Rev. Bras. Anestesiol. vol.65 número2

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

Comparative

study

between

fast

and

slow

induction

of

propofol

given

by

target-controlled

infusion:

expected

propofol

concentration

at

the

effect

site.

Randomized

controlled

trial

夽

Ricardo

Francisco

Simoni

,

Luiz

Eduardo

de

Paula

Gomes

Miziara

,

Luis

Otávio

Esteves

,

Diógenes

de

Oliveira

Silva

,

Cristina

Alves

Ribeiro

,

Mariana

Oki

Smith

,

Leonardo

Ferreira

de

Paula

,

Luis

Henrique

Cangiani

a_{DepartmentofPharmacology,UniversidadeEstadualdeCampinas(Unicamp),Campinas,SP,Brazil}

b_{CentrodeEnsinoeTreinamentodaSociedadeBrasileiradeAnestesiologia(CET/SBA),CentroMédicodeCampinas,Campinas,}

SP,Brazil

c_{Fundac¸ãoCentroMédicodeCampinas,Campinas,SP,Brazil}

d_{SociedadeBrasileiradeAnestesiologia,Brazil}

e_{CentrodeMedicinadoAparelhoDigestivodeSantaCatarina,SC,Brazil}

f_{HospitalSãoFranciscodeAssisdeSantoAmarodaImperatriz,SantoAmarodaImperatriz,SC,Brazil}

Received2May2013;accepted15July2013 Availableonline28November2014

KEYWORDS Anesthetics; Intravenous; Propofol; Pharmacology; Anesthetic techniques; General; Intravenous

Abstract

Backgroundandobjective: Studieshaveshownthattherateofpropofolinfusionmayinfluence the predicted propofol concentration atthe effectsite (Es). The aimof thisstudy was to evaluate the Es predicted by the Marshpharmacokinetic model (ke00.26min−1_{) inloss of}

consciousnessduringfastorslowinduction.

Method: Thestudyincluded28patientsrandomlydividedintotwoequalgroups.Inslow induc-tiongroup(S),target-controlledinfusion(TCI)ofpropofolwithplasma,Marshpharmacokinetic model(ke00.26min−1_{)withtargetconcentration(Tc)at}

2.0-␮gmL−1wereadministered.When

thepredictedpropofolconcentrationattheeffectsite(Es)reachedhalfofEsvalue,Eswas increasedtopreviousEs+1␮gmL−1,successively,untillossofconsciousness.Inrapidinduction

group(R),patientswereinducedwithTCIofpropofolwithplasma(6.0␮gmL−1)ateffectsite,

andwaiteduntillossofconsciousness.

夽

StudydevelopedatCET/SBAofInstitutoPenidoBurniereCentroMédicodeCampinas.

∗_{Correspondingauthor.}

E-mail:ricaboss@gmail.com(R.F.Simoni).

http://dx.doi.org/10.1016/j.bjane.2013.07.015

Results:Inrapidinductiongroup,Tcforlossofconsciousnesswassignificantlylowercompared toslowinductiongroup(1.67±0.76and2.50±0.56␮gmL−1,respectively,p=0.004).

Conclusion:Thepredictedpropofolconcentrationattheeffectsiteforlossofconsciousnessis differentforrapidinductionandslowinduction,evenwiththesamepharmacokineticmodel ofpropofolandthesamebalanceconstantbetweenplasmaandeffectsite.

©2014SociedadeBrasileiradeAnestesiologia.PublishedbyElsevier EditoraLtda.Allrights reserved.

PALAVRAS-CHAVE Anestésicos; Venoso; Propofol; Farmacologia; Técnicasanestésicas; Geral;

Venosa

Estudocomparativoentreinduc¸ãorápidaelentadepropofoleminfusão

alvo-controlada:concentrac¸ãodepropofolprevistanolocaldeac¸ão.Ensaioclínico aleatório

Resumo

Justificativaeobjetivo:Estudosmostraramqueataxadeinfusãodepropofolpodeinfluenciar naconcentrac¸ãoprevistadepropofolnolocaldeac¸ão(Ce).Oobjetivodesteestudofoiavaliar aCeprevistapelomodelofarmacocinéticodeMarsh(ke00,26min−1_{)naperdadaconsciência}

duranteinduc¸ãorápidaoulenta.

