No Idea • Sleep to avoid attracting predators in the night • Highly conserved.

All vertebrates sleep • “Unlearning” mechanism whereby sleep erases unwantedthoughts or erroneous information Benefits of Sleep • Replenishes glucose and neurotransmitters in the brain • Sleep determines our waking success in terms of: • Mood, Alertness, Energy, Thinking, Productivity, and Safety • Promotes General Health and Longevity

Why do we Sleep?

Evolution of Sleep
• Rest but no sleep
– amphibians, fish

• Non-REM sleep only
– lower reptiles

• A little REM
– chameleons, crocodiles, birds (when babies) – echidna

• REM and NonREM
– All placental mammals

Development of Sleep
• Babies spend 16 hours sleeping, initially half in REM. REM sleep in infants represents a larger percentage of the total sleep at the expense of stages III and IV. Until age 3-4 months, newborns transition from wake into REM sleep. Thereafter, wake begins to transition directly into NREM. • Over lifespan, total sleep decreases • Over lifespan, proportion of REM decreases

In elderly persons, the time spent in stages III and IV sleep decreases by 10–15% and the time in stage II increases by 5% compared to young adults, representing an overall decrease in total sleep duration. Latency to fall asleep and the number and duration of overnight arousal periods increase. Thus to have a fully restorative sleep, the total time in bed must increase. If the elderly person does not increase the total time in bed, complaints of insomnia and chronic sleepiness may occur.

Sleep Facts
• Adults need an average 8.2 hours of sleep per 24 hours1 • Impairment of performance occurs with as little as 2 hours less sleep than normal per night2 • Sleep debt from restricting sleep to 5 hours a night accumulates with time, and awareness of sleepiness declines2 • The significance of circadian timing is rarely addressed when considering the effects of shift work
• National Heart, Lung, and Blood Institute Working Group on Problem Sleepiness. 1997. • Carskadon MA, et al. Sleep restriction. In: Monk T, ed. Sleep, Sleepiness and Performance. 1991.

Purpose of Sleep
• Excessive sleep deprivation kills rats • Sleep deprivation makes people more tired

How Much Sleep Is Enough?
• The amount that allows you to feel alert when rested and relaxed (eg, grand rounds) • There is little variation of sleep need (8.2 hours) among individuals • 1 night with 2 hours less than your usual sleep is sufficient to produce significant decrements in waking performance • After several nights of 5-hour sleep, most adults do not realize they are pathologically sleepy
Carskadon MA, et al. In: Monk T, ed. Sleep, Sleepiness and Performance. 1991.

• Sleep-reversible state of consciousness • Brain relatively more responsive to internal than to external
• Historically, sleep a passive state initiated through withdrawal of sensory input. • Currently, withdrawal of sensory awareness believed to be a factor in sleep, but an active initiation mechanism that facilitates brain withdrawal recognized. stimuli (visual, auditory, and other environmental stimuli) during the transition from wake to sleep

Why Do We Feel Sleepy? The 2-Process Model
• 2 processes combined determine sleep propensity and the duration of sleep
– Homeostatic sleep drive:
• Process driven by amount of time awake • Linear and cumulative—one gets progressively more tired with each passing hour (“sleep load” increases)

– Circadian rhythm:
• Process driven by biological clock (time of day) • Cyclical—periods of sleepiness occur at roughly the same times each day

Combined Sleep Processes
Increases
The physiological pressure to sleep progresses linearly Sleep Sleep

Sleepiness

The biological pressure to sleep occurs cyclically

Wake

Wake

Decreases

Noon

Midnight

Noon

Midnight

Time (48 hours)

• Sleep is an active process that cycles at an ultradian rhythm
of about 90 minutes.

