Intraoperative Use of a2- Agonists in Neuroanesthesia

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Intraoperative Use of a2- Agonists in Neuroanesthesia Powered By Docstoc
					Dexmedetomidine in Neurosurgery:
 New Drug or More of the Same?

          Alex Bekker M.D., Ph.D.
       Professor of Anesthesiology and
                Neurosurgery
           Vice Chair for Research
        Department of Anesthesiology
            NYU Medical Center
Progress may have been all right once,
but it went on too long.

                          Ogden Nash
                Outline
• Alpha-2 receptors and agonists
• Physiologic effects mediated by alpha-2
  agonists
• Selected clinical effects
• Neuropharmacology of dexmedetomidine
• Intraoperative uses
         a2 Adrenergic Receptor
             Pharmacology
• Adrenergic receptors
  – Regulate release of
    neurotransmitters
  – Control epinephrine,
    norepinephrine release
  – Modulate sympathetic
    response via “negative
    feedback loop”
 Activation of a2-Receptors Leads To:
• Dose dependent sedation and anxiolysis without
  respiratory depression
• 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
• Decrease oxygen demand
 Qualifications for Inclusion Into
 the Neuroanesthesia Drug Club:
• Stability of intracranial homeostasis
• Hemodynamic stability
• Noninterference with neurophysiologic
  monitoring
• Cooperative sedation (for functional neurosurgery)
• Controllability (e.g. rapid onset and offset of
  effect)
• Neuroprotection
• Antinonociception
Effect of Dex 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 M, Anesth Analg 1990
                      Fale A, Anesth Analg 1994
                      Karlsson A, Anesth Analg1991
                       Cerebral Blood Flow

 Baseline   Low Infusion   High Infusion   30 min post-
                                                              Both low and high doses
                                           termination           – Reduced global CBF by one
                                                                   third
                                                                 – Decreased mean systemic
                                                                   BP, HR, and CO 15% to
                                                                   20%
                                                                 – Increased PaCO2 no more
                                                                   than 5 mm Hg
                                                              CBF decreased from
                                                               baseline throughout
                                                               dexmedetomidine infusion
                                                               and for at least 30 minutes
Note: Color intensity correlates with CBF                      thereafter



                                                          Prielipp RC, Anesth Analg 2002
                                  Cerebral Blood Flow
                               and Cerebral Metabolic Rate
                50
CBFV (cm/sec)




                                                               Dexmedetomidine
                                                     *
                                  *                            produces a dose-
                40
                                           *
                                                                dependent reduction in
                30                                              both cerebral blood
                                                                flow velocity (CBFV)
                20                                              and cerebral metabolic
                      PreSed   0.6 Dex   1.2 Dex   Recovery     rate equivalent (CMRe)
                3.0
                                            *                  *P<.05 versus pre-
CMRe




                2.0
                                                               sedation (PreSed)
                1.0                                            †P<.05 versus 0.6 ng/ml
                                                               dex
                0.0                                            ‡P<.05 versus 1.2 ng/ml
                      PreSed   0.6 Dex   1.2 Dex   Recovery
                                                               dex
                                                              Drummond JC, Anesthesiology 2008
          Effect of Dex 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 M, Anesth Analg 1992
• Human study
   – Dex has no effect on lumbar CSF pressure in patients
     undergoing transphenoidal pituitary tumor resection

                     Talke P, Anesth Analg 1997
      Median Nerve SSEPs Tracings after
    Switching from Propofol to Dex Infusion


Left




Right



                          Bekker A, J Neurosurg Anesth 2002
Dexmedetomidine Effect on Evoked
   Potentials (Animal Model)
• Dex maintains technically adequate
  conditions for SEP monitoring in rats
• Increasing plasma concentrations of Dex
  more than the clinical range did not change
  the cortical SEP amplitude and latency



                       Bai-Han Li, Anesth Analg 2003
  SSEP Amplitude and MEP Voltage
     versus Experimental Phase




SSEPs: posterior tibial nerve (P37)   MEPs: dorsal interossei
        median nerve (N20)                   abductor hallucis longus

                                         Bala E, Anesthesiology 2008
Dexmedetomidine and EEG




            Oda Y, Anesth Analg 2007
            Talke P, J Neurosurg Anesth 2007
 Characteristics of Cooperative Sedation

 In cooperative sedation, patients easily transition from
  sleep to wakefulness and task performance when aroused

 Patients are able to resume rest when not stimulated

 Cooperative sedation is most useful during procedures in
  which communication with the patient must be maintained

 Facilitates participation in therapeutic maneuvers

 Reduces risk of developing drug-induced complications
                              Bekker A, Sturaitis M, Neurosurgery 2005
   “The brain is not a sausage, it’s more like a
         well tuned musical instrument”
Endogenous sleep                Rudolfo Llinas


Loss of response to external
  stimuli


Sedative component of
  anesthesia
                     Key Components of the
                    Ascending Arousal System