Método: Participaramdeste estudo 28 pacientes, divididos aleatoriamente em dois grupos iguais.Nogrupoinduc¸ãolenta(L),foraminduzidoscompropofoleminfusãoalvo-controlada (IAC)plasmática,modelofarmacocinéticodeMarsh(ke00,26min−1_{),comconcentrac¸ãoalvo}

(Ca)em2,0␮g.ml−1.Quandoaconcentrac¸ãodepropofolprevistanolocaldeac¸ão(Ce)atingia

metadedovalordaCa,aumentava-seaCaparaCaanterior+1␮g.ml−1.Assimsucessivamente

atéomomentodaperdadaconsciênciadopaciente.Nogrupoinduc¸ãorápida(R),ospacientes foraminduzidoscompropofolemIACplasmáticacomCaem6,0␮g.ml−1eaguardava-seaperda

daconsciênciadopaciente.

Resultados: Nogrupoinduc¸ãorápida,aCenaperdadaconsciênciafoisignificativamentemais baixa em relac¸ãoao grupo deinduc¸ãolenta (1,67±0,76e 2,50±0,56␮g.ml−1,

respectiva-mente,p=0,004).

Conclusão:A concentrac¸ão previstade propofol nolocal de ac¸ãodurante aperda da con-sciência édiferentenuma induc¸ãorápida enumainduc¸ão lenta,atécomomesmomodelo farmacocinéticodepropofoleamesmaconstantedeequilíbrioentreoplasmaeolocalde ac¸ão.

©2014SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos direitosreservados.

Introduction

Recently several studies have shown a good correlation between the predicted propofol concentration at the effect site (Es) by Marsh pharmacokinetic model (ke0 0.26min−1_{)andsedationdegree,bispectralindex(BIS)} val-ues,entropy,evokedpotentialindex,andlossandrecovery ofconsciousness.1---5

Becauseof thisgoodcorrelation with

pharmacodynam-ics,someauthorssuggested thatthetargetconcentration

ofpropofolshouldbetitratedduringmaintenanceof

anes-thesiabasedonEsreachedinlossofconsciousness.3,4,6

However, other studies show that the rate of infusion

ofpropofolmayinfluencethebalancebetweentheplasma

concentrationandtheconcentrationattheeffectsite;that is,inthefirst-ordermathematicalconstantcalledKe0.7,8

The main objective of this study was to evaluate

the Es predicted by the Marsh pharmacokinetic model

(ke0 0.26min−1_{) on loss of consciousness during rapid}

or slow induction of patients undergoing laparoscopic

cholecystectomy under total intravenous anesthesia with

propofol and remifentanil. Es was also evaluated during

anesthesiamaintenanceandrecovery.

Thehypothesistobetestedisthat,evenusingthesame

pharmacokineticmodelandthesameequilibriumconstant

between plasma and effect site, the effect site in rapid

inductionisdifferentfromthatinslowinductionduringloss

ofconsciousnesses.

Method

AfterapprovalbytheResearchEthicsCommitteeand

receiv-ingthewritteninformedconsent,28patients,agedbetween

18and65years,ofbothsexes,ASAphysicalstatus1and2,

and undergoing laparoscopic cholecystectomy under total

intravenousanesthesiawithpropofolandremifentanil,were

enrolledinthisrandomizedclinicaltrial.

The sample size was based on a previous pilot study.

Table1 Age,weight,heightandsexofpatientspergroup. Group Age(years) Weight(kg) Height(cm) Sex

(m/f)

S 43.1±11.8 70.7±16.9 167.1±9.3 5/9 R 46.8±12.0 76.5±8.64 166.2±8.8 6/8

S,slowinductiongroup;R,rapidinductiongroup;p>0.05.

betweenthepropofolconcentrationsprovidedontheeffect siteduringlossofconsciousnesswithrapidandslowinfusion was67%,thepower analysiswithalphaof 1%andbetaof 5% showedthat11 patients wouldberequired per group. Threemorepatientspergroupwereaddedtocompensate forpossiblelossesduringtheclinicaltrial.

