12/3/2019 SLEEP The Neglected Vital Sign Karl Doghramji, MD Professor of Psychiatry, Neurology, and Medicine Director, Jefferson Sleep Disorders Center Program Director, Fellowship in Sleep Medicine Thomas Jefferson University Objectives • To understand the neurophysiological processes underlying sleep and wakefulness • To appreciate the consequences of disrupted sleep quality and quantity • To recite an evidence-based approach to manage sleep related difficulties in clinical settings Vital Sign • Definition • Vital: A function that is necessary for life • Sign: Indicates status of a body function • Types • Primary (1-4): Objective, detected during routine PE • Temp, pulse, RR, BP • Fifth: Pain, menstrual cycle, SaO2, glucose • Sixth: Discipline-dependent Dorland’s, 2012;Wikipedia, accessed 11/16/2019 1 12/3/2019 Sleep •Actively produced by the brain, not a result of passive inactivity •Highly regulated •Governed by homeostatic and circadian processes •Affects the entire organism, not limited to the CNS •Necessary for vital physiological and cognitive functioning •Deprivation leads to functional impairments and eventual death Carskadon MA, Dement WC (2005), Normal human sleep: an overview. In: Principles and Practice of Sleep Medicine, 4th ed., Kryger MH et al., eds. Philadelphia: Elsevier/Saunders, pp13-23 Typical Sleep Architectural Pattern of a Young Human Adult Awake Stage 1 and REM sleep Stage 2 sleep Delta sleep Time:Hours 1 2 3 4 5678 Stage I and REM sleep (red) are graphed on the same level because their EEG patterns are very similar. Adapted from Hauri P. The Sleep Disorders. Kalamazoo, Mich: Upjohn;1982:8. 2 12/3/2019 Arousal and Sleep-Promoting Systems Arousal Sleep Posterior lateral hypothalamus (orexin) 5-HT = serotonin; Ach = acetylcholine; BF = basal forebrain; DA = dopamine; DR = dorsal raphe nucleus; GABA = gamma-aminobutyricacid; Gal = galanin; LC = locus coeruleus; LH = lateral hypothalamic; MCH = melanin-concentrating hormone; NE = norepinephrine; ORX = orexin; PPT/LDT = pedunculopontine and laterodorsal tegmental; TMN = tuberomammillary nucleus; VLPO = ventrolateral preoptic nucleus; vPAG = ventral periaqueductal gray matter. Modified from Fuller PM, et al. J Biol Rhythms. 2006;21(6):482-493. Silber MH, et al. Neurology. 2001;56(12):1616-1618. Sleep Neurotransmitters CNS Structure Neurotransmitter VLPO GABA Galanin Homeostatic factor Adenosine Pineal gland Melatonin The Biological Clock: The SCN Adapted from Brzezinski A. N Engl J Med. 1997. 3 12/3/2019 Sleep Homeostasis: Highly Regulated 40 20 NREM Percent of Time 0 61218 24 61218 24 61218 24 61218 24 Basal (Hrs) Deprivation Recovery Recovery of Sleep (Hrs) Day 1 (Hrs) Day 2 (Hrs) Rebound sleep stages after sleep deprivation Modified from Rechtschaffen et al., Sleep, 1999 Systemic Physiology of NREM vs. REM Sleep Compared to wakefulness… Variable NREM REM Heart rate Regular Variable Respiratory rate Regular Variable Blood pressure Regular Variable Skeletal muscle tone Preserved or ↓ Absent Brain O2 cons Reduced Increased Response to CO2 Depressed Further depressed Response to O2 Same as W Same as W Temperature Homeothermic Poikilothermic Penile tumescence Infrequent Frequent Kryger MH et al. (2005), Principles and Practice of Sleep Medicine. Philadelphia: Elsevier/Saunders Survival During Deprivation of Basic Needs Rat Water 13 days Food 17 to 19 days Sleep 19 to 21 days Human Water 7 to 10 days Food 30 to 60 days Sleep > 10 days ? 4 12/3/2019 Systemic Consequences of Sleep Deprivation in Humans • Increased pain sensitivity • Major depression • Aggravate hypoxemia • Cardiovascular • Increase BP, CRP, pro-inflammatory cytokines • Metabolic • Increase hunger for high-calorie foods • Decrease adipose weight loss during dieting • Decrease glucose tolerance/increased insulin resistance • Decrease leptin, increase ghrelin • Immune response • Reduced natural killer cell activity • Increased TNF, IL-6 Mullington JM et al. Prog Cardiovasc Dis 2009;51:294-302; Nedletcheva AV et al. Ann Int Med 2010;153:435-441; Leproult R, Van Cauter E. Endocr Dev 2010;17:11-21; Banks S et al. J Clin Sleep Med 2007;3:519-528 Cognitive Effects of Sleep Deprivation in Humans • Slower response time • Errors of omission and commission • Decline in memory • Reduced learning • Diminished concentration • Lapses in attention • Diminished insight into subtle meanings • Typically without subjective awareness Dinges D. Clin Psychiatry News. 2002;5:5 Wagner U, Gais S, Haider H, et al. Nature 427, 352 – 355, 2004 5 12/3/2019 Sleep •Actively produced by the brain, not a result of passive inactivity •Highly regulated •Governed by homeostatic and circadian processes •Affects the entire organism, not limited to the CNS •Necessary for vital