Sleep in the ICUSleep in the ICUThe Next Delirium Frontier?The Next Delirium Frontier?

Paula L. Watson, M.D.Paula L. Watson, M.D.

Assistant ProfessorAssistant Professor

Pulmonary/Critical Care/Sleep MedicinePulmonary/Critical Care/Sleep Medicine

Vanderbilt University Medical CenterVanderbilt University Medical Center

NIH AG027472-01A1, VA-GRECC,CTSA 1 UL1 RR024975, ASPECT

Presenter DisclosuresPresenter DisclosuresPaula L. Watson, MDPaula L. Watson, MD

The following relationships with The following relationships with

commercial interests related to this commercial interests related to this

presentation existed during the past presentation existed during the past presentation existed during the past presentation existed during the past

12 months:12 months:

Industry sponsored grant: Aspect Industry sponsored grant: Aspect

Risk Factors for ICU DeliriumRisk Factors for ICU Delirium

AgingAging

Baseline dementiaBaseline dementia

Underlying illnessUnderlying illness

–– InflammationInflammation

Sleep DeprivationSleep Deprivation

Psychoactive Psychoactive Medications (Medications (sedativessedatives))–– InflammationInflammation

–– CoagulationCoagulation

Metabolic Metabolic DisturbancesDisturbances

HypoxemiaHypoxemia

Pain / pain Pain / pain managementmanagement

Medications (Medications (sedativessedatives))

Inouye, JAMA 1996;275:852-57Dubois, Intens Care Med 2001;27:1297-1304Inouye, NEJM 1999;340:669-676Jacobi, Crit Care Med 2002;30:119-141 Vaurio, Anesth Analg 2006; 102:1267-1273Milbrandt, Crit Care Med. 2005;33:226-9

Perception of problems during Perception of problems during ICU stayICU stay

Pain relief Pain relief problemsproblems

94%94%

AnxietyAnxiety 62%62%

Sleep Sleep deprivationdeprivation

61%61%

Simini, Lancet 1999;354:571-572

Characteristics of Sleep in the ICUCharacteristics of Sleep in the ICU

Severely fragmented Severely fragmented

–– (>80 arousals/ hour)(>80 arousals/ hour)

Increased stage 1Increased stage 1

Decreased or absent Decreased or absent Slow Wave & REMSlow Wave & REMSlow Wave & REMSlow Wave & REM

Distributed over day Distributed over day and nightand night

Aurell et al., BMJ 1985;290:1029-32

Cooper et al., Chest 2000;117:809-18

Orr et al., Am J Card 1977;39:196-201

Freedman et al., AJRCCM 2001;163:451-7

Sleep Deprivation

DeliriumDelirium

Sleep Deprivation and DeliriumSleep Deprivation and DeliriumCommon Neurocognitive TraitsCommon Neurocognitive Traits

InattentionInattention

Fluctuating mental statusFluctuating mental status

Altered level of consciousnessAltered level of consciousnessAltered level of consciousnessAltered level of consciousness

Cognitive slowingCognitive slowing

IncoordinationIncoordination

IrritabilityIrritabilityForest & Godbout, Sleep Deprivation: Basic Science, Physiology,

and Behaviour 2005:199-222

Durmer & Dinges, Sem Neuro 2005;25:117-129

The Psychosis of Sleep DeprivationThe Psychosis of Sleep DeprivationCase reports of Case reports of hallucinations and hallucinations and persecutory delusionspersecutory delusions

On the 4On the 4thth and 5and 5thth day, he day, he began to experience began to experience began to experience began to experience “waking dreams”“waking dreams”

Heightened Heightened suspiciousness, feeling of suspiciousness, feeling of resentmentresentment

Patrick & Gilbert, Psychol Rev 1896;3:469-83 Katz & Landis, Arch Neurol Psychiat 1935;34:307-16 Luby et al., Psychosom Med 1960;22:182-92 West, Ann NY Acad Sci 1962;96:66-70 Gulevich & Dement Arch Gen Psychiat 1966;15:29-35

Randy Gardner, 264 hours

Sleep Deprivation Preferentially Sleep Deprivation Preferentially Affects the PreAffects the Pre--frontal Cortexfrontal Cortex

