Sleep and Clinical Outcomes in Critical Care and Perioperative Settings

Transcription

1 Sleep and Clinical Outcomes in Critical Care and Perioperative Settings Dr Mervyn Maze MB ChB, FRCP, FRCA, FMedSci Department of Anesthesia and Perioperative Care, Questions to be Addressed Why is sleep so important? What happens to sleep in the ICU? Do sedative-hypnotic produce sleep? Are clinical outcomes in the ICU influenced by sleep hygiene? University California San Francisco 1 2 EEG Stages of Sleep Why do we need the different phases of sleep? REM Memory consolidation Emotional & psychological adaptation thro dreams NREM (deeper stages) produces immobility Prevents wasteful expenditure of energy Cools the body and brain re-organizes memory 3 4

2 Benefits of Natural Sleep Sleep Homeostasis Tononi and Cirelli 2006 Restoration and Repair Avoid Sleep Deprivation Cognitive Dysfunction Hypoactive delirium-like state 5 6 Benefits of Natural Sleep Restoration and Repair Avoid Sleep Deprivation Cognitive Dysfunction Hypoactive delirium-like state Immune Dysfunction High Mortality Rate from Sepsis Depressed Response to PAMPs W Wang et al. Nature 470, (2011) 7 8

3 Effect of Sleep Deprivation (12h) on Antibody Response to FluVaccination Spiegel, K. et al. JAMA 2002;288:1471 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 2001 Copyright restrictions may apply Special Considerations for Sedative Practices in the Adult ICU Many co-morbidities high rate of complications Prolonged Exposure to sedative/hypnotics Widespread use of care bundles Reduce complications Reduce LOS Reduce costs Sedation Interruption Kress et al, NEJM

4 Physiologic Changes with Sedation Interruption Kress et al CCM, Goals of Sedation for Mechanical Ventilation Minimize discomfort analgesia Anxiolysis Facilitate Care Bundles Permit wake-up Without agitation Hemodynamic instability Avoid Respiratory Depression Coma/Delirium 15 Are Benzodiazepines the Panacea? Known molecular mechanism of action Binding site on GABA A receptor Interface between α and γ subunits Modulates GABA-mediated chloride conductance Desirable Profile for Pharmacokinetics Pharmacodynamics Subunit Specificity α 1 for Sedative, amnestic, anticonvulsant α 1 β2/β3 for hypnosis α 2 for anxiolysis Potential Problems with Benzodiazepines 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

5 Potential Problems with Benzodiazepines 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 Relative consumption of midazolam in WT and α1 mutated mice Tan et al Nature

6 Cl Clonidine H Cl N N Clonidine N 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 α 2 Agonists Dexmedetomidine H CH 3 CH 3 CH 3 Dexmedetomidine 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 N N Potential Conflict of Interest - Dexmedetomidine Patented for sedative-hypnotic properties In 1987 with Mika Scheinin Reassigned rights of patent to Orion $250K to $tanford University in 1988 Orion/ Abbott Labs/Hospira Research Grants/Contracts Honoraria Accrue no financial benefit from sales 1. Maze. White paper; Khan et al. Anaesthesia. 1999;54: Kamibayashi, Maze. Anesthesiology. 2000;93: Molecular and Neuronal Action of α 2 agonists Initiated in the locus coeruleus (LC) Correa-Sales et al Anesthesiology 1992 α 2A adrenergic receptors Lakhlani et al PNAS

7 Molecular and Neuronal Action of α 2 agonists Ca ++ Ca ++ Ca ++ Decrease in action potential due to hyperpolarization Initiated in the locus coeruleus (LC) Correa-Sales et al Anesthesiology 1992 α 2A adrenergic receptors Lakhlani et al PNAS 1997 Transduced by mechanisms which hyperpolarize the membrane Correa-Sales et al Pharmacol Biochem Behav 1992 Correa-Sales et al JPET 1992 Nacif-Coelho et al Anesthesiology 1994 Mizobe et al JCI, 1996 Decrease firing rate of the LC neurons Nelson et al Anesthesiology 2003 Decrease in influx of Ca ++ α 2 A α 2 AR G o G k K + + K + K Molecular and Neuronal Action of α 2 agonists Initiated in the locus coeruleus (LC) Correa-Sales et al Anesthesiology 1992 α 2A adrenergic receptors Lakhlani et al PNAS 1997 Transduced by mechanisms which hyperpolarize the membrane Correa-Sales et al Pharmacol Biochem Behav 1992 Correa-Sales et al JPET 1992 Nacif-Coelho et al Anesthesiology 1994 Mizobe et al JCI, 1996 Decrease firing rate of the LC neurons Nelson et al Anesthesiology