• Normal sleep is divided into NREM & REM • NREM has 4 stages
i) Stage I (Light sleep or slow wave sleep) ii) Stage II iii) Stage III (SWS) iv) Stage IV (Deep or delta wave sleep) (SWS)

• In adults, sleep of 8-8.4 hours is considered fully

restorative. In some cultures, total sleep often is divided into an overnight sleep period of 6-7 hours and a midafternoon nap of 1-2 hours. • Stage I is considered a transition between wake and sleep. It occurs upon falling asleep and during brief arousal periods within sleep and usually accounts for 510% of total sleep time. Stage II occurs throughout the sleep period and represents 40-50% of total sleep time. Stages III and IV delta sleep occur mostly in the first third of the night. They are distinguished from each other only by the percentage of delta activity and represent up to 20% of total sleep time. REM represents 20-25% of total sleep time.

Normal Sleep Patterns in Young Adults
AWAKE

The the purpose of analysis, overnightduringhas been - in The first REM period alters sleep the night Waking usually transitions For frequency of sleep Stages of One hours of of REM sleep The proportionREM-nonREM falls rapidly the earlycycle of sleep SWS dominates, whereas REM divided into sleep less thansleep in the periods: the night 3 equal time minutes into occurs may be followed by part of first third lastsNREM 90-100 in thethe it fallspercentage of about sleep plateaus at 25% until highest further in often second sleep. The and night, moreduration, while of the 10 minuteswhichfollowed by alters with age - in in comprises REM 4-5 REM the middle third of the night; and sleep in and then portion sleep in sleep during night and, age. cycles occur during sleep time and NREM; of Children have more old last may REM sleep 60 for 50%, pre-mature newborn thelast third of9-hour sleep NREM babies exceed lastsmajority of which is REM. the normal 4 sleep than adults. stage 8- to the night, the infants 80% & in a full night's sleep is usually from REM minutes. Awakening after adults for 20%.

REM Stage NREM

period during night REM
Sleep Stages
sleep.

1 2 3 4

1

2

3 4 Hours of Sleep

5

6

7

8

Adapted from Berger RJ. The sleep and dream cycle. In: Kales A, ed. Sleep Physiology & Pathology: A Symposium. Philadelphia: J.B. Lippincott; 1969.

Human Sleep Stages
Awake—low voltage-random, fast
50µV 1 sec

Drowsy—8 to 12 cps-alpha waves

Stage 1—3 to 7 cps-theta waves
Theta Waves

Sleep spindles begin appearing in the second month of life with a density greater than that seen in adults . After the first year, the spindles begin decreasing in density and progress toward adult patterns. K complexes begin by the sixth month of life.

Human Sleep Stages
Stage 2—12 to 14 cps-sleep spindles and K complexes
sleep spindle K complex

Stage 3/4—1/2 to 2 cps-delta waves>75µV

REM Sleep—low voltage-random, fast with sawtooth waves*

*

*

Brain Waves in Sleep
• Waking
– low amplitude, high frequency

• Stage 1
– mostly theta waves

• Stage 2
– sleep spindles
• brief period of high amp,high f

– K-complex

• Stage 3
– appearance of delta waves

• Stage 4 (slow wave sleep)
– mostly delta

• REM
– like Stage 1, but with REM

Circadian Cycle • The Biological Clock…the regular bodily rhythms that operates on a 24-hour cycle • Independent of environmental stimulus • Maintain appropriate sleep and wakefulness cycle SCN (Suprachiasmatic Nucleus) • Photoreceptors that containing Melanopsin • Synchronization of the circadian cycle with the day/night cycle • Regulates body temperature, hormone secretion, urine production, and blood pressure to match the Circadian Cycle • Stimulation of Pineal gland that releases Melatonin – Neuro-hormone that promotes sleep

Physiology of Sleep I

Diencephalic sleep zone (Post hyp+ ant hyp N) Medullary synchronizing zone (RF at level of NTS) Basal forebrain sleep zone Serotonin agonist- suppression of sleep Serotonin antagonist (ritanserin)- SWS inc Adenosine- Sleep increase, Role of Coffee?

