1. Using the Pathophysiology of Obstructive Sleep Apnea (OSA) to Teach Cardiopulmonary Integration Michael G. Levitzky, Ph.D. Department of Physiology Louisiana State University Health Sciences Center 1901 Perdido Street New Orleans, Louisiana 70112-1393 Phone: 504 568-6184 Fax: 504 568-6158 E-mail: mlevit@lsuhsc.edu

2. Outline I. Introduction: Clinical Aspects of OSA A. Case scenario B. Definition and epidemiology C. Symptoms and signs D. Description of sleep apnea event E. Diagnosis: polysomnography II. Pathophysiology of OSA A. Mechanical/Anatomic B. Pulmonary 1. Mechanics of breathing in OSA 2. Effects of obstruction/apnea on gas exchange C. Cardiovascular effects of OSA 1. Effects on the pulmonary circulation 2. Effects on the systemic circulation D. Disturbances in sleep architecture and hypersomnolence III. Treatment of OSA: CPAP IV. References

3. Case Scenario A 61 year old professor comes to the family physician because he feels tired all the time. He often falls asleep when he attends lectures, seminars, or boring meetings. Although he says he sleeps through the night (except to get up to urinate), his wife says he snores loudly and often seems to stop breathing and gasp for breath. He is restless and thrashes around in bed. He almost always wakes up with a headache and for the past year he has been having trouble remembering things. He is 5 feet 7 inches tall and weighs 250 pounds. His heart rate is 80/min, blood pressure is 135/95 mmHg and his respiratory rate is 15/min. His electrocardiogram, chest radiograph, and echocardiogram strongly suggest pulmonary hypertension. Diagnosis: Obstructive Sleep Apnea

4. Obstructive Sleep Apnea (OSA): Definition and Epidemiology Definition: ≥ 15 apneas (> 10 sec) and/or hypopneas per hour of sleep because of sleep-related collapse of the upper airway (Note that as much as 40-70% of resistance to airflow is normally in upper airway) Associated with snoring, but not everyone who snores has OSA May occur in 9% of middle-aged men and 4% of middle-aged women in US; estimates in the literature have a very wide range—one source stated that 85% of people with OSA are undiagnosed Prevalence increases with age, body weight, pregnancy High prevalence in 3- to 5-year old children: may be as high as 5%

5. Symptoms of Obstructive Sleep Apnea (In descending order of approximate incidence) Loud snoring Hypersomnolence (Excessive Daytime Sleepiness) Depressed mentation Altered personality Impotence Headaches upon waking Nocturia

6. Signs of Obstructive Sleep Apnea Systemic hypertension Pulmonary hypertension (right axis deviation on ECG) Polycythemia Cor pulmonale Bradycardia during apneic event Tachycardia after airflow restored Typically no respiratory abnormality while awake Arterial blood gasses while awake may show metabolic alkalosis

7. Description of Sleep Apnea Event Upper airway obstruction Intermittent obstruction: snoring Complete obstruction Decreased alveolar ventilation Decreased alveolar PO 2 ; increased alveolar PCO 2 Decreased arterial PO 2 ; increased arterial PCO 2 Stimulation of arterial chemoreceptors; central chemoreceptors Arousal Secondary hyperventilation?

8. 102030 100 80 40 20 Time (sec) O2O2 CO 2 Arterial Partial Pressure (mmHg) Effects of Breathhold on Arterial P O 2 and P CO 2 60 All figures created by Betsy Giaimo

9. Pa CO 2, torr 102030405060 Carotid Body Activity Effects of Arterial PO 2 and PCO 2 on Carotid Body Activity 406080100120140 Pa O 2, torr 20

10. Diagnosis: Polysomnography Variables that may be determined include: EEG and electrooculogram (for sleep state); EMG Airflow at nose or mouth (thermistor, pneumotachograph) End-tidal CO 2 Chest and abdominal motion (impedance plethysmography) ECG Blood pressure Pulse oximetry Esophageal pressure (intrapleural pressure) Autonomic nervous system activity (finger tonometer)

11. Vt (air flow) EEG EMG ECG Abd Chest Time (minutes) 100 75 Pulse Oxygen Saturation Normal Polysomnograph BP 20 sec

12. EEG ECG Abd Chest Vt (air flow) Time (minutes) 100 75 Pulse Oxygen Saturation Obstructive Sleep Apnea BP 20 sec

13. Pathophysiology of Obstructive Sleep Apnea Mechanical Short, thick neck Neck flexion, supine position Nasal obstruction, congestion, polyps Surface tension of upper airway lining fluid

