Are there limits to ga?

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Ci sono limiti alla Anestesia
generale?
Claudio Melloni
Servizio di Anestesia e Rianimazione
Ospedale degli Infermi
Faenza(RA)

I limiti della anestesia generale
Claudio Melloni
Servizio di Anestesia e Rianimazione
Ospedale degli Infermi di Faenza
Faenza(RA)

Lecture outline
l What is GA?
l GA and awareness;skipped!
l Inhalations vs tiva:experience vs mathematics
l PK-PD and tiva trainer:from theory to practice
l From practice to theory and back to
practice-……………….
l We cannot became what we need to
be by remaining what we are(Maxwell De
Pree,Author and Chairman Emeritus,Hermann Miller Inc,Zeeland
.Michigan)

Definitions of anaesthesiaDefinitions of anaesthesia
R ees & Gray 1950,Gray 1960R ees & Gray 1950,Gray 1960
D rug induced uncosciousness:the patientdoes notperceivenorrecall noxious stimulationD rug induced uncosciousness:the patientdoes notperceivenorrecall noxious stimulation
Prys-Roberts C. Anaesthesia: a practical or impractical construct? [editorial]. Br J Anaesth 1987; 59:1341-5.Prys-Roberts C. Anaesthesia: a practical or impractical construct? [editorial]. Br J Anaesth 1987; 59:1341-5.
Paralysis uncosciousness & attenuation of thestress responseParalysis uncosciousness & attenuation of thestress response
Pinsker MC. Anesthesia: a pragmatic construct. Anesth Analg 1986; 65:819-20.Pinsker MC. Anesthesia: a pragmatic construct. Anesth Analg 1986; 65:819-20.
Sensory block,motorblock,blockof reflexes,mentalblockSensory block,motorblock,blockof reflexes,mentalblock
WoodbrigeWoodbrige
A ll separate effects useful toprotect the patient fromthestress of surgeryA ll separate effects useful toprotect the patient fromthestress of surgery
Kissin I, Gelman S. Components of anaesthesia. Br J Anaesth 1988; 61:237-42.Kissin I, Gelman S. Components of anaesthesia. Br J Anaesth 1988; 61:237-42.
R eversibleoblivionandimmobilityR eversibleoblivionandimmobility
Eger EI II. What is general anesthetic action? [editorial]. Anesth Analg 1993; 77:408.Eger EI II. What is general anesthetic action? [editorial]. Anesth Analg 1993; 77:408.

Modern balanced anesthesiaModern balanced anesthesia
Do they fir together?Do they fir together?
Hy pnos isHy pnos is Amnes iaAmnes ia Analges iaAnalges ia Mus cle relax ationMus cle relax ation
Str es s protec tionStr es s protec tion Reflex es pr otectionReflex es pr otection Absenc e of movementAbsenc e of movement

Muscle
relaxation
Control of
stress
response
Unconsciousness
Hypnotics + inhalation agents
Muscle relaxants
Analgesic
drugs
Modern balanced anesthesia

Assessing anesthetic depthAssessing anesthetic depth
Autonomic signsAutonomic signs HR,BP,sweat,tears(PRST score...)HR,BP,sweat,tears(PRST score...)
Som atic signsSom atic signs moving,coughing.breathing...moving,coughing.breathing...
Response to stimulationResponse to stimulation
voice,eyelash
reflex,pinprick,incision,intubation,visceral
traction
voice,eyelash
reflex,pinprick,incision,intubation,visceral
traction
Anesthetic concentrationAnesthetic concentration
MAC,plasma conc,effect site conc....MAC,plasma conc,effect site conc....

