Rev. Bras. Anestesiol. vol.64 número6

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

The

effect

of

different

doses

of

esmolol

on

hemodynamic,

bispectral

index

and

movement

response

during

orotracheal

intubation:

prospective,

randomized,

double-blind

study

Mensure

Yılmaz

C

¸akırgöz

,

Aydın

Tas

¸dö˘

gen

,

C

¸imen

Olguner

,

Hülya

Korkmaz

_,

_Ertu˘

_grul

_Ö˘

_gün

_,

_Burak

_Küc

_¸ükebe

_,

_Esra

_Duran

a_{DepartmentofAnesthesiologyandReanimation,OkmeydaniTrainingandResearchHospital,Istanbul,Turkey} b_{DepartmentofAnesthesiologyandReanimation,DokuzEylülUniversity,SchoolofMedicine,Izmir,Turkey}

Received12August2013;accepted2September2013 Availableonline30October2013

KEYWORDS

Depthofanesthesia; Propofol;

Intubation; Bispectralindex; Esmolol

Abstract

Objective: Aprospective,randomizedanddouble-blindstudywasplannedtoidentifythe

opti-mum dose of esmolol infusionto suppress the increase in bispectralindex values andthe

movementandhemodynamicresponsestotrachealintubation.

Materialsandmethods: Onehundredandtwentypatientswererandomlyallocatedtooneof

threegroupsinadouble-blindfashion.2.5mgkg−1_{propofolwasadministeredforanesthesia}

induction.Afterlossofconsciousness,andbefore administrationof0.6mgkg−1_rocuronium,

atourniquetwasappliedtoonearmandinflatedto50mmHggreaterthansystolicpressure.

Thepatientsweredividedinto3groups;1mgkg−1_h−1_{esmololwasgivenastheloadingdose}

and inGroup Es50 50␮gkg−1_min−1_{,in Group Es150 150␮gkg}−1_min−1_{,and inGroup Es250}

250␮gkg−1_min−1_{esmololinfusionwasstarted.Fiveminutesaftertheesmololhasbeenbegun,}

thetracheawasintubated;grossmovementwithinthefirstminuteafterorotrachealintubation

wasrecorded.

Results:Incidenceofmovementresponseandthe_{BISmaxvalueswerecomparableinGroup}

Es250andGroupEs150,butthesevaluesweresignificantlyhigherinGroupEs50thaninthe

othertwogroups.Inallthreegroupsinthe1stminuteaftertrachealintubationheartrateand

mean arterialpressure weresignificantlyhighercompared tovaluesfrombefore intubation

(p<0.05).Inthestudyperiodtherewasnosignificantdifferencebetweenthegroupsinterms

ofheartrateandmeanarterialpressure.

Conclusion: Inclinicalpractisewebelievethatafter1mgkg−1_{loadingdose,150␮gkg}−1_min−1

ivesmololdoseissufficienttosuppressresponsestotrachealintubationwithoutincreasingside

effects.

© 2013SociedadeBrasileirade Anestesiologia.Publishedby ElsevierEditoraLtda.Allrights

reserved.

∗_{Correspondingauthor.}

E-mail:[email protected](M.Y.C¸akırgöz).

0104-0014/$–seefrontmatter©2013SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.Allrightsreserved.

PALAVRAS-CHAVE

Profundidadeda anestesia; Propofol; Intubac¸ão; Índicebispectral; Esmolol

Efeitodediferentesdosesdeesmololsobrearespostahemodinâmica,BISeresposta demovimentoduranteaintubac¸ãoorotraqueal:estudoprospectivo,randômicoe duplo-cego

Resumo

Objetivo:Estudoprospectivo,randômicoeduplo-cegoplanejadoparaidentificaradoseideal

deperfusãodeesmololparasuprimiroaumentodosvaloresdoBISeosmovimentoserespostas

hemodinâmicasàintubac¸ãotraqueal.

