Can We Prevent Delirium in the ICU?

Transcription

1 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 1

2 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? 2

3 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 3

4 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 4

5 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 5

6 Sleep in the ICU Longer periods of wakefulness 1 Shorter periods of Deep Sleep Less time in stages III/IV NREM 2 Less periods of REM sleep 3 Loss of circadian rhythm 4 References: 1 Aurell and Elhmqvist, BMJ Cooper et al Chest Gabor et al Am J Resp Crit Care Freedman et al Am J Resp Crit Care

7 Conflict of Interest Dexmedetomidine patented for sedativehypnotic 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 7

8 Cl Clonidine H N N α 2 Agonists Dexmedetomidine H CH 3 N Cl N CH 3 CH 3 N Clonidine Dexmedetomidine Selectivity: α 2 :α 1 200:1 1 t 1/2 β 8 hrs 1 PO, patch, epidural 2 Antihypertensive 1 Analgesic adjunct 1 IV formulation not available in US Selectivity: α 2 :α :1 3 t 1/2 β 2 hrs 3 Intravenous 3 Sedative-analgesic 3 Only IV α 2 available for use in the US 1. Maze. White paper; Khan et al. Anaesthesia. 1999;54: Kamibayashi, Maze. Anesthesiology. 2000;93:

9 Ca ++ Ca ++ Ca ++ Decrease in action potential due to hyperpolarization α 2 A α 2 AR G o G k K + K + + Decrease in influx of Ca ++ K + 9

10 Molecular and Neuronal Action of α 2 agonists Initiated in the locus coeruleus (LC) Transduced by mechanisms which hyperpolarize the membrane Decrease firing rate of the LC neurons 10

11 Hypnotic Mechanism of Benzodiazepine Decreases wakefulness by positive allosteric modulation of α subunit of the GABA A receptor Similar to alcohol and barbiturates Decreases deeper phases of NREM sleep Increase dopamine release in VTA 1 similar reward mechanism as present in addictive drugs Withdrawal results in Anxiety Delirium Seizures 1. Tan et al Nature

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

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14 Saper et al,

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16 Dexmedetomidine Induces similar changes as NREM sleep in Brain Nuclei Nelson et al, Anesthesiology

17 Sedation by Dexmedetomidine Nelson et al Anesthesiology 2003 TMN DRN VLPO PPTg LC TMN: Tuberomammilary nulcleus VLPO: Ventrolateral preoptic nucleus LC: Locus Coeruleus PPTg: Pedunculopontine tegemental nucleus DRN: Dorsal raphe nucleus 2 17

18 fmri placebo - dexmedetomidine 18

19 GABAergics don t Produce NREM sleep changes in Locus Ceruleus (LC) Nelson et al, Nat Neurosci

20 fmri placebo - midazolam 20

21 INTERPRETATION Hypnotics do not converge on the sleep pathway at the same point α 2 agonists within the brainstem GABAmimetics within the hypothalamus Results in different hypnotic responses 21

22 Ability to be aroused by noise to perform a task during sedation by dexmedetomidine vs midazolam Task & Noise Task alone PLA DEX MDZ Drug Coull et al,

23 Immunostaining for co-localization of orexin and cfos in Peri-Fornical Area during Anesthesia 23

24 Activity in Orexinergic Neurons during equi-hypnotic doses of General Anesthetics * * * * 10 0 SAL DEX ISO PTB PRO MUS 24

25 Neural substrates required for BDZ- vs a 2 -sedation Nelson et al, Nature Neuroscience 2002; Anesthesiology

26 INTERPRETATION Hypnotic action of dexmedetomidine is similar to natural sleep with an active arousal system 26

27 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 27

28 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 28

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30 Maximize Efficacy of targeted sedation and reduce Neurological Dysfunction MENDS Trial To determine if changing sedation paradigms by targeting α 2 receptors 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 30

31 MENDS Study Double blind randomized controlled trial Pandharipande et al, JAMA

32 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 32

33 Baseline Characteristics Demographic Lorazepam (n=51) Dexmed (n=52) P value Age 59 (45, 67) 60 (49,65) 0.96 Males 45% 58% 0.20 APACHE II 27 (24,32) 29 (24, 32) 0.75 SOFA score 9 (7,11) 10 (8,12) 0.23 Admitting Diagnosis Sepsis/ARDS 39% 37% 0.78 COPD 4% 4% 0.99 Pulmonary other 22% 23%

34 Baseline Characteristics Demographic Lorazepam (n=51) Dexmed (n=52) P value ICU type MICU 69% 71% 0.78 SICU 31% 29% 0.78 MV and enrollment Pre-enrollment lorazepam (mg) 17h (8,27) 22h (14,35) (0,3) 0.25 (0,4.25)

35 Efficacy of Sedation Outcome Loraz n=51 Dexmed n=52 P value % Days at Nurse Target 67 (48,83) 80 (58,100) 0.04 % Days at Physician Target 55 (8,67) 67 (50,85)

36 p=.01 Brain Dysfunction p=.09 p=.001 Dexmedetomidine Lorazepam Delirium/Coma-Free Days Delirium-Free Days Coma-Free Days Pandharipande et al, JAMA

37 Other Clinical Outcomes Outcome Loraz n=50 Dexmed n=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%

38 INTERPRETATION A strategy targeting the α 2 receptors and sparing the GABA receptors can Achieve target sedation goals Increase days free of delirium/ coma Increase days alive 38

39 Dex Long-Term Study MICU Ventilated on Sedatives 2(Dex):1 (Mdz) randomization Control Midazolam (GABA) +/- Fentanyl Intervention Dexmedetomidine (α2) +/- Fentanyl Riker R. et al JAMA

40 Prevalence of Delirium With Dexmedetomidine vs Midazolam Riker, R. R. et al. JAMA 2009;301: Copyright restrictions may apply. 40

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42 Septic subgroup analysis Mechanical Ventilation Mortality Rate Length of Stay Pandharipande et al Critical Care

43 Demographics of septic subgroup Variable Lorazepam (n=20) Dexmedetomidine (n=19) P value Age 55 (44,65) 57 (49,66) 0.66 Males 35% 53% 0.17 Medical 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 1 st evaluation -4 (-4,-3) -3 (-4,-2) 0.24 Study drug dose (units) 3 (2,4) 0.9 (4.5,1.1) NA 43

44 Acute Brain Dysfunction in Sedated Septic ICU Patients 44

45 Pandharipande et al Critical Care

46 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 46

47 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 47

48 Neuroapoptosis following GABAergics in Neonatal Mice 48

49 α 2 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

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51 Dexmedetomidine attenuates Isoflurane-induced Apoptotic Neurodegeneration Sanders et al 2009 Anesthesiology 51

52 Dex attenuates isoflurane-induced memory deficit 52

53 Dexmedetomidine prevents downregulation of perk by isoflurane Bcl-2 perk2 perk1 α-tubulin C Iso Iso + Dex 53

54 Poor sleep hygiene Conclusions Common in ICU patients Capable of producing delirium Sedatives can contribute to delirium Benzodiazepines preclude normal sleep α 2 agonists produce near-normal sleep Neonatal neuroapoptosis Provoked by benzodiazepines Prevented by α 2 agonists 54

55 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 55