MACMAC
Mac
awake50-95
Mac
awake50-95
Anesthetic
alveolar
concentration
preventing
awareness in 50%
or 95% of
subjects…(Stoelting
1970);
Anesthetic
alveolar
concentration
preventing
awareness in 50%
or 95% of
subjects…(Stoelting
1970);
MACMAC
Minimum alveolar
concentration of
anesthetic
preventing movement
in response to
incision in 50-95% of
subjects..
Minimum alveolar
concentration of
anesthetic
preventing movement
in response to
incision in 50-95% of
subjects..
MAC bar50-95MAC bar50-95
Minimum alveolar
concentration of
anesthetic preventing
stress response to
surgical stimulation in
50-95% of patients
Minimum alveolar
concentration of
anesthetic preventing
stress response to
surgical stimulation in
50-95% of patients

MAC TablesMAC Tables
Mac
awake
Mac
awake
MAC in
O2
MAC in
O2
MAC in
N2O 60%
MAC in
N2O 60%
MAC
bar
MAC
bar
halothanehalothane 0.410.41 0.70.7 0.30.3 1.3Mac1.3Mac
isofluraneisoflurane 0.380.38 1.141.14 0.500.50 1.3 Mac1.3 Mac
sevofluranesevoflurane 0.620.62 22 0.600.60 1.5 Mac1.5 Mac
desfluranedesflurane 2.422.42 66 2.832.83 1.5 Mac1.5 Mac

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) fraction of MAC
0.
5
1.0
1.5

Muscle
relaxation
Control of
stress
response
Unconsciousness
Inhalation agents
Muscle relaxants Analgesic drugs
Neuroleptics
Hypnotics and BDZs
Drugs for general anesthesia

balance of anesthesiabalance of anesthesia
Anesthesi aAnesthesi a
respiratory
depressi on
respiratory
depressi on
cardiovascular
depressi on
cardiovascular
depressi on

Steadystate alveolar concentrationSteadystate alveolar concentration
what does it meanswhat does it means
PA=kCAPA=kCA
where PA is maintained at a constant value for
at least 10 min
where PA is maintained at a constant value for
at least 10 min
PA=CA=BrainPA=CA=Brain

Rate of rise of alveolar(FA) anesthetic concentration toward
the inspired (Fi) concentration
Min .of administration

Logistic regression curves relating end tidal isoflurane
concentrations and multiple stimulations Zbinden AM, Maggiorini M,
Petersen-Felix S, Lauber R, Thomson DA, Minder CE: Anesthetic depth defined using multiple
noxious stimuli during isoflurane/oxygen anesthesia: I. Motor reactions. ANESTHESIOLOGY
80:253-260, 1994
Tetanic
stimulation
Intubation
Trapezius squeeze
Laringoscopy
Skin incision

EFFETTO
CONCENTRAZIONE
Concentration/effect curves for iv drugs
Inclinazione  margine
terapeutico
EC50  ED50

Probabilityofno-response Cp50 concept

Isobolograms:
A: additive
B: sinergistic
C: infraadditive

Interaction between propofol, midazolam and
alfentanil for LOC

IOT induzione mantenim. risveglio sedazione
0
2
4
6
8
10
12
concentrazioneematicadi
propofol(mg/ml)
Maitre PO, 1994
?
Propofol: effective Cp50 relative to different
stimulations

10
8
6
4
2
0
sedazione TIVA: minore: maggiore: TIVA:
Propofol- Propofol- Propofol- solo Propofol
oppioide N2O N2O
Propofol(mg/ml)
Propofol: relationship between plasma
concentration and CNS depression
Shafer SL, Stanski DR, 1991

Loading dose correctedLoading dose corrected
loading doseloading dose
based on Vd
incorporating the
biophase
based on Vd
incorporating the
biophase
drug choice
and timing
drug choice
and timing
based on Keo and
its time to peak
effect
based on Keo and
its time to peak
effect

Vpeak effectVpeak effect
Proportionality constant which,whenmultipliedby thetarget concentration,
shouldproducethedesiredpeak effect inthenumber of minutes noted.
Proportionality constant which,whenmultipliedby thetarget concentration,
shouldproducethedesiredpeak effect inthenumber of minutes noted.
V peak
effect(Lt)
V peak
effect(Lt)
Time to peak
effect(min)
Time to peak
effect(min)
fentanylfentanyl 7575 3,63,6
alfentanilalfentanil 5959 1,41,4
sufentanilsufentanil 8989 5,65,6
propofolpropofol 2424 22
Shafer SL,Kern DE,Stanki DR
.The scientific basis of infusion
techniques in anesthesia .
North Reading,Ma.Bard
Medical Division 1990.