PGD2- medial POA of hyp- SWS + Rem inc PGE2- Wake Resrpine depletes serotonin and catecholmine, blocks SWS and REM but increases PGO spike Barbiturates Dec SWS

Functional dissociation b/w brainstem and cerebral cortex

Cerebral cortex

Intralamin ar nuclei of thalamus

Rostral

Histamine Posteroinfundibualr region

Inhibitory signal Ant Hyp POA
1) Dec in ascending cholinergic pathway 2) Dec cortical responsiveness

Brainstem RF & Post Hyp

Pontine reticular Centre inhibited GABA + Ach

NREM is an active state that is maintained partly through oscillations between the thalamus and the cortex. The 3 major oscillation systems are sleep spindles, delta oscillations, and slow cortical oscillations. Sleep spindles, a hallmark of stage II sleep, are generated by bursts of hyperpolarizing GABAnergic thalamic reticular neurons. These bursts inhibit thalamocortical projection neurons.

The functions of NREM sleep speculative, several theories have been put forth. - One theory : that decreased metabolic demand facilitates replenishment of glycogen stores. -Another theory, which utilizes neuronal plasticity, suggests that the oscillating depolarizations and hyperpolarizations consolidate memory and remove redundant or excess synapses.

During NREM sleep, the metabolic demand of the brain decreases. This is supported by oxygen positron emission tomography (PET) studies, which show that, during NREM sleep, the blood flow throughout the entire brain progressively decreases.

REM sleep is generated by mesencephalic and pontine cholinergic neurons, hence these are referred to as REM-on neurons. As REM sleep initiates, monoadrenergic locus ceruleus (NA) and serotonergic raphe neurons become inactive and are called REM-off neurons.

Control of REM by Pontine Nuclei

Physiologic correlates of Sleep states NREM- HR & BP inc & reverse during REM Cardiac dysrhythmia- REM sleep fR regular- NREM Opp during REM High PCO2 during NREM due to dec in VE SWS- inc GH, dec TSH, ACTH cortisol axis NREM Sleep- Attenuated thermoregulatory fn to cold and heat, REM complete unresponsiveness

REM Sleep • • • • EEG is remarkably similar to awakestate Each sleep cycle is 90 minutes Increasing REM intervals Characterization: • Rapid Eye Movement (REM) •Increase in Blood Pressure, Heart Rate, and Metabolism • Paralysis of large muscles (Tone of sk ms in neck dec) • Genital Arousal • Dreaming and Visual Hallucinations • Lack of self-reflection • Lack of Volitional Control • periodic skeletal muscle twitches, pupil dilation, and increased respiratory rate • “Active Brain in an Inactive Body”

PET studies also show that, during REM sleep, blood flow increases in the thalamus and the primary visual, motor, and sensory cortices, while remaining comparatively decreased in the prefrontal and parietal associational regions. The increase in blood flow to the primary cortical regions may explain the vivid nature of REM dreaming, while the continued decrease in blood flow to the prefrontal cortex may explain the unquestioning acceptance of even the most bizarre dream content.

An essential method in human clinical and basic sleep research is polysomnography. It is composed of measuring electroencephalogram (EEG), electrooculogram (EOG) and electromyogram (EMG)

Figure :Placement of electrodes of polysomnographic measurement

The Description of Brain Waves
• Two parameters
– frequency
• the number of waves per second, measured as Hertz, Hz

– amplitude

• Synchronization

• the height of waves, measured in EEG recordings as microvolts, or V • synchronized: waves are aligned with each other in time • desynchronized: waves occur randomly with each other in time

Physiological Measures
• Brain waves
– Electroencephalograph (EEG)
• • • • Beta waves 14 - 30 Hz, <20 V Alpha waves 8 - 13 Hz, 25-100 V Theta waves 4 - 7 Hz, 20 V Delta waves .5 - 4 Hz, 20-200 V

• Eyemovements • Muscle tension

– Electrooculagraph (EOG) – Electromyograph (EMG)

Additional Bodily Changes
• Decreased threshold of awareness of external events • Vestibular activation during REM • Autonomic arousal in REM • Genital arousal in REM

Impact and Recognition of Sleep Deprivation

What Is Good Performance?
• • • • • • • • Motivation Ability to see the “big picture” Memory for details Prompt decision making Accurate and consistent motor performance Good communication Contingency planning Professionalism

Clinical Signs of Excessive Sleepiness

• Irritability, moodiness, and disinhibition • Frontal lobe signs
– Apathy, impoverished speech, flattened affect – Impaired memory – Inflexible thinking and impaired planning skills—an inability to be novel or to multitask

• Intrusive sleepiness
– Microsleeps (5 to 10 seconds) cause lapses in attention – Nodding off when sedentary – REM phenomena (hypnagogic hallucinations)
Dinges D, et al. In: Monk T, ed. Sleep, Sleepiness and Performance. 1991. Rosekind MR, et al. Behav Med. 1996.