8 Saper et al, Sedation by Dexmedetomidine Nelson et al Anesthesiology 2003 Rabin et al Eur J Pharmacol 1996 TMN DRN VLPO PPTg LC TMN: Tuberomammilary nulcleus VLPO: Ventrolateral preoptic nucleus LC: Locus Coeruleus PPTg: Pedunculopontine tegemental nucleus DRN: Dorsal raphe nucleus

9 fmri placebo - dexmedetomidine fmri placebo - midazolam INTERPRETATION Ability to be aroused by noise to perform a task during sedation by dexmedetomidine vs midazolam Hypnotics do not converge on the sleep pathway at the same point α 2 agonists within the brainstem GABAmimetics within the hypothalamus Results in qualitatively different hypnotic responses Task & Noise Task alone PLA DEX Drug MDZ Coull et al,

10 Tonically firing Orexinergic Neurons during wakefulness Zecharia et al J Neurosci Activity in Orexinergic Neurons during equi-hypnotic doses of General Anesthetics Neural substrates required for BDZ- vs α 2 -sedation Rabin et al Eur J Pharmacol 1996 Nelson et al, Nature Neuroscience 2002; Nelson et al, Anesthesiology 2003 Zecharia et al, J Neuroscience, * * * * 0 SAL DEX ISO PTB PRO MUS 41 42

11 INTERPRETATION Hypnotic action of dexmedetomidine is similar to natural sleep with an active arousal system MENDS Study Double blind randomized controlled trial 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) Pandharipande et al, JAMA

12 p=.01 Delirium/Coma-Free Days Brain Dysfunction p=.09 Delirium-Free Days p=.001 Dexmedetomidine Lorazepam Coma-Free Days Outcome Other Clinical Outcomes 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% 0.18 Pandharipande et al, JAMA Dexmedetomidine vs Midazolam for ICU Sedation MICU Ventilated on Sedatives 2(Dex):1 (Mdz) randomization Control Midazolam (GABA) +/- Fentanyl Intervention Dexmedetomidine (α2) +/- Fentanyl Riker R. et al JAMA

13 Septic subgroup analysis Duration of Mechanical Ventilation ICU Length of Stay 28 day Mortality Rate Pandharipande et al Critical Care 2010 Pandharipande et al Critical Care Effect of Sedatives on ICU Outcome ICU delirium vs Lorazepam Dose (24h) Pandharipande et al, Anesthesiology 104:21-26, 2006 Benzodiazepines enhance likelihood of developing acute brain failure (delirium) 53 54

14 Effect of Sedatives on ICU Outcome Benzodiazepines enhance likelihood of developing acute brain failure Dexmedetomidine may be beneficial Putative inducer of better sleep that enables Synaptic Downscaling provides space for processing new information Improves Immune system function Future Research Develop useful sleep-detection technology for ICU Postoperative setting Measure efficacy of goal-directed therapy to improve sleep hygiene in ICU and Postop Delirium Postoperative Cognitive Dysfunction RCT Dex vs GABAergic for sedation in septic patients 90 day all cause mortality rate 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 57 58

15 Developmental Neuroapoptosis Neurons programmed to die if developmental milestones not achieved Achievement of milestones perturbed by Developmental aberrations Drugs NMDA antagonists GABAergics Midazolam-induced neuroapoptosis in neonatal rats Young et al, British Journal of Pharmacology Acknowledgments Guo Tianzhi Nick Franks, Daqing Ma Laura Nelson, Anna Zecharia, Rob Sanders Clif Saper, Tom Scammell Wes Ely, Pratik Pandharipande, Lee Limbird Funding Agencies NIH, MRC, Wellcome, Action Medical Research Industrial Collaborators Orion-Farmos, Abbott, Hospira, Masimo 61