Cerebral Blood FlowCerebral Blood Flow

Harrison et al. Sleep 2000;23:1-7

Tabor & Hurley J Neuropsych Clin Neurosci 2006;18:1-5

Neurotransmitters Neurotransmitters Sleep Deprivation & DeliriumSleep Deprivation & Delirium

histaminehistamine

orexinorexin

GABA melatonin

Cholinergic

Dopaminergic

activation

acetylcholineacetylcholinenorepinephrinenorepinephrine

dopaminedopamine

serotoninserotonin

adenosine

Espana & Scammell, Sleep 2004;27:811-20Trzepacz, Sem Clin Neuropsych 2000;5:132-48Camarini, Braz J Med Biol Res 1997;30:641-47Ebert, Adv Biol Psych 1998;153-69

Cholinergic

deficiency

Investigating the relationship of Investigating the relationship of sleep deprivation and ICU deliriumsleep deprivation and ICU delirium

Sleep Deprivation and ICU DeliriumSleep Deprivation and ICU Delirium

25

30

35

40

45

50

% Patients Mental Status

0

5

10

15

20

25

None Moderate Severe

Mental Status Changes

Helton et al., Heart & Lung 1980;9:464-68

Severity of Sleep Deprivation

N = 62

Sleep disturbances associated with Sleep disturbances associated with deliriumdelirium

ICU patients with delirium:ICU patients with delirium:–– Longer REM latencyLonger REM latency

–– Shorter REM durationShorter REM duration

–– Fewer REM periodsFewer REM periodsTrompeo, Ranieri, 2005 Int Care Med Abstract

Study designed to investigate sleep quality Study designed to investigate sleep quality on noninvasive ventilation failureon noninvasive ventilation failure

–– circadian abnormalities, circadian abnormalities, ↓↓ REM associated REM associated with development of deliriumwith development of delirium

Trompeo, Ranieri, 2005 Int Care Med Abstract

Campo, Brochard, Crit Care Med 2010;38

Measuring Sleep in the ICUMeasuring Sleep in the ICU

Polysomnography:Polysomnography:

–– Labor intensiveLabor intensive

–– ExpenseExpense

–– Difficulty interpretingDifficulty interpreting

MedicationsMedications

Metabolic effectsMetabolic effects

DeliriumDelirium

Decreased Spindles & K complexesDecreased Spindles & K complexes

Effect of primary illness or sedatives/analgesics?

Scored as stage 1 due to lack of Spindles and K-complexes

EEG findings in the critically illEEG findings in the critically ill

Polymorphic delta

Burst suppression

Isoelectric

The EEG and DeliriumThe EEG and Delirium

RASS -2, CAM-ICU +

Consent to show full photo provided by patient

Delta waves

Approach to Scoring in ICU PatientsApproach to Scoring in ICU Patients

Assess Behavioral Sleep State

WakeSleep

Wake

Assess Sleep Stage Using Revised PSG

Criteria

Watson & Gehlbach -manuscript in progress

AtypicalClassic

Sedatives in Sleep & DeliriumSedatives in Sleep & Delirium

Sedation Sedation ≠ Sleep≠ Sleep

SleepSleepEssential biologic functionEssential biologic functionEasily reversed by stimuliEasily reversed by stimuliCircadian rhythmCircadian rhythmCyclic progression of Cyclic progression of sleep stagessleep stages

Weinhouse & Watson, Crit Care Clinics 2009;25:539-49

RASS -5 (unresponsive)

Lorazepam and Midazolam are associated Lorazepam and Midazolam are associated with increased risk of deliriumwith increased risk of delirium

Delirium Risk- lorazepam

Pandharipande et al., Anesthesiology 2006;104:21-6

Pandharipande et al., J Trauma 2008;65(1):34-41

Benzodiazepines and the EEGBenzodiazepines and the EEG

Normal

Stage 2

Sleep

Benzodiazepines and opioids suppress REM and Slow Benzodiazepines and opioids suppress REM and Slow Wave Sleep.Wave Sleep.Does sedation deprive patients of true sleep?Does sedation deprive patients of true sleep?What restorative benefits of natural sleep are provided by What restorative benefits of natural sleep are provided by sedation? sedation?

lorazepam

Bourne and Mills, Anaesthesia 2004;59:374-84Kuehn, JAMA 2006;296:2427-2428Tung et al., Anesthesiology 2004;100:1419-26

