Introduction to Remifentanil

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TIVA
TIVAE
Total IntraVenous Anesthesia
Total IntraVenous Awareness
Total IntraVenous Anesthesia
with Ephedrine
Steven L. Shafer, MD Professor of Anesthesia,
Stanford University Adjunct Professor of
Biopharmaceutical Science, UCSF Staff
Anesthesiologist, Palo Alto VA Health Care System
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What is TIVA in 2005?

• Pure
• Propofol _at_ 50-75 mg/kg/min
• Remifentanil _at_ 0.1-0.3 mg/kg/min
• Cheating
• Propofol _at_ 20-75 mg/kg/min
• Remifentanil _at_ 0.01-0.3 mg/kg/min
• 70 Nitrous Oxide

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Are there any questions?
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Basic PharmacologicalPrinciples of TIVA
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Simple Pharmacokinetic Model Volume of
Distribution
Volume
Amount

Concentrat
ion
Volume
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Simple Pharmacokinetic Model Clearance
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More complex PK ModelMulti-compartment
100
Rapid
10
Concentration
Intermediate
Slow
1
0
120
240
360
480
600
Minutes since bolus injection
8
Opioid Half-Lives (minutes)
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Opioid Pharmacokinetics
100
10
Percent of peak plasma opioid concentration
fentanyl
1
sufentanil
alfentanil
0.1
0
120
240
360
480
600
Minutes since bolus injection
10
Context-Sensitive Half-Time
120
fentanyl
90
alfentanil
Minutes required
60
sufentanil
30
0
0
120
240
360
480
600
Minutes since beginning of infusion
Hughes MA, Glass PS, Jacobs JR. Anesthesiology.
1992 76334-41.
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Awake EEG
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
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Profound Opioid EEG Effect
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
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EEG Time Course with Fentanyl
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
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EEG Time Course with Alfentanil
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
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Extended PK/PD Concept The Effect Site
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Effect site concentrations over time
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50 Effect Site Decrement Time
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80 Effect Site Decrement Time
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Remifentanil vs. other opioids
100
remifentanil
80
state
-
60
alfentanil
effect site opioid concentration
Percent of steady
40
sufentanil
20
fentanyl
0
0
10
20
30
40
50
60
Minutes since beginning of continuous infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Remifentanil vs. other opioids
100
10
Percent of peak plasma opioid concentration
fentanyl
1
sufentanil
alfentanil
remifentanil
0.1
0
120
240
360
480
600
Minutes since bolus injection
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Remifentanil vs. other opioids
100
sufentanil
80
fentanyl
60
Percent of peak effect site opioid concentration
40
alfentanil
20
remifentanil
0
0
2
4
6
8
10
Minutes since bolus injection
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50 effect sitedecrement curves
Minutes required
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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80 effect sitedecrement curves
Minutes required
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Propofol/opioid vs Isoflurane/opioid
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Propofol/opioid vs Isoflurane/opioid
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Propofol-RemifentanilInteraction and TIVA
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Propofol/Alfentanil Interaction
400

• Adapted from Vuyk et al, Anesthesiology 838-22,
  1995
• Characterizes the concentrations for
• intubation
• maintenance
• on emergence
• Concentrations are 50 response level

Intubation
300
Maintenance
200
Alfentanil Concentration (ng/ml)
Emergence
100
0
0
2
4
6
8
10
Propofol Concentration (mg/ml)
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Propofol/Remifentanil TIVA

• Remifentanil
• 0.25 mg/kg/min
• Propofol
• 80 mg/kg/min
• Requires controlled ventilation

Shafer SL, ASA Refresher Course, Chapter 19, 1996

• Little tolerance for interruption of
  remifentanil or propofol infusion

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10 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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60 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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600 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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Hierarchical Model of Drug Interaction
Hypnotics
Opioids,N2O
Conscious,Responsive
Cortex
AmbientStimuli
Unconscious,Unresponsive
SystemicOpioids
Pain projection
Midbrain, Thalamus
Severe
N2O
to cortex
None
Spinal
Local
Opioids
Anesthetics
Pain projection
Severe
to midbrain
Peripheral nerves, Spinal cord
None
Inspired by Glass PS.. Anesthesiology. 1998
885-6.
Pain
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Hierarchical Model of Drug Interaction
AmbientStimuli
Afferent Stimuli
Pain projection
to cortex
Pain
Pain
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Propofol-RemifentanilInteraction Surface
Laryngoscopy
Bouillon et al, Anesthesiology 2004
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Propofol-RemifentanilInteraction Surface
Laryngoscopy
Bouillon et al, Anesthesiology 2004
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Propofol-RemifentanilInteraction Surface BIS
Bouillon et al, Anesthesiology 2004
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Propofol-RemifentanilInteraction Surface BIS
Bouillon et al, Anesthesiology 2004
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Awareness and TIVA
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My two cases

• 1. Treat light anesthesia, then pontificate.
• 2. Dont turn off your anesthetic for extended
  periods.

