useOfDexmedetomidine - Clinical Use of Dexmedetomidine...

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Unformatted text preview: 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 Objectives Objectives • Pharmacology of dex – alpha 2 agonist • Molecular targets + neural substrates – locus caeruleus – natural sleep pathways • Clinical paradigms for use of dex in anesthesia – sedation + analgesia w/o resp depression – attenuation of tachycardia – smooth emergence + weaning from mech vent Pharmacology Pharmacology • Establish and maintain adequate drug concentration at effector site to produce desired effect – sedation – hypnosis – analgesia – paralysis • Predict the time course of drug onset + offset Pharmacodynamics Pharmacodynamics • • • Relationship between drug conc + effect Interaction of drug with receptor Receptor – cell component – interacts with drug – biochemical change • Examples of receptors: – AchR, GABA, opioid, β + α adrenergic Receptors Receptors • Coupled to ion channels – neural signaling, 2nd messenger effects • Drug effects at receptor – agonist, antagonist or mixed effects – stereospecificity, racemic mixture of isomers • Receptor alterations – upregulated or downregulated (e.g., CHF) ↑ or ↓ number (e.g., burns, myasthenia gravis) Pharmacodynamics Pharmacodynamics • • • • • • • • Sedation/hypnosis Anxiolysis Analgesia Sympatholysis (BP/HR, NE) Reduces shivering Neuroprotective effects No effect on ICP No respiratory depression Pharmacokinetics Pharmacokinetics Rapid redistribution: 6 min Elimination half­life: 2 h Vd steady state: 118 L Clearance: 39 L/h Protein binding: 94% Metabolism: biotransformation in liver to inactive metabolites + excreted in urine • No accumulation after infusions 12­24 h • Pharmacokinetics similar in young adults + elderly • • • • • • α 2 Agonists Clonidine Dexmedetomidine • Selectivity: α2:α1 200:1 • t1/2 β 8 hrs1 • Selectivity: α2:α1 1620:1 • t1/2 β 2 hrs • • • • • • • PO, patch, epidural Antihypertensive Analgesic adjunct IV formulation not available in US Intravenous Sedative­analgesic Primary sedative • Only IV α2 available for use in the US Mechanism for the Hypnotic Effect Mechanism for the Hypnotic Effect • Hyperpolarization of locus ceruleus neurons – α2A­Adrenoreceptor subtype – Activation of K+ channels – Inhibition of Ca++ channels – Inhibition of adenylyl cyclase Firing rate of locus caeruleus neurons Activity in ascending noradrenergic pathway Restorative Properties of Sleep Restorative Properties of Sleep • Activates natural sleep pathways • Increased rate of healing – Promotes anabolism • Facilitates growth hormone release – Counteracts catabolism • Inhibits cortisol release • Inhibits catecholamine release Harmful Effects of Sleep Deprivation Harmful Effects of Sleep Deprivation ∀ ↑ pressor response to sympathetic stimulation • Impaired CV response to positioning change ∀ ↑ BP, HR + urine norepinephrine • Immune dysfunction ↓ ability of lymphocytes to synthesize DNA ↓ leukocyte phagocytic activity ↑ interferon production by lymphocytes • Cognitive dysfunction – Impaired memory, communication skills – Impaired decision­making – Confusional state [ICU]: apathy, delirium Mechanisms for Analgesic Effect Mechanisms for Analgesic Effect Opioids α2 Agonists Peripheral nociceptors ↓ inflammation [e.g., bradykinin, other kinins] Inhibit sympathetic­ mediated pain Primary afferent neurons Inhibit release of SP and glutamate Inhibit release of SP and glutamate Second order neurons Inhibit firing Inhibit firing Subcortical + cortex Decrease emotive aspects Decrease emotive aspects Descending inhibitory Activate PAG; activate pathways