Upper airway function in the pathogenesis of obstructive sleep apnea: A review of the current literature

Current Opinion in Pulmonary Medicine

Volumn 14, Issue 6, 2008, Pages 519-524

  Owens, Robert L ^a   Eckert, Danny J ^a   Yeh, Susie Yim ^a   Malhotra, Atul ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

Control of ventilation; Lung; Pharynx; Upper airway; Upper airway muscle activation

Indexed keywords

DONEPEZIL; MIRTAZAPINE; PROTON PUMP INHIBITOR; TRAZODONE;

AGING; AROUSAL; BLOOD VESSEL PERMEABILITY; BREATHING MUSCLE; BRONCHOSPASM; CHEMOSENSITIVITY; COMORBIDITY; DEVELOPMENTAL STAGE; EXPIRATORY RESERVE VOLUME; GASTROESOPHAGEAL REFLUX; HUMAN; HYPERCAPNIA; KIDNEY FAILURE; LEG EDEMA; LUNG FUNCTION; LUNG VENTILATION; NEUROMUSCULAR FUNCTION; PATHOGENESIS; POSITIVE END EXPIRATORY PRESSURE; PREVALENCE; REVIEW; SEX DIFFERENCE; SLEEP APNEA SYNDROME; SLEEP WAKING CYCLE; UPPER RESPIRATORY TRACT; UPPER RESPIRATORY TRACT OBSTRUCTION; UVULOPALATOPHARYNGOPLASTY; WAKEFULNESS;

CONTINUOUS POSITIVE AIRWAY PRESSURE; HUMANS; PHARYNX; POSITIVE-PRESSURE RESPIRATION; RESPIRATORY MUSCLES; RESPIRATORY SYSTEM; SLEEP APNEA, OBSTRUCTIVE;

EID: 55149107603     PISSN: 10705287     EISSN: 15316971     Source Type: Journal    
DOI: 10.1097/MCP.0b013e3283130f66     Document Type: Review

References (53)