14. Pathophysiology of Obstructive Sleep Apnea (continued) Anatomic Enlarged tonsils and adenoids (esp. ages 3-5), enlarged uvula Macroglossia Retrognathia, craniofacial abnormalities Compliant (floppy) pharynx, especially soft palate Fat deposition in lateral walls of pharynx, pharyngeal dilator muscles (obesity) Submucosal edema in lateral walls of pharynx

15. Pathophysiology of Obstructive Sleep Apnea (continued) Physiologic Decreased function of upper airway dilator muscles (more than 20 skeletal muscles normally involved) Decreased pharyngeal dilator reflex response Decreased chemoreceptor drive/central drive (mixed with central sleep apnea) Impaired arousal response Alcohol, depressant drugs

16. Alveolar pressure: 0 cm H 2 O Alveolar pressure: 0 cm H 2 O END EXPIRATION Intrapleural pressure: -5 cmH 2 O Transmural pressure= -1 cmH 2 O - (-8cmH 2 O)= +7 cmH 2 O DURING INSPIRATION Alveolar pressure: 0 cm H 2 O Outward recoil of chest wall Inward recoil of alveoli Alveolar pressure: -1 cm H 2 O Transmural pressure= 0 cmH 2 O - (-5cmH 2 O)= +5 cmH 2 O Intrapleural pressure: -8 cmH 2 O No flow Inspiratory force Flow in Atmospheric Pressure : 0 cm H 2 O Eupneic Inspiration (Revised from Fig. 2-1 in Levitzky’s Pulmonary Physiology)

17. END EXPIRATIONDURING INSPIRATION Atmospheric Pressure : 0 cm H 2 O Alveolar pressure: 0 cm H 2 O Alveolar pressure: 0 cm H 2 O Intrapleural pressure: -5 cmH 2 O Transmural pressure= -23 cmH 2 O - (-30 cmH 2 O)= +7 cmH 2 O Alveolar pressure: 0 cm H 2 O Outward recoil of chest wall Inward recoil of alveoli Alveolar pressure: -23 cm H 2 O Transmural pressure= 0 cmH 2 O - (-5cmH 2 O)= +5 cmH 2 O Intrapleural pressure: -30 cmH 2 O No flow Inspiratory force Flow in Forced Inspiration (Revised from Fig. 4-10C in Levitzky’s Pulmonary Physiology)

18. Mechanics of Breathing in Obstructive Sleep Apnea Does negative pressure in the upper airway cause obstruction or does obstruction cause negative pressure in the upper airway? Forced inhalation through the nose causes increased nasal resistance to airflow Mueller maneuver causes intrapleural pressure to fall to approximately -30 cm H 2 O; as low as -80 cm H 2 O during episodes of obstructive sleep apnea?

19. Upper airway anatomy Sites of obstruction during sleep apnea Laryngopharynx Hard Palate Soft Palate Nasopharynx Hyoid bone Larynx Epiglottis Oropharynx Tongue Obstructive Sleep Apnea

20. Upper airway anatomy Hard Palate Soft Palate Nasopharynx Hyoid bone Larynx Epiglottis Oropharynx Sites of obstruction during sleep apnea Laryngopharynx Tongue Obstructive Sleep Apnea

21. Why Obstruction Occurs During Sleep Supine position Control of breathing during normal non-rapid eye movement sleep Lack of “wakefulness” drive Minute volume decreases about 16% PaCO 2 increases 4-6 mmHg SaO 2 decreases as much as 2% Decreased tone of pharyngeal muscles Depressed reflexes, including pharyngeal dilator Depressed response to hypoxia in men REM sleep decreases tone of intercostal and accessory muscles, less effect on diaphragm; depression of minute volume, increase in CO 2 not as great, depression of response to hypoxia greater

22. Possible Explanation for Metabolic Alkalosis When Patient is Awake Chronic repeated obstructions cause carbon dioxide retention and therefore respiratory acidosis Compensatory renal retention of bicarbonate and excretion of hydrogen ions leads to metabolic alkalosis when PaCO 2 is normal during awake state

