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
• 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
 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
 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