Sleep Dysfunction and Sleep-Disordered Breathing P3 Research Summit

1. Sleep Dysfunction and Sleep-Disordered Breathing P3 Research Summit Klar Yaggi M.D., M.P.H. Assistant Professor Yale University School of Medicine Section of Pulmonary and Critical Care

2. Journal of the Canadian Medical Association; 2006

5. Outline • Basic clinical aspects of sleep/sleep-disordered breathing • Interactions between pain, sleep, opiods, central sleep apnea • Sleep, TBI, and PTSD

6. Outline • Basic clinical aspects of sleep/sleep-disordered breathing

7. Differential Diagnosis of Hypersomnia • Sleep-disordered breathing (sleep apnea) • Self-imposed sleep restriction • Medication effects • Narcolepsy • Periodic limb movement disorder • Circadian rhythm disorders

8. Epworth Sleepiness Scale Point Scale for “chance of dozing” in various situations 0= never 1= slight 2= moderate 3= high • Situations (8 total)Score • Sitting inactive in a public place __________ • Sitting and reading __________ • Watching TV __________ • Passenger in a car for an hour without a break __________ • Lying down to rest in the afternoon __________ • Sitting and talking to someone __________ • Sitting quietly after lunch without alcohol __________ • In a car, while stopped for a few minutes in traffic __________ Johns; Chest 1993

9. EEG, EOG, EMG EKG Airflow Chest/abd, bands Pulse oximetry Left/right leg EMG Presence/stage of sleep Cardiac rate/rhythm Apnea/hypopnea Respiratory effort Arterial oxygen sat Leg movements (PLMs) Standard Polysomnography

10. Normal Sleep Architecture

11. NREM Sleep (80%) ↓ Sympathetic nerve activity, HR, and BP (‘nocturnal dipping’) ↓ Cerebral blood flow Regular breathing pattern ↓ Minute Ventilation ↓ Muscle tone REM Sleep (20%) Sympathetic nerve activity, HR, and BP similar to awake ↑ Cerebral blood flow Irregular breathing pattern Breathing dependent on diaphragm Absent muscle tone Physiology of Normal Sleep Somers; NEJM 1993

13. Definitions and Severity Criteria • Apnea:Cessation of airflow > 10 sec (valid measure of breathing) • Hypopnea:Decrease in airflow by 30%, associated with a >4% oxygen desaturation (best inter/intrascorer reliability) • Severity Criteria: • Mild: 5-15 events per hour • Moderate: >15-30 events per hour • Severe: >30 events per hour AASM Task Force; Sleep 1999

14. % Men% Women AHI ≥ 5 24 9 AHI ≥ 5 + daytime somnolence 4 2 Prevalence in Middle Aged Adults AHI = Apnea Hypopnea Index Young; NEJM 1993

15. Risk Factors for Sleep Apnea • Obesity • Increasing age • Post-menopausal state • Hypothyroidism • Alcohol/sedating medications • Obstructive lesions of the upper airway • Craniofacial abnormalities (e.g. retrognathia)

16. Pathogenesis of Obstructive Sleep Apnea White; AJRCCM 2005

17. Common Symptoms • Loud snoring • Excessive daytime sleepiness • Morning headaches (cerebral vasodilation) • Neuropsychiatric and cognitive symptoms • Depression/emotional instability • Short-term memory loss • Impaired concentration • Breathing pauses (bed partner history is key)

19. Sleep Apnea Cycle Sleep Apnea Hypoxia Reoxygenation Pleural pressure Δ Sympathetic activation Ventilation Arousal

20. Sleep Apnea and Incident Hypertension Peppard; NEJM 2000 Apnea Hyponea Index Events/hour 0 0.1-4.9 5-14.9 ≥15 Adjusted* Odds Ratio 1.0 1.42 2.03 2.89 *adjusted for baseline hypertension, age, gender, BMI, waist circumference, alcohol, and tobacco use P for trend=0.002

21. Other Consequences of Sleep Apnea • Excessive daytime sleepiness • Cognitive dysfunction • Decreased quality of life • Depression • Motor vehicle crashes • Occupational accidents • Pulmonary hypertension • Cardiovascular morbidity and mortality Young; AJRCCM 2003

22. Event-free Survival (TIA, Stroke, Death) Kaplan-Meier Estimates of the Probability of Event-free Survival among Patients with the Obstructive Sleep Apnea Syndrome and Controls Yaggi, H. et al. N Engl J Med 2005;353:2034-2041 Yaggi; NEJM 2005

