University of California,San Francisco 1Department of Anesthesia and Perioperative Care

Can We Prevent Delirium in the ICU?

Dr Mervyn Maze MB ChB, FRCP, FRCA, FMedSci

Department of Anesthesia and Perioperative Care,

University California San Francisco

University of California,San Francisco 2Department of Anesthesia and Perioperative Care

Questions regarding ICU Delirium

• What are the clinical manifestations?

• What are the etiogenic factors?

– Is sleep important?

– Is the choice of sedative agent important?

• What Level 1 evidence can guide pre-emptive therapy?

University of California,San Francisco 3Department of Anesthesia and Perioperative Care

Clinical Manifestations and Diagnosis

• Newly-diagnosed fluctuating disturbance in– Level of consciousness including

attentiveness– Cognitive function especially memory– DSM IV - attributable to a medical condition

• Hyper- vs hypo-active delirium• Long-lasting consequences• Diagnosis

– CAM ICU

University of California,San Francisco 4Department of Anesthesia and Perioperative Care

Risk Factors for Delirium in the ICU• Patient-related

– Age– Existing psychopathology (incl Alcoholism and TBI)

• Environmental– Sleep deprivation

• Noise• Light• interventions

• CNS-altering Drugs– Sedative/Analgesics– Anticholinergics

University of California,San Francisco 5Department of Anesthesia and Perioperative Care

Benefits of Natural Sleep

• Avoid Sleep Deprivation– Cognitive Dysfunction

• Hypoactive delirium-like state– Immune Dysfunction

• Susceptibility for infection• High Mortality Rate from Sepsis

• Restoration and Repair

University of California,San Francisco 6Department of Anesthesia and Perioperative Care

Sleep in the ICU• Longer periods of wakefulness 1

• Shorter periods of “Deep Sleep”– Less time in stages III/IV NREM2

• Less periods of REM sleep3

• Loss of circadian rhythm4

References:1 Aurell and Elhmqvist, BMJ 19852 Cooper et al Chest 20003 Gabor et al Am J Resp Crit Care 20034 Freedman et al Am J Resp Crit Care 2001

University of California,San Francisco 7Department of Anesthesia and Perioperative Care

Conflict of Interest– Dexmedetomidine patented for sedative-

hypnotic properties in 1986• with Mika Scheinin

– Reassigned rights to Farmos in 1987• $250K to support preclinical research at

Stanford• Farmos acquired by Orion• Dexmedetomidine licensed to Abbott/Hospira

– Accrue no financial benefit from sales

University of California,San Francisco 8Department of Anesthesia and Perioperative Care

α2 AgonistsN

N

H

N

Cl

Cl

ClonidineDexmedetomidine

CH3

CH3

N

N

CH3H

Clonidine

• Selectivity: α2 :α1 200:11

• t1/2 β

8 hrs1

• PO, patch, epidural2

• Antihypertensive1

• Analgesic adjunct1

• IV formulation not available in US

Dexmedetomidine

• Selectivity: α2 :α1 1620:13

• t1/2 β

2 hrs3

• Intravenous3

• Sedative-analgesic3

• Only IV α2 available for use in the US

1. Maze. White paper; 2000. 2. Khan et al. Anaesthesia. 1999;54:146-155. 3. Kamibayashi, Maze. Anesthesiology. 2000;93:1345-1349.