Benzodiazepine & propofol - GABA receptor in ventrolateral preoptic nucleus

Dexmedetomidine –α2adrenoreceptor in the locus coerulus

Nelson et al., Nature 2002;5:979-84

Nelson et al, Anesthes 2003;98:428-36

DexmedetomidineDexmedetomidine

Properties similar to natural sleepProperties similar to natural sleep

–– Clinically sedated but arousableClinically sedated but arousable

EEG activity similar to stage 2 sleepEEG activity similar to stage 2 sleep

Nelson, Maze et al., Anesthesiology 2003;98:428-36

Huupponen et al., Acta Anaesthesiol Scand 2008; 52:289-94

Mason et al., Pediatric Anesthesia 2009;19:1175-83

Daily Prevalence of DeliriumDaily Prevalence of Delirium

Prevalence of delirium similar prior to starting study drugPrevalence of delirium similar prior to starting study drug

Dexmedetomidine resulted in 24.9% Dexmedetomidine resulted in 24.9% ↓ in delirium during in delirium during

treatment phase (54% dex vs. 76.6% mdz)treatment phase (54% dex vs. 76.6% mdz)

Riker et al., Riker et al., JAMAJAMA 2009;301(5):4892009;301(5):489--9999

SummarySummary

Sleep deprivation and deliriumSleep deprivation and delirium

–– epidemiologic, biochemical, anatomic epidemiologic, biochemical, anatomic similaritiessimilarities

Investigating the relationship of sleep Investigating the relationship of sleep Investigating the relationship of sleep Investigating the relationship of sleep deprivation and ICU deliriumdeprivation and ICU delirium

–– measuring sleep, not an easy taskmeasuring sleep, not an easy task

Sleep and sedationSleep and sedation

–– not the same and not equalnot the same and not equal

Future ResearchFuture ResearchThe Unanswered QuestionsThe Unanswered Questions

Is sleep deprivation a cause of ICU Is sleep deprivation a cause of ICU delirium?delirium?

Does sleep deprivation lower the Does sleep deprivation lower the Does sleep deprivation lower the Does sleep deprivation lower the threshold for developing delirium?threshold for developing delirium?

Does sedation provide benefits of Does sedation provide benefits of natural sleep?natural sleep?

www.ICUdelirium.orgwww.ICUdelirium.org

Educational Delirium WebsiteEducational Delirium Website

ICU RecallICU Recall

Pain 28%28%

Short of breath while on mech vent 20%20%

Being terrified about my situation 38%38%

N = 146

Being terrified about my situation 38%38%

Had hallucinations or nightmares 51%51%

Think that some memories were from

Situations that never really happened 49%49%

Weinert & Sprenkle Int Care Med 2008;34:82-90

Memories of Critical CareMemories of Critical Care

“I have memories of jumbled “I have memories of jumbled thoughts…..it was thoughts…..it was petrifying. I could hardly petrifying. I could hardly tell what was real and tell what was real and tell what was real and tell what was real and what wasn’t. This sounds what wasn’t. This sounds like some kind of a novel like some kind of a novel doesn’t it? Was I doesn’t it? Was I dreaming it all?”dreaming it all?”

Cox et al., Crit Care Med 2009;37:2702-2708Illustration by Steven Stahlberg

The Psychosis of Sleep DeprivationThe Psychosis of Sleep Deprivation

Case reports of Case reports of hallucinations and hallucinations and persecutory delusionspersecutory delusions

“inevitable” if sleep “inevitable” if sleep deprivation continued deprivation continued longer than 100 hourslonger than 100 hours

Patrick & Gilbert, Psychol Rev 1896;3:469-83

Katz & Landis, Arch Neurol Psychiat 1935;34:307-16

Luby et al., Psychosom Med 1960;22:182-92

West, Ann NY Acad Sci 1962;96:66-70

Photo by Peter Tonningsen

Randy Gardner Randy Gardner Case of Prolonged (264 hrs) WakefulnessCase of Prolonged (264 hrs) Wakefulness

On the 4On the 4thth and 5and 5thth day, he day, he began to experience “waking began to experience “waking dreams”dreams”Heightened suspiciousness, Heightened suspiciousness, feeling of resentmentfeeling of resentment

Gulevich & Dement Arch Gen

IrritabilityIrritabilityMemory losses, difficulty Memory losses, difficulty concentratingconcentratingHallucinations, paranoiaHallucinations, paranoia

