Clinical Use of Dexmedetomidine

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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

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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

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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

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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

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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)

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Pharmacodynamics

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

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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

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?2 Agonists

• Clonidine
• Selectivity ?2?1 2001
• t1/2 ? 8 hrs1
• PO, patch, epidural
• Antihypertensive
• Analgesic adjunct
• IV formulation not available in US

• Dexmedetomidine
• Selectivity ?2?1 16201
• t1/2 ? 2 hrs
• Intravenous
• Sedative-analgesic
• Primary sedative
• Only IV ?2 available for use in the US

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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

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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

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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

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

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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

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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

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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

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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 lt 0.03)
• Pain score better in dex gp 1.8 vs 3.4 (P lt
  0.01)
• time pain free in PACU ? in dex gp
• 44 vs 0 (P lt 0.002)
• Better control of HR in dex gp

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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

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Coronary Artery Surgery Patients

• Herr study, n300 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 gt 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)

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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 gt 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

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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

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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, n41. 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

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Meta- Analysis of Alpha-2 Agonists

• 23 trials, n3395.
• 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

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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

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Perioperative Dex Infusion Protocol
Example 70 kg patient. Assess BP, HR, volume
status
Hypovolemic
Normovolemic
Monitor BP/HR throughout If bradycardia, ?
infusion
Volume preload500 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
Dexdexmedetomidine.
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Considerations With AnesthesiaUse 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

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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

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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

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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