1. Eckert DJ, Malhotra A. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008; 5:144-153.
2. Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002; 360:237-245.
3. Schwab RJ. Upper airway imaging. Clin Chest Med 1998; 19:33-54.
4. Isono S, Remmers JE, Tanaka A, et al. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol 1997; 82:1319-1326.
5. Sforza E, Petiau C, Weiss T, et al. Pharyngeal critical pressure in patients with obstructive sleep apnea syndrome. Clinical implications. Am J Respir Crit Care Med 1999; 159:149-157.
6. Younes M. Contributions of upper airway mechanics and control mechanisms to severity of obstructive apnea. Am J Respir Crit Care Med 2003; 148:645-658.
7. Jordan AS, Wellman A, Heinzer RC, et al. Mechanisms used to restore ventilation after partial upper airway collapse during sleep in humans. Thorax 2007; 62:861-867. The study demonstrated that patients with OSA and controls can restore normal breathing without an EEG arousal, but OSA patients are less often able to do so. OSA patients not only have a tendency toward pharyngeal collapse but an inability to restore flow normally.
8. Schwab R, Pasirstein M, Pierson R, et al. Identification of upper airway anatomic risk factors for obstructive sleep apnea with volumetric magnetic resonance imaging. Am J Respir Crit Care Med 2003; 168:522-530.
9. Kim HY, Bok KH, Dhong HJ, et al. The correlation between pharyngeal narrowing and the severity of sleep-disordered breathing. Otolaryngol Head Neck Surg 2008; 138:289-293.
10. Bachar G, Feinmesser R, Shpitzer T, et al. Laryngeal and hypopharyngeal obstruction in sleep disordered breathing patients, evaluated by sleep endoscopy. Eur Arch Otorhinolaryngol 2008; 8 Mar. [Epub ahead of print] Sleep endoscopy was used in patients with OSA referred for surgery to evaluate sites of obstruction. Most patients had multiple sites of obstruction, and the RDI increased with more sites of obstruction. This study may help to explain the relatively high failure rate of single-site surgery.
11. Lin HC, Friedman M, Chang HW, et al. The efficacy of multilevel surgery of the upper airway in adults with obstructive sleep apnea/hypopnea syndrome. Laryngoscope 2008; 118:902-908.
12. Mohsenin V. Gender differences in the expression of sleep-disordered breathing: role of upper airway dimensions. Chest 2001; 120:1442-1447.
13. Malhotra A, Huang Y, Fogel R, et al. Aging influences on pharyngeal anatomy and physiology: the predisposition to pharyngeal collapse. Am J Med 2006; 119:72.
14. Malhotra A, Huang Y, Fogel RB, et al. The male predisposition to pharyngeal collapse: importance of airway length. Am J Respir Crit Care Med 2002; 166:1388-1395.
15. Huang Y, White DP, Malhotra A. Use of computational modeling to predict responses to upper airway surgery in obstructive sleep apnea. Laryngoscope 2007; 117:648-653. The authors showed the feasibility of using a computational model to simulate the upper airway. The effects of various upper airway intervention strategies (palatal stiffening, resection, etc.) can then be simulated.
16. Segal Y, Malhotra, A, Pillar, G. Upper airway length may be associated with the severity of obstructive sleep apnea syndrome. Sleep Breath 2008; 31 May. [Epub ahead of print].
17. Ronen O, Malhotra A, Pillar G. Influence of gender and age on upper-airway length during development. Pediatrics 2007; 120:e1028-e1034. Pharyngeal airway length was measured radiographically in boys and girls before and after puberty. Although similar prior to puberty, postpubertal boys had a longer airway length than did postpubertal girls. This study may help to explain the sex difference in OSA prevalence. Airway length is likely a more relevant measurement than cross-sectional area.
18. crit have OSA, suggesting other nonanatomical traits are also important in OSA pathogenesis.
19. Eikermann M, Jordan AS, Chamberlin NL, et al. The influence of aging on pharyngeal collapsibility during sleep. Chest 2007; 131:1702-1709.
20. Marcus CL, Lutz J, Hamer A, et al. Developmental changes in response to subatmospheric pressure loading of the upper airway. J Appl Physiol 1999; 87:626-633.
21. Chiu KL, Ryan CM, Shiota S, et al. Fluid shift by lower body positive pressure increases pharyngeal resistance in healthy subjects. Am J Respir Crit Care Med 2006; 174:1378-1383.
22. Shiota S, Ryan CM, Chiu KL, et al. Alterations in upper airway cross-sectional area in response to lower body positive pressure in healthy subjects. Thorax 2007; 62:868-872.
23. Iftikhar I, Ahmed M, Tarr S, et al. Comparison of obstructive sleep apnea patients with and without leg edema. Sleep Med 2008; 11 Feb. [Epub ahead of print].
24. Beecroft JM, Hoffstein V, Pierratos A, et al. Pharyngeal narrowing in end-stage renal disease: implications for obstructive sleep apnoea. Eur Respir J 2007; 30:965-971.
25. Eckert DJ, Saboisky JP, Jordan AS, et al. Upper airway myopathy is not important in the pathophysiology of obstructive sleep apnea. J Clin Sleep Med 2007; 3:570-573.
26. Beecroft JM, Hoffstein V, Pierratos A, et al. Nocturnal haemodialysis increases pharyngeal size in patients with sleep apnoea and end-stage renal disease. Nephrol Dial Transplant 2008; 23:673-679. A small subset of patients (three of 16 patients) with OSA and ESRD on hemodialysis showed an improvement in AHI with conversion to nocturnal dialysis. This and other studies [21-24], when taken together, suggest an important mechanism for dynamic airway changes that may contribute to OSA.
27. Kirkness J, Madronio M, Stavrinou R, et al. Relationship between surface tension of upper airway lining liquid and upper airway collapsibility during sleep in obstructive sleep apnea hypopnea syndrome. J Appl Physiol 2003; 95:1761-1767.
28. Hilditch CJ, McEvoy RD, George KE, et al. Upper airway surface tension but not upper airway collapsibility is elevated in primary Sjogren's syndrome. Sleep 2008; 31:367-374. Patients with Sjogren's syndrome have elevated upper airway surface tension compared with control subjects; however, this difference did not correlate with a difference in upper airway collapsibility. The difference in surface tension was small.
29. Green BT, Broughton WA, O'Connor JB. Marked improvement in nocturnal gastroesophageal reflux in a large cohort of patients with obstructive sleep apnea treated with continuous positive airway pressure. Arch Intern Med 2003; 163:41-45.
