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    • Intraoperative Use of    Agonists in Neuroanesthesia Alex Bekker M.D., Ph.D. Director of Neuroanesthesia New York University School of Medicine
    • Progress may have been all right once, but it went on too long. Ogden Nash
    • Activation of    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
    • 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
    • Pharmacokinetics of IV agents 1 2.5 1.5 2 T 1/2   hr 4 6 4 6 T 1/2  , min 0.3 0.8 1.8 0.6 Cl, l/min 30 330 350 200 Vdss, l 10 30 16 16 Vdcc, l Alfenta Fentanyl Propofol Dex
    • Context-sensitive Dexmedetomidine recovery times as a function of duration of infusion
    • Effect of Dexmedetomidine on Cerebral Blood Flow
      • Animal models
        • Dex causes a reduction in CBF up to 45%
        • Dex has no effect on the CMRO 2
        • 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
    • 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
    • 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
    • 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
    • Median nerve SSEPs tracings after switching from propofol to Dexmedetomidine infusion Left Right
    • Amplitudes of early and late SSEP waves at various stages of the surgery
    • 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  g/kg/hr
      • 60 at 0.6  g/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
    • BIS before and after subjects were asked to perform various tasks Hall et al. Anesth Analg 2000
    • 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
    • Dexmedetomidine and Antinociception
      •  2 – Agonists attenuate hemodynamic responses to laryngoscopy and intubation
      • Lawrence CJ et al Anaesthesia 1997
      •  2 – 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
    • 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.
    • Dexmedetomidine: Side Effects
      • Hypotension
      • Transient hypertension
      • Bradycardia
      • Dry mouth
      • Limited amnestic effect
      • Animal studies show reduction in the CBF/CMRO 2 ratio
      • Excessive sedation
    • 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
    • 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
    •  2 – Agonists and Cognitive Function
      • There is strong evidence that  2 – 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
      • NE’s beneficial action in the PFC appear to result from stimulation of  2 (A) – receptors postjunctional to NE terminals
      • Arnstein et el. Arch Gen Psychiatry 1996
    • 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
    • Clinical Experience: Functional Neurosurgery
      • Dex infusion at 0.1 – 0.2  g/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
    • 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