University of California,San Francisco 9Department of Anesthesia and Perioperative Care

Ca++

Ca++

Ca++

–

–+

Decrease in influx of Ca++

Decrease in action potential due to

hyperpolarization

α2 A

α2 AR

Go Gk K+

K+

K+

University of California,San Francisco 10Department of Anesthesia and Perioperative Care

Molecular and Neuronal Action of α2

agonists

• Initiated in the locus coeruleus (LC)

• Transduced by mechanisms which hyperpolarize the membrane

• Decrease firing rate of the LC neurons

University of California,San Francisco 11Department of Anesthesia and Perioperative Care

Hypnotic Mechanism of Benzodiazepine

• Decreases wakefulness by positive allosteric modulation of α

subunit of the GABAA receptor

– Similar to alcohol and barbiturates• Decreases deeper phases of NREM sleep• Increase dopamine release in VTA1

– similar ”reward” mechanism as present in addictive drugs– Withdrawal results in

• Anxiety• Delirium• Seizures

1. Tan et al Nature 2010

University of California,San Francisco 12Department of Anesthesia and Perioperative Care

Lorazepam and ICU Delirium Pandharipande et al, Anesthesiology 104:21-26, 2006

University of California,San Francisco 13Department of Anesthesia and Perioperative Care

University of California,San Francisco 14Department of Anesthesia and Perioperative Care

Saper et al,2005

University of California,San Francisco 15Department of Anesthesia and Perioperative Care

University of California,San Francisco 16Department of Anesthesia and Perioperative Care

Dexmedetomidine Induces similar changes as NREM sleep in Brain Nuclei

Nelson et al, Anesthesiology 2003

University of California,San Francisco 17Department of Anesthesia and Perioperative Care

VLPO

LC

DRN PPTg

TMN

Sedation by Dexmedetomidine

TMN: Tuberomammilary nulcleusVLPO: Ventrolateral preoptic nucleusLC: Locus CoeruleusPPTg: Pedunculopontine tegemental nucleusDRN: Dorsal raphe nucleus

2

Nelson et al Anesthesiology 2003

University of California,San Francisco 18Department of Anesthesia and Perioperative Care

fMRI placebo -

dexmedetomidine

University of California,San Francisco 19Department of Anesthesia and Perioperative Care

GABAergics don’t Produce NREM sleep changes in Locus Ceruleus (LC)

Nelson et al, Nat Neurosci 2002

University of California,San Francisco 20Department of Anesthesia and Perioperative Care

fMRI placebo -

midazolam

University of California,San Francisco 21Department of Anesthesia and Perioperative Care

INTERPRETATION• Hypnotics do not converge on the sleep

pathway at the same point

– α2 agonists within the brainstem

– GABAmimetics within the hypothalamus

• Results in different hypnotic responses

University of California,San Francisco 22Department of Anesthesia and Perioperative Care

5060708090

100110

PLA DEX MDZDrug

Task & Noise Task alone

Ability to be aroused by noise to perform a task during sedation by dexmedetomidine vs midazolam

Coull et al, 2004

University of California,San Francisco 23Department of Anesthesia and Perioperative Care

Immunostaining for co-localization of orexin and cFOS in Peri-Fornical Area during Anesthesia

University of California,San Francisco 24Department of Anesthesia and Perioperative Care

Activity in Orexinergic Neurons during equi-hypnotic doses of General Anesthetics

SAL DEX ISO PTB PRO MUS0

10

20

30

40

50

60

** *

*

University of California,San Francisco 25Department of Anesthesia and Perioperative Care

Neural substrates required for BDZ- vs a2 -sedation Nelson et al, Nature Neuroscience 2002; Anesthesiology 2003

University of California,San Francisco 26Department of Anesthesia and Perioperative Care

INTERPRETATION

Hypnotic action of dexmedetomidine is similar

to natural sleep with an active arousal system

University of California,San Francisco 27Department of Anesthesia and Perioperative Care

Potential Problems with ICU Sedative Regimens

• Produce Poor Sleep Hygiene

• Prolonged sedation provokes– difficulty in weaning from mechanical ventilation

– increased length of stay in intensive care unit

• Precludes neurological examination

• Predisposes to delirium

• Predisposes to infection

University of California,San Francisco 28Department of Anesthesia and Perioperative Care