Materiaisemétodos:120 pacientes foram randomicamente alocados um dos três grupos,

usandoométododuplo-cego.Propofol(2,5mgkg−1_{)foiadministradoparainduc¸ãodaanestesia.}

Apósaperdadaconsciênciaeantesdaadministrac¸ãoderocurônio(0,6mgkg−1_{),umtorniquete}

foiaplicadoaumbrac¸oeinsufladoa50mmHgacimadapressãosistólica.Ospacientesforam

divididosemtrêsgrupos;umadosede1mgkg−1_h−1_{deesmololfoiadministradacomocarga}

eperfusão de50␮gkg−1_min−1 _{deesmololfoi iniciada noGrupo ES50,150␮gkg}−1_min−1 _no

GrupoEs150e250␮gkg−1_min−1_{noGrupoES250.Cincominutosapósoiníciodaperfusão,a}

traqueiafoiintubada;ototaldemovimentosnoprimeirominutoapósaintubac¸ãoorotraqueal

foiregistrado.

Resultados: Aincidênciadarespostademovimentoseosvaloresmáximosde_BISforam

com-paráveisnosgruposES250eEs150,masessesvaloresforamsignificativamentemaiselevados

noGrupoES50quenosoutrosdoisgrupos.Nostrêsgrupos,osvaloresdefrequênciacardíaca

epressãoarterialmédiaforamsignificativamentemaioresnoprimeirominutopós-intubac¸ão,

comparados aosvalores pré-intubac¸ão(p<0,05). Nãohouvediferenc¸a significativaentreos

gruposemrelac¸ãoàfrequênciacardíacaepressãoarterialmédiaduranteoperíododeestudo.

Conclusão:Napráticaclínica,acreditamosqueapósumadosecomcargade1mgkg−1_,uma

dose de 150␮gkg−1_min−1 _{de esmolol IV ésuficiente para suprimir a respostaà intubac¸ão}

traquealsemaumentarosefeitoscolaterais.

©2013SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos

direitosreservados.

Introduction

Duringanesthesiainductiontrachealintubationisoneofthe mostintensivenoxiousstimuliandcaninducehemodynamic andmovementresponsesandincreasethebispectralindex (BIS).1---3_{Hemodynamicchangesduetotrachealintubation,}

similartochangesduetoothersurgery-relatedstimulisuch asanesthesiaandskin incisions,areoftentransient. How-ever,inpatientswithcoronaryarterydisease,hypertension (HT)orwithahistoryofcerebrovasculardisease,apossible increaseinhemodynamicparametersmaycausemyocardial ischemia,arrhythmia,infarctionorcerebralbleeding.1,2_The

closerelationshipoftachycardiacheartrate(HR)to myocar-dialischemiahassuggestedtheuseof␤-adrenergicreceptor blockersfor thesuppressionofthehemodynamicresponse totrachealintubation.3---5

DuringanesthesiaprimarilyforthetreatmentofHTand tachycardia ␤1 adrenoreceptor antagonists are indicated,

whichhave been proven in clinical studies tohave a role inpain modulation.6---13 _{Whilethe mechanism is unknown,}

esmololinfusionisknowntosuppresstheBISincreaseand movementresponselinkedtotrachealintubationcompared toplacebo.14,15 _{Howevernostudy was found onthe}

rela-tionshipbetweentheeffectsofesmololatdifferentinfusion doses.Thehypothesisofthisstudyisthattheresponsesto trachealintubationofincreasedmovementandBISwillbe suppressedduetotheantinociceptiveeffectofesmololina dose-linkedfashion,causingareductioninBISincreaseand movementaftertrachealintubation.Totestthishypothesis

and identify the optimum infusion dose to suppress BIS increaseandmovementresponse,alongwithhemodynamic response,totrachealintubation,aprospective,randomized anddouble-blindstudywasdesigned.

Methods

AfterreceivingDokuzEylülUniversity,FacultyofMedicine ClinicalTrialsLocalEthicsCommitteeapprovalandinformed patientconsentthisprospective,randomized,double-blind study was completed. One hundred and twenty adult patientsinASAI---IIriskgroups,betweentheagesof18and 65,undergoingelectivesurgery,apartfromhead,neckand cardiacsurgery,wereenrolledinthestudy.