physiological and cognitive functioning •Deprivation leads to functional impairments and eventual death Carskadon MA, Dement WC (2005), Normal human sleep: an overview. In: Principles and Practice of Sleep Medicine, 4th ed., Kryger MH et al., eds. Philadelphia: Elsevier/Saunders, pp13-23 Types of Sleep Disturbance • Curtailed sleep quantity (sleep deprivation) • Impaired sleep quality (sleep fragmentation) • Causes • Sleep hygiene impairments (poor sleep practices) • Primary insomnia • Medical and psychiatric disorders • Primary sleep disorders: Emerge from sleep • Sleep apnea • Periodic limb movement disorder • Circadian misalignment: Trying to sleep when the body should be awake, trying to work when the body should be asleep • Shift work • Jet lag Sleep and Age Young Old McCall V, et al. J Ambul Monitor. 1993;6:135-140. 6 12/3/2019 The Dos of Sleep Hygiene Do… • Allow adequate time for sleep! • Establish a daily activity routine • Wake up at the same time every day • Increase exposure to bright light during the day • Decrease light exposure in the evening • Exercise regularly in the morning and/or afternoon • Set aside a worry time • Do something relaxing prior to bedtime • Try a warm bath The Don’ts of Sleep Hygiene Avoid… • Alcohol • caffeine, nicotine, and other stimulants • Heavy meals or drinking within 3 hours of bedtime • Using your bed for things other than sleep (or sex) • Watching the clock • Staying in bed awake too long • Napping, unless a shiftworker 7 12/3/2019 Avoid Staying in Bed Too Long Get Out of Bed • If you can’t fall asleep in 30 minutes • Or, if you wake up and can’t fall back to sleep within 30 minutes • Get out of bed • Do something relaxing and/or boring • Return to bed when you feel sleepy Insomnia and Hyperarousal Hyperarousal HPA axis Increased activation body metabolic rate Sympathetic Cognitive activation arousal Heightened EEG brain arousal metabolism 8 12/3/2019 Psychological and Behavioral Treatments for Primary Insomnia Techniques Method Stimulus control therapy* If unable to fall asleep within 20 minutes, get OOB and repeat as necessary Relaxation therapies* Biofeedback, progressive muscle relaxation Restriction of time in bed Decrease time in bed to equal time actually asleep (sleep restriction) and increase as sleep efficiency improves Cognitive therapy Talk therapy to dispel unrealistic and exaggerated notions about sleep Paradoxic intention Try to stay awake Sleep hygiene education Promote habits that help sleep; eliminate habits that interfere with sleep Cognitive-Behavioral Combines sleep restriction, stimulus control and Therapy* sleep hygiene education with cognitive therapy *Standard Treatment according to American Academy of Sleep Medicine Morgenthaler T et al. Sleep. 2006;29:1415 Bootzin RR, Perlis ML (1992), J Clin Psychiatry (53 Suppl):37-41 What People Take for Insomnia Formal Sleep Indication? No Yes Dietary Over-the-Counter Supplements Sleep Aids Assorted Sedating FDA-Approved Yes No Yes Medications Insomnia Medications “Off-label” Prescription Required? FDA, US Food and Drug Administration 26 Non-prescription Agents for Insomnia: Limited Evidence for Hypnotic Efficacy Meoli AL, et al. J Clin Sleep Med. 2005;1(2):173-187. 27 9 12/3/2019 Nonprescription Agents for Insomnia: Insufficient Evidence for Hypnotic Efficacy Meoli AL et al. J Clin Sleep Med 2005;1(2):173-187 Nonprescription Agents for Insomnia: No Evidence of Hypnotic Efficacy or Significant Safety Concerns Meoli AL et al. J Clin Sleep Med 2005;1(2):173-187 Selective Benzodiazepine Receptor Agonists Zaleplon Zolpidem Zolpidem Eszopiclone ER Dose – mg 5,10,20 [5] 5,10 [5] 6.25,12.5 [6.25] 1,2,3 [1] [elderly] Tmax (hours) 11.61.51 Half-life [elderly] 1 2.5 [2.9] 2.8 [2.9] 6 [9] (hrs.) Sleep latency ↓↓ ↓ ↓ Wake After Sleep -- -- ↓ ↓ Onset Total sleep time ↑ ↑↑ ↑ (20 mg) Schedule IV IV IV IV US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. 10 12/3/2019 Newer Hypnotics Ramelteon Doxepin Suvorexant Dose – mg [elderly] 8 3,6 [3] 10-20 Tmax (hours) 0.75 3.5 2 Half-life [elderly] 1-2.6 15.3 12 (hrs.) Sleep latency ↓ -- ↓ Wake After Sleep -- ↓ ↓ Onset Total sleep time -- -- ↑ Schedule None None IV US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Hypnotics Under Development • Dual and single orexin • Melatonin receptor agonists receptor antagonists • Controlled release melatonin • Lemborexant for elderly (Circadin®) • TCS-OX2-29 • Piromelatine • Seltorexant • Others • Benzodiazepine receptor • Beta-blockers agonists • Histamine H1 antagonists • Controlled release zaleplon • 5-HT2A receptor antagonists • Inhaled zaleplon • Adenosine receptor agonists • Lorediplon • EVT-201 • Angiotensin II receptor 1 antagonist • Cannabinoid agonist ACGME Standards for