Less than 3 hrs/night: • Increase in Blood Pressure • Increase in blood Glucose level • Decrease in Leptin level • Hypertension, Obesity, Heart Attack, and Stroke Less than 6 hrs/night: • Increase in Cytokine level • Inflammation of arteries, Hypertension, and Stroke • Increase in production of C-Reactive Proteins by the Liver • Breaks down heart chambers • Increase in risk of Type-II Diabetes • Reduction of resistance to Viral Infections

Results of Deprivation

laboratory studies indicate that nocturnal sleep periods reduced by as little as 1.3 to 1.5 hours for 1 night result in reduction of daytime alertness by as much as 32% as measured by the Multiple Sleep Latency Test (MSLT).

Physiological effects of sleep deprivation include: hypoxemia, insulin resistance, elevated sympathetic activity, and blunted arousal response.

Increases

Circadian Rhythm

Decreases
12 24

Sleepiness

Most vulnerable times to feel sleepy are 5-8 AM and 2-4 PM (independent of lunch) Most likely times to feel alert are 10 AM to 12 noon, and again in the evening

Time (h)
University of Virginia Center for Biological Timing. Available at:

Performance Errors
Meter Reading Errors
11,000 10,000 9000 Sweden N = 74,927

No. of Errors

8000 7000 6000 5000 4000

Time of Day
Midnight 6 AM Noon 6 PM Midnight

Mitler MM, et al. Sleep. 1988.

Vehicle Accident Data
Fatigue-Related Accidents
1200 1100 1000 900 International Data N = 6052

No. of Accidents

800 700 600 500 400 300 200 100
Time of Day
Midnight 6 AM Noon 6 PM Midnight

Mitler MM, et al. Sleep. 1988.

Overlay of Vehicle Accident Data, Performance Errors, and Circadian Rhythm

Midnight

6 AM

Noon

6 PM

Midnight

Survey of Pediatric On-Call House Staff and Faculty
House Staff (on call every 4th night) N = 70 Response rate Average hours sleep Fell asleep at stop light Fell asleep while driving* Fell asleep at the wheel† 87% 2.7 ± 0.9 44% 23% 49% Faculty Members (sleep undisturbed) N = 85 87% 6.5 ± 0.8 12.5% 8% 13% P<.001 NS P<.001 Statistical significance

*While car in motion

While car in motion or at stop light

Marcus CL, et al. Sleep. 1996.

National Survey of 963 Emergency Medicine Residents
Motor Vehicle Accidents
8% had >1 MVAs
(mean = 1.3 accidents) N = 963 (1554 polled, 62% response rate)

76 (8%)

26% 74%

MVA = motor vehicle accident

74% of MVAs were related to night shift
Steele MT, et al. Acad Emerg Med. 1999.

National Survey of 963 Emergency Medicine Residents (continued)

Near-Crashes
80% 553 (58%)

N = 963 (62% response rate)

20%

58% had >1 near-crashes
(mean = 2.6 near-crashes)

80% of near-crashes were related to night shift
Steele MT, et al. Acad Emerg Med. 1999.

Sleep Deprivation and Medical Performance

Patient Care Is Jeopardized
• During laparoscopic surgery after a night on call with an average sleep time of 1.5 hours1:
– Fine motor control degrades – More time taken to complete surgery – More complications postop

• Prescribing errors made connected with physical and mental well being2:
– Tired – Hungry – Unwell
• • Grantcharov TP, et al. BMJ. 2001. Dean B, et al. Lancet. 2002.

