3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Objectives

• Identify factors involved w/jet lag & shift in Aviation: work disorder sleep disorders • Describe the evaluation of circadian rhythm sleep disorders (CRSD) Bascom K. Bradshaw, DO, MPH, MAS • List treatments for jet lag &

Outline Fatigue Management Recap

• Past fatigue management recap • Fatigue Factors – Circadian Factors • Case presentation – Sleep Factors • Jet lag – Domestic Factors • Shift work sleep disorder • Coping Strategies – Work Schedules • Summary – Alertness Management – Evidence-Base & Operational Considerations

Two-process model of sleep regulation Two-process model of sleep regulation

Beersma DG, Gordijn MC. Circadian control of the sleep-wake cycle. Physiol Behav 2007;90:190–195

Q-1 3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Case 1

• 45yo female diplomat is going to Europe for a series of conferences • She is scheduled to be away for 21 days • Unremarkable past medical Hx • Reports significant difficulty adjusting to local time when going to Europe – at night and sleepiness during the early day for up to 1 week or more • She would like advice on optimizing her adjustment to eastward travel

Adapted from: American Academy of . International classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester, Illinois: American Academy of Sleep Medicine; 2005.

Circadian desynchronization Circadian desynchronization

• Circadian rhythm sleep disorders • Sleep and wakefulness are conceptually governed by 2 processes – Dyssynchrony b/w body’s internal clock (Borbely & Achermann 1992) and external 24-hr light-dark cycle – “process S” – “process C” – Typically presents w/insomnia or excessive • Process S – May be an intrinsic disorder (delayed or advanced sleep- – Homeostatic drive to sleep phase disorder) – Proportional to duration of sleep restriction – May be the result of transmeridian air travel or working – Maximal after ~ 40 hrs (Carskadon & Dement 1979) nonstandard shifts • Process C – Symptomatic Tx is available – Creates drive for wakefulness • Tx based on understanding of sleep regulation – Variably opposes process S – Depends on intrinsic circadian rhythms of individual (Beersma & Gordijn – Important to determine circadian phase 2007) • Clinical approach • Neurons of the suprachiasmatic nuclei of the – Coordinates sleep-wake rhythm, as well as numerous other behavioral – Specific interventions can be adjusted and physiologic processes (Ralph et al. 1990; Moore & Eichler 1972)

Circadian Rhythm Sleep Disorder Circadian desynchronization Evaluation • Intrinsic human circadian period (Czeisler et al. 1999) • Clinical interview – Slightly longer than 24 hrs – Synchronized, or entrained, to 24-hr day by various – Hx is cornerstone of evaluation environmental inputs, or • Jet lag disorder Hx: – Most important zeitgebers is light exposure (Waterhouse & DeCoursey 2004) – Degree of before and during travel • Misalignment of internal clock w/the sun – Innate circadian preference, “night owl” or “early bird” – Daytime anergia – Alcohol and caffeine intake – Alternating complaints of insomnia and – Emotional disturbances • Shift work disorder Hx: – Gastrointestinal distress – Sleep-wake schedule on working days vs nonworking • Intrinsic clock unable to adjust rapidly w/long-distance air days travel or nocturnal work schedule – Jet lag sleep disorder or shift work sleep disorder – External contributors to poor sleep

Q-2 3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Circadian Rhythm Sleep Disorder Circadian Rhythm Sleep Disorder Evaluation Evaluation • Sleep diary or sleep log • Actigraphy – Record time of , consolidated sleep, wake – Wristwatch-size motion detector/light exposure time – Typically worn continuously for 7 days or longer – Record estimated sleep latency, awakening after – Surrogate measure of various sleep-wake , time in , medication and caffeine variables (Morgenthaler et al. 2007) intake, and restorative quality of sleep – Valuable in assessing Tx response • Insight into counteractive sleep-related • Either sleep diary or actigraphy can demonstrate stability of sleep patterns and behaviors and sleep/wake misperceptions circadian preference – Compliance is often limited – Actigraphy typically generates more reliable data – Best used in conjunction w/actigraphy (Bradshaw DA et al. 2007)

Circadian Rhythm Sleep Disorder Circadian Rhythm Sleep Disorder Evaluation Evaluation • Morningness-Eveningness questionnaire • – 19 items – Used primarily to rule out sleep-disordered – Night owls tend to score lower than early birds breathing (Horne & Ostberg 1976) – Not indicated for routine evaluation of • Assist w/identifying non-optimal work shifts circadian rhythm sleep disorders – “Early bird” on permanent night-shift schedule

