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
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
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
Relationship between drug conc + effect Interaction of drug with receptor Receptor
cell component interacts with drug biochemical change

Examples of receptors:
AchR, GABA, opioid, + adrenergic

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
Sedation/hypnosis Anxiolysis Analgesia Sympatholysis (BP/HR, NE) Reduces shivering Neuroprotective effects No effect on ICP No respiratory depression

Pharmacokinetics
Rapid redistribution: 6 min Elimination half-life: 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 12-24 h Pharmacokinetics similar in young adults + elderly

2 Agonists
Clonidine Dexmedetomidine

Selectivity: 2:1 200:1 t1/2 8 hrs1 PO, patch, epidural Antihypertensive Analgesic adjunct IV formulation not available in US

Selectivity: 2:1 1620:1 t1/2 2 hrs Intravenous Sedative-analgesic Primary sedative Only IV 2 available for use in the US

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 ascending noradrenergic pathway

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

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 decision-making Confusional state [ICU]: apathy, delirium

Mechanisms for Analgesic Effect

Opioids
Peripheral nociceptors Primary afferent neurons Second order neurons
inflammation [e.g., bradykinin, other kinins]

2 Agonists
Inhibit sympatheticmediated pain Inhibit release of SP and glutamate Inhibit firing

Inhibit release of SP and glutamate Inhibit firing

Subcortical + cortex

Decrease emotive aspects Activate PAG; activate noradrenergic pathways

Decrease emotive aspects Disinhibit A5/A7 noradrenergic pathways

Descending inhibitory pathways

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

Bariatric surgery Sleep apnea patients Craniotomy: aneurysm, AVM [hypothermia] Cervical spine surgery Off-pump 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

Dexmedetomodine Anesthetic adjunct to minimize opioid + sedative use

Ogan OU, Plevak DJ: Mayo Clinic; www.sleepapnea.org

upper airway muscle activity inhibition of normal arousal patterns upper airway swelling from laryngoscopy, surgery, intubation

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 Dex pts more likely to be normotensive w HR

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 Morphine use in dex gp (P < 0.03) Pain score better in dex gp: 1.8 vs 3.4 (P < 0.01) % time pain free in PACU in dex gp:
Better control of HR in dex gp
Ramsay MA, et al: Anesthesiology, 2002: A-910 and A-165. Baylor

44% vs 0 (P < 0.002)

Craniotomy for Aneurysm / AVM

Anesthesia considerations Smooth induction + emergence Prevent rupture Avoid cerebral ischemia Hypothermia (33 oC) CMRO2, CBF, CBV, CSF, ICP 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, KY

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 94% did not require propofol 70% did not require morphine Dex pts had less Afib (7 vs 12 pts)
Herr DL: Crit Care Med 2000;28:M248. Washington

by 1 hr

(vs. 34% controls)

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:

No difference in PaCO2 between gps 30 min after extub: 37.9 v. 34.9 mmHg
Sumping ST: CCM 2000;28:M249. Duke

7.8 + 4.6 h v. 16.5 + 11.8 h

Thoracotomy + Thoracoscopy
Thoracotomy + thoracoscopy patients COPD, pleural effusion, marginal pulmonary fct pCO2 + pO2 with opioids for analgesia Thoracic epidural: mainly for thoracotomy Dex: mainly for thoracoscopy
Dexmedetomidine Patients are arousable, but sedated Does not ventilatory drive Greatly need for opioids 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 HR in dex gp at emergence Better control of HR in dex gp Plasma NE levels in dex gp
Talke et al: Anesth Analg 2000;90:834. Multicenter

73 + 11 v. 83 + 20 bpm

Meta- Analysis of Alpha-2 Agonists

23 trials, n=3395. All surgeries: Vascular: Cardiac: Cardiac: mortality + ischemia MI + mortality ischemia BP (more hypotension)

Conclusions: Not class 1 evidence yet, but trials look promising

Especially vascular surgery

Wijeysundera, Am J Med 2003;114:742. Univ of Toronto

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

Example: 70 kg patient. Assess BP, HR, volume status

Hypovolemic Volume preload 500 to 1000 cc LR

Normovolemic

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 10-15 min Stop load if HR Monitor BP/HR throughout If bradycardia, infusion

Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr] Dex=dexmedetomidine.

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] Geriatrics: more hypotension + bradycardia: dose

Use of Dexmedetomidine in the Burn Unit

2 agonist effect assists in the management of burn patients; blunts catecholamine surge Use in intubated and non-intubated 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 non-intubated patients
0.2 to 0.4 mcg/kg/hr for routine burn care outpatient dressing changes, instead of ketamine

Alcohol Withdrawal and Trauma

Trauma often occurs in males who are intoxicated Trauma pt may experience 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
Goal is to establish + maintain adequate drug conc at effector site to produce desired effect Dex can help optimize anesthesia via: Sedation, analgesia + sympathetic activity Attenuation of stress response + HR 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