23. Modalities of Treatment • Behavioral • Weight reduction • Position training • Surgery • Tracheostomy • Bariatric Surgery • Upper airway modification: Uvulopalatopharyngoplasty (UPPP), Maxillo-mandibular advancement • Application of Devices • Mandibular advancement devices • Continuous positive airway pressure (CPAP)

24. Positive Airway Pressure(CPAP)

25. Outline • Basic clinical aspects of sleep/sleep-disordered breathing • Interactions between pain, sleep, opiods, central sleep apnea

26. Chronic Pain Impairing Sleep: Example of Fibromyalgia and Alpha-Delta Sleep • Chronic pain sufferers often have impaired sleep • Arousal augmenting aspects of pain may inhibit sleep initiation and continuity • Alpha rhythm is an EEG rhythm with a frequency of 8-13Hz • When alpha rhythm intrudes into SWS it is commonly referred to as “alpha delta” sleep. • Alpha intrusion is associated chronic pain syndromes (e.g. fibromyalgia) • Increased arousal during slow wave sleep may interfere with restorative function of sleep Moldofsky; Psychosom Med 1975

27. Alpha-Delta Sleep 25 seconds

28. Impaired Sleep Contributing to Pain: Selected Human Data • Sleep deprivation produces “hyperalgesic changes” (increased pain sensitivity to noxious stimuli) in healthy subjects1,2 • Slow wave sleep deprivation appeared to exert this effect • Mainly observed in pressure pain stimulation • Recovery of slow wave sleep increases pain tolerance • Sleep deprivation produces sleepiness, increased fatigue, negative mood, cognitive impairment which may cause or mimic a modulation of pain processing3 • Lentz; J Rheumatol 1999 • Onen; J Sleep Res 2001 • Kundermann; Pain Res Manage 2004

29. Impaired Sleep Contributing to Pain: Selected Animal Data • Sleep deprivation produces “hyperalgesic changes” (increased pain sensitivity to noxious stimuli) in rats • REM sleep deprivation especially appeared to exert this effect • Observed in pressure pain stimulation, electrical stimuli • REM sleep deprivation appeared to prevent analgesic action of endogenous/exogenous opiods • Hicks; Percept Mot Skills 1978 • Ukponmwan; Gen Pharmacol 1984 • Kundermann; Pain Res Manage 2004

30. Effect of Opiods on Sleep Architecture • ↑ wakefulness and stage shifts • ↓ total sleep time • ↓ sleep efficiency • ↓ slow wave sleep • ↓ REM sleep • ↑ lighter stage NREM sleep Dimsdale; J Clin Sleep Med 2006 Lautenbacher; Sleep Med Rev, 2006

31. PAIN IMPAIRED SLEEP OPIODS

32. Chronic Opiate use as a Risk Factor for Central Sleep Apnea and Ataxic Breathing • Observational cohort study of 60 patients taking chronic opiods matched with controls • Patients taking chronic opiods • Significantly higher AHI (due to central apneas) • Lower arterial oxygen saturation • Dose-response relationship Walker;J Clin Sleep Med 2007

33. Central Sleep Apnea and Ataxic Breathing Walker;J Clin Sleep Med 2007

34. Determining Risk of Vascular Events by Apnea MonitoringVA CSR&D Merit Review Program DREAM

35. Adaptive Pressure Support Servo-ventilation (APPSV) Treated Cheyne-Stokes Respiration Untreated Cheyne-Stokes Respiration Teschler; AJRCCM 2001

36. APPSV: A Novel Treatment for Sleep Apnea Associated with Use of Opiods Javaheri; J Clin Sleep Med 2008

37. Does the treatment of coexistent sleep disorders (e.g. sleep apnea) represent a novel therapeutic target help to improve outcomes among patients with pain, PTSD, TBI?

38. VA HSR&D Merit Review Program

39. Outline • Basic clinical aspects of sleep/sleep-disordered breathing • Interactions between pain, sleep, opiods, central sleep apnea • Sleep, TBI, and PTSD

40. Sleep and TBI • Castriotta RJ, Wilde MC, Lai JM, Atanasov S, Masel BE, Kuna ST. Prevalence and consequences of sleep disorders in traumatic brain injury. J Clin Sleep Med. 2007:349-56. 2. Wilde MC, Castritta RJ, Lai JM, Atanasov S, Masel BE, Kuna, ST. Cognitive Impairment in patients with Traumatic Brain Injury and Obstructive Sleep Apnea. Arch Phys Med Rehabil. 2007: 1284-8

41. Sleep in PTSD 1. Germain A, Buysee D, Nofzinger E. Sleep Specific Mechanisms Underlying Post-Traumatic Stress Disorder: Integrative review and Neurobiological Hypoetheses. Sleep Med Rev. 2008: 185-195