Clinical Utilization of Dexmedetomidine.

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Targets. Pharmacology of dexalpha 2 agonistMolecular targets neural substrateslocus caeruleusnatural rest pathwaysClinical ideal models for utilization of dex in anesthesiasedation absense of pain w/o resp depressionattenuation of tachycardiasmooth rise weaning from mech vent. Pharmacology. Build up and keep up sufficient medication focus at effector site to create fancied impact sedationhypnosis
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Clinical Use of Dexmedetomidine Charles E. Smith, MD Professor of Anesthesia Director, Cardiothoracic Anesthesia MetroHealth Medical Center Case Western Reserve University Cleveland, Ohio, USA October 7, 2003

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Objectives Pharmacology of dex alpha 2 agonist Molecular targets + neural substrates locus caeruleus regular rest pathways Clinical ideal models for utilization of dex in anesthesia sedation + absense of pain w/o resp sadness weakening of tachycardia smooth development + weaning from mech vent

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Pharmacology Establish and keep up sufficient medication fixation at effector site to create craved impact sedation entrancing absense of pain loss of motion Predict the time course of medication onset + counterbalance

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Pharmacodynamics Relationship between medication conc + impact Interaction of medication with Receptor cell part associates with medication biochemical change Examples of receptors: AchR, GABA, opioid,  +  adrenergic

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Receptors Coupled to particle channels neural flagging, second detachment impacts Drug impacts at receptor agonist, opponent or blended impacts stereospecificity, racemic blend of isomers Receptor modifications upregulated or downregulated (e.g., CHF)  or  number (e.g., copies, myasthenia gravis)

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Pharmacodynamics Sedation/trance Anxiolysis Analgesia Sympatholysis (BP/HR, NE) Reduces shuddering Neuroprotective impacts No impact on ICP No respiratory melancholy

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Pharmacokinetics Rapid redistribution: 6 min Elimination half-life: 2 h Vd consistent state: 118 L Clearance: 39 L/h Protein official: 94% Metabolism: biotransformation in liver to inert metabolites + discharged in pee No collection after mixtures 12-24 h Pharmacokinetics comparable in youthful grown-ups + elderly

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Clonidine Selectivity:  2 : 1 200:1 t 1/2  8 hrs 1 PO, patch, epidural Antihypertensive Analgesic assistant IV plan not accessible in US Dexmedetomidine Selectivity:  2 : 1 1620:1 t 1/2  2 hrs Intravenous Sedative-pain relieving Primary narcotic Only IV  2 accessible for use in the US  2 Agonists

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Mechanism for the Hypnotic Effect Hyperpolarization of locus ceruleus neurons –  2A - Adrenoreceptor subtype Activation of K + channels Inhibition of Ca ++ channels Inhibition of adenylyl cyclase  Firing rate of locus caeruleus neurons  Activity in rising noradrenergic pathway

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Restorative Properties of Sleep Activates characteristic rest pathways Increased rate of recuperating Promotes anabolism Facilitates development hormone discharge Counteracts catabolism Inhibits cortisol discharge Inhibits catecholamine discharge

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Harmful Effects of Sleep Deprivation  pressor reaction to thoughtful incitement Impaired CV reaction to situating change  BP, HR + pee norepinephrine Immune brokenness  capacity of lymphocytes to integrate DNA  leukocyte phagocytic action  interferon generation by lymphocytes Cognitive brokenness Impaired memory, relational abilities Impaired basic leadership Confusional state [ICU]: lack of care, incoherence

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Mechanisms for Analgesic Effect Opioids  2 Agonists Peripheral nociceptors  aggravation [e.g., bradykinin, different kinins ] Inhibit thoughtful intervened torment Primary afferent neurons Inhibit arrival of SP and glutamate Inhibit arrival of SP and glutamate Second request neurons Inhibit terminating Inhibit terminating Subcortical + cortex Decrease emotive perspectives Decrease emotive viewpoints Descending inhibitory pathways Activate PAG; enact noradrenergic pathways Disinhibit A5/A7 noradrenergic pathways

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Dex: Package Insert Info Indications Sedation of intubated and ventilated patients amid treatment in an ICU setting x 24 h Contraindications Caution in patients with cutting edge heart square, serious ventricular brokenness, stun Drug collaborations Vagal impacts can be checked by atropine/glyco Clearance is lower w hepatic debilitation Withdrawal sx after suspension: not seen after 24 h use Adrenal inadequacy: no impact on cortisol reaction to ACTH

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Bariatric surgery Sleep apnea patients Craniotomy: aneurysm, AVM [hypothermia] Cervical spine surgery Off-pump CABG Vascular surgery Thoracic surgery Conventional CABG Back surgery, evoked possibilities Head damage Burn Trauma Alcohol withdrawal Awake intubation Clinical Uses of Dex in Anesthesia

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Sleep Apnea Patients Anesthesia contemplations Morbid corpulence, at danger for desire Difficult IV access Systemic + pulm HTN, cor pulmonale Postop aviation route deterrent + ventilatory capture with soporific medications  upper aviation route muscle action restraint of typical excitement designs upper aviation route swelling from laryngoscopy, surgery, intubation Dexmedetomodine Anesthetic aide to minimize opioid + narcotic use Ogan OU, Plevak DJ: Mayo Clinic;