Time course of serum concentration
versus EEG spectral edge:Remifentanil
(Anesthesiology 84:821-33,1996)

Fentanyl(150 microgr/kg) and EEG (Anesthesiology
90,566-99,1999)

Ausems ME, Vuyk J, Hug CC Jr, Stanski DR. Comparison of a computer
assisted infusion versus intermittent bolus administration of alfentanil
as a supplement to nitrous oxide for lower abdominal surgery.
Anesthesiology 1988; 68:851-61.

The interaction between fentanyl and
isoflurane(BJA 1998,81,38-50)

Interaction between remifentanil and isoflurane
Isoflurane concentration reduction by increasing remifentanil whole blood
concentration.Anesthesiology 85:721-8, 1996

Mac reduction of desflurane by fentanyl
Sebel PS., Glass PSA,Fletcher JE,Murphy M,Gallagher C,Quill T.Reduction of rhe Mac of
desflurane with fentanyl. Anesthesiology
76:52-59, 1992

Sevoflurane Mac awake reduction by fentanyl
Katoh T,Iked K. The Effects of Fentanyl on Sevoflurane Requirements for Loss of Consciousness
and Skin Incision ANESTHESIOLOGY 1998; 88:5—6.

MAC reduction of isoflurane
by sufentanil
+:no movement
-:movement

Plasma alfentanil vs propofol blood concentrations for 95%
probability of no response to surgical stimulation(Vuyk et al.Propofol
Anesthesia and Rational Opioid Selection: Determination of Optimal EC50-EC95 Propofol—Opioid
Concentrations that Assure Adequate Anesthesia and a Rapid Return of Consciousness Anesthesiology
87:1549-62, 1997

manual opioid infusion schemesmanual opioid infusion schemes
from many sources...from many sources...
drugdrug plasma target
concentation(ngml)
plasma target
concentation(ngml) bolus(microgr/kg)bolus(microgr/kg)
infusion rate
(microgr/kg/min
infusion rate
(microgr/kg/min
fentanylfentanyl 11 33 0.0200.020
fentanylfentanyl 44 1010 0.0700.070
alfentanilalfentanil 4040 2020 0.250.25
alfentanilalfentanil 160160 8080 1.001.00
sufentanilsufentanil 0.150.15 0.150.15 0.0030.003
sufentanilsufentanil 0.500.50 0.500.50 0.0100.010
remifentanilremifentanil 66 11 0.020.02
remifentanilremifentanil 12-2012-20 1-21-2 0.4-1.00.4-1.0

Fiset, P. Practical pharmacokinetics as applied to our daily
anesthesia practice .Can J Anesth 1999 / 46 / R122-R126

Finestra terapeuticaFinestra terapeutica
oppioidioppioidi
f ent(ng/ml)f ent(ng/ml)alf ent(ng/ml)alf ent(ng/ml)suf ent(ng/ml)suf ent(ng/ml)
induz & intub con
tps
induz & intub con
tps
3-53-5 250-400250-400 0,4-0,60,4-0,6
induz & intub con
N2O
induz & intub con
N2O
8-108-10 400-750400-750 0,8-1,20,8-1,2
mant con
N2O+inhalat
mant con
N2O+inhalat
1.5-41.5-4 100-300100-300 0,25-0,50,25-0,5
mant con N2O solomant con N2O solo1.5-101.5-10 100-750100-750 0,25-10,25-1
mant con O2 solomant con O2 solo 15-60 1000-40001000-4000 00
RS suf f all'emergRS suf f all'emerg 1,5 125125 0,250,25