It makes sense, when you don’t think about it
                 Resident’s comment
                                                Saper CB, Nature 2005
       Cognitive Function During Propofol
                    Sedation




Short-term memory is significantly reduced at light sedation with propofol


                                            Andrade J, Anesth Analg 1996
         Cognitive Function During
         Dexmedetomidine Sedation




Target doses of dexmedetomidine of 0.5-1.25 ng/ml produce sedation, with
preservation of memory (free recall and recognition) and a modest level of
analgesia

                                                       Ebert T, Anesthesiology 2000
               Arousability From Sedation During
                  Dexmedetomidine Infusion
            Just prior to cognitive and cold pressor testing   • Patients were infused with
            During cognitive and cold pressor testing            placebo or 1 of 2 doses of
      100                                                        dexmedetomidine and
                                                                 monitored with the Bispectral
      80
                                                                 Index System (BIS) before
      60                                                         stimulation and immediately
BIS




      40                                                         after being asked to perform
      20
                                                                 cognitive and cold pressor tests

       0
                Placebo           0.2            0.6           • Patients receiving either infusion
                                Dexmedetomidine                  of dexmedetomidine could be
                                    Infusion                     completely aroused by a mild
                                   (mcg/kg/h)                    stimulus

                                                                             Hall JE, Anesth Analg 2000
    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
Context-sensitive Dex recovery times as a
    function of duration of infusion
    Neuroprotective Effects of Dex
• 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, Europ J Pharm 1999
       Hoffman WE, Anesthesiology 1991
• Dex enhances glutamine disposal by oxydative metabolism
  in astrocytes
       Huang R, J Cereb Blood Metab 2000
             Morphine-Sparing Effects in
                 Inpatient Surgery
                                                       12
 34 patients scheduled for                                       Morphine




                               Cumulative Morphine
                                                       10         Dexmedetomidine
  inpatient surgery                                     8




                                   Used, mg
 Randomized to either                                  6
  dexmedetomidine or                                    4
                                                                                                   P<.01
  morphine                                              2

 Agents were started 30                                0
                                                              0   10   20    30     40   50   60   70
  minutes before the end of
                                                                       Minutes in PACU
  surgery                                              12.5

 Dexmedetomidine             Average Total Morphine    10
                                                                              P<.01
  reduced the early                 Used, mg
                                                        7.5
  postoperative need for
                                                         5
  morphine by 66%
                                                        2.5

                                                         0
                                                                  Morphine                     24
                                                                                  Dexmedetomidine
                                                                             Arain SR, Anesth Analg 2004
                              Reduction of Postoperative Requirement for
                                  Opioids With Dexmedetomidine
Requirement for Supplemental Epidural (ED)
                 Fentanyl                                            •   The requirement for
                                                                         supplemental ED fentanyl
                             80                                          analgesia was significantly
  Total Fentanyl Used, mcg




                                                                         greater in the placebo group
                             70      66.1    P=.039
                                                                     •   Dexmedetomidine is a
                             60
                                                                         potentially effective
                             50                                          analgesic adjunct to
                             40                                          thoracic ED bupivacaine
                                                                         infusion and may decrease
                             30                                          the requirement for opioids
                             20                                          and potential for respiratory
                                                                         depression
                             10                       5.3

                              0
                                   Placebo      Dexmedetomidine



                                                             Wahlander S, J Cardiothorac Vasc Anesth 2005
        Advantageous Properties of
     Dexmedetomidine in Neurosurgery

• Intraoperative hemodynamic stability
• Lack of respiratory depression
• Patients easily transition from sleep to
  wakefulness and task performance when aroused,
  and then back to sleep when not stimulated
• Does not increase intracranial pressure
• Allows for consistent and reliable somatosensory
  evoked potential amplitudes or latencies



                                Bekker A, Sturaitis M, Neurosurgery 2005
    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.
             Dex: Side Effects
• Hypotension
• Transient hypertension
• Bradycardia
• Dry mouth
• Limited amnestic effect
• Animal studies show reduction in the
  CBF/CMRO2 ratio
• Excessive sedation
 Intracranial Surgery Under General
              Anesthesia
• Postoperative infusion of Dex in patients recovering
  from transphenoidal hypophysectomy reduced plasma
  catecholamines by 70%
             Talke P, Anesth Analg 1997


• DEX-Remi anesthesia offered a better hemodynamic
  stability and lower analgesic requirements in the PACU
  than Propofol-Remi regimen
             Gunes Y, Neurosurgery Q 2005




• DEX as an anesthetic adjuvant improves hemodynamic
  stability in patients anesthetized with Iso-N2O-Fentanyl
             Tanskanen P, Br J Anaesth 2006
       Hemodynamics During Craniotomy