Patients with predicted difficult intubation or airway management, body mass index>30kg/m2_{, HR<60beats}

min−1_{, systolic arterial pressure (SAP)<100mmHg,}

car-diacdiseases,diabetesmellitus,renalfailure,liverfailure, COPD,asthma, reactive airwaydisease, symptomatic gas-troesophageal reflux, patients with neuropsychiatric or neurological diseases, pregnant and lactating patients, patients with a history of use of opioids, tricyclic antidepressants, benzodiazepines, anticonvulsants, cloni-dine,␤-adrenergicreceptorblockers,oralcoholabuse,and patientswithahistoryofallergicreactiontothestudydrugs wereexcluded.

Induction LTI End of study 0.min 5.min 10.min 15.min

2.5 mg/kg propofol bolus + propofol infusion (8 mg/kg/hr)

1mg/kg esmolol bolus + esmolol infusion

Rocuronium (0.6 mg/kg)

Figure1 Studyflowdiagram.

accesscannulaopening.Afterbeingtakentotheoperating table6L/minoxygenwasadministeredthroughamask. In allpatients,non-invasivebloodpressure,electrocardiogram (ECG), pulse oximetry, andesophageal temperature after intubation were monitored. Baseline values for HR, non-invasivemeanarterialpressure(MAP)andperipheraloxygen saturation (SpO2) were recorded.After standard

monitor-ing,patientsweremonitoredwiththeA-2000BISXPdevice (AspectMedicalSystems,Newton,MA,USA).Measured con-trol BIS values were recorded after contact testing was completed.

After pre-oxygenationtoinduce anesthesia2.5mgkg−1

propofol(1%PropofolR,Fresenius,Austria)wasappliedfor 20s and8mgkg−1_h−1 _{propofol infusionwasstarted. After}

loss of eyelash reflex in patients, manual end-tidal CO2

(ETCO2)35---40mmHgwasmaintainedbyinhalationof100%

O2throughthemask(Fig.1).Movementresponsetotracheal

intubationwasassessedbytheisolatedforearmtechnique. Forthispurpose,afterlossofconsciousness,thecuffonthe armwithout theIVwasinflated. Aftersystolicblood pres-sureof50mmHgwasreached,rocuronium0.6mgkg−1_dose

wasgivenformusclerelaxation.16_{After5minofinfusionof}

propofol,allpatientsweregiven1mgkg−1 _esmolol

(Brevi-blocREczacıbas¸ı,Baxter, USA) loadingdosein 15mL total volume0.9%NaClsolution.Patientswererandomly(sealed envelopemethod)allocatedtothreegroupsandafter1min, study medicationwasadministered byan anesthesiologist awareofthemedicationamount.The dosewascalculated for each patient by a 50mL syringe(10mg/mL)perfusor; Group Es50(n=40) 50mgkg−1_min−1 _{esmolol;Group Es150}

(n=40)150mgkg−1_min−1_{esmolol;andGroupEs250(n=40)}

250mgkg−1_min−1_{infusionofesmolol.After5minofesmolol}

infusion, an anesthesia assistant blind to the amount of studydrugadministeredintubatedthepatients.Five min-utesafterintubationesmololinfusionwasterminated.Inthe studyperiod,anesthesiawasmaintainedwith8mgkg−1_h−1

infusionofpropofoland50%air---O2mixture.Attheendof

thestudyperiodanestheticmanagementresponsibleforthe operatingtheater andawareof the amount of anesthetic drugsappliedtothepatientslefttheteam.

Before induction by an anesthesiologist blind to the amountofstudydrug(control),at1st,3rdand5thminute after the start of propofol infusion, and from the start of esmolol infusion to 5min after intubation at minute intervals, HR, MAP, BIS, and SpO2 values were recorded.