TCI systems
From clinical experience and literature
recommendations to target
concentration ,where the system
calculates the infusion rate necessary
to achieve that concentration over time

Kinetic-dynamic dissociation and the effect
compartment

Pharmacokinetic parameters for PropofolPharmacokinetic parameters for Propofol
Gepts Anesth Analg 66;1256;1987 & Marsh.BJA 67;41:1991 &Gepts Anesth Analg 66;1256;1987 & Marsh.BJA 67;41:1991 &
GeptsGepts MarshMarsh
V1V1 767767 228 ml/kg228 ml/kg
K10K10 0.0350.035 0.119/min0.119/min
KeoKeo 0.630.63 0.26/min0.26/min
K12K12 0.28660.2866 0.114/min0.114/min
K21K21 0.08660.0866 0.055/min0.055/min
K13K13 0.27300.2730 0.0419/min0.0419/min
K31K31 0.0360.036 0.0033/min0.0033/min

PharmacodynamicsPharmacodynamics
assumptionsassumptions
MEACMEAC
fent:0.6
ng/ml
fent:0.6
ng/ml
Resp
depression
Resp
depression
>2 ng/ml>2 ng/ml
MAC
reduction
MAC
reduction CSHTCSHT
RecoveryRecovery
ED95 intraop for surgery/ED95 for recovery of consciousness & spont.resp.ED95 intraop for surgery/ED95 for recovery of consciousness & spont.resp.

Decrement times of desflurane,sevoflurane,isoflurane and
enflurane as a function of the duration of anesthetic
administration Bailey, J M.Anesth Analg 1997; 85:681-6
50%
80%
90%

Some significant decrement times for the modern
inhalatory agents.
0
10
20
30
40
50
60
70
80
90
100
min
50% decr.times 80% decr times after
60 min
90% decr times after
300 min
desflurane
sevoflurane
isoflurane
enflurane

Context sensitive half times as a
function of infusion duration
remifentanil

Three dimensional
surface
isobolograms
relating drugs A &
B with probability
of no
response;two
dimensional
isobolograms only
produces the line
at 50%
probability….
Minto CF, et al: Anesthesiology 92,1603-15,2000

l The software used in this investigation and other
software useful for modeling dose—response surfaces is
available via the World Wide Web at URL
http://pkpd.icon.palo-alto.med.va.gov in the directory
interaction.dir. The Appendices for this article and the
data set used for the analysis can be found on the
ANESTHESIOLOGY Web site (www.anesthesiology.org).
l Address reprint requests to Dr. Shafer: Pharsight
Corporation, 800 West El Camino Real # 200, Mountain
View, California 94040. Address electronic mail to:
sshafer@pharsight.com

Response
surface for each
of the paired
interactions.Max
effect is failure
to open eyes to
verbal command
Minto CF, et al: Anesthesiology 92,1603-15,2000

time
Propofol blood concOpioid blood concentration
Three dimensional planes in the
graphs from Vuyk et al.

Diprifusor

Calculations behind the target……

The “Tiva trainer”
Blood
conc(target)
Effect site concentration

Controlling the effect site concentration of propofol with
Diprifusor……….

Graphical TCI

TCI and monitoring

PK-PD & surgery…

Closing the loop..

SurgerySurgery StimulationStimulation
ArousalArousal
Mov ementMov ement
Autonomic effec tsAutonomic effec ts
Aw arenes sAw arenes s
rec allrec all
analgesics
hypnotics
anxyolysis
Amnesia

Closing the loop:Servoanesthesia(AEP by GC Kenny)

Theory and practice:1

New definition of
anesthesi..ology
l Anesthesiology ..is the
practice of pharmacology
synergism using central
nervous system
depressant..T.D.Egan ,2003 .

(lecture)

Are there limits to ga?

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Editor's Notes