Are there limits for general anesthesia

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

� 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 protection Reflexes protectionReflexes protection Absence of movementAbsence of movement

MuscleMusclerelaxationrelaxation

Control ofControl ofstress stress

responseresponse

UnconsciousnessUnconsciousness

Hypnotics + inhalation agentsHypnotics + inhalation agents

Muscle relaxantsMuscle relaxantsAnalgesicAnalgesic

drugsdrugs

Modern balanced anesthesiaModern balanced anesthesia

Assessing anesthetic depthAssessing anesthetic depth

Autonomic signsAutonomic signs HR,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

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

MACMAC

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

MAC TablesMAC Tables

MacawakeMacawake

MAC inO2MAC inO2

MAC inN2O 60%MAC inN2O 60%

MACbarMACbar

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

MAC PyramidMAC Pyramid

Stressresponsecontrol

Stressresponse

controlMAC barMAC bar

MovementMovement

MACMAC

UncosciousnessUncosciousness

Mac awakeMac awake

fraction of MAC

MuscleMusclerelaxationrelaxation

Control ofControl ofstress stress

responseresponse

UnconsciousnessUnconsciousness

Inhalation agents

Muscle relaxantsMuscle relaxants Analgesic drugsAnalgesic drugs

NeurolepticsNeuroleptics

Hypnotics and BDZs

Drugs for general anesthesiaDrugs for general anesthesia

balance of anesthesiabalance of anesthesia

AnesthesiaAnesthesia

respiratorydepressionrespiratorydepression

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

CONCENTRAZIONE

Concentration/effect curves for iv drugs

Inclinazione margine terapeutico

EC50 ED50

seCp50 concept

Isobolograms:

A: additive

B: sinergistic

C: infraadditive

Interaction between propofol, midazolam and alfentanil for LOC

IOT induzione mantenim. risveglio sedazione0

l ( µ

Maitre PO, 1994

Propofol: effective Cp50 relative to different stimulations

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

Propofol: relationship between plasma concentration and CNS depression

Shafer SL, Stanski DR, 1991

Loss of consciousnessLoss of consciousnessknowledge ofknowledge of

LOCLOC

time to peakeffect

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

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

alfentanilalfentanil 5959 1,41,4

sufentanilsufentanil 8989 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 solo 1.5-101.5-10 100-750100-750 0,25-10,25-1

mant con O2 solomant con O2 solo 15-60 1000-40001000-4000 00

RS suff all'emergRS suff 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 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 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

PharmacodynamicsPharmacodynamicsassumptionsassumptions

MEACMEAC

fent:0.6ng/mlfent:0.6ng/ml

Respdepression

>2 ng/ml>2 ng/ml

MACreduction

MACreduction 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

Some significant decrement times for the modern inhalatory agents.

0102030405060708090

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: 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

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

Propofol blood concOpioid blood concentration

Three dimensional planes in the graphs from Vuyk et al.

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

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

ArousalArousalMovementMovement

Autonomic effectsAutonomic effects

AwarenessAwareness

recallrecall

analgesics

hypnotics

anxyolysis

Amnesia

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.

Blaise PascalBlaise Pascal

(lecture)

Are there limits for general anesthesia

Health & Medicine

Transcript of Are there limits for general anesthesia

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