Studies on Impact of Sleep Deprivation
• Why do studies in the clinical setting produce mixed results when laboratory studies clearly show the impact of sleep deprivation on performance?
– Lack of well-rested residents for control groups
• Studies essentially compare effects of chronic partial sleep restriction (residents not on call) versus chronic partial sleep restriction plus short-term sleep loss (residents on call or immediately post call)

– Differences in general health status and sleep/wake habits – Failure to control for caffeine and food intake, recent physical activity, and ambient temperatures – Effects on specific tasks may be overcome by motivation and focused attention; more difficult to measure continuous performance

Impact of Sleep Deprivation on Resident Health
• Increased risk of obstetrical complications for pregnant residents versus other working women1
– Premature labor is twice as common – Preeclampsia is twice as likely

• High rates of depression occur among residents2
– 30% of first-year residents report depressive symptoms for an average of 5 months – Some reported to have suicidal ideation with plan – Among married residents, 46% in depressed group versus 7% in the nondepressed group had marital problems (none of the depressed individuals had ever had martial problems prior to depression onset)
1. Osborn LM, et al. J Fam Pract. 1990. 2. Valko RJ, et al. Dis Nerv Syst. 1975.

The Cultural Environment
“We believe that long hours are an inherent part of our profession, and if we don’t train in the way we will work in the future, we will not be able to function adequately. This is analogous to pilots; if they don’t practice flying at night, how can we expect them to fly at night?” “Who are we? The answer is that we are physicians, a highly selected group, and we are not representative of the population as a whole.”

Preventive and Operational Countermeasures

Preventive and Operational Countermeasures
Scheduling
• Limit continuous performance schedules to 12-16 hours • Time off duty to protect sleep and sanity

Working With Circadian Rhythm
• Know the times of greatest impairment and maximum alertness

Avoid Alcohol

Preventive and Operational Countermeasures Education
• No substitute for sleep • Avoid driving between 2 AM and 9 AM • Behavioral changes may indicate dangerous levels of fatigue • Need for performance backups during times of impairment • Interaction between alcohol and sleep loss can be deadly • Benefits of prophylactic naps

Does Napping Help?
Night shift workers after 2-hour nap prior to shift
• Prevented sleepiness • Later naps produced a deeper sleep, but workers awakened with grogginess due to sleep inertia

ER residents after 1-hour nap prior to a night shift
• EEGs show clearly enhanced awake activity • Reduced stress • Workload perceived as less onerous
Dinges DF, et al. Sleep. 1997. Rosekind MR, et al. Behav Med. 1996. Frey R, et al. Crit Care Med. 2002.

Preventive and Operational Countermeasures Pharmacology
• Caffeine—widely available, widely accepted
– – – – – Boosts alertness Tolerance to benefits develops quickly Erodes sleep quality Undesirable side effects on mood Less-predictable GI absorption; active longer than half-life suggests

Preventive and Operational Countermeasures Pharmacology
• Alcohol
– Induces sleep initially – Increases fragmentation – Overall, a bad choice for sleep

Sleep Disorders
• Narcolepsy (high levels of REM) • Hypersomnia (high levels of NREM) • Parasomnias
– Night terrors – Sleepwalking – Sleeptalking

• Insomnias

Sleep Disorders
Non-REM Sleep Disorders (Stage IV) • Enuresis (Bed-wetting) • Sleep - Walking • Sleep - Talking • Sleep – Eating • Night Terror • Insomnia REM Sleep Disorders • Sleep Apnea • Narcolepsy

Narcolepsy
• Clinical symptoms: the narcoleptic tetrad
– excessive sleepiness during the day – cataplexy
• abrupt loss of muscle tone, without loss of awareness

– sleep paralysis
• muscle paralysis of sleep

– hypnagogic hallucination

• Waking usually transitions into NREM sleep followed by
REM and then followed by NREM • The first REM period of the night may be less than 10 minutes in duration, while the last may exceed 60 minutes. • One cycle of REM-nonREM lasts about 90-100 minutes and, 45 cycles occur during normal 8- to 9-hour sleep period during night

The Cycles of Sleep Stages

For the purpose of analysis, overnight sleep has been divided into 3 equal time periods: sleep in the first third of the night, which comprises the highest percentage of NREM; sleep in the middle third of the night; and sleep in the last third of the night, the majority of which is REM. Awakening after a full night's sleep is usually from REM sleep.

