Intraoperative%20Use%20of%20a2-%20Agonists%20in%20Neuroanesthesia

1
Intraoperative Use of a2- Agonists in
Neuroanesthesia

• Alex Bekker M.D., Ph.D.
• Director of Neuroanesthesia
• New York University School of Medicine

2
Progress may have been all right once, but it
went on too long.
Ogden Nash
3
Activation of a2-receptors leads to

• Dose dependent sedation and anxiolysis
• Analgesia (supraspinal and spinal sites)
• Decrease plasma catecholamines
• Centrally mediated bradycardic and hypotensive
  effects
• Diuresis due to inhibition of ADH release and
  antagonism of ADH tubular effects
• Decongestant and antisialogogue effects

4
Qualifications for inclusion into the
neuroanesthesia drug club

• Controllability (e.g. rapid onset and offset of
  effect)
• Stability of intracranial homeostasis
• Hemodynamic stability
• Noninterference with neurophysiologic monitoring
• Neuroprotection
• Antinonociception

5
Pharmacokinetics of IV agents
Dex Propofol Fentanyl Alfenta
Vdcc, l 16 16 30 10
Vdss, l 200 350 330 30
Cl, l/min 0.6 1.8 0.8 0.3
T1/2a, min 6 4 6 4
T1/2b, hr 2 1.5 2.5 1
6
Context-sensitive Dexmedetomidine recovery times
as a function of duration of infusion
7
Effect of Dexmedetomidine on Cerebral Blood Flow

• Animal models
• Dex causes a reduction in CBF up to 45
• Dex has no effect on the CMRO2
• Dex produces the concentration-dependent
  constriction of pial arteries and veins
• Dex limits hypercapnea- and hypoxia-induced
  cerebral vasodilation

Zornow MH et al, Anesth Analg 1990 Fale A et al,
Anesth Analg 1994 Karlsson et al, Anesth Analg
1991
8
Effect of Dexmedetomidine on Cerebral Blood Flow

• Human study (TCD)
• Mean CBF velocity decreased with an increase in
  plasma concentration of Dex
• Pulsatility index increased at higher level of
  Dex (indicates an increase in CVR)

Zornow MH et al, J Cereb Blood Flow Metab 1993
9
Effect of Dexmedetomidine on ICP

• Animal model
• ICP was unchanged despite an increase in systemic
  blood pressure in rabbits
• ICP was decreased in the presence of intracranial
  hypertension
• Zornow MH et al, Anesth Analg 1992
• Human study
• Dex has no effect on lumbar CSF pressure in
  patients undergoing transphenoidal pituitary
  tumor resection
• Talke P et al. Anesth Analg 1997

10
Dexmedetomidine effect on SSEPs and AEP

• There is a lack of effect on cortical AEP
• Dex does not affect cortical (P25-N35) response
• Dex depresses median nerve P15-N20 amplitudes

Thornton C et al. Br J Anaesth 1999
11
Median nerve SSEPs tracings after switching from
propofol to Dexmedetomidine infusion
Left
Right
12
Amplitudes of early and late SSEP waves at
various stages of the surgery
13
Dexmedetomidine effect on the EEG

• Dex decreased MPF and 95 PF in cats
• Dex increased delta band power
• Halothane 2 produced similar EEG changes
• Animals on Dex responded to tail clamping
  purposefully

• BIS values after Dex infusion for 1 hour were
• 65 at 0.2 mg/kg/hr
• 60 at 0.6 mg/kg/hr
• The volunteers were readily awakened from
  hypnosis by talking to them BIS returned to
  awake level

Farber NE et al. Brain Research 1997
Hall JE et al. Anesth Analg 2000
14
BIS before and after subjects were asked to
perform various tasks
Hall et al. Anesth Analg 2000
15
Neuroprotective effects of Dexmedetomidine

