Karl Doghramji, MD

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

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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.

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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.

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Sleep Homeostasis: Highly Regulated

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 ?

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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

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Sleep

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.

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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

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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

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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

Non-prescription Agents for Insomnia: Limited Evidence for Hypnotic Efficacy

Meoli AL, et al. J Clin Sleep Med. 2005;1(2):173-187. 27

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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.

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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 House Staff: July 1, 2017

• 80 hours maximum per week averaged over 4-week period • Rotation-specific exceptions up to 88 hours • 8 hours off between scheduled work, with exceptions • > 14 hours free after 24 hours of in-house call • > 1 day in 7 free of clinical work/education • Exceptions (rare), count towards 80 hour limit • Continue care to severely ill or unstable patient • Humanistic need of patient or family • Unique educational events

ACGME, Accreditation Council for Graduate Medical Education, 2017

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Prevention and Management • Sleep 8 hours per day on a consistent basis • Limit work to 12 hours per day • Adhere to work shifts that make sense • Planned napping • Healthy sleep habits • Bright light at work, darkness and quiet while asleep • Avoid driving if sleepy •Caffeine • Melatonin • Hypnotics and stimulants

Timed Melatonin Administration

• Prior to daytime sleep1 • 0.5-10 mg, usually 1.8-3 mg1 • Demonstrated improvements • Daytime sleep quality and duration1,2 • Shift in circadian phase (DLMO)1 • Not been shown to enhance alertness during night shift1 • Unregulated • Possible vascular and fertility changes3,4 • Possibly should not be utilized with3 • Immunosuppressants or corticosteroids • Pregnancy or lactating women • Vascular disorders

1Morgenthaler TI et al. Sleep. 2007;30:1445-1459; 2Dollins AB et al. Proc Natl Acad Sci. 1994;91:1824-1828; 3Arendt J, Deacon S. Chronobiol Int. 1997;14:185-204; 4Cook JS et al. Am J Physiol Heart Circ Physiol. 2011;300:H670-674.

Caffeine for Excessive Sleepiness

• Judicious use • Mitigates sleepiness and enhances performance • Controlled forced wakefulness for 28.6 hours • Caffeine 0.3 mg/kg/hr or placebo administered hourly (approximately 1 cup of coffee every 3 hours) • Enhanced cognitive performance • Enhanced ability to stay awake • Field trial with shift workers • Caffeine 4 mg/kg 30 min prior to night shift • 2.5 hour nap prior to night shift • Diminished sleepiness alone, better in combination with napping

This agent is not FDA approved for excessive sleepiness Wyatt JK et al. Sleep. 2004;27:374-381 Schweitzer PK et al. Sleep. 2006;29:39-50

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Pharmacologic Therapies for Shift Work Disorder

Therapy Recommendation

Timed melatonin administration Indicated (guideline)

Hypnotics Indicated (guideline)

Stimulants (eg, caffeine) Indicated (option)

Alerting agents (eg, modafinil/armodafinil) Indicated (guideline)

AASM Levels of Recommendations Standard: Reflects a high degree of clinical certainty, implies the use of level 1 evidence or overwhelming level 2 evidence. Guideline: Reflects a moderate degree of clinical certainty, implies the use of level 2 evidence or a consensus of level 3 evidence. Option: Reflects uncertain clinical use, implies either inconclusive or conflicting evidence or conflicting expert opinion. 37 Morgenthaler TI, et al. Sleep. 2007;30:1445-1459.

Conclusions

• Sleep is a vital function that is necessary for life • It critically affects the status of other body functions • Sleep quality and quantity is affected by many poor sleep practices, medical and psychiatric disorders, and primary sleep disorders • Attention to proper sleep habits can address many sleep related complaints • If symptoms persistent, underlying disorders should be identified and managed