[ppt]applications of pk/pd in support of total...
TRANSCRIPT
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EEG In AnesthesiaEEG In Anesthesia
Steven L. Shafer, M.D.Palo Alto VA Health Care SystemAssociate Professor of Anesthesia
Stanford University, Palo Alto, California
Control of Anesthetic Depth:Integrating Effect Site Anesthetic Concentrations
with Measures of Anesthetic Drug Effect
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EEG In AnesthesiaEEG In Anesthesia
How do we measure anesthetic depth?Blood pressureHeart rateResponse to noxious stimulation
D blood pressure, D heart rate, and movement
How well do these work?How should we titrate anesthetic drugs?
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The ASPECT Data BaseThe ASPECT Data Base
Aspect Medical SystemInventor of the “Bispectral Index”
mysteriously called the “BIS”Validating Bispectral Index as a measure of anesthetic
depthMovement in response to noxious stimulation
- in > 300 patients undergoing surgeryRecall, Sedation, Eyelash reflex
- in >100 volunteers
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The ASPECT Data BaseThe ASPECT Data Base
Patient trials (movement):ThiopentalPropofolFentanyl/Alfentanil/SufentanilIsofluraneNitrous Oxide
Volunteer trials (recall, sedation, eyelash):PropofolIsofluraneAlfentanilMidazolam
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The ASPECT Data BaseThe ASPECT Data Base
Aspect Investigators:Peter Sebel (Emory)Peter Glass (Duke)Carl Rosow (Harvard/MGH)Lee Kearse (Harvard/MGH)Marc Bloom (University of Pittsburgh)Ira Rampil (University of California, San Francisco)Randy Cork (University of Arizona)Mark Jopling (Ohio State University)N. Ty Smith (University of California, San Diego)Paul White (University of Texas at Dallas)
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RecallRecallHeart Rate Heart Rate vsvs Blood Pressure Blood Pressure
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RecallRecallBIS BIS vsvs Blood Pressure Blood Pressure
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RecallRecallBispectral Index Bispectral Index vsvs Concentration Concentration
01
23
45
Effect Site Concentration
3040
5060
7080
90100
BIS
00.
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40.
60.
81
prob
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MovementMovementHeart Rate Heart Rate vsvs Blood Pressure Blood Pressure
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MovementMovementDD Heart Rate Heart Rate vsvs DD Blood Pressure Blood Pressure
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MovementMovementBispectral Index Bispectral Index vsvs Blood Pressure Blood Pressure
4060
80100
120
140 Blood Pressure (MAP)
020
4060
80100
BIS
00.
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60.
81
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MovementMovementBispectral Index Bispectral Index vsvs Concentration Concentration
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MovementMovementBlood Pressure Blood Pressure vsvs Concentration Concentration
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Eyelash ReflexEyelash ReflexBispectral Index Bispectral Index vsvs Concentration Concentration
020
4060
80100
BIS0
24
68
10
Effect Site Concentration
0
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0.4
0.6
0.8
1
Probability of No Lash Reflex
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SedationSedationBispectral Index Bispectral Index vsvs Concentration Concentration
020
4060
80100
BIS0
24
68
10
Effect Site Concentration
0
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0.4
0.6
0.8
1.0
Probability of Deep Sedation
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Application of PK/PD in Support of Application of PK/PD in Support of Total Intravenous AnesthesiaTotal Intravenous Anesthesia
Most important predictor of movement is the predicted concentration
The EEG, based on the Bispectral Index, offers additional information about the probability of
sedation/eyelash reflexrecallmovement in response to noxious stimulation
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Application of PK/PD in Support of Application of PK/PD in Support of Total Intravenous AnesthesiaTotal Intravenous Anesthesia
The predicted concentration is available to anesthesiologists using many available software programs
IVA-SIM (J. Schüttler)STANPUMP (S. Shafer)STELPUMP (J. Coetzee/R. Pina)
All of the above are available on the WWW at:http://pkpd.icon.palo-alto.med.va.gov
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Application of PK/PD in Support of Application of PK/PD in Support of Total Intravenous AnesthesiaTotal Intravenous Anesthesia
The predicted concentration is the basis of open-loop infusion devices:
Commercially available:Diprifusor®
For research purposesSTANPUMPSTELPUMPIVA-SIMCACI
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Application of PK/PD in Support of Application of PK/PD in Support of Total Intravenous AnesthesiaTotal Intravenous Anesthesia
Closed-loop controlPK/PD models used to predict concentration
effect-site concentration, based on drug interaction models, is the primary feedback for the system
The Bispectral Index adds information about the probability of sedation/recall/movement
Only to the extent supported by the data and prospective validation
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In the mean time……….In the mean time……….