No patientreceived premedication and allwere moni-toredwithelectrocardiogram(DIIandV1),pulseoximetry, non-invasivemeanarterialbloodpressure(MAP),bispectral index(BIS),andend-tidalCO2aftertrachealintubation.

Patientswererandomlyallocatedintotwoequalgroups throughadefinedsequencebycomputer.Theslowinduction group (Group S) received propofol by plasma target-controlledinfusion(TCI),Marshpharmacokineticmodel(ke0 0.26min−1_{),withtargetconcentration(Tc)of2.0}

␮gmL−1.

When the predicted propofol concentration at the effect site(Es)reached halfthevalueofTc,Tcwasincreasedto previousTc+1␮gmL−1,andsoonuntilthepatient’slossof

consciousness(lossofverbalresponseandeye-blinkreflex). Therapidinductiongroup(GroupR)receivedplasma propo-folviaTCIwith6␮gmL−1Tcandwaiteduntilpatient’sloss

ofconsciousness.

In both groups, after loss of consciousness, TCI remifentanil was initiated to an effect site of 5gmL−1 (Minto’s pharmacokinetic model), rocuronium 0.6mgkg−1 wasadministered,andaftertwominutestrachealintubation wasperformed.

During the intraoperative period, Tc of propofol was adjusted to maintainBIS between 35 and 50,while Tcof remifentanilwasadjustedtomaintainMAPbetween±20% oftheinitialMAP.

Aftersurgery,bothinfusionswereturnedoff.

Es of propofol was recorded at the time of loss and recoveryofconsciousness(BIS=70)andeveryminuteofthe intraoperativeperiod.

All patients received dipyrone30mgkg−1 _and ketopro-fen1.5mgkg−1_{forpostoperativeanalgesiaandmethadone} 0.1mgkg−1_{asrescueanalgesicinthePost-AnesthesiaCare} Unit.

For infusion management and data collection, the Anestfusor®_{software,coupledtotwoPilot2syringepumps} (Fresenius-Kabi)andBIS,wasused.

Forstatistical analysisof parametricdata, Student’st -testwasusedandthedifferencewasconsideredsignificant whenpvalueswere<0.05.

Results

Therewasno significantdifferencebetween demographic variablesofthetwogroups(p>0.05)(Table1).

InductiontimeinGroupSwashighercomparedtoGroup

R,4.54and1.46min,respectively(p<0.001).Therewasno

Table2 Induction,durationofsurgery,awakeningtimes, andpropofolandremifentanilconsumption.

L R

Inductiontime(min) 4.54±0.67 1.46±1.02a

Durationofsurgery(min) 47.6±13.2 50.6±13.1 Awakeningtime(min) 7.21±3.81 7.07±5.18 Propofol(mgkg−1_h−1_{) 8.27±2.15 8.40±1.68}

Remifentanil(␮gkg−1min−1) 0.16±0.02 0.13±0.03

a _p<0.001.

significant differenceinsurgery andawakening timesand

consumptionofpropofolandremifentanilbetweenthetwo

groups(p>0.05)(Table2).

Thepredictedpropofoleffect-siteconcentration(Es)in

loss of consciousness was higherin Group S compared to

Group R, 2.50 and 1.67␮gmL−1 respectively (p=0.004).

Eswassignificantly differentat loss andrecovery of

con-sciousnessin Group S, 2.5 and 1.60␮gmL−1, respectively

(p<0.001). InGroup R,Eswaslowerat lossof conscious-nesscomparedtointraoperativeEs,1.67and2.52␮gmL−1,

respectively (p=0.002). There was no significant

differ-ence between groups regarding Es values’ intraoperative

andatrecoveryofconsciousness(p>0.05).Therewasalso

nosignificant differenceinEs duringloss andrecovery of

consciousnessinGroupR(p>0.05)(Fig.1).

Discussion

ThemaindifferencefoundinthisstudywastheEspredicted bytheMarshpharmacokineticmodel(ke00.26min−1_)during

lossofconsciousnessbetweenrapidandslowinduction.