Circadian Rhythm Sleep Disorder Evaluation • Minimum core body temperature & peak secretion (6-sulphatoxymelatonin) Back to Case 1… – Follow a 24-hour cycle. – Often used in research – Not routinely used in clinical practice

Q-3 3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Jet Lag Sleep Disorder Jet Lag Sleep Disorder

• Results from air travel across multiple time • Rapid travel across 1 or 2 time zones – Only transient sxs zones • Westward travel is normally less severe than eastward • Discordance b/w internal circadian clock – Requires later adjustment of internal clock and destination’s light-dark cycle • Circadian period tends to exceed 24 hours – Internal clock can move later ~2 hrs/day • Sleeping poorly at night and feeling groggy – Can move earlier 1-1.5 hrs/day during the day (Waterhouse et al. 2007; Eastman et al. 2005) • More time zones crossed • Experience general malaise and – Longer-lasting and more severe sxs gastrointestinal distress – Longer re-entrainment required for circadian pacemaker

Jet Lag Sleep Disorder/ Jet Lag Sleep Disorder Light exposure • Age effects on severity of jet lag is not yet known • Light exposure (Sack et al. 2007; Burgess et al. 2002; Lewy et al. 1998) – Methodologic differences preclude direct comparisons of studies – Primary influence in shifting circadian clock – Direction of shift depends on timing of the exposure • Study of simulated jet lag (requiring 6-hr advance) • Core body temperature (Moline et al. 1992) – Lowest point ~ 2-3 hrs before habitualy wake time – Subjects ages 37-52 > fragmented sleep than ages 18-25 • Phase delay (Desirable for westward travel) – Older group also > impairment in daytime alertness – Exposure to bright light in hours leading up to core body temp minimum – Sets internal clock later • Decrease in phase tolerance? • Phase advance (Desirable for eastward travel) • Decrease in ability to sleep at an abnormal time in circadian cycle – Exposure to bright light after core body temp minimum • 2 field studies involving both eastward and westward travel – Sets internal clock earlier yielded opposite results • “Antidromic re-entrainment” (Waterhouse et al. 2002; Tresguerres et al. 2001; Sack et al. – Inadvertent shifting of circadian phase in wrong direction 2007) – Delays circadian reacclimation – Older age protective against jet lag (?) – Prolongs jet lag sxs

Human phase-response curve to Jet Lag Sleep Disorder light and exogenous melatonin • Example of “Antidromic re-entrainment” – Flight from Chicago to Paris (7 time zones) • Arrives in Paris 8AM local time • Traveler’s internal clock, 1AM – Core body temp minimum ~ 4AM Chicago time, or 11AM Paris time – Light exposure immediately after landing (Daan & Lewy 1984) • Promotes phase delay (not desired) • Prolongs circadian re-entrainment

Burgess HJ, et al. Bright light, dark, and melatonin can promote circadian adaptation in night shift workers. Sleep Med Rev 2002;6:407-420

Q-4 3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Jet Lag Sleep Disorder Jet lag plan for 7 time zones east

• Other factors (typically, transient effects) – Sleep deprivation (before flight or en route) – Acute discomfort at cruising altitude (Muhm et al. 2007) – Excessive alcohol or caffeine intake inflight

Burgess HJ, Eastman CT. Prevention of Jet Lag. American College of Physicians, 2010. http://pier.acponline.org/physicians/screning /prev1015/prev1015.html.

Jet Lag Sleep Disorder/ Jet Lag Sleep Disorder/ Nondrug therapies Nondrug therapies • Business travel • If traveler intends to remain at destination for – Often requires frequent shifts to different time extended period zones – Optimal adjustment via strategic avoidance/exposure – May benefit from keeping home-based schedule to light (Daan & Lewy 1984) – Avoid antidromic shift • Home-based sleep hrs vs. local sleep hrs (Lowden & Akerstedt 1998) • Burgess & Eastman (2010; 2009) – Phase delay vs. phase advance (?) – 2-day stay after 9-hr westward flight – Depends on number of time zones crossed – Travelers sleeping on home-based hrs were – Shifts earlier in time are required for eastward flights less sleepy and reported lower global jet lag ratings – Shifts later in time are required for westward flights – Advances > 8 hrs are more readily accomplished by – ~ 1/3 preferred to adhere to local schedule phase delay (Cagnacci et al. 1992)

Jet Lag Sleep Disorder/ Jet lag plan for 9 time zones east Nondrug therapies • Traveling east (< 8 time zones) – Set clocks ahead (phase advance) – Avoid light exposure 3 hrs leading up to time of minimum core body temp – THEN, seek light exposure during 3 hrs immediately after minimum core body temp

Burgess HJ, Eastman CT. Prevention of Jet Lag. American College of Physicians, 2010. http://pier.acponline.org/physicians/screning /prev1015/prev1015.html.

