Dexmedetomidine is an alpha-2 agonist sedative that provides sedation, analgesia and reduces sympathetic activity without respiratory depression by acting on natural sleep pathways. It has various clinical uses in anesthesia such as attenuating the stress response during surgery, providing smooth emergence from anesthesia, and is useful as an adjunct for many surgery types including vascular, cardiac, thoracic and neurosurgeries. Dexmedetomidine establishes drug concentrations at receptor sites to produce desired sedative, analgesic and hemodynamic effects.

1. 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

2. 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

3. 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

4. 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

5. 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)

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

7. 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

8. 2 Agonists
Clonidine
• Selectivity: 2:1 200:1
• t1/2  8 hrs1
• PO, patch, epidural
• Antihypertensive
• Analgesic adjunct
• IV formulation not
available in US
Dexmedetomidine
• Selectivity: 2:1 1620:1
• t1/2  2 hrs
• Intravenous
• Sedative-analgesic
• Primary sedative
• Only IV 2 available for use
in the US

9. 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

10. 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

11. 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

12. Mechanisms for Analgesic Effect
Disinhibit A5/A7
noradrenergic
pathways
Activate PAG; activate
noradrenergic
pathways
Descending inhibitory
pathways
Decrease emotive
aspects
Decrease emotive
aspects
Subcortical + cortex
Inhibit firing
Inhibit firing
Second order neurons
Inhibit release of
SP and glutamate
Inhibit release of
SP and glutamate
Primary afferent
neurons
Inhibit sympathetic-
mediated pain
 inflammation [e.g.,
bradykinin, other kinins]
Peripheral nociceptors
2 Agonists
Opioids

13. 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

14. 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

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

16. Craig MG et al: IARS abstract,
2002. Baylor
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

17. Ramsay MA, et al: Anesthesiology,
2002: A-910 and A-165. 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

18. Doufas AG et al: Stroke 2003;34.
Louisville, KY
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

19. Herr DL: Crit Care Med
2000;28:M248. Washington
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)

20. Sumping ST: CCM 2000;28:M249.
Duke
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

21. 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

22. Talke et al: Anesth Analg
2000;90:834. Multicenter
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

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

24. 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

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

26. 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

27. 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

28. 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

29. 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