Althoughthesamepharmacokineticmodelandthesame

equilibrium constant plasma/effect-site (Ke0) have been

used, Es at loss of consciousness was significantly lower

in Group R comparedto Group S, 1.67 and 2.50␮gmL−1,

respectively. This difference was also found by other

authors.8

Studies have shown that the pharmacokinetic models

ofpropofol usedin target-controlledinfusion systems are

poorlyaccurateforearlypredictionofpropofolactualblood

concentrationafterbolusorrapidinfusion,whenmaximum

LOC S LOV R IO S IO R ROC S ROC R 1.0

1.5 2.0 2.5 3.0 3.5 4.0

Data

a

Figure1 Effect-site concentration ofpropofol (mcgmL−1_).

effect is observed.7,9---11 _{These conventional nipple}

multi-compartmentalpharmacokinetic models assumethatdrug

mixingincentralcompartmentoccursimmediatelyandthe

mixtureimmediatelyappearsinthearterialcirculation.In

fact,thereisadelaybetweenthedrugadministrationand

itsappearanceinarterialblood.Thishasbeenreportedin

severalstudies.7,12,13

Among other factors, this delay depends on the

pul-monaryextractionof propofolduringthefirst pass.14,15 _In

Marshpharmacokinetic model, thisinitial error is evident

duringthefirstfiveminutes,whichmakesthemodelnotso

preciseforthesefirstminutes.7

Byassuminganinstantaneousmixtureafterabolus

injec-tion,thetraditionalpharmacokinetic modelsoverestimate

thecentralvolume.Becausethebolusdosedependsonthe

size of the central compartment, its overestimation may

resultinalargebolus,whichmayexceedthetarget concen-trationwheneverthetargetisincreased.14,15

Because of this poor predictability of pharmacokinetic

model in the first minutes after a bolus injection, some

authorshaveshown thattherateof propofolinfusioncan

influence the equilibrium constant between plasma and

effectsite.7_{Apparently,theplasma/effect-siteequilibrium}

constantisfaster forbolus administrationthanfor slower

infusions.This mayanswerwhydifferentke0arefoundin

theliterature,evenwhenusingthesamepharmacokinetic

model.7

Maybetherearephysiologicalreasonsforthesedifferent

valuesofke0obtainedthroughbolusandslowerinfusions.

Onestudyshowedthatpropofolreducescerebralbloodflow

inadose-dependentmanner.16_{So,whenusingabolus}

injec-tion to extract ke0, the achieved high concentrations of

propofolmayreducecerebralbloodflow.Ontheotherhand,

whenslowerinfusionsareused,thispropofoleffecton

cere-bralbloodflowshouldbereduced.

With the use of a conventional continuous infusion

scheme,the valuesfor propofolt½ _{ke0 inliterature vary}

between 2.3and 3.5min.17---19 _{The Marshpharmacokinetic}

model,whichispresentinthefirsttarget-controlled

infu-sionsystemcommerciallyavailable(Diprifusor),wasbased

ondatafromaslowinfusionandisassociatedwithat½ _ke0

of2.65min.17

As an option to reduce this initial error of the

propo-fol pharmacokinetic models,some authors have proposed

toincorporate intothe Schnidermodel different ke0

val-uesfor different infusion rates.7 _{Ifthe maximum infusion}

rateremains between 300 and 900mLh−1_{, t}½ _ke0should

beabout2.2min(ke0=0.32min−1_{).However,iftheinfusion} issimilartoabolusinjection,ashortert½ _{ke0of 1.2min}

shouldbeused.

For other pharmacokinetic models of propofol as the

Marsh,forexample,ifthepump iscapableofdeliveringa

bolusinductioninaminuteorless,thetimemustbe

imple-mentedtomaximumeffectof1.5min.7_{Withtheseoptions,}

thismodelpredictedeffectconcentrationismoreaccurate

overtime.