Q-5 3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Jet Lag Sleep Disorder/ Plotting grid for travel Nondrug therapies • Flying from Chicago to Paris • Make a grid; concurrent listing of home & destination times (7 time zones) • On Day 0, draw a rectangle around time representing home-based sleep hrs – Avoid light exposure on arrival • Mark time of minimum core body temp (inverted triangle) – Remain in darkness in hotel room – If usual sleep/night < 7 hrs, then it is 2 hrs before usual wake time – Wear dark (blue-blocker) sunglasses – If usual sleep/night > 7 hrs, then it is 3 hrs before usual • Flight and layover patterns often do not wake time permit strict adherence to these measures • Process is repeated at bottom of grid to represent desired sleep schedule at destination • Required degree of circadian realignment – Distance b/w home & destination minimum core body temp

Jet Lag Sleep Disorder/ Plotting grid for travel Melatonin • If phase advance is required (Chicago to Paris) • Sold over-the-counter as a nutritional supplement; not – Core body temp symbol is drawn on Day 1 in same location as regulated by FDA Day 0 • Short-term use of melatonin, 10 mg/day or less in healthy – Moved earlier 1 hr each subsequent day adults appears to be safe (National Academy of Sciences, – Typical rate of internal clock advancement 2005) (Waterhouse et al. 2007; Eastman & Burgess 2009) • Immediate-release appears to be more effective than slow- – Continued until w/in 1 hr of desired destination core body temp release (Suhner et al. 1998) time • Most field studies, 2–8 mg QHS improve quality of sleep or • If phase delay is required (New York City to Los Angeles) alleviate daytime sxs of jet lag (Sack et al. 2007; Suhner et al. – Core body temp symbol is drawn 2 hrs later on day 1 than on 2001, 1998; Paul et al. 2004) day 0 • Most studies looked only at adaptation to eastward travel – Moved later 2 hrs each day • One studied westward travel (Petrie et al. 1993) – Continued until w/in 1 hr of desired destination minimum core body temp time • Petrie et al. (1989) assessed melatonin’s effects during both departure and return trips across 11 time zones

Jet Lag Sleep Disorder/ Jet Lag Sleep Disorder/ Melatonin Benzodiazepine • In studies of preflight dosing • Use of standard hypnotics during circadian – Scheduled 3 days before departure (and en route) at realignment (Sack et al. 2007) corresponding to nocturnal sleep period at travel destination (consistent times daily) – Common, but not well studied – Subsequent 3-4 days at destination , 10PM-midnight • Trials of newer benzodiazepine receptor agonists • Several studies only administered nocturnal melatonin on – Consistently favorable subjective and objective arrival, either for eastward or for westward travel outcomes for jet-lag-induced insomnia • Study involving westward travel (both eastward and westward travel) (Los Angeles to New Zealand) – Evidence is less clear for daytime sxs of jet lag – Only study w/positive findings allowing comparisons b/w participants who received melatonin 3 days before departure – 3 studies of zolpidem 10 mg and continued 5 days after vs. beginning after arrival (Suhner et al. 2001; Jamieson et al. 2001; Hirschfeld – Significantly better jet lag outcomes found in those beginning et al. 1996) only on arrival – 2 studies of zopiclone 5-7.5 mg (Paul et al. 2004; Daurat et al. 2000)

Q-6 3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Jet Lag Sleep Disorder/ Jet Lag Sleep Disorder/ Benzodiazepine Stimulants • Differential medication effects (zolpidem vs zopiclone) • Caffeine is commonly used to combat – May influence discrepancy b/w studies incorporating systematic daytime assessments sleepiness of jet lag • 2 studies compared standard hypnotics to oral melatonin • Only 2 controlled field studies have – Zopiclone 5 mg and melatonin 2 mg were equally assessed its efficacy beneficial w/respect to sleep variables (other jet lag sxs were not assessed) (Paul et al. 2004) (Pierard et al. 2001; Beaumont et al. 2004) – Zolpidem 10 mg was superior to melatonin 5 mg for sleep and other jet lag sxs (Suhner et al. 2001) – Both used slow-release preparations at daily • Combination of zolpidem and melatonin was no better than zolpidem alone dosage of 300 mg • Adverse effects were more frequent w/ zolpidem (, vomiting, and )

Jet Lag Sleep Disorder/ Stimulants • Eastward flight, 7 time zones (Pierard et al. 2001) – Dosed at 8AM destination time every day for 5 days – Alertness and other jet lag sxs were not assessed (?) – Circadian rhythms (levels of cortisol in saliva) were reentrained at a more rapid rate w/caffeine than w/placebo, and to a degree comparable w/that achieved by exogenous melatonin Next case… • Follow-up study by same group – Caffeine group was objectively less sleepy than melatonin or placebo – Subjective differences b/w groups were not identified (Beaumont et al. 2004) – Caffeine had significantly more nocturnal sleep complaints, both objectively and subjectively • Randomized, double-blind, placebo-controlled trial of 150 mg (Rosenberg et al. 2010) – Less sleepiness on multiple sleep latency testing – Decrease in jet leg sxs

Shift Work Sleep Disorder: Case 2 definition, predisposing factors • 48yo male presents to clinic w/ c/o difficulty • Shift work refers to nonstandard work w/ sleep schedules • Pt works 14 consecutive nights, 7p to 7a, on – On-call duty, rotating shifts, and permanent night an oil platform in the Gulf of Mexico work • Reports severe sleepiness during the first • 1 in 5 workers work nonstandard shifts nights, then notes some gradual adjustment (Sack et al. 2007) • Following return home after this 14-night working period, he struggles w/re-adaptation • May afflict nearly 1/3 of workers back to his normal day-oriented rhythm (Drake et al. 2004) • Pt requests advice on adjusting to his shift – Potential adverse effects on safety, health, and work schedule quality of life

Q-7 3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Shift Work Sleep Disorder: Shift Work Syndrome definition, predisposing factors • Shift work, and night work in particular a/w negative effects • Dx of shift work sleep disorder (Akerstedt 1990; Boivin et al. 2007) – Shortened and disturbed sleep (ICSD 2005) – Fatigue – Decreased alertness – Chronic insomnia or sleepiness – Cognitive decrements – At times that are not conducive to externally – Increased injuries and accidents – Reproductive problems demanded sleep-wake schedule – Risks to cardiovascular and gastrointestinal health • Older workers less able to recover after several night shifts – Individual has opportunity for sufficient (Harma et al. 1994) daytime sleep • Large survey of police officers working night shift (Smith & Mason 2001) – More sleep disruption – On-duty sleepiness

Shift Work Syndrome Shift Work Syndrome/Tx

• Shift workers rarely shift their endogenous circadian • Timed bright light and darkness can promote rhythms to align w/sleep-wake schedule of night shift adaptation to night work – Night workers in constant state of circadian misalignment (Czeisler et al. 1990; Bjorvatn et al. 1999, 2007) – Both work and sleep at ‘‘wrong’’ circadian phase • Bright light before nadir of core body temperature • Sxs d/t circadian misalignment can be reduced rhythm will facilitate adaptation to night work – Even if optimal phase relationship is not completely • Nadir is estimated based on clinical interview established – Wake ~ 7AM and based on prior night work experience, pt • Magnitude of phase shift (Burgess et al. 2002) especially sleepy ~ 5AM – Positively related to extent of improved performance and – Nadir of core body temperature rhythm is ~ 5AM alertness during night shift – Bright light is advised before pt’s nadir (30 min, 10,000 lux) – Better daytime sleep at home – Pt advised to avoid bright light after 5AM on Night 1 – Night 2, bright light exposure at 6AM; avoid light after 7AM

Shift Work Syndrome/Tx Shift Work Syndrome/Tx

• Thorough interview helps estimate core body temp nadir • Core body temp nadir “pushed” after – Pt sleeping until ~ 5PM at end of 2-wk night shift period work shift – Likely core body temp nadir ~ 3PM – Likely feel less sleepy during night shift • To avoid phase delay – Bright light exposure advised before 3PM – Sleep better during day – Pt advised on natural or artificial light exposure prior to 3PM – Avoid bright light after 3PM (dark sunglasses or stay inside) • 2-4 days of Tx may be sufficient • Day 2 – Pt advised on bright light before 5PM • Following 2-wk night shift period – Avoid light after 5PM – Additional bright light exposure for reentrainment • Day 3 – Bright light exposure before 7PM – Timing of Tx is more complicated – Avoid after 7PM, and so on – Core body temp nadir is difficult to estimate