 Double-blind, placebo-controlled study in patients
  undergoing intracranial surgery
 Comparison of patients receiving either sevoflurane-
  opioid-placebo anesthesia (n = 28) or sevoflurane-opioid-
  dexmedetomidine anesthesia (n = 28)
 Data collected:
   – Hemodynamic variables – systolic blood pressure (SBP)
     and heart rate (HR)
   – Administration of sevoflurane, opioids, and/or antihypertensive
     agents intraoperatively
   – Time spent in PACU and administration of opioids and/or
     antihypertensive agents postoperatively
                                                Bekker A, Anesth Analg 2008
            Dexmedetomidine Attenuates
           Hemodynamic Responses During
                Intracranial Surgery
  mm Hg




  130
SBP




      90




              Time

                             Bekker A, Anesth Analg 2008
            Hemodynamics During Craniotomy

                             Placebo (n = 28)   Dexmedetomidine (n = 28)

    AUCSBP (mmHg×min/hr)      Median (IQR)            Median (IQR)
     >130 mmHg                 35 (10-101)              9 (1-49)‡
     <90 mmHg                   27 (8-58)              48 (10-96)
    AUCHR (beats×min/hr)
     >90 bpm                    12 (0-59)               8 (0-26)
     <50 bpm                     0 (0-2)                 0 (0-4)
    Intraoperative Average     Mean (SD)               Mean (SD)
     SBP (mmHg)                106.5 (9.9)             102.2 (9.4)
     HR (bpm)                  74.6 (13.0)             67.9 (1.7)‡

‡   P<.05
                                                       Bekker A, Anesth Analg 2008
            Hemodynamics During Craniotomy
                              Placebo (n = 28)   Dexmedetomidine (n = 28)

Intraoperative Drugs
    Sevoflurane, mean (%ET)      1.16 (0.38)            1.00 (0.37)
    Fentanyl, μg/kg               2.6 (1.9)              1.9 (1.0)
    Remifentanil, μg/kg           27 (13)                 19(11)‡
    Any BP med, n (%)            24 (86%)               12 (43%)†
Postoperative Measures
    PACU duration (min)           130 (27)               91 (17)@
    Times SBP >130 mmHg           2.5 (2.0)            1.25 (1.55)‡
    Any analgesic, n (%)         18 (64%)                15 (54%)
    Any BP med, n (%)            14 (50%)                10 (36%)
‡P<.05 compared with placebo
†P=.0008 compared with placebo
@P<.0001 compared with placebo                       Bekker A, Anesth Analg 2008
   Clinical Experience: Spinal Fusion
• Neurological assessment was more consistently performed
  on postoperative ventilated spinal patients using Dex as the
  sedative compared to propofol
               Urban M, Anesthesiology 2004, A158

• 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
                 Bekker A, J Neurosurg Anesth 2001
Patient Comfort under Regional Anesthesia
Intraoperative Assessment of Sedation Level
          by the Blinded Observer




                          Bekker A, J Neurosurg Anesth 2004
         Dexmedetomidine as a Primary
           Sedative in CEA Patients?
“ We caution the authors and others eager to use dexmedetomidine for
sedation during CEA that reduction of systolic and diastolic blood
pressure may cause harm than good in this patient population”

               Shetty S, J Neurosurg Anesthesiol 2004


“…the trend is concerning as it may reflect cerebral vasoconstriction
without a change in global cerebral metabolism that is known to occur
with this drug”

               Pasternak J, Lanier W, J Neurosurg Anesthesiol 2005
       The Safety of Dexmedetomidine as
       Primary Sedative for Awake CEA
                                  Total number of patients
                                          N=151



   General Anesthesia                  Regional/Dex                   Regional/No Dex
        N=10                              N=123                            N=18



No Shunt          Shunt           No Shunt      Shunt              No Shunt       Shunt
 N=0              N=10             N=111        N=12                N=12          N=6



       Elective      Obligatory          Elective     Obligatory       Elective   Obligatory
        N=10           N=0                N=8           N=4             N=4         N=2
                                                               Bekker A, Anesth Analg 2006
Clinical Experience: Awake Craniotomy

• 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, Anesth Analg 2001
Clinical Experience: Awake Craniotomy

1. Lotto M, Anesthesiology 2003, 12 pts
   (Abstract)

2. Mack-Fogarty P, J Neurosurg Anesth
   2004, 10 pts

3. Ard J, Surg Neurol 2004 17 pts
   Is There a Reason to Add Dex to
             Our Practice?
• Dex properties include:
   –   Cooperative sedation without respiratory depression
   –   Analgesia (opioid sparing effect)
   –   Coupled reduction of CBF/CMRO2
   –   Minimal interference with SSEPs, MEPs, and EEG
   –   Cardiovascular stability
   –   Has minimal effect on ICP
   –   May offer neuroprotection
   –   Hypotension
   –   Bradycardia
   –   Dex is not a complete anesthetic
   –   Unfavorable pharmacokinetics
                  Final Thought

  If the human brain were simple enough for us to
understand it, we would be too simple to understand it

				
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