Some authors have assessed more appropriate

phar-macokinetic models for this initial kinetic phase and the

correlation with possible covariates such as age, weight,

and infusion rate.20 _{In these more sophisticated models,}

itwasdemonstrated thatthe use ofa singleke0 value is

appropriate and can be applied to the target controlled

infusion systems, which use syringe pumps with infusion

ratebetween10and160mgkg−1_h−1_{.Therefore,forthese}

studies,pharmacodynamicsisnotinfluencedbytherateof

propofolinfusion.20,21

ThemeanvaluesofEsinrapidandslowinductiongroups

were similar during the intraoperative and recovery of

consciousness times, 2.52±0.43 and 2.52±0.76␮gmL−1,

respectively, and 1.63±0.42 and 1.60±0.58␮gmL−1,

respectively.

As shown in some studies, Es of propofol for loss

and recovery of consciousness aresimilarwhen using the

Marsh pharmacokinetic model (ke0 0.26min−1_).3,4

There-fore,someauthorssuggestedthatthetargetconcentration

ofpropofolshouldbetitratedduringmaintenanceof

anes-thesiabasedonEsduringlossofconsciousness.3,4,6_Themain

objectivewouldbetoreducethepossibilityofpatient awak-eningduringsurgery.Itisworthnotingthatthisisonlyvalid

whenanalgesiaiscompletethroughouttheprocedure.

Todate,theliteratureonthesubjectdoesnotallow say-ingthattheactualpropofolconcentrationattheeffectsite issimilaratlossandrecoveryofconsciousnessorthatitis reallydifferent.

Recently,astudyshowedthatregardlessofthe

pharma-cokineticmodelofpropofolused(Schnider:ke00.45min−1

and time to peak effect 1.7min; Marsh: ke0 1.21min−1

andtimetopeakeffect1.7min;or Marsh:ke0 0.26min−1

and time to peakeffect of 4.5min), the predicted value

of propofolat the effectsiteduring lossof consciousness

afterabolusinjectionshouldnotbeusedasreferencevalue

fortitrationofhypnosisduringmaintenanceofanesthesia,

astheeffectconcentrationofpropofolpredictedbythese

modelsduringlossofconsciousnessisverydifferent(4.40,

3.55and1.28␮gmL−1,respectively).8

Inthisstudy,therapidandslowinductiongroupsshowed

similarEsatrecoveryofconsciousness.However,Esatloss

andrecoveryofconsciousnesswassimilaronlyintherapid

inductiongroup(Fig.1).

Basedonthepresentedresults,wecanconcludethatin

casesofrapidinductionwithMarshmodel(ke00.26min−1_), Esatlossandrecoveryofconsciousnessissimilar(1.63and 1.60␮gmL−1,respectively).However,Esduringthe

intraop-erativeperiodshouldbeabout50%higher.

Incasesofslowinduction,thetargetmaintenancedose

maybesimilartotheEsduringlossofconsciousness.This

result was expected, as the ke0 used in this study was

derived fromslow infusion data.17 _{Consequently, the}

pre-dicted effect-site concentration of propofol over time is

moreprecise.

Althoughthegoalwastoevaluatethepredicted

effect-siteconcentration ofpropofol,themain limitationof this

studywasnotmeasuringtheplasmaconcentrationof

propo-folatdifferenttimes.

Another aspect to be considered is that the use of

patientsofbothsexesmayhaveincreasedthestudybias,as

sexisanimportantvariableinpropofolpharmacokinetics.22

However, there was no significant difference between

groupsinthenumberofpatientsofbothgenders.

Conclusion

induction, even withthe same pharmacokinetic model of

propofolandthesameequilibriumconstantbetweenplasma

andeffectsite.Recognizingthisdifferenceiscrucialto

per-formatotalintravenousanesthesiawithtarget-controlled

infusionofpropofolsafelyforthepatient.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

References

1.Gajraj RJ, Doi M, Mantzaridis H. Comparison of bispectral EEG analysis and auditory evoked potentials for monitoring depthofanaesthesiaduringpropofolanaesthesia.BrJAnaesth. 1999;82:672---8.

2.Barakat AR, Sutcliffe N, Schwab M. Effect site concen-tration during propofol TCI sedation: a comparison of sedationscorewithtwopharmacokineticmodels.Anaesthesia. 2007;62:661---6.

