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Clinical Use of Dexmedetomidine
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
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Sedation/hypnosis
Anxiolysis
Analgesia
Sympatholysis (BP/HR, NE)
Reduces shivering
Neuroprotective effects
No effect on ICP
No respiratory depression
Pharmacokinetics
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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
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Selectivity: 2:1 200:1
t1/2  8 hrs1
PO, patch, epidural
Antihypertensive
Analgesic adjunct
IV formulation not
available in US
Dexmedetomidine
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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
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– Impaired memory, communication skills
– Impaired decision-making
– Confusional state [ICU]: apathy, delirium
Mechanisms for Analgesic Effect
Opioids
2 Agonists
Peripheral nociceptors
 inflammation [e.g.,
bradykinin, other kinins]
Inhibit sympatheticmediated 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
pathways
Activate PAG; activate
noradrenergic
pathways
Disinhibit A5/A7
noradrenergic
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
–  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:
• Vascular:
• Cardiac:
• Cardiac:
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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
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 10-15 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
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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
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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