noradrenergic pathways Disinhibit A5/A7 noradrenergic pathways Dex: Package Insert Info Dex: Package Insert Info • Indications – Sedation of intubated and ventilated patients during treatment in an ICU setting x 24 h • Contraindications – Caution in patients with advanced heart block, severe ventricular dysfunction, shock • Drug interactions – Vagal effects can be counteracted by atropine / glyco • Clearance is lower w hepatic impairment • Withdrawal sx after discontinuation: not seen after 24 h use • Adrenal insufficiency: no effect on cortisol response to ACTH Clinical Uses of Dex in Anesthesia Clinical Uses of Dex in Anesthesia • • • • • • • Bariatric surgery Sleep apnea patients Craniotomy: aneurysm, AVM [hypothermia] Cervical spine surgery Off­pump CABG Vascular surgery Thoracic surgery • Conventional CABG • Back surgery, evoked potentials • Head injury • Burn • Trauma • Alcohol withdrawal • Awake intubation Sleep Apnea Patients Anesthesia considerations • Morbid obesity, at risk for aspiration • Difficult IV access • Systemic + pulm HTN, cor pulmonale • Postop airway obstruction + ventilatory arrest with anesthetic drugs ↓ upper airway muscle activity – inhibition of normal arousal patterns – upper airway swelling from laryngoscopy, surgery, intubation Dexmedetomodine • Anesthetic adjunct to minimize opioid + sedative use Ogan OU, Plevak DJ: Mayo Clinic; www.slee Gastric Bypass Surgery Patients Morbidly obese patients • Prone to hypoxemia • Sleep apnea is common • Respiratory depression w opioids Dexmedetomidine, 0.1 to 0.7 ug/kg/hr, prospectively studied in 32 pts ∀ ↓ opioid use in dex group • 1 pt in control gp needed reintubation HR • Dex pts more likely to be normotensive w ↓ Craig MG et al: IARS abstract, 2002. Baylor Dex Improves Postop Pain Mgt after Bariatric Surgery RCT, n= 25. Dex started at 0.5 to 0.7 ug/kg/hr 1 hr prior to end of surgery [vs.saline]. Double­ blind • Infusion adjusted according to need • Dex continued in PACU • PACU pain control with PCA Dexmedetomidine in dex gp (P < 0.03) • Morphine use ↓ • Pain score better in dex gp: 1.8 vs 3.4 (P < 0.01) • % time pain free in PACU ↑ in dex gp: – 44% vs 0 (P < 0.002) • Better control of HR in dex gp Ramsay MA, et al: Anesthesiology, 2002: A­ Craniotomy for Aneurysm / AVM Anesthesia considerations • Smooth induction + emergence • Prevent rupture • Avoid cerebral ischemia CMRO2, CBF, CBV, CSF, ICP • Hypothermia (33 oC) ↓ Dexmedetomodine ∀ ↓ sympathetic stimulation ∀ ↓ or no change in ICP ∀ ↓ shivering w/o resp depression • Preserved cognitive fct – reliable serial neuro exams Doufas AG et al: Stroke 2003;34. Louisville, Coronary Artery Surgery Patients Herr study, n=300: Dex vs. controls [propofol] • RCT, dex started at sternal closure, 0.4 ug/kg/hr after loading dose, and 0.2 to 0.7 ug/kg/hr for 6­ 24 hrs after extubation • Ramsay > 3 before 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 – (vs. 34% controls) • Dex pts had less Afib (7 vs 12 pts) Herr DL: Crit Care Med 2000;28:M248. Was CABG and Lung Disease Lung Disease • Often delays tracheal extubation • RCT, n= 20. Dex started at end of surgery, 0.2 to 0.7 ug/kg/hr, + continued 6 hr after extubation vs. controls (propofol) • Ramsay > 3 before extub, Ramsay 2 after extub Dexmedetomidine • Faster time to extub: – 7.8 + 4.6 h v. 16.5 + 11.8 h • No difference in PaCO2 between gps 30 min after extub: 37.9 v. 34.9 mmHg Sumping ST: CCM 2000;28:M249. Duke Thoracotomy + Thoracoscopy Thoracotomy + Thoracoscopy Thoracotomy + thoracoscopy patients • COPD, pleural effusion, marginal pulmonary fct ∀ ↑ pCO2 + ↓ 2 with opioids for analgesia pO • Thoracic epidural: mainly for