Using the Pathophysiology of Obstructive Sleep Apnea (OSA) to Teach Cardiopulmonary Integration

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 approximateincidence) • 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 PO2 ; increased alveolar PCO2 • Decreased arterial PO2 ; increased arterial PCO2 • Stimulation of arterial chemoreceptors; central chemoreceptors • Arousal • Secondary hyperventilation?

8. Effects of Breathhold on Arterial PO2 and PCO2 O2 100 80 Arterial Partial Pressure (mmHg) 60 40 CO2 20 10 20 30 Time (sec) All figures created by Betsy Giaimo

9. Effects of Arterial PO2 and PCO2 on Carotid Body Activity Pa , torr O 2 20 40 60 80 100 120 140 Carotid Body Activity 10 20 30 40 50 60 , torr Pa CO 2

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 CO2 • Chest and abdominal motion (impedance plethysmography) • ECG • Blood pressure • Pulse oximetry • Esophageal pressure (intrapleural pressure) • Autonomic nervous system activity (finger tonometer)

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

12. Obstructive Sleep Apnea EEG ECG BP Abd Chest Vt (air flow) 100 75 Pulse Oxygen Saturation Time (minutes) 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. Eupneic Inspiration (Revised from Fig. 2-1 in Levitzky’s Pulmonary Physiology) Atmospheric Pressure : 0 cm H2O Atmospheric Pressure : 0 cm H2O Flow in No flow Inspiratory force Outward recoil of chest wall Alveolar pressure: 0 cm H2O Alveolar pressure: 0 cm H2O Alveolar pressure: -1 cm H2O Inward recoil of alveoli Intrapleural pressure: -5 cmH2O Intrapleural pressure: -8 cmH2O Transmural pressure= 0 cmH2O - (-5cmH2O)= +5 cmH2O Transmural pressure= -1 cmH2O - (-8cmH2O)= +7 cmH2O DURING INSPIRATION END EXPIRATION

17. Forced Inspiration (Revised from Fig. 4-10C in Levitzky’s Pulmonary Physiology) Atmospheric Pressure : 0 cm H2O Atmospheric Pressure : 0 cm H2O Flow in No flow Inspiratory force Outward recoil of chest wall Alveolar pressure: 0 cm H2O Alveolar pressure: 0 cm H2O Alveolar pressure: -23 cm H2O Inward recoil of alveoli Intrapleural pressure: -5 cmH2O Intrapleural pressure: -30 cmH2O Transmural pressure= 0 cmH2O - (-5cmH2O)= +5 cmH2O Transmural pressure= -23 cmH2O - (-30 cmH2O)= +7 cmH2O END EXPIRATION DURING INSPIRATION

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 H2O; as low as -80 cm H2O during episodes of obstructive sleep apnea?

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

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

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% PaCO2 increases 4-6 mmHg SaO2 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 CO2 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 PaCO2 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. Hypoventilation with HPV O2 = 150 torr CO2 = 0 torr Decreased O2 Increased CO2 O2 = 40 torr CO2 = 45 torr Decreased O2 Increased CO2

25. Effects of Hematocrit on Human Blood Viscosity 8 6 Relative Viscosity 4 2 0.2 0.4 0.6 0.8 Hematocrit

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. Effects of Arterial PO2 and PCO2 on Cerebral Blood Flow Arterial PCO2 (mm Hg) 20 40 60 80 100 100 75 Cerebral Blood Flow (ml/100mg/min) 50 25 20 40 60 80 100 Arterial PO2 (mm Hg)

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 CO2 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. Obstructive Sleep Apnea Sites of obstruction during sleep apnea With CPAP Tongue Tongue Laryngopharynx

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 (7th 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