After the painful stimulus _{BIS (difference between BIS}

value pre-tracheal intubation and after 5st minute post-trachealintubation)and_{BISmax(differencebetweenBIS}

valuespre-tracheal intubation andmaximum value within 5thminutepost-trachealintubation)valueswererecorded afterintubation.16 _{The timebetweentheopening ofeach}

patient’s mouth andwhen the trachealtube cuffinflated

was defined as the intubation time and was recorded. Repeatedintubationattemptsandpatientsrequiringmore than 30s intubation time were removed from the study. Within1minafterintubationmovementofthepatient’sarm thecuffwasplacedonwasacceptedasapositivevalueand theairsleevewasdepressurized.

During the study period, for hypotension (MAP<60mmHg) first the intravenous infusion of fluid wasincreased and if no improvement within 5min, 5mg of ephedrine (Ephedrine, Haver, Istanbul, Turkey) was administered.Forbradycardia (HR<50beatsmin−1_)0.5mg

atropine (atropine sulfate, Haver, Istanbul, Turkey) was implemented. Side effects including hypotension, brady-cardia, arrhythmia, cough, hiccups, increased airway resistance,bronchospasm,etc.,wererecorded.

After1hintherecoveryunitpatientswereasked ques-tionssuchas‘‘Doyourememberanyeventfrombeginning orendoftheoperation?’’todetermineawarenessof intra-operativeeventsandresponseswererecorded.

Poweranalysis

InthestudybyMenigauxetal.14_{consideringchangeinBIS}

values,toreach80%power(˛_{=0.05)eachgroupshould}

con-tainat least 19 patients; Guignard etal.17 _{revealed that}

21patientswererequiredaccordingtomovementresponse findings.Thethreegroupsinthisstudycontainedatotalof 120patients(n=40).

Statistics

DatawerecompiledusingSPSS11.0forWindowsprogram. Todeterminewhether parametershadnormaldistribution the Kolmogorov---Smirnov test and box-plot graphics were completed.Tocomparemeanvaluesbetweenthe3groups one-wayanalysisofvariance(one-wayANOVA)andposthoc Tukey were used.Variations withingroups were analyzed usingthepaired-samplest-test.Non-parametricdatawere analyzedwiththechi-squaretest.p<0.05wasconsidered statisticallysignificant.

Results

Betweenthegroupstherewasnodifferenceintermsofage, bodyweight, height,sex, ASA risk class andthe tracheal intubationduration.Trachealintubationwasperformed in 9---14s(Table1).TwopatientsingroupEs250wereexcluded fromthestudybecauseofHR<60beatsmin−1 _after

induc-tion,and1patientwasexcludedduetodifficultintubation. Thedatafromatotalof117patientswereanalyzed.

Table1 DemographicdataandLTIduration(mean±standarddeviation).

Group GroupEs250

(n=38)

GroupEs150

(n=39)

GroupEs50

(n=40)

Age(year) 36.63±10.55 40.12±9.66 37.20±9.01

Weight(kg) 67.16±10.55 68.39±12.23 66.90±10.84

Height(cm) 168.37±7.64 168.36±8.47 166.75±8.62

ASA(I/II) 37/1 39/0 40/0

Sex(F/M) 27/11 27/12 30/10

LTIduration(s) 10.47±1.47 10.89±1.13 10.30±1.02

90

85

80

75

70

65

Baseline Pre e nt

Prp.1.min Prp.3.minPrp.5.minEsm 1.minEsm 2.minEsm 3.minEsm 4.minEsm 5.minEmb 1.minEmb 2.minEmb 3.minEmb 4.minEmb 5.min

Periods

HR (be ats/min)

Group Es250 Group Es150

#: p<0.05 (compared to basal values in Group Es50)

+: p<0.05 (compared to basal values in Group Es150)

*: p<0.05 (compared to basal values in Group Es250)

Group Es50

+

+ + + + * * * *

#

# # # #

# _# #

Figure2 ChangesinmeanHRinthegroups.

reducedcomparedtobasalvaluesintheperiodbefore tra-chealintubation(p<0.05).Inthe1stminuteaftertracheal intubationinallthreegroups MAPwassignificantlyhigher comparedtovaluesbeforeintubation(p<0.001)(Fig.3).In

thestudyperiodtherewasnosignificantdifferencebetween thegroupsintermsofHRandMAP.

