Are there limits to ga?

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Ci sono limiti alla Anestesia generale?

Claudio MelloniServizio di Anestesia e Rianimazione

Ospedale degli Infermi Faenza(RA)


I limiti della anestesia generale

Claudio MelloniServizio di Anestesia e Rianimazione

Ospedale degli Infermi di FaenzaFaenza(RA)


Lecture outline What is GA? GA and awareness;skipped! Inhalations vs tiva:experience vs mathematics PK-PD and tiva trainer:from theory to practice From practice to theory and back to

practice-………………. 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 anaesthesiaRees & Gray 1950,Gray 1960Rees & Gray 1950,Gray 1960

Drug induced uncosciousness:the patient does not perceive nor recall noxious stimulationDrug induced uncosciousness:the patient does not perceive nor recall 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 the stress responseParalysis uncosciousness & attenuation of the stress 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,motor block,block of reflexes,mental blockSensory block,motor block,block of reflexes,mental block

WoodbrigeWoodbrige

All separate effects useful to protect the patient from the stress of surgeryAll separate effects useful to protect the patient from the stress 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.

Reversible oblivion and immobilityReversible oblivion and immobility

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 anesthesiaDo they fir together?Do they fir together?

HypnosisHypnosis AmnesiaAmnesia AnalgesiaAnalgesia Muscle relaxationMuscle relaxation

Stress protectionStress protectionReflexes protectionReflexes protectionAbsence of movementAbsence of movement


Musclerelaxation

Control ofstress

response

Unconsciousness

Hypnotics + inhalation agents

Muscle relaxants Analgesicdrugs

Modern balanced anesthesia


Assessing anesthetic depthAssessing anesthetic depth

Autonomic signsAutonomic signsHR,BP,sweat,tears(PRST score...)HR,BP,sweat,tears(PRST score...)

Somatic signsSomatic signs moving,coughing.breathing...moving,coughing.breathing...

Response to stimulationResponse to stimulationvoice,eyelashreflex,pinprick,incision,intubation,visceraltraction

voice,eyelashreflex,pinprick,incision,intubation,visceraltraction

Anesthetic concentrationAnesthetic concentrationMAC,plasma conc,effect site conc....MAC,plasma conc,effect site conc....


MACMAC

Macawake50-95

Macawake50-95

Anestheticalveolarconcentrationpreventingawareness in 50%or 95% ofsubjects…(Stoelting1970);

Anestheticalveolarconcentrationpreventingawareness in 50%or 95% ofsubjects…(Stoelting1970);

MACMAC

Minimum alveolarconcentration ofanestheticpreventing movementin response toincision in 50-95% ofsubjects..

Minimum alveolarconcentration ofanestheticpreventing movementin response toincision in 50-95% ofsubjects..

MAC bar50-95MAC bar50-95

Minimum alveolarconcentration ofanesthetic preventingstress response tosurgical stimulation in50-95% of patients

Minimum alveolarconcentration ofanesthetic preventingstress response tosurgical stimulation in50-95% of patients


MAC TablesMAC Tables

MacawakeMacawake

MAC inO2MAC inO2

MAC inN2O 60%MAC inN2O 60%

MACbarMACbar

halothanehalothane0.410.41 0.70.7 0.30.31.3Mac1.3Mac

isofluraneisoflurane0.380.38 1.141.14 0.500.501.3 Mac1.3 Mac

sevofluranesevoflurane0.620.62 22 0.600.601.5 Mac1.5 Mac

desfluranedesflurane2.422.42 66 2.832.831.5 Mac1.5 Mac


MAC PyramidMAC Pyramid

Stressresponse

control

Stressresponse

controlMAC barMAC bar

MovementMovement

MACMAC

UncosciousnessUncosciousness

Mac awakeMac awake

fraction of MAC

0.5

1.0

1.5


Musclerelaxation

Control ofstress

response

Unconsciousness

Inhalation agents

Muscle relaxants Analgesic drugs

Neuroleptics

Hypnotics and BDZs

Drugs for general anesthesia


balance of anesthesiabalance of anesthesia

AnesthesiaAnesthesia

respiratorydepressionrespiratorydepression

cardiovasculardepression

cardiovasculardepression


Steady state alveolar concentrationSteady state alveolar concentrationwhat does it meanswhat does it means

PA=kCAPA=kCA

where PA is maintained at a constant value forat least 10 minwhere PA is maintained at a constant value forat 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

IntubationTrapezius squeeze

Laringoscopy

Skin incision


EFFE

TTO

CONCENTRAZIONE

Concentration/effect curves for iv drugs

Inclinazione margine terapeutico

EC50 ED50


Prob

abili

ty o

f no-

res

pons

eCp50 concept


Isobolograms:A: additiveB: sinergisticC: infraadditive


Interaction between propofol, midazolam and alfentanil for LOC


IOT induzione mantenim. risveglio sedazione0

2

4

6

8

10

12

conc

entr

azio

ne e

mat

ica

di

prop

ofol

(mg/

ml)

Maitre PO, 1994

?