thoracotomy • Dex: mainly for thoracoscopy Dexmedetomidine • Patients are arousable, but sedated ventilatory drive • Does not ↓ need for opioids • Greatly ↓ • Alternative to thoracic epidural • Continue after extubation Vascular Surgery Vascular surgery patients • Usually at risk for CAD, ischemia, HTN, tachycardia • Dex attenuates periop stress response • Dex attenuates ↑ BP w AXC, especially thoracic aorta Dexmedetomidine • RCT, n=41. Dex continued 48 hr postop in dex gp at emergence • HR ↓ – 73 + 11 v. 83 + 20 bpm • Better control of HR in dex gp in dex gp • Plasma NE levels ↓ Talke et al: Anesth Analg 2000;90:834. Multi Meta­ Analysis of Alpha­2 Agonists 23 trials, n=3395. mortality + ischemia • All surgeries: ↓ MI + mortality • Vascular: ↓ ischemia • Cardiac: ↓ BP (more hypotension) • Cardiac: ↓ Conclusions: • Not class 1 evidence yet, but trials look promising – Especially vascular surgery Wijeysundera, Am J Med 2003;114:742. Uni Other Surgical Procedures Other Surgical Procedures • Neck + back surgery – Dex causes minimal effect on SSEP monitoring – Smooth emergence, especially cervical spine – Easy to evalute neuro fct prior to + after extub • Abdominal surgery – Dexmedetomidine provides analgesia without respiratory depression – Especially useful in elderly undergoing colon resections, TAH, + other stressful procedures Perioperative Dex Infusion Protocol Perioperative Dex Infusion Protocol Example: 70 kg patient. Assess BP, HR, volume status Hypovolemic Normovolemic 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 load: 25 to 35 ug or 6 to 9 mL over 10­15 min Stop load if ↓ HR Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr] Dex=dexmedetomidine. Monitor BP/HR throughout If bradycardia, ↓ infusion Considerations With Anesthesia Use of Dexmedetomidine • Dilute in 0.9% saline: 4 mcg/mL • Requires infusion pump: mcg/kg/h • Transient HTN: with rapid bolus • Hypotension may occur, especially if hypovolemia ∀ ↓ HR (attenuation of tachycardia): usually desirable ∀ ↓ conc of inhaled agents: BIS monitoring • Continue infusion after extubation for 30 min [PACU] • L + D: not studied • Pediatrics: abstracts + case reports [Lerman, Toronto] dose • Geriatrics: more hypotension + bradycardia: ↓ Use of Dexmedetomidine in Use of Dexmedetomidine in the Burn Unit ∀ α2 agonist effect assists in the management of burn patients; blunts catecholamine surge • Use in intubated and non­intubated burn patients • Administer as a standard load once patient is normovolemic (range: 0.4 to 0.7 mcg/kg/hr) ∀ ↓ dose for less severe burns and non­intubated patients – 0.2 to 0.4 mcg/kg/hr for routine burn care – outpatient dressing changes, instead of ketamine Alcohol Withdrawal and Trauma Alcohol Withdrawal and Trauma • Trauma often occurs in males who are intoxicated • Trauma pt mayexperience agitation and is at risk for exacerbating underlying injuries (e.g., SCI) • Benzodiazepines typically used – Intubation and ventilation often required if extreme agitation • Dexmedetomidine is an alternative – – – – – Spontaneous breathing Hemodynamic stability Adequate sedation Prevention of autonomic effects of withdrawal Pain control Summary Summary • Goal is to establish + maintain adequate drug conc at effector site to produce desired effect • Dex can help optimize anesthesia via: sympathetic activity – Sedation, analgesia + ↓ HR – Attenuation of stress response + ↓ – Smooth emergence + tracheal extubation • Unique mechanism of action on natural sleep pathway permits sedation + analgesia w/o respiratory depression • Adjunct agent of choice for many surgeries ...
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