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

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

T1/2, min 6 4 6 4

T1/2hr 2 1.5 2.5 1

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 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; 1990Fale A et al, Anesth Analg; 1994Karlsson 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

EP Amplitudes

0

1

2

3

4

5

6

7

8

10:17 11:33 11:39 11:49 12:11 12:16 12:21 13:06 13:09 13:19

Time

uV

R P25-N35

L P25-N35

R N20-P25

L N20-P25

R P15-N20

L P15-N20

dd

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 consumptionTaittonen 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/CMRO2 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/hrallowed 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