Potential Benefits of ICU Sedation with Dexmedetomidine

• Active Arousal System– Co-operative Sedation

• Responsive to Healthcare Team• Assessment of System Function• Less Isolation

– Permits wake-up while maintaining sedation• Less Sleep Deprivation

– Less Delirium– Less Infection– Less MR from Sepsis

University of California,San Francisco 29Department of Anesthesia and Perioperative Care

University of California,San Francisco 30Department of Anesthesia and Perioperative Care

Maximize Efficacy of targeted sedation and reduce Neurological Dysfunction

MENDS Trial

To determine if changing sedation paradigms by targeting α2receptors instead of GABA receptors will

–reduce duration and prevalence of acute brain dysfunction (delirium and coma)–achieve equivalent efficacy of sedation

Other outcomes–ventilator free days–ICU and hospital lengths of stay–neuropsychological function at discharge–mortality at 28-days–mortality rate from sepsis

University of California,San Francisco 31Department of Anesthesia and Perioperative Care

MENDS Study Double blind randomized controlled trial

Pandharipande et al, JAMA 2007

University of California,San Francisco 32Department of Anesthesia and Perioperative Care

Assessment of End Points

• Efficacy of sedation-ability to achieve sedation established by ICU team

• Duration of delirium - defined as “delirium and coma free days,” i.e the days alive and free of delirium or coma

• Mortality Rate at 28 days

University of California,San Francisco 33Department of Anesthesia and Perioperative Care

Baseline CharacteristicsDemographic Lorazepam

(n=51)Dexmed(n=52)

P value

Age 59 (45, 67) 60 (49,65) 0.96Males 45% 58% 0.20APACHE II 27 (24,32) 29 (24, 32) 0.75SOFA score 9 (7,11) 10 (8,12) 0.23Admitting Diagnosis

Sepsis/ARDS 39% 37% 0.78

COPD 4% 4% 0.99

Pulmonary other 22% 23% 0.85

University of California,San Francisco 34Department of Anesthesia and Perioperative Care

Baseline CharacteristicsDemographic Lorazepam

(n=51)Dexmed(n=52)

P value

ICU typeMICU 69% 71% 0.78SICU 31% 29% 0.78

MV and enrollment 17h (8,27) 22h (14,35) 0.18

Pre-enrollment lorazepam (mg) 0 (0,3) 0.25 (0,4.25) 0.69

University of California,San Francisco 35Department of Anesthesia and Perioperative Care

Efficacy of Sedation

Outcome Lorazn=51

Dexmedn=52

P value

% Days at Nurse Target 67 (48,83) 80 (58,100) 0.04

% Days at Physician

Target55 (8,67) 67 (50,85) 0.008

University of California,San Francisco 36Department of Anesthesia and Perioperative Care

Delirium/Coma-Free Days

02

46

810

12

p=.01

Delirium-Free Days

p=.09 p=.001

Coma-Free Days

DexmedetomidineLorazepam

Brain Dysfunction

Pandharipande et al, JAMA 2007

University of California,San Francisco 37Department of Anesthesia and Perioperative Care

Other Clinical Outcomes

Outcome Lorazn=50

Dexmedn=51

P value

MV free days 18 (0,23) 22 (0,24) 0.22

ICU stay 9

(6,13.5)

7.5

(5,18)

0.31

Mortality (28 days) 27% 17% 0.18

University of California,San Francisco 38Department of Anesthesia and Perioperative Care

INTERPRETATIONA strategy targeting the α2 receptors and sparing the GABA receptors can

• Achieve target sedation goals • Increase days free of delirium/ coma• Increase days alive

University of California,San Francisco 39Department of Anesthesia and Perioperative Care

Dex Long-Term Study

ControlMidazolam (GABA)

+/- Fentanyl

InterventionDexmedetomidine (α2)

+/- Fentanyl

MICU Ventilated on Sedatives2(Dex):1 (Mdz) randomization

Riker R. et al JAMA 2009

University of California,San Francisco 40Department of Anesthesia and Perioperative Care Copyright restrictions may apply.

Riker, R. R. et al. JAMA 2009;301:489-499.