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Gastric Bypass Surgery Patients Morbidly stout patients Prone to hypoxemia Sleep apnea is basic Respiratory wretchedness w opioids Dexmedetomidine, 0.1 to 0.7 ug/kg/hr, tentatively studied in 32 pts  opioid use in dex bunch 1 pt in control gp required reintubation Dex pts more inclined to be normotensive w  HR Craig MG et al: IARS unique, 2002. Baylor

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Dex Improves Postop Pain Mgt after Bariatric Surgery RCT, n= 25. Dex began at 0.5 to 0.7 ug/kg/hr 1 hr before end of surgery [vs.saline]. Twofold visually impaired Infusion balanced by Dex proceeded in PACU torment control with PCA Dexmedetomidine Morphine use  in dex gp (P < 0.03) Pain score better in dex gp: 1.8 versus 3.4 (P < 0.01) % time torment free in PACU  in dex gp: 44% versus 0 (P < 0.002) Better control of HR in dex gp Ramsay MA, et al: Anesthesiology, 2002: A-910 and A-165. Baylor

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Craniotomy for Aneurysm/AVM Anesthesia contemplations Smooth enlistment + rise Prevent break Avoid cerebral ischemia Hypothermia (33 o C)  CMRO 2 , CBF, CBV, CSF, ICP Dexmedetomodine  thoughtful incitement  or no change in ICP  shuddering w/o resp melancholy Preserved intellectual fct solid serial neuro exams Doufas AG et al: Stroke 2003;34. Louisville, KY

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Coronary Artery Surgery Patients Herr study, n=300: Dex versus controls [propofol] RCT, dex began at sternal conclusion, 0.4 ug/kg/hr in the wake of stacking measurements, and 0.2 to 0.7 ug/kg/hr for 6-24 hrs after extubation Ramsay > 3 preceding extub, Ramsay 2 after extub Dexmedetomidine Faster time to extub in dex gp by 1 hr 94% did not require propofol 70% did not require morphine (versus 34% controls) Dex pts had less Afib (7 versus 12 pts) Herr DL: Crit Care Med 2000;28:M248. Washington Hospital

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CABG and Lung Disease Lung Disease Often defers tracheal extubation RCT, n= 20. Dex began at end of surgery, 0.2 to 0.7 ug/kg/hr, + proceeded with 6 hr after extubation versus controls (propofol) Ramsay > 3 preceding extub, Ramsay 2 after extub Dexmedetomidine Faster time to extub: 7.8 + 4.6 h v. 16.5 + 11.8 h No distinction in PaCO2 between gps 30 min after extub: 37.9 v. 34.9 mmHg Sumping ST: CCM 2000;28:M249. Duke

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Thoracotomy + Thoracoscopy Thoracotomy + thoracoscopy patients COPD, pleural emission, peripheral pneumonic fct  pCO 2 +  pO 2 with opioids for absense of pain Thoracic epidural: for the most part for thoracotomy Dex: predominantly for thoracoscopy Dexmedetomidine Patients are arousable, yet calmed Does not  ventilatory drive Greatly  requirement for opioids Alternative to thoracic epidural Continue after extubation

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Vascular Surgery Vascular surgery patients Usually at danger for CAD, ischemia, HTN, tachycardia Dex constricts periop stress reaction Dex weakens  BP w AXC, particularly thoracic aorta Dexmedetomidine RCT, n=41. Dex proceeded with 48 hr postop HR  in dex gp at rise 73 + 11 v. 83 + 20 bpm Better control of HR in dex gp Plasma NE levels  in dex gp Talke et al: Anesth Analg 2000;90:834. Multicenter

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Meta-Analysis of Alpha-2 Agonists 23 trials, n=3395. All surgeries:  mortality + ischemia Vascular:  MI + mortality Cardiac:  ischemia Cardiac:  BP (more hypotension) Conclusions: Not class 1 prove yet, yet trials look encouraging Especially vascular surgery Wijeysundera, Am J Med 2003;114:742. Univ of Toronto

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Other Surgical Procedures Neck + back surgery Dex causes insignificant impact on SSEP checking Smooth rise, particularly cervical spine Easy to evalute neuro fct before + after extub Abdominal surgery Dexmedetomidine gives absense of pain without respiratory sadness Especially helpful in elderly experiencing colon resections, TAH, + other unpleasant methodology

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Perioperative Dex Infusion Protocol Example: 70 kg understanding. Evaluate BP, HR, volume status Hypovolemic Normovolemic Monitor BP/HR all through If bradycardia,  mixture Volume preload 500 to 1000 cc LR 2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml Start at 40 mL/hr Usual burden: 25 to 35 ug or 6 to 9 mL more than 10-15 min Stop load if  HR Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr] Dex=dexmedetomidine.

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Considerations With Anesthesia Use of Dexmedetomidine Dilute in 0.9% saline: 4 mcg/mL Requires implantation pump: mcg/kg/h Transient HTN: with fast bolus H ypotension may happen, particularly if hypovolemia  HR (weakening of tachycardia): typically alluring  conc of breathed in specialists: BIS checking Continue imbuement after extubation for 30 min [PACU] L + D: not concentrated on Pediatrics: abstracts + case reports [Lerman, Toronto] Geriatrics: more hypotension + bradycardia:  measurement

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Use of Dexmedetomidine in the Burn Unit  2 agonist impact helps with the administration of smolder patients; blunts catecholamine surge Use in intubated and non-intubated blaze patients Administer as a standard load once patient is normovolemic (range: 0.4 to 0.7 mcg/kg/hr)  dosage for less se

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