• Inhibition of ischemia induced NE release may be
  associated with neuroprotection
• Dex prevents delayed neuronal death after focal
  ischemia
• Dex decreased total ischemic volume by 40
  compared to placebo
• Jolkkonen J et al. Euro J Pharm 1999
• Hoffman WE et al Anesthesiology 1991
• Dex enhances glutamine disposal by oxydative
  metabolism in astrocytes
• Huang R et al. J Cereb Blood Metab 2000

16
Dexmedetomidine and Antinociception

• a2 Agonists attenuate hemodynamic responses to
  laryngoscopy and intubation
• Lawrence CJ et al Anaesthesia 1997
• a2 Agonists decrease perioperative oxygen
  consumption
• Taittonen MT Br J Anaesth 1997
• Dex reduces NE level during emergence from
  anesthesia (2 to 3 times lower than in placebo
  group)
• Talke P et al. Anesth Analg 2000

17
Law of Conservation of Tsouris
The amount of aggravation in the universe is a
constant. If things are going well in one
area, they are going wrong in another.
18
Dexmedetomidine Side Effects

• Hypotension
• Transient hypertension
• Bradycardia
• Dry mouth
• Limited amnestic effect
• Animal studies show reduction in the CBF/CMRO2
  ratio
• Excessive sedation

19
Clinical Experience Craniotomy

• In patient undergoing craniotomy, premedication
  with clonidine
• reduced anesthetic requirements
• attenuated hemodynamic responses to intubation
  and pin fixation
• Costello T et al Anesth Analg 1998
• Postoperative infusion of Dex in patients
  recovering from transphenoidal hypophysectomy
  reduced plasma catecholamines by 70
• Talke P et al Anesth Analg 1997

20
Clinical Experience Spinal Fusion

• Perioperative administration of clonidine reduced
  postoperative morphine requirements by a factor
  of 3 in patients undergoing spinal fusion
• Bernard et al Anesthesiology 1991
• Intraoperative switching from a propofol infusion
  to Dex in patients undergoing cervical fusion
  resulted in
• A neurological examination that was successfully
  performed in the OR on an intubated patient
• Clinically insignificant hemodynamic changes
  during and after the switchover

Bloom M et al J Neurosurg Anesth 2001
21
a2 Agonists and Cognitive Function

• There is strong evidence that a2 agonists
  improve prefrontal cortical function (PFC)
• PFC shares reciprocal projections with
• Parietal association cortex specialized for
  visuospatial processing
• Medial temporal lobe important to memory
  abilities
• Anterior cingulate cortex involved in organizing
  complex cognitive function
• Caudate nucleus that regulates motor behavior
• NEs beneficial action in the PFC appear to
  result from stimulation of a2 (A) receptors
  postjunctional to NE terminals
• Arnstein et el. Arch Gen Psychiatry 1996

22
Clinical Experience Carotid Endartrectomy

• A combination of superficial and deep cervical
  plexus blocks is the most common regional
  anesthetic technique in the NYU medical center
• Sedation with dexmedetomidine (0.2-0.4 mcg/kg/hr)
  offers a comfortable and cooperative patient
  during the operation
• Less agitation and respiratory depression than
  with a continuous infusion of propofol or
  repeated doses of fentanyl and/or midazolam

23
Clinical Experience Functional Neurosurgery

• Dex infusion at 0.1 0.2 mg/kg/hr allowed us to
  achieve a tranquil state sufficient to complete
  neuropsychiatric testing required for mapping of
  the cortical speech area, as well as to perform
  an awake tumor resection
• A lack of respiratory depression offers an
  advantage over other technique

Bekker A et al. Anesth Analg 2001
24
Is there a reason to add Dexmedetomidine to our
practice?

• Dex properties include
• Reversible sedation without respiratory
  depression
• Analgesia
• Anesthetic sparing effect
• Cardiovascular stability
• Has minimal effect on ICP
• May offer neuroprotection
• A unique type of sedation in which a patient
  could be aroused readily
• Theoretical advantages have to be objectively
  justified in clinical studies