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 Selectivity: 2:1 1620:1
t1/2 8 hrs1 t1/2 2 hrs
PO, patch, epidural Intravenous
Antihypertensive Sedative-analgesic
Analgesic adjunct Primary sedative
IV formulation not Only IV 2 available for use
available in US 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 2 Agonists

Peripheral nociceptors inflammation [e.g., Inhibit sympathetic-

bradykinin, other kinins] mediated pain

Primary afferent Inhibit release of Inhibit release of

neurons SP and glutamate SP and glutamate

Second order neurons Inhibit firing Inhibit firing

Subcortical + cortex Decrease emotive Decrease emotive

aspects aspects

Descending inhibitory Activate PAG; activate Disinhibit A5/A7

pathways noradrenergic noradrenergic
pathways 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 Conventional CABG

Sleep apnea patients Back surgery, evoked
Craniotomy: aneurysm, potentials
AVM [hypothermia] Head injury
Cervical spine surgery Burn
Off-pump CABG Trauma
Vascular surgery Alcohol withdrawal
Thoracic surgery 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.sleepapnea.org
 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:
44% vs 0 (P < 0.002)
Better control of HR in dex gp
Ramsay MA, et al: Anesthesiology,
2002: A-910 and A-165. Baylor
 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
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. Washington
 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 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
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
 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 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 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

Monitor BP/HR
throughout
Start at 40 mL/hr

If bradycardia,
Usual load: 25 to 35 ug or 6 to 9 mL over 10-15 min
infusion

Stop load if HR

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