3.IwakiriH,NishiharaN,NagataO.Individualeffect-site concen-trationsofpropofolaresimilaratlossofconsciousnessandat awakening.AnesthAnalg.2005;100:107---10.

4.SimoniRF,EstevesLO,MiziaraLEPG,etal.Avaliac¸ãoclínicade duaske0nomesmomodelofarmacocinéticodepropofol:estudo daperdaerecuperac¸ãodaconsciência.RevBrasAnestesiol. 2011;61:397---408.

5.IannuzziM, Iannuzzi E, Rossi F, et al. Relationship between bispectral index, electroencephalografic state entropy, and effect-siteEC50forpropofolatdifferentclinicalendpoints.Br JAnaesth.2005;94:613---6.

6.LysakowskyC,EliaN,CzarnetzkiC,etal.Bispectraland spec-tralentropyindicesatpropofol-inducedlossofconsciousness inyoungandelderlypatients.BrJAnaesth.2009;103:387---93.

7.StruysMMRF,CoppensMJ,NeveND,etal.Influenceof admin-istration rate on propofol plasma-effect site equilibration. Anesthesiology.2007;107:386---96.

8.SepulvedaPO,CortinezLI,RecartA,etal.Predictiveabilityof propofoleffect-siteconcentrationsduringfastandslowinfusion rates.ActaAnaesthesiolScand.2010;54:447---52.

9.SchniderTW,MintoCF,ShaferSL,etal.Theinfluenceofagein propofolpharmacodynamics.Anesthesiology.1999;90:1502---16.

10.Kasama T, MoritaK, IkedaT,et al. Comparisonofpredicted inductiondosewithpredeterminedphysiologiccharacteristics of patients and with pharmacokinetic models incorpo-rating those characteristics as covariates. Anesthesiology. 2003;98:299---305.

11.SchuttlerJ,IhmsenH.Populationpharmacokineticsofpropofol: amulticenterstudy.Anesthesiology.2000;92:727---38.

12.KrejcieTC,HenthornTK,NiemannCU,etal.Recirculatory phar-macokineticsmodelsofmakersofblood,extracellularfluidand totalbodywateradministeredconcomitantly.JPharmacolExp Ther.1996;278:1050---7.

13.UptonRN,GrantC,MartinezAM,etal.Recirculatorymodelof fentanyl dispositionwiththebrainas thetargetorgan. BrJ Anaesth.2004;93:687---97.

14.Avram MJ, Krejcie TC. Using front-end kinetics to opti-mizetarget-controlleddruginfusion.Anesthesiology.2003;99: 1078---86.

15.HenthornTK, Krejcie TC, AvramMJ.Earlydrug distribution: agenerallyneglectedaspectofpharmacokineticsofparticular relevancetointravenouslyadministeredanesthesicagents.Clin PharmacolTher.2008;84:18---22.

16.Ludbrook GL, Visco E, Lam AM. Propofol: relation between brainconcentrations,electroencephalogram, middlecerebral arterybloodflowvelocity,andcerebraloxygenextraction dur-inginductionofanesthesia.Anesthesiology.2002;97:1363---70.

17.SchwildenH,StoeckelH,SchuttlerJ.Closed-loopfeedback con-trol of propofol anaesthesiaby quantitative EEG analysisin humans.BrJAnaesth.1989;62:290---6.

18.BillardV,GambusPL,ChamounN,etal.Acomparisonof spec-traledge,deltapower,andbispectralindexasEEGmeasuresof alfentanil,propofol,andmidazolamdrugeffect.ClinPharmacol Ther.1997;61:45---58.

19.WhiteM,SchenkelsMJ,EngbersFH,etal.Effect-sitemodelling of propofol using auditory evoked potentials. Br J Anaesth. 1999;82:333---9.

20.MasuiK,KiraM,KasamaT,etal.Earlyphasepharmacokinetics butnotpharmacodynamicsareinfluencedbypropofolinfusuion rate.Anesthesiology.2009;111:805---17.

21.DoufasAG,BakhshandehM,BjorkstenAR,etal.Inductionspeed isnotadeterminantofpropofolpharmacodynamics. Anesthe-siology.2004;101:1112---21.