BISvaluesin thefirstminute after induction of propo-fol reached the minimum value (Fig. 4). After tracheal

120

100

80

60

40

20

0

Bas eline

Pre ent

Prp. 1.minPrp. 3.minPrp. 5.min Esm. 1.minEsm. 2.minEsm. 3.minEsm. 4.minEsm. 5.minEntb 1.minEntb 2.minEntb 3.minEntb 4.minEntb 5.min

Periods

MAP

(mm Hg)

Group Es250 Group Es150 Group Es50

+ + + + + ₊ + ₊ + + + +

* * * * * *

*

* *

# _# #

# # # # # # #

* * *

#: p<0.05 (compared to basal values in Group Es50) +: p<0.05 (compared to basal values in Group Es150) *: p<0.05 (compared to basal values in Group Es250)

Baseline Pre ent

Prp. 1.minPrp. 3.minPrp. 5.min Esm. 1.minEsm. 2.min Esm. 3.minEsm. 4.minEsm. 5.minEntb 1.minEntb 2.minEntb 3.minEntb 4.minEntb 5.min Periods

Group Es250 Group Es150 Group Es50

100 90 80 70 60 50 40 30 20 10 0

BIS (0-100)

+ + +

+ + + ₊ + + + ₊ +

# # # # # # # # # # # #

* * *

* * * _* * * * _* *

#: p<0.05 (compared to values after 1st minute propofol in Group Es50) +: p<0.05 (compared to values after 1st minute propofol in Group Es150) *: p<0.05 (compared to values after 1st minute propofol in Group Es250)

Figure4 ChangesinmeanBISvaluesinthegroups.

intubation in the 1st and 2nd minutes BIS values in all three groups showed a significant increase compared to values from before tracheal intubation (p<0.05). There wasno significant difference between all threegroups in terms of BIS values during the study period. When the Groups are compared based on the average value _BIS

and_{BISmaxtherewasnosignificant differencebetween}

GroupsEs250andEs150,butboth groups hadsignificantly lowervaluesthanGroupEs50(p<0.05)(Table2). Compar-ingthegroupsinterms ofmovementresponsetotracheal intubation, there was no significant difference between Group Es250(50%) andGroup Es150(56%)but Group Es50 (87.5%)wassignificantlyhigherthantheothertwogroups (Table3).

Nohypotension,bradycardia,arrhythmia,cough,hiccup, bronchospasm,orincreasedairwayresistancewasobserved inanypatient.Noneofthepatientsindicatedany intraop-erativeawarenessinthepostoperativeperiod.BIS,HRand MAPduringthepre-inductionperiodwerealsosimilarinall 3groups.

Discussion

Thisstudyshowsthatinpatientsanesthetizedwithpropofol, esmolol suppressed awareness reactions, shown by move-ment and BIS, to tracheal intubation, in a dose-linked fashion.

Duetothe shortactiveduration ofesmolol, bolus and infusionprotocol, constant plasma concentrationand tra-cheal intubation with anesthetic agents were chosen to assess more clearly the effect on BIS values, hemody-namicandmovementresponse.GroupEs250weregivenan infusion dose known in the literature to suppress the BIS response;14,15_{GroupEs150weregivenadosethathasbeen}

showntobe effectivein thetreatment of intra-operative HTandtachycardia18,19_{andGroupEs50weregiventhe}

low-est infusion dose proposed to suppress the hemodynamic response.2,20

In induction, comparisons have been made on the suppressionofthehemodynamicresponsetotracheal intu-bationbetween different doses ofesmolol, as infusion or

Table2 Averagechangein_BIS.

Group GroupEs250(n=38) GroