Sunday, January 8, 2017

Sleep apnoea - are we sleeping ourselves to death?

I.              Introduction

Sleep apnoea is common, underdiagnosed and, left untreated, significantly increases mortality (He, Kryger, Zorick, Conway, & Roth, 1988). This report describes upper airway anatomy and nocturnal respiratory physiology. Pathogenesis of central and obstructive sleep apnoea is discussed, along with medical and psychosocial sequelae. Reflection concludes the document.

II.           The pharynx and upper airway

The pharynx is a fibromuscular tube from the skull’s base to the level of C6, and is common to the gastrointestinal and respiratory tracts.

The nasopharynx runs between the sphenoid bone and uvula’s tip. The oropharynx runs from the uvula’s tip to the superior limit of the epiglottis. The laryngopharynx runs from the epiglottis to the level of the cricoid cartilage (Last, 1999).

A.            Nasal cavity/nasopharynx

Figure 1 shows the nasal cavity laterally. In Figure 2, conchae are removed.

The nasal cavity’s pseudostratified columnar epithelium (with goblet cells) has cilia and mucus to trap/remove particles, vasculature and serous secretions to warm/humidify air. Superiorly, olfactory receptors detect smells, transmitting information to the olfactory nerve and bulb (Last, 1999). The cavity communicates with paranasal sinuses, middle ear (via Eustachian tube) and nasopharynx (via choanae) (Figure 3) (Williams, Warwick,_Dyson,_&_Bannister, 1989).

Figure 3 shows components of the velopharyngeal sphincter, consisting of tensor and levator veli palatini, musculus uvulae, palatoglossus, palatopharyngeus and superior constrictor (Table 1). These assist maintenance of airway patency (Phillipson, 1993).

B.            Tongue and mouth

The mouth lies between the lips and palatoglossal arches. It consists of a vestibule (between cheeks/lips and gingivae/teeth), and oral cavity proper (posteriorly). Superiorly, it is bounded by the hard and soft palates (Table 1).

The tongue consists of skeletal muscle running longitudinally, transversely and vertically (Table 2). Genioglossus protrudes the tongue, widening the oropharyngeal (airway) lumen. On the posterior third of the tongue is the lingual tonsil (Figure 4). The lingual, palatine, tubal and pharyngeal tonsils comprise Waldeyer’s ring: lymphoid tissue immunologically protecting the upper openings of the respiratory and gastrointestinal tracts. Tonsillitis can therefore occlude the airway (Last, 1999).

C.            Pharyngeal musculature

The pharynx consists of telescoped superior, middle and inferior pharyngeal constrictors and a pharyngobasilar fascia. The constrictors attach posteriorly at the pharyngeal raphe (Figures 5 and 6)(Last, 1999).

III.        Respiratory physiology during sleep

A.            Airway patency maintenance

Neurological control of pharyngeal dilator muscles (including genioglossus, levator palitini) maintains nocturnal airway patency.

Sauerland & Harper (1976) demonstrated tonic activity of the genioglossi during quiet sleep. In REM sleep, phasic contractions of genioglossi coincide with inspiration (Figure 7).

Genioglossus activity is stimulated by:
1.     Negative airway pressure, which activates laryngeal mechanoreceptors, stimulating genioglossus via hypoglossal nerve (Horner, Innes, Murphy, & Guz, 1991).
2.     Medullary respiratory pattern generating neurons (White, 2005).
3.     Neurons moderating arousal (Fogel et al., 2003).
Nocturnally, responses #1 and #2 are reduced, and #3 is unchanged: overall predisposing to collapse in susceptible people (White, 2005).

B.            Nocturnal ventilation control

White (2005) defines respiratory stability by “loop gain”. Apnoea causes high blood carbon dioxide, which, detected by chemoreceptors, causes hyperpnoea. Loop gain is the ratio of the response (hyperpnoea) to the disturbance (apnoea). If loop gain is less than 1, the feedback response will stabilise respiration. If loop gain exceeds 1, compensatory hyperpnoea causes enough decrease in blood carbon dioxide to suppress respiratory drive and cause repeated apnoea (Figure 8).

Loop gain depends on controller and plant gain.

Controller gain represents chemoreceptor sensitivity. Plant gain represents the size of blood carbon dioxide decrease due to a given increase in ventilation (White, 2005).

Figure 9 shows alveolar ventilation versus alveolar carbon dioxide. Broken lines represent responses to falling carbon dioxide: where they meet the axis represents apnoea.

The slope of the broken lines represents controller gain. Due to the curve’s shape, a given change in ventilation has a larger impact on carbon dioxide levels in hypercapnic individuals (Figure 9A). Thus hypercapnia causes elevated plant gain.

Figure 9B demonstrates how high controller gain (steeper lines) results in apnoea due to smaller carbon dioxide decrements.

IV.        Sleep apnoea

A.            Definition

Sleep apnoea may be obstructive (84%), central (0.4%) or mixed (a combination of the two, 15%). An apnoea is a pause in breathing lasting ≥10s (Morgenthaler, Kagramanov, Hanak, & Decker, 2006).

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is the commonest form. In hypopnoea, ventilation is reduced by ≥50% for ≥10s (though breathing continues). OSAHS is defined as the combination of a) ≥5 occurrences of apnoea or hypopnoea per sleeping hour and b) inexplicable daytime sleepiness. It involves upper airway obstruction. Central sleep apnoea (CSA) is characterised by pauses in nocturnal ventilation resulting from lack of respiratory drive (Fauci et al., 2008).

B.            Epidemiology

OSAHS is twice as common in men as in women, with 1-4% of adult males (aged 40-65) affected. 26% of Australian adult males have a respiratory disturbance index (RDI) above 5[1] (Bearpark et al., 1995).

Young (2004) and Fauci et al. (2008) describe OSAHS risk factors:
·      Obesity
·      Hypertension
·      Middle age (40-65)
·      Male gender
·      Upper airway/craniofacial abnormalities (e.g. acromegaly)
·      Hypothyroidism
·      Myotonic dystrophy
·      Ehlers-Danlos syndrome

Childhood-specific factors include enlarged adenoids/tonsils, during rapid tonsillar proliferation (Arens et al., 2001).

Suspected risk factors include smoking, alcohol and genetics (Young, 2004).

Isolated CSA is a rare condition, and usually appears in combination with OSAHS (Table 3). Dugdale & Hadjiliadis (2011) describe CSA risk factors:
·      Arthritis of cervical spine
·      Surgical complications
·      Encephalitis
·      Poliomyelitis
·      Obesity
·      Stroke
·      Narcotic use
·      Radiation
·      Neurodegenerative diseases

Childhood-specific risk factors include congenital neurological disorders (e.g. primary alveolar hypoventilation).

C.            Pathophysiology

1.              OSAHS

Apnoea is caused by nocturnal airway closure. Airway patency consists of a balance of: 1) Dilation: via contraction of pharyngeal dilators and 2) Collapse: via negative pressure in inspiration, and airway compression by adiposity or small bony architecture. In OSAHS, nocturnal relaxation of dilators causes occlusion, reducing ventilation and causing hypercapnia/hypoxia. Chemoreceptors respond, causing arousal and return of muscle tone until sleep resumes (Fauci et al., 2008).

Negative pressure during inspiration alone cannot cause airway collapse. Occlusion in OSAHS patients is due to positive extraluminal pressure (due to fat deposition or small mandible), which exerts undue force on the airway (Figure 10) (Schwartz, Smith, Wise, Bankman, & Permutt, 1989).

Airway occlusion by enlarged adenoids or tonsils can cause OSAHS (Figure 11). This commonly occurs in age 2-6 years, due to tonsillitis and lymphoid proliferation (Arens et al., 2001).

a)             Mechanism for mechanical obstruction

A posteriorly situated maxilla/mandible reduce space for the airway, competing with the actions of the velopharyngeal sphincter and genioglossus to maintain patency. OSAHS upper airway diameters are about 66% those of controls.  The size of the soft palate is also increased, reducing luminal diameter. The smaller intermaxillary space in these patients displaces the tongue posteriorly, and with their relatively larger tongue size, tends to occlude the airway (Johal, Patel, & Battagel, 2007). Together, these factors predispose to nocturnal airway closure by the soft palate and tongue.

2.              CSA

CSA is due to high loop gain in respiratory feedback. Examples include:
·      Transient CSA in high altitude (increased controller gain due to hypoxia) (Fauci et al., 2008).
·      Idiopathic CSA due to innately high controller gain (White, 2005).
·      Congestive heart failure, due to increased controller gain (chemoreceptor sensitivity) and slower circulation (Leung & Bradley, 2001).
·      Hypercapnia (obesity hypoventilation syndrome, central alveolar hypoventilation) causing high plant gain and respiratory drive reduction (Mellins, Balfour, Turino, & Winters, 1970).

CSA can cause pharyngeal muscle tone reduction and collapse (OSAHS), producing mixed sleep apnoea (Badr, Roiber, Skatrud, & Dempsey, 1995).

Infantile CSA can be fatal and apnoea-like neurorespiratory patterns are associated with sudden infant death syndrome (Katz, 2005).

D.            Clinical manifestation

Table 4 summarises the clinical manifestations of sleep apnoea variants.

E.            Diagnosis

>80% of OSAHS cases remain undiagnosed (Kapur et al., 1999).
Sleep history is obtained from the patient and their partner (Epworth Sleepiness Score, Table 5). Examination includes assessing jaw and upper airway anatomy, obesity, blood pressure and other risk factors. Diagnostic investigation includes polysomnography (Fauci et al., 2008).

Below we present the diagnostic procedure used in Sydney Children’s Hospital.

F.             Psychosocial impact

Kales et al. (1985) showed 66% of sleep apnoea patients report damaged interpersonal relationships and marriages. Loss of libido and impotence also occur. Patients report reduced occupational productivity and resignation. Affected students nap in class and report reduced grades.

Sleep apnoea is known to produce abnormalities of brain anatomy, causing cognitive deficits (Morrell, 2003). Psychiatric impacts of these deficits are measurable (Table 6), and predispose to depression and damaged relationships (Bixler et al., 2005). Therefore the disease has significant adverse social effects on patients.

Patients with sleep apnoea are also financially affected. Figure 12 shows the relationship between apnoea-hypopnoea index (AHI)[2] and annual medical expenditure.

G.            Complications and outcome

Sleep apnoea patients report more illnesses/hospitalisations than controls, and are more likely to be undergoing some medical treatment (Kales et al., 1985). Figure 13 shows apnoea index (AI)[3] versus patient mortality.

Complications include:

1.              Increased cardiovascular risk

OSAHS increases the risk of cardiovascular events (Marin, Carrizo, Vicente, & Agusti, 2005). OSAHS raises mean blood pressure, increasing the risks of stroke and myocardial infarction (Fauci et al., 2008).
CSA is predisposes to atrial fibrillation (Leung et al., 2005).

2.              Hepatic disease

OSAHS increases liver steatosis/fibrosis, and upregulates liver enzymes (Tanné et al., 2005).

3.              Diabetes mellitus

OSAHS is a risk factor for insulin resistance, independent of obesity (Ip et al., 2002).

4.              Anaesthesia complications

Both OSAHS and CSA increase risk of respiratory arrest associated with anaesthesia, and a restricted upper airway complicates intubation (Benumof, 2004).

5.              Developmental abnormalities

In the infant, sleep apnoea can cause failure to thrive, learning/memory and emotional difficulties (von Hofsten, 2004).

V.           Conclusion

Sleep apnoea is a common disorder with serious medical/psychosocial implications. Its aetiology and sequelae differ between child and adult. Despite its importance, sleep apnoea often goes undiagnosed. Further research into public health strategies to more effectively identify and treat this disease seems prudent.

VI.              References

Arens, R., McDonough, J. M., Costarino, A. T., Mahboubi, S., Tayag-Kier, C. E., Maislin, G., Schwab, R. J., et al. (2001). Magnetic resonance imaging of the upper airway structure of children with obstructive sleep apnea syndrome. American journal of respiratory and critical care medicine, 164(4), 698–703.
Badr, M., Roiber, F., Skatrud, J., & Dempsey, J. (1995). Pharyngeal narrowing/occlusion during central sleep apnea. Journal of Applied Physiology, 78, 1806–1815.
Bixler, E. O., Vgontzas, A. N., Ten Have, T., Tyson, K., & Kales, A. (1998). Effects of Age on Sleep Apnea in Men I. Prevalence and Severity. American Journal of Respiratory and Critical Care Medicine, 157(1), 144–148.
Benumof, J. L. (2004). Obesity, sleep apnea, the airway and anesthesia. Current opinion in Anesthesiology, 17(1), 21.
Drake, R. L., Vogl, W., & Mitchell, M. (2010). Gray’s Anatomy for Students (2nd ed.). Philadelphia: Churchill Livingstone Elsevier.
Dugdale, D., & Hadjiliadis, D. (2011). Central sleep apnea. Medline Plus. Retrieved May 19, 2012, from
Fauci, A. S., Branwald, E., Kasper, D. L., Hauser, S. L., Longo, D. L., Jameson, J. L., & Loscalzo, J. (2008). Harrison’s Principles of Internal Medicine (17th ed.). McGraw-Hill.
Fogel, R. B., Trinder, J., Malhotra, A., Stanchina, M., Edwards, J. K., Schory, K. E., & White, D. P. (2003). Withinbreath control of genioglossal muscle activation in humans: effect of sleepwake state. The Journal of physiology, 550(3), 899–910.
Fouke, J. M., & Strohl, K. P. (1987). Effect of position and lung volume on upper airway geometry. Journal of Applied Physiology, 63(1), 375–380.
Johns, M. W. (1992). Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep, 15(4), 376–381.
Hall, J. E. (2011). Guyton and Hall: Textbook of Medical Physiology (12th ed.).
He, J., Kryger, M. H., Zorick, F. J., Conway, W., & Roth, T. (1988). Mortality and Apnea Index in Obstructive Sleep Apnea. Experience in 385 Male Patients. Chest, 94(1), 9–14. doi:10.1378/chest.94.1.9
Horner, R. L., Innes, J. A., Murphy, K., & Guz, A. (1991). Evidence for reflex upper airway dilator muscle activation by sudden negative airway pressure in man. The Journal of physiology, 436(1), 15–29.
Ip, M. S. M., Lam, B., Ng, M. M. T., Lam, W. K., Tsang, K. W. T., & Lam, K. S. L. (2002). Obstructive Sleep Apnea Is Independently Associated with Insulin Resistance. American Journal of Respiratory and Critical Care Medicine, 165(5), 670–676.
Johal, A., Patel, S. I., & Battagel, J. M. (2007). The relationship between craniofacial anatomy and obstructive sleep apnoea: a casecontrolled study. Journal of Sleep Research, 16(3), 319–326. doi:10.1111/j.1365-2869.2007.00599.x
Kapur, V., Blough, D. K., Sandblom, R. E., Hert, R., James, B., & Sean, D. (1999). The medical cost of undiagnosed sleep apnea. Sleep, 22(6), 749.
Katz, D. M. (2005). Regulation of respiratory neuron development by neurotrophic and transcriptional signaling mechanisms. Respiratory Physiology & Neurobiology, 149(1-3), 99–109. doi:10.1016/j.resp.2005.02.007
Last, R. (1999). Last’s anatomy: regional and applied (10th ed.). Edinburgh [u.a.]: Churchill Livingstone.
Leung, R., & Bradley, T. (2001). Sleep apnea and cardiovascular disease. American Journal of Respiratory and Critical Care Medicine, 164, 2147–2165.
Marin, J. M., Carrizo, S. J., Vicente, E., & Agusti, A. G. (2005). Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. The Lancet, 365(9464), 1046–1053. doi:10.1016/S0140-6736(05)71141-7
Mellins, R., Balfour, H., Turino, G., & Winters, R. (1970). Failure of automatic control of ventilation (Ondine’s curse). Medicine (Baltimore), 49, 487–504.
Morgenthaler, T. I., Kagramanov, V., Hanak, V., & Decker, P. A. (2006). Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep, 29(9), 1203.
Morrell, M. (2003). Changes in brain morphology associated with obstructive sleep apnea. Sleep Medicine, 4(5), 451–454. doi:10.1016/S1389-9457(03)00159-X
Olson, L., Fouke, J. M., Hokje, P., & Strohl, K. P. (1988). A biomechanical view of the upper airway. The respiratory function of the upper airway. (pp. 359–390). New York: Marcel Dekker.
Phillipson, E. A. (1993). Sleep Apnea - A Major Public Health Problem. New England Journal of Medicine, 328(17), 1271–1273. doi:10.1056/NEJM199304293281712
Ruehland, W. R., Rochford, P. D., O’Donoghue, F. J., Pierce, R. J., Singh, P., & Thornton, A. T. (2009). The new AASM criteria for scoring hypopneas: impact on the apnea hypopnea index. Sleep, 32(2), 150–157.
Sauerland, E. K., & Harper, R. M. (1976). The human tongue during sleep: Electromyographic activity of the genioglossus muscle. Experimental Neurology, 51(1), 160–170. doi:10.1016/0014-4886(76)90061-3
Schmitz, P. G., & Martin, K. J. (2008). Internal Medicine: Just the Facts. McGraw-Hill Prof Med/Tech.
Schwartz, A. R., Smith, P. L., Wise, R. A., Bankman, I., & Permutt, S. (1989). Effect of positive nasal pressure on upper airway pressure-flow relationships. Journal of Applied Physiology, 66(4), 1626–1634.
Tanné, F., Gagnadoux, F., Chazouillères, O., Fleury, B., Wendum, D., Lasnier, E., Lebeau, B., et al. (2005). Chronic liver injury during obstructive sleep apnea. Hepatology, 41(6), 1290–1296. doi:10.1002/hep.20725
von Hofsten, C. (2004). An action perspective on motor development. Trends in Cognitive Sciences, 8(6), 266–272. doi:10.1016/j.tics.2004.04.002
Walker, J. M., Farney, R. J., Rhondeau, S. M., Boyle, K. M., Valentine, K., Cloward, T. V., & Shilling, K. C. (2007). Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. Journal of Clinical Sleep Medicine, 3(5), 455.
Watanabe, T., Isono, S., Tanaka, A., Tanzawa, H., & Nishino, T. (2002). Contribution of body habitus and craniofacial characteristics to segmental closing pressures of the passive pharynx in patients with sleep-disordered breathing. American Journal of Respiratory and Critical Care Medicine, 165, 260–265.
White, D. P. (2005). Pathogenesis of Obstructive and Central Sleep Apnea. American Journal of Respiratory and Critical Care Medicine, 172(11), 1363–1370. doi:10.1164/rccm.200412-1631SO
Williams, P. L., Warwick, R., Dyson, M., & Bannister, L. H. (1989). Gray’s Anatomy (37th ed.). New York: Churchill Livingstone.

[1] RDI_=_(Respiratory_effort-related_arousals_+_hypopnoeas_+_apnoeas)/(Hours_spent_asleep) (Schmitz_&_Martin,_2008)
[2] AHI_=_(Hypopnoeas_+_apnoeas)/(Hours_spent_asleep) Ruehland_et al.,_2009).
[3] AI_=_(Apnoeas)/(Hours spent asleep)_(He,_Kryger,_Zorick,_Conway,_&_Roth,_1988)


  1. Nice review! Are you thinking about publishing this as well? If not you should!

    1. Thanks, glad you liked it.
      I'm not sure, don't know if I can be bothered when the info is all easily available to those who are curious.
      Food for thought!