30. Kerr P, Shoenut JP, Millar T, et al. Nasal CPAP reduces gastroesophageal reflux in obstructive sleep apnea syndrome. Chest 1992; 101:1539-1544.
31. Yim S, Fredberg JJ, Malhotra A. Continuous positive airway pressure for asthma: not a big stretch? Eur Respir J 2007; 29:226-228.
32. Dickman R, Green C, Fass SS, et al. Relationships between sleep quality and pH monitoring findings in persons with gastroesophageal reflux disease. J Clin Sleep Med 2007; 3:505-513. Subjective measurements of sleep quality and GERD symptoms were collected and patients were studied with esophageal pH probe. A subset of patients also had a PSG during pH monitoring. Subjective and objective measurements of GERD severity correlated with sleep quality. Acid reflux events were associated with short arousals.
33. Harding SM. Sleep related gastroesophageal reflux. The tip of the iceberg is showing! J Clin Sleep Med 2007; 3:514-515.
34. Friedman M, Gurpinar B, Lin HC, et al. Impact of treatment of gastroesophageal reflux on obstructive sleep apnea-hypopnea syndrome. Ann Otol Rhinol Laryngol 2007; 116:805-811. Intriguing study of patients with OSA and not on CPAP therapy who underwent esophageal pH monitoring. In those patients whose pH improved with proton-pump inhibitor therapy, AHI (from 37.9 ± 19.1 to 28.8± 11.5; P=.006), snoring and subjective sleepiness all improved. Only 29 patients completed the protocol, which did not include a placebo arm. A larger placebo controlled randomized trial is reportedly ongoing.
35. Malhotra A, Pillar G, Fogel R, et al. Genioglossal but not palatal muscle activity relates closely to pharyngeal pressure. Am J Respir Crit Care Med 2000; 162:1058-1062.
36. Pierce R, White D, Malhotra A, et al. Upper airway collapsibility, dilator muscle activation and resistance in sleep apnoea. Eur Respir J 2007; 30:345-353. Muscle activity and collapsing pressure were measured in awake OSA patients. Dilator muscle activity was greater in patients with higher collapsing pressures.
37. McGinley BM, Schwartz AR, Schneider H, et al. Upper airway neuromuscular compensation during sleep is defective in obstructive sleep apnea. J Appl Physiol 2008; 105:197-205. In this study, upper airway muscle EMG, inspiratory flow and transmural pharyngeal pressure were studied in control and OSA subjects during periods of induced airway collapse. OSA patients could not augment muscle activity, pressure or flow as much as control patients could. This again supports the concept that OSA patients have other deficits of upper airway control, in addition to anatomic factors, that predispose to airway collapse.
38. Younes M. Role of arousals in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med 2004; 169:623-633.
39. Younes M, Ostrowski M, Atkar R, et al. Mechanisms of breathing instability in patients with obstructive sleep apnea. J Appl Physiol 2007; 103:1929-1941. Patients with OSA were exposed to chemical and mechanical stimuli until arousal. Across 21 patients there was wide variation in response to these stimuli. Patients with higher chemoresponsiveness and lower arousal threshold had more ventilatory instability.
40. Lo YL, Jordan AS, Malhotra A, et al. Influence of wakefulness on pharyngeal airway muscle activity. Thorax 2007; 62:799-805.
41. Kimoff RJ. Upperairway myopathy is important in the pathophysiology of obstructive sleep apnea. J Clin Sleep Med 2007; 3:567-569.
42. Dunleavy M, Bradford A, O'Halloran KD. Oxidative stress impairs upper airway muscle endurance in an animal model of sleep-disordered breathing. Adv Exp Med Biol 2008; 605:458-462.
43. Van de Graaff WB. Thoracic influence on upper airway patency. J Appl Physiol 1988; 65:2124-2131.
44. Kairaitis K, Byth K, Parikh R, et al. Tracheal traction effects on upper airway patency in rabbits: the role of tissue pressure. Sleep 2007; 30:179-186. In an animal model, direct traction applied to the trachea stabilized the upper airway. The data support the concept that lung volume influences upper airway resistance.
45. Heinzer RC, Stanchina ML, Malhotra A, et al. Effect of increased lung volume on sleep disordered breathing in patients with sleep apnoea. Thorax 2006; 61:435-439.
46. Heinzer RC, Stanchina ML, Malhotra A, et al. Lung volume and continuous positive airway pressure requirements in obstructive sleep apnea. Am J Respir Crit Care Med 2005; 172:114-117.
47. Heinzer R, White D, Malhotra A, et al. Effect of expiratory positive airway pressure on sleep disordered breathing. Sleep 2008; 31:429-432.
48. Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control and airway anatomy in obstructive sleep apnea. Am J Respir Crit Care Med 2004; 170:1225-1232.
49. Ibrahim LH, Patel SR, Modarres M, et al. A measure of ventilatory variability at wake-sleep transition predicts sleep apnea severity. Chest 2008; 134:73-78. PSG data from 485 patients were evaluated and a ventilatory variability index (VVI) was calculated on the basis of ventilatory variation measured at awake-to-sleep transitions. The AHI correlated with the VVI even after correction for other potential covariates. These data suggest that ventilatory control can be measured with PSG and that this value may have clinical significance.
50. Imadojemu VA, Mawji Z, Kunselman A, et al. Sympathetic chemoreflex responses in obstructive sleep apnea and effects of continuous positive airway pressure therapy. Chest 2007; 131:1406-1413.
51. Moraes W, Poyares D, Sukys-Claudino L, et al. Donepezil improves obstructive sleep apnea in Alzheimer disease: a double-blind, placebo-controlled study. Chest 2008; 133:677-683. Randomized, double-blind, placebo-controlled study of 23 patients with mild-to-moderate Alzheimer disease and OSA. PSG and cognitive evaluation using Alzheimer disease assessment scale-cognitive (ADAS-cog) subscale were performed at baseline and after 3 months. AHI and oxygen saturation improved significantly after donepezil treatment compared with baseline and placebo. ADAS-cog scores also improved after donepezil treatment. It is unclear by what mechanism the drug is effective, but it represents a nonanatomical treatment modality.
52. Carley DW, Olopade C, Ruigt GS, et al. Efficacy of mirtazapine in obstructive sleep apnea syndrome. Sleep 2007; 30:35-41.
53. 2 levels. However, there was no difference in response to mechanical stimulation, suggesting that individual ventilation control variables might be pharmacologically manipulated.