Gulevich & Dement Arch Gen

Psychiat 1966;15:29-35

Ross Arch Neuro 1966;12:399-403

Sleep in Critically ill Patients Sleep in Critically ill Patients Requiring Mechanical VentilationRequiring Mechanical Ventilation

N=20, Disrupted sleep (8 pts)N=20, Disrupted sleep (8 pts)

–– PSG features of NREM and REM sleepPSG features of NREM and REM sleep

Atypical sleepAtypical sleep (5 pts) (5 pts) Atypical sleepAtypical sleep (5 pts) (5 pts)

–– virtual absence of stage 2virtual absence of stage 2

–– no K Complex’s or sleep spindles no K Complex’s or sleep spindles

–– higher dose of higher dose of sedativesedative medicationsmedications

Coma (7 pts) Coma (7 pts)

Cooper et al., Chest 2000;117:809-818

Sedation Sedation ≠ Sleep≠ Sleep

RASS – 5 (unresponsive)

Severe Sleep FragmentationSevere Sleep Fragmentation

Watson, Crit Care Clinics 2009;25:539-49

RASS -5

TMN

Natural Sleep Dexmedetomidine Benzo / Propofol

tuberomammillary

Cortex & Subcortical areas

histamine

X

(-)

TMN

(-) (-)

XX

sleep sleep convergence hypnosis

TMN

histamine histamine

LC

VLPO

LC LClocus ceruleus

ventrolateral preoptic nucleus

norepinephrine

X

galanin & GABA

Peruzzi, Pharmacotherapy 2005;25(5pt 2):34S-39S

+VLPOVLPO

(-)

+norepinephrine

X Xnorepinephrine

galanin & GABA+

Delirium is Associated with a Delirium is Associated with a Malfunction of the PreMalfunction of the Pre--frontal Cortexfrontal Cortex

Pilot fMRI data:

Depressed activation -dorsolateral pre-frontal cortex on testing working

Mesulam et al., J Neurol Neurosurg Psych 1979;39:84-89Koponen et al., J Nerv Men Dis 1989;177:226-31Doyle & Warden Am J Psych 1996;153:838-9

cortex on testing working memory in previously delirious vs. non-delirious ICU patients

Gunther et al., Crit Care Med 2008;36:12

Sedatives in Sleep & DeliriumSedatives in Sleep & Delirium

Probability of transitioning from Probability of transitioning from normalnormal to delirium after lorazepamto delirium after lorazepam

0.8

0.9

1

Delirium Risk

0.5

0.6

0.7

No Drug

Lorazepam Dose

Log scale

Original scale(mg)

0-1 1-2 2-3 3-4 4+

0-2.7 2.7-7.4 7.4-20 20-55 55+

Delirium Risk

Pandharipande PP, et al. Anesthesiology 206;104:21-6

Sleep DeprivationSleep DeprivationIt doesn’t end at hospital dischargeIt doesn’t end at hospital discharge

Patient 1

Patient 2

Watson, unpublished data

68

10

12

p=.01 p=.09 p=.001

Brain DysfunctionBrain Dysfunction

Delirium/Coma-Free Days

02

46

Delirium-Free Days Coma-Free Days

DexmedetomidineLorazepam

Pandharipande PP, et al. JAMA 2007;298:2644-53

DeliriumDeliriumAcute confusional stateAcute confusional state

–– Fluctuating mental statusFluctuating mental status

–– InattentionInattention

–– Cognitive dysfunctionCognitive dysfunction

IncidenceIncidence

–– lower severity ICU patients lower severity ICU patients –– lower severity ICU patients lower severity ICU patients

–– 6060--80% of ventilated patients 80% of ventilated patients

Delirium is associated with:Delirium is associated with:

–– $15k$15k-- $25k higher hospital $25k higher hospital costscosts

–– 3 times higher risk of death by 6 3 times higher risk of death by 6 months months

Pun & Ely, Chest 2007;132

FlipFlip--Flop Switch ModelFlop Switch Model

Saber et al, Nature 2005;247:1257-63

Neural Pathways of Sleep and SedationNeural Pathways of Sleep and Sedation

Peruzzi, Pharmacotherapy 2005;25(5pt 2):34S-39S

Ayptical Sleep and DeliriumAyptical Sleep and Delirium

Watson, 2007 ATS abstract