Prevalence of Delirium With Dexmedetomidine vs Midazolam

University of California,San Francisco 41Department of Anesthesia and Perioperative Care

University of California,San Francisco 42Department of Anesthesia and Perioperative Care

Septic subgroup analysis

Pandharipande et al Critical Care 2010

•Mechanical Ventilation

•Mortality Rate

•Length of Stay

University of California,San Francisco 43Department of Anesthesia and Perioperative Care

Demographics of septic subgroupVariable Lorazepam

(n=20)Dexmedetomidine

(n=19) P value

Age 55 (44,65) 57 (49,66) 0.66Males 35% 53% 0.17Medical ICU 85% 84% 0.95

APACHE II 28 (25,32) 30 (24,32) 0.86

IQCODE 3 (3,3) 3 (3,3) 0.34

RASS 1st evaluation -4 (-4,-3) -3 (-4,-2) 0.24Study drug dose (units) 3 (2,4) 0.9 (4.5,1.1) NA

University of California,San Francisco 44Department of Anesthesia and Perioperative Care

Acute Brain Dysfunction in Sedated Septic ICU Patients

University of California,San Francisco 45Department of Anesthesia and Perioperative Care

Pandharipande et al Critical Care 2010

University of California,San Francisco 46Department of Anesthesia and Perioperative Care

Effect of Sedatives on ICU Delirium

• Benzodiazepines enhance likelihood of developing “acute brain failure”

• Dexmedetomidine may be beneficial– Induces “better” sleep that enables

• Synaptic Downscaling– provides “space” for processing new information– Tononi & Cirelli

• Maintains immune system function

University of California,San Francisco 47Department of Anesthesia and Perioperative Care

Safety of Midazolam in the NICU Ng et al, Cochrane Meta-analysis, 2010

• Adverse neurological outcomes more prevalent after midazolam

• No definitive data to support the safety and effectiveness of benzodiazepines for neonatal sedation

University of California,San Francisco 48Department of Anesthesia and Perioperative Care

Neuroapoptosis following GABAergics in Neonatal Mice

University of California,San Francisco 49Department of Anesthesia and Perioperative Care

α2

Adrenoceptor Agonist Properties during Neurodevelopment

• Trophic Effects in CNS through ERK– Winzer-Serhan & Leslie 1999; Wang et al 2006

• Hypnotic and Analgesic properties– Sanders et al 2005

• Anti-apoptotic properties– Ma et al 2003– Sanders et al 2005

University of California,San Francisco 50Department of Anesthesia and Perioperative Care

University of California,San Francisco 51Department of Anesthesia and Perioperative Care

Dexmedetomidine attenuates Isoflurane-inducedApoptotic Neurodegeneration

Sanders et al 2009 Anesthesiology

University of California,San Francisco 52Department of Anesthesia and Perioperative Care

Dex attenuates isoflurane-induced memory deficit

University of California,San Francisco 53Department of Anesthesia and Perioperative Care

Dexmedetomidine prevents downregulation of pERK by isoflurane

C Iso Iso + Dex

pERK1

pERK2

Bcl-2

α-Tubulin

University of California,San Francisco 54Department of Anesthesia and Perioperative Care

Conclusions• Poor sleep hygiene

– Common in ICU patients– Capable of producing delirium

• Sedatives can contribute to delirium– Benzodiazepines preclude normal sleepα2 agonists produce near-normal sleep

• Neonatal neuroapoptosis– Provoked by benzodiazepines– Prevented by α2 agonists

University of California,San Francisco 55Department of Anesthesia and Perioperative Care

Acknowledgements• Nick Franks (Bill Lieb)

• Guo Tianzhi

• Daqing Ma

• Bing-Xue Chen

• Pratik Pandharipande, Wes Ely

• Laura Nelson, Anna Zacharia, Rob Sanders

• Clif Saper, Lee Limbird

• NIH

• MRC

• Wellcome Trust