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The ASPECT Data Base

• Patient trials (movement)
• Thiopental
• Propofol
• Fentanyl/Alfentanil/Sufentanil
• Isoflurane
• Nitrous Oxide
• Volunteer trials (recall, sedation, eyelash)
• Propofol
• Isoflurane
• Alfentanil
• Midazolam

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Recall vs. Heart Rate and Blood Pressure
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RecallBIS vs Blood Pressure
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RecallBispectral Index vs Concentration
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MovementD Heart Rate vs D Blood Pressure
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Predictors of Movement
Measure
Pk
0.74
Blood propofol
0.76
Effect-site propofol
Bispectral Index
0.86
Relative delta power
0.79
Relative beta power
0.83
95 SEF (Hz)
0.81
Median Frequency (Hz)
0.8
Leslie et al, Anesthesiology 8452-63, 1996
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Sedation, BIS, and Propofol
Glass et al, Anesthesiology 86836-847, 1997
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BIS Interpretation
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Conscious/Unconscious Prediction (Pk)
Target
Measured
Agent (n)
BIS
Concentration
Concentration
Propofol (399)
0.976 0.006
0.936 0.010
0.937 0.013
Isoflurane (70)
0.959 0.021
0.965 0.015
0.967 0.016
Midazolam (50)
0.885 0.047
0.859 0.045
0.886 0.048
Significantly different from Pk value for Target
Concentration (p lt 0.001),
and Measured concentration (p lt 0.01)
Glass et al, Anesthesiology 86836-847, 1997
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PK for AAI, BIS, and Predicted Propofol
Concentrations(when combined with remifentanil)
Struys et al, Anesthesiology 99802-812
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BIS and Clinical Ranges
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Bottom line on awareness

• Give enough drug.
• Dont completely paralyze patients unless
  absolutely necessary.
• Look for changes in heart rate.
• Respond to light anesthesia with a bolus of
  propofol.
• BIS contains valuable additional information
• Did I mention you need to give enough drug?

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Why do TIVA?
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Top 10 reasons to do TIVA

• Patients like waking up from TIVA
• Patients like waking up from TIVA
• Patients like waking up from TIVA
• Patients like waking up from TIVA
• Patients like waking up from TIVA
• Patients like waking up from TIVA
• Patients like waking up from TIVA
• Patients like waking up from TIVA
• Patients like waking up from TIVA
• Patients like waking up from TIVA

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Isoflurane Hyperalgesia
Pamela Flood, preliminary data
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Propofol vs. Isoflurane
Pamela Flood, preliminary data
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What is the role of N2O?

• Excellent analgesic in sub-MAC doses
• MAC is around 110.
• MACasleep tends to be about 60 of MAC.
• MACasleep for N2O is 68-73
• Well tolerated by most patients.
• At N2O concentrations of 70, there may be no
  need for additional drugs to ensure lack of
  awareness.
• Has the fastest elimination of any hypnotic agent
  used in anesthesia.
• If you want your patients to wake up quickly,
  keep them within N2O of being awake!

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Key Concept

• If you want your patients to wake up quickly,
  keep them within N2O of being awake!

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Practical Aspects of TIVA
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Setting up your pump

• Check out your infusion pump as thoroughly as you
  check out your anesthesia machine.
• Is your drug dilution correct?
• Is the syringe and plunger properly held in the
  clamp?
• Are your infusion units correct?
• Is the weight correct (for calculator pumps)?
• Has the dead space been taken out of the line?
• Have the batteries been checked?
• Think of the check out as though you were going
  to infuse sodium nitroprusside.

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Setting up drug infusions

• Always infuse drug as close to the catheter as
  possible.
• Typical IV tubing contains 5-8 mls of dead space
  between injection ports and catheter.

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Easy Propofol - Remifentanil

• Add 1 mg of remifentanil to your 50 cc propofol
  syringe
• Remifentanil concentration will be 20 mg/ml
• Approach gives a bit less remi than you might
  otherwise use.
• Use with 70 N2O, or increase propofol dose to
  100-120 mg/kg/min

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Remifentanil Maintenance Infusion Rates

• 1.0 mg/kg/min
• Profound analgesia
• 0.5 mg/kg/min
• Paralysis required
• 0.25 mg/kg/min
• Ventilation required
• gt 50 MAC reduction
• 0.1 mg/kg/min
• May be satisfactoryfor spontaneous ventilation

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Steves TIVA Approach

• Unremarkable IV induction
• Propofol, fentanyl, relaxant
• After induction, just run 66-70 nitrous oxide.
  Dont start propofol/remi until BP recovers.
• Remifentanil
• Start _at_ 0.1 mg/kg/min
• Maintain _at_ 0.05-0.3 mg/kg/min
• Propofol
• Start _at_ 40 mg/kg/min
• Maintain _at_ 25-76 mg/kg/min
• Either monitor BIS, or dont fully paralyze

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Transition to postoperative analgesia

• Local Anesthesia
• Methadone 5-10 mg
• 45-60 minutes before the end of anesthesia
• Morphine 5-10 mg
• 15-30 minutes before the end of anesthesia
• Fentanyl 50-100 mg
• 5-10 minutes before the end of anesthesia

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Download athttp//anesthesia.stanford.eduOnline
Lectures/Pharmacology
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