The frequency of sleep Stages alters during the night - in the early hours of sleep SWS dominates, whereas REM sleep occurs more often in the second part of sleep. The portion of REM sleep during night alters with age in newborn babies REM sleep lasts for 50%, pre-mature infants 80% & in adults for 20%.

The proportion of REM sleep falls rapidly and plateaus at 25% until it falls further in old age. Children have more sleep time and stage 4 sleep than adults.

Preventive and Operational Countermeasures Monitoring: Self-Assessment Tools
• Epworth Sleepiness Scale (ESS)1 • Pittsburgh Sleep Quality Index (PSQI)2 • Beck Depression Inventory (BDI)3 and Zung SelfRating Depression Scale (SDS/ZDS)4 • Maslach Burnout Inventory (MBI)5
• • • • • Johns MW. Sleep. 1991. Buysse DJ, et al. J Psychiatric Res.1989. Beck AT, et al. Manual for the Beck Depression Inventory. 2nd ed. 1996. Zung WW. Arch Gen Psychiatry. 1965. Maslach C, et al. The Maslach Burnout Inventory. 3rd ed. 1996.

Epworth Sleepiness Scale
Situation Sitting and reading Watching television Sitting inactive in a public place—for example, a theater or meeting As a 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 (when you’ve had no alcohol) In a car, while stopped in traffic Chance of dozing (0-3) 0 1 2 3 0 0 0 0 0 0 0 1 1 1 1 1 1 1 2 2 2 2 2 2 2 3 3 3 3 3 3 3

Total Score
0 = would never doze 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing

Johns MW. Sleep. 1991.

Preventive and Operational Countermeasures Pharmacology
• Modafinil—schedule IV wake-promoting agent
– Headache – Nausea – Rhinitis

• Pemoline—schedule IV stimulant
– Insomnia – Hepatic dysfunction – Anorexia/weight loss

Physician’s Desk Reference. 2002.

Preventive and Operational Countermeasures Pharmacology
• Dextroamphetamine—schedule II stimulant
– – – – Palpitations Tachycardia Elevation of blood pressure Overstimulation

• Methylphenidate—schedule II stimulant
– Nervousness – Insomnia – Anorexia
Physician’s Desk Reference. 2002.

Preventive and Operational Countermeasures Pharmacology
• Triazolam, zolpidem, zaleplon—schedule IV shortacting sedative hypnotics
– – – – Headache Drowsiness Dizziness Nausea

Physician’s Desk Reference. 2002.

Summary
• In response to the new ACGME standards, this presentation has:
– Reviewed the impact of sleep loss and fatigue on cognitive function and performance – Described the signs of fatigue and sleepiness from sleep deprivation – Outlined preventive and operational countermeasures

• While there are short-term countermeasures available, ultimately, the only cure for sleep deprivation is sleep.

Sleep initiation may begin with the emergence of inhibitory signals from the anterior hypothalamic preoptic nucleus directed caudally toward the brainstem reticular core and posterior hypothalamus. The preoptic nucleus inhibits the histaminergic posterior hypothalamic tuberoinfundibular region through GABA and probably acetylcholine.

The tuberoinfundibular region projects rostrally to the intralaminar nuclei of the thalamus and to the cerebral cortex. Inhibition of the tuberoinfundibular region is a critical step toward falling asleep because it results in functional disconnection between the brain stem and the more rostral thalamus and cortex. A decrease in ascending thalamic cholinergic transmissions occurs in association with decreasing cortical responsiveness. In addition to inhibiting higher cortical consciousness, the tuberoinfundibular tract projects caudally into the pontine reticular system and inhibits afferent transmissions from ascending cholinergic tracts.