Can use dosage nomograms:designed on same PK/PD concepts
specific measures of anesthetic depthpharmacokinetics of intravenous anestheticsmodels of drug interaction
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Dosage NomogramDosage Nomogram
Vuyk, et al: Pharmacodynamic Interaction of Propofol and Alfentanil
Anesthesiology 83:8-22, 1995
Stanski and Shafer: Quantifying Anesthetic Drug Interaction: Implications for Drug Dosing
Anesthesiology 83:1-5, 1995
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Propofol/Alfentanil InteractionPropofol/Alfentanil InteractionVuyk et al, Anesthesiology 83:8-22, 1995Vuyk et al, Anesthesiology 83:8-22, 1995
Intubation
0
100
200
300
400
500
600
0 5 10Propofol IC50 (g/ml)
Alfe
ntan
il IC
50 (n
g/m
l)
Maintenance
0
100
200
300
400
500
600
0 5 10 15 20Propofol IC50 (g/ml)
Alfe
ntan
il IC
50 (n
g/m
l)
Emergence
0
50
100
150
200
250
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0 2 4Propofol IC50 (g/ml)
Alfe
ntan
il IC
50 (n
g/m
l)
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““Optimal Dosing”Optimal Dosing”Stanski/Shafer, Anesthesiology 83:1-5, 1995Stanski/Shafer, Anesthesiology 83:1-5, 1995
Time (Minutes)0 120 240 360 480 600
Rec
over
y Pe
rcen
t
0255075
100
Alfe
ntan
il (n
g/m
l)
0100200300400
Prop
ofol
(g/
ml)
0
2
4
6
Infu
sion
Rat
es
0100200300400
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over
y Ti
me
05
101520
Minutes from ending the infusions to awakening
Maintenance concentrationConcentration on emergence
Maintenance concentrationConcentration on emergence
Propofol (g/kg/min)
Alfentanil (ng/kg/min)
Propofol percent decrement for emergence
Alfentanil percent decrement for emergence
A
B
C
D
E
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Dosing Nomogram for TIVA Dosing Nomogram for TIVA
Minutes since beginning of infusion
Infu
sion
rate
s to
mai
ntai
n st
able
pla
sma
conc
entra
tions
0
1
2
3
4
5
( g/kg/hr)Fe
ntan
yl (n
g/m
l)
0.91.21.51.82.12.42.73.0
3.64.56.0
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100
200
300
400
500
600
( g/kg/min)
Alfe
ntan
il (n
g/m
l)
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0.75
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0.8
1.0( g/kg/hr)
Suf
enta
nil (
ng/m
l)
0.150.3
0.50.60.70.80.91.0
1.2
1.52.0
0 60 120 180 240 3000
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4
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8
( g/kg/min)
Pro
pofo
l ( g
/ml)
255075100120140160180200
250300
Suggested Initial Target
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Dosing Nomogram for TIVADosing Nomogram for TIVA
Minutes since beginning of infusion
Infu
sion
rate
s to
mai
ntai
n st
able
pla
sma
conc
entra
tions
0
1
2
3
4
5 ( g/kg/hr)
Fent
anyl
(ng/
ml)
0.91.21.51.82.12.42.73.0
3.64.56.0
0
100
200
300
400
500
600 ( g/kg/min)
Alfe
ntan
il (n
g/m
l)3.0 2.5 2.25 2.0 1.75
1.5
1.25
1.0
0.75
0.25
0.5
0.0
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0.4
0.6
0.8
1.0 ( g/kg/hr)
Suf
enta
nil (
ng/m
l)
0.150.3
0.50.60.70.80.91.0
1.2
1.52.0
0 60 120 180 240 3000
2
4
6
8 ( g/kg/min)
Pro
pofo
l ( g/
ml)
255075100120140160180200
250300
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Application of PK/PD in Support of Application of PK/PD in Support of Total Intravenous AnesthesiaTotal Intravenous Anesthesia
Conclusions1. Heart rate and blood pressure are poor
predictors of anesthetic depth.2. The best predictor of the probability of
movement, recall, level of sedation, andeyelash reflex is predicted effect siteconcentration.
Requires a model of drug interaction
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Application of PK/PD in Support of Application of PK/PD in Support of Total Intravenous AnesthesiaTotal Intravenous Anesthesia
Conclusions3. The Bispectral Index adds information as a
predictor of:Sedation/eyelash reflexrecallmovement in response to noxious stimulation
4. Nomograms and the Bispectral Analysisare presently available
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Application of PK/PD in Support of Application of PK/PD in Support of Total Intravenous AnesthesiaTotal Intravenous Anesthesia
Conclusion5. Open loop systems will be available soon:
Diprifusor®Research Systems
6. Closed-loop systems have been developedfor research purposes:
EEG-Based (Schwilden/Schüttler)Auditory evoked potentials (Kenny)