23. Effects of Obstruction on Pulmonary Circulation and Right Ventricle Hypoxic and hypercapnic pulmonary vasoconstriction cause pulmonary hypertension Chronic nighttime hypoxia may cause erythropoiesis and polycythemia Increased hematocrit increases blood viscosity Hypoxic pulmonary vasoconstriction (HPV), increased blood viscosity, pulmonary hypertension increase right ventricular afterload Increased right ventricular afterload may lead to right ventricular hypertrophy and eventually cor pulmonale

24. O 2 = 150 torr CO 2 = 0 torr Hypoventilation with HPV Decreased O 2 Increased CO 2 Decreased O 2 Increased CO 2 O 2 = 40 torr CO 2 = 45 torr

25. 0.20.40.60.8 Hematocrit 8 6 4 2 Relative Viscosity Effects of Hematocrit on Human Blood Viscosity

26. Possible Explanation for Systemic Hypertension Repeated increases in sympathetic tone and systemic blood pressure during arousals may cause vascular remodeling and changes in endothelial function

27. Explanation for Morning Headaches Hypoxia and hypercapnia during obstruction cause dilatation of cerebral blood vessels

28. 40100 Arterial PO 2 (mm Hg) 100 75 50 25 Cerebral Blood Flow (ml/100mg/min) Arterial PCO 2 (mm Hg) 206080 40100206080 Effects of Arterial P O 2 and P CO 2 on Cerebral Blood Flow

29. Possible Explanations for Bradycardia During Obstruction, Tachycardia after Airflow Restored Stimulation of arterial chemoreceptors usually increases heart rate because it increases tidal volume (lung inflation reflex) Stimulation of arterial chemoreceptors without stretching the lungs causes bradycardia After arousal leads to restoration of airflow, large tidal volumes stretch lungs and cause tachycardia May hyperventilate immediately after arousal, then hypoventilate until CO 2 is restored

30. Possible Explanation for Nocturia HPV, increased blood viscosity, pulmonary hypertension increase right ventricular afterload Increased afterload leads to increased right ventricular end diastolic pressure and volume Increased right ventricular end diastolic pressure and volume lead to increased right atrial volume Increased right atrial volume increases secretion of atrial natriuretic peptide from atrial myocytes, which increases sodium excretion, and stretches receptors that suppress ADH secretion from the posterior pituitary gland

31. Explanation for Hypersomnolence or Excessive Daytime Sleepiness Repeated arousals (may be hundreds per night) interfere with sleep architecture, especially rapid eye movement sleep Abnormal sleep architecture leads to daytime somnolence, decreased attentiveness, blunted mentation, depression, personality changes Hypersomnolence increases risk of motor vehicle accidents

32. Ethanol Exacerbates Obstructive Sleep Apnea Ethanol depresses the responses to hypoxia and hypercapnia Ethanol depresses the activity and tone of the genioglossal and pharyngeal dilator muscles Ethanol depresses protective respiratory reflexes

33. Treatment of OSA Lifestyle: Body position during sleep Weight loss Decreased ethanol consumption Oral appliances Continuous Positive Airway Pressure (CPAP) Surgical: Uvulopalatopharyngoplasty Tracheostomy

34. CPAP Mask Photo of CPAP Mask

35. Sites of obstruction during sleep apnea Laryngopharynx With CPAP Tongue Obstructive Sleep Apnea

36. Obstructive Sleep Apnea Web Sites http://www.aafp.org/afp/991115ap/2279.html http://www.sleepdisorderchannel.com/osa/

37. References Caples SM, Gami AS, Somers, VK. Obstructive sleep apnea. Ann. Intern. Med. 142: 187-197, 2005 Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Annu. Rev. Med. 27: 465-484, 1976 Kirkness JP, Krishnan V, Patil SP, Schneider H. Upper airway obstruction in snoring and upper airway resistance syndrome. In: Randerath WJ, Sanner BM, Somers VK (eds): Sleep Apnea. Prog. Respir. Res. Basel, Karger, 35: 79-89, 2006 Levitzky, Michael G. Pulmonary Physiology (7 th ed.). 2007. New York: McGraw Hill Ryan CM, Bradley TD. Pathogenesis of obstructive sleep apnea. J. Appl. Physiol. 99: 2440-2450, 2005 Schaefer T. Physiology of breathing during sleep. In: Randerath WJ, Sanner BM, Somers VK (eds): Sleep Apnea. Prog. Respir. Res. Basel, Karger, 35: 21-28, 2006