not dependant on the site of UA obstruction during sleep.

Figure 5: The site of airway obstruction varies within and between patients with OSA.

This material is being provided in electronic format for the sole purpose of reference material for the creation of slide sets as directed by the Sleep Research Society, and should not be used for reproduction or other purposes without the express written approval of the Sleep Research Society.

Fregosi, R. F., and D. D. Fuller. 1997. Respiratory-related control of extrinsic tongue muscle activity. Respiration Physiology 110(2-3):295-306. Horner, R. L. 1996. Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea. Sleep 19:827-53. Horner, R. L. 2001. The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea. Respiratory Research 2:286-94. Kubin, L., R. O. Davies, and L. Pack. 1998. Control of upper airway motoneurons during REM sleep. News in Physiological Sciences 13:637-656. Kuna, S., and J. E. Remmers. 2000. Anatomy and physiology of upper airway obstruction. In M. H. Kryger, T. Roth and W. C. Dement, editors. Principles and Practice of Sleep Medicine, 3 ed. Saunders, W. B., Philadelphia. 840-58. Schwab, R. J. 1998. Upper airway imaging. Clinics in Chest Medicine 19:33-54. Smith, P. L., and A. R. Schwartz. 2002. Biomechanics of the upper airway during sleep. In A. I. Pack, editor. Sleep Apnea: Pathogenesis, Diagnosis and Treatment. Dekker, New York. 31-56. Veasey, S. C. 2003. Molecular and physiologic basis of obstructive sleep apnea. Clinics in Chest Medicine 24:179-93.

Chapter 10: Respiratory Physiology: Control of the Upper Airway

97

This material is being provided in electronic format for the sole purpose of reference material for the creation of slide sets as directed by the Sleep Research Society, and should not be used for reproduction or other purposes without the express written approval of the Sleep Research Society.

Notes

98

Chapter 10: Respiratory Physiology: Control of the Upper Airway