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Shift Work Syndrome/Tx Shift Work Syndrome/Tx

• Individual Tx • Melatonin also shown to be efficient in alleviating complaints a/w night work – Based on nadir estimations (Burgess et al. 2002; Bjorvatn et al. 2007; Dawson – Individual’s circadian type et al. 1995; Sharkey et al. 2001) (morning lark or evening owl) – Most studies conducted under simulated conditions • Evening owls adapt easier by phase delay – Timing of melatonin is important; may be changed • For this case, phase delay was advised for from day to day to maximize effect on circadian shift • Re-entrainment best applied to schedules > 1 readaptation following night shift week • In other cases, phase advance may be more – Questionable utility for rapid rotating night shift appropriate schedules – Re-adaptation back to day-oriented schedule is – When nadir of core body temp is earlier in day typically difficult

Shift Work Syndrome/Tx Drug Tx of shift work sleep disorder

• Additional strategies for shift work sxs • Melatonin, mixed results – 2 field studies, melatonin 5-6 mg before daytime sleep (Barion & Zee 2007) period had favorable impact on subjective sleep quality (Folkard et al. 1993; Yoon & Song 2002) – Improve sleep (hypnotics) – 2 other studies found no such benefit; doses 6-10 mg (James et al. 1998; Jorgensen & Witting 1998) – Alertness (caffeine, modafinil, scheduled – Differences b/w studies preclude definitive comparisons naps) – Effects of melatonin on workplace alertness are indeterminate b/c inconsistent measurements – Simulated shift work study found no phaseshifting advantages (Crowley et al. 2003) • Concomitantly use of bright light during shift w/ or w/o morning protective eyewear

Drug Tx of shift work sleep disorder Drug Tx of shift work sleep disorder

• Hypnotic drugs, improved sleep • Stimulants – Benzodiazepine receptor agonists consistently – Modafinil 200 mg (only drug currently FDA-approved for improved subjective sleep quality shift work sleep disorder) (Czeisler et al. 2005) (Walsh et al. 1988, 1991; Porcu et al. 1996, 1997; • Significant benefits compared w/placebo w/respect to objective measurements of workplace sleepiness, reaction time Monchesky et al. 1989; Moon et al. 1990) performance testing, and self-rated improvement of sxs – Simulation study noted additional benefit of ability to • Both groups continued to manifest sleepiness w/in pathologic stay alert during night shift (Porcu et al. 1997) range on objective testing – 2 other studies saw no changes in manifest – Efficacy of caffeine is well documented as countermeasure sleepiness by objective testing (Walsh et al. 1988, for sleepiness during experimentally induced sleep 1991) deprivation • Very few field trials specifically address shift work sleep disorder – Only field study to assess post-sleep psychomotor • Caffeine dosed at 4 mg/kg taken 30 min before starting night performance found no impairments after taking shift provided objective improvement in both performance and zopiclone 7.5 mg (Moon et al. 1990) alertness (Schweitzer et al. 2006)

Q-9 3/11/2012 American Osteopathic College of Occupational and Preventive Medicine 2012 Mid-Year Educational Conference St. Petersburg, Florida

Shift Work Syndrome/ Shift Work Syndrome/ Strategic napping Adjusting post-night shift • Shift workers must maintain workday sleep-wake schedule continuously to • Cumulative data indicate objective and subjective benefit from phase adjustment strategies improvements in alertness and performance – Includes off-duty (Sallinen et al. 1998; Garbarino et al. 2004) – Not likely realistic given domestic & social demands • Smith et al (2009) developed a “compromise” phase position • Naps < 20 min, before or during early portion of a – Facilitate alertness during work and sleepiness during the day – Allows adopting a non-workday sleep schedule amenable to family and social shift (Sallinen et al. 1998; Purnell et al. 2002) schedule – Produce maximal benefit • Non-workday sleep starts ~ 5.5 hrs earlier than workday sleep – All sleep episodes are followed by brief exposure to bright light (to avoid excessive – Avoids phase delay) – No effect on subsequent daytime sleep episode – Both workplace bright light and protection from morning light are implemented. • Study participants achieving desired partial phase shifts (Smith et al. 2009) • Napping combined w/caffeine – Performance ratings on a par w/ baseline levels (Schweitzer et al. 2006) – Comparable performance ratings to those w/ complete circadian reentrainment – Greater degree of increased objective alertness than either intervention alone

Summary

• Fatigue factors/coping strategies recap • Case presentations • Jet lag Questions? • Shift work sleep disorder

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