Propofol: effective Cp50 relative to different stimulations


10

8

6

4

2

0sedazione TIVA: minore: maggiore: TIVA: Propofol- Propofol- Propofol- solo Propofol oppioide N2O N2O

Prop

ofol

(mg/

ml)

Propofol: relationship between plasma concentration and CNS depression

Shafer SL, Stanski DR, 1991


Loss of consciousnessLoss of consciousnessknowledge ofknowledge of

LOCLOC

time to peakeffect

time to peakeffect

haemodynamiceffects

haemodynamiceffects

impact ofdrug

combination

impact ofdrug

combination


Loading dose correctedLoading dose corrected

loading doseloading dosebased on Vdincorporating thebiophase

based on Vdincorporating thebiophase

drug choiceand timing

drug choiceand timing

based on Keo andits time to peakeffect

based on Keo andits time to peakeffect


Vpeak effectVpeak effectProportionality constant which,when multiplied by the target concentration,

should produce the desired peak effect in the number of minutes noted.Proportionality constant which,when multiplied by the target concentration,

should produce the desired peak effect in the number of minutes noted.

V peakeffect(Lt)V peakeffect(Lt)

Time to peakeffect(min)Time to peakeffect(min)

fentanylfentanyl 7575 3,63,6

alfentanilalfentanil5959 1,41,4

sufentanilsufentanil8989 5,65,6

propofolpropofol 2424 22Shafer 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 isofluraneIsoflurane 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. Anesthesiology76:52-59, 1992


Sevoflurane Mac awake reduction by fentanylKatoh 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 Anesthesiology87:1549-62, 1997


manual opioid infusion schemesmanual opioid infusion schemesfrom many sources...from many sources...

drugdrug plasma targetconcentation(ngml)plasma targetconcentation(ngml) bolus(microgr/kg)bolus(microgr/kg)

infusion rate(microgr/kg/mininfusion 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 terapeuticaoppioidioppioidi

fent(ng/ml)fent(ng/ml)alfent(ng/ml)alfent(ng/ml)sufent(ng/ml)sufent(ng/ml)

induz & intub contpsinduz & intub contps

3-53-5 250-400250-400 0,4-0,60,4-0,6

induz & intub conN2Oinduz & intub conN2O

8-108-10 400-750400-750 0,8-1,20,8-1,2

mant conN2O+inhalatmant conN2O+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 solo15-60 1000-40001000-400000

RS suff all'emergRS suff all'emerg1,5 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 PropofolGepts Anesth Analg 66;1256;1987 & Marsh.BJA 67;41:1991 &Gepts Anesth Analg 66;1256;1987 & Marsh.BJA 67;41:1991 &

GeptsGepts MarshMarsh

V1V1 767767228 ml/kg228 ml/kgK10K10 0.0350.0350.119/min0.119/minKeoKeo 0.630.630.26/min0.26/minK12K120.28660.28660.114/min0.114/minK21K210.08660.08660.055/min0.055/minK13K130.27300.27300.0419/min0.0419/minK31K31 0.0360.0360.0033/min0.0033/min


PharmacodynamicsPharmacodynamicsassumptionsassumptions

MEACMEAC

fent:0.6ng/mlfent:0.6ng/ml

Respdepression

Respdepression

>2 ng/ml>2 ng/ml

MACreduction

MACreductionCSHTCSHT

RecoveryRecoveryED95 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.

0102030405060708090

100

min

50% decr.times 80% decr times after60 min

90% decr times after300 min

desfluranesevofluraneisofluraneenflurane


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


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).

Address reprint requests to Dr. Shafer: Pharsight Corporation, 800 West El Camino Real # 200, Mountain View, California 94040. Address electronic mail to: [email protected]


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

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

time

Propofol blood concOpioid blood concentration

Threedimensional 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

ArousalArousalMovementMovement

Autonomic effectsAutonomic effects

AwarenessAwareness

recallrecall

analgesics

hypnotics

anxyolysisAmnesia


Closing the loop:Servoanesthesia(AEP by GC Kenny)


Theory and practice:1


New definition of anesthesi..ology

Anesthesiology ..is the practice of pharmacology synergism using central nervous system depressant..T.D.Egan ,2003 .


I have made this letter longer thanusual, because I lack the time tomake it short.

I have made this letter longer thanusual, because I lack the time tomake it short.

Blaise PascalBlaise Pascal

(lecture)

Are there limits to ga?

Health & Medicine

Transcript of Are there limits to ga?