1. How can Obstructive Sleep Apnea be Evaluated Beyond Anatomy? David P. White, MD Professor of Medicine Harvard Medical School Chief Medical Officer: Philips Respironics

2. Obstructive Sleep Apnea Phenotypic Traits Anatomy. Pharyngeal dilator muscle control asleep. Arousal Threshold. Loop Gain/Control of breathing.

3. Hyoid Bone Mandible Maxilla Nasal Passage Trachea Epiglottis Tongue (Genioglossus) Soft Palate Choanae

4. Richard Schwab Clinics in Chest Medicine, 1998

6. Pcrit measurement 60s 10 2 Pmask +0.5 -0.5 Flow

7. Pcrit measurement 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5 012345678 Mask pressure (cm H 2 O) Flow Pcrit

8. Sforza and Kreiger Am J Respir Crit Care Med, 1999

9. Pharyngeal Anatomy in Obstructive Sleep Apnea Anatomy alone, at least as measured by P crit, explains little of the variability in apnea severity (as measured by RDI).

10. Obstructive Sleep Apnea Phenotypic Traits Anatomy. Pharyngeal dilator muscle control asleep. Arousal Threshold. Loop gain/ control of breathing.

12. Arousal and Obstructive Sleep Apnea What is required for the pharyngeal dilator muscles to open the upper airway during sleep? The muscles must be recruitable and effective. The individual must stay asleep long enough for the muscles to be recruited.

13. Berry et al – AJRCCM, 1997

14. Gleeson et al – 1990 Am Rev Respir Dis

15. Guilleminault et al – Chest, 1993

16. Arousal and Obstructive Sleep Apnea Combined individual variability in: Respiratory arousal threshold. Upper airway muscle responsiveness and effectiveness. May explain much of the variability in the severity of obstructive sleep apnea.

17. Obstructive Sleep Apnea Phenotypic Traits Anatomy. Pharyngeal dilator muscle control asleep. Arousal threshold. Loop gain/ Control of breathing.

18. Ventilatory Instability and Upper Airway Obstruction R UA Ventilatory Motor Output Nadir of motor output Obstruction

19. Baseline

20. Chemical Feedback Loop PCO 2 Circulatory Delay  V E (R)  PCO 2 PC02 Ve Ventilatory disturbance  V E (D) Plant Controller Ve

21. Loop Gain A measure of the susceptibility to periodic breathing. Ventilatory Response Ventilatory Disturbance Loop Gain =

22. Loop Gain = 0.5 Disturbance Response Ventilatory Response Ventilatory Disturbance Loop Gain = LG = 0.5

23. Loop Gain = 0.5 Disturbance Response Ventilatory Response Ventilatory Disturbance Loop Gain = LG = 0.5

24. Loop Gain = 0.5 Disturbance Response Ventilatory Response Ventilatory Disturbance Loop Gain = LG = 0.5

25. Loop Gain  1 Disturbance Response Ventilatory Response Ventilatory Disturbance Loop Gain = Disturbance Response LG = 0.5 LG = 1

26. Loop Gain  1 Disturbance Response Ventilatory Response Ventilatory Disturbance Loop Gain = Disturbance Response LG = 0.5 LG = 1

27. Proportional Assist Ventilator (PAV) delivers pressure in proportion to the patients effort. Thus we can increase the Ventilation Response for a given Ventilatory Disturbance. Loop Gain Measurement Ventilatory Response Ventilatory Disturbance Loop Gain =

28. Proportional Assist Ventilation PAV amplifies the underlying loop gain and can induce periodic breathing. LG = 0.5 LG = 0.2 PAV amplification

29. 50% assist VTAF 1.65 VTAFs 60% assist VTAF 2.08

30. 75% assist VTAF 2.44 80%

31. 75% VTAF 2.44

32. 80% 85% 60%

33. r = 0.36 p = 0.076

34. P crit measurement 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5 012345678 Mask pressure (cm H 2 O) Flow P crit

35. Baseline info NAgeBMI Low risk (Pcrit < -1) 7 47.4  2.734.3  3.2 Borderline risk (Pcrit -1 to +1) 9 44.9  3.231.9  2.5 High risk (Pcrit > +1) 742.7  3.834.2  4.0

36. r = -0.31 p = 0.45

37. r = 0.88 p = 0.0016

38. r = 0.19 p = 0.66

39. Loop Gain Can probably be determined fairly easily during NREM sleep. Will likely turn out to be an important cause of OSA is a subset (20-25%) of patients. As loop gain can be manipulated with drugs, oxygen etc, novel therapies may emerge for these patients if they can be identified.

40. Obstructive Sleep Apnea Phenotypic Traits Anatomy. Pharyngeal dilator muscle control asleep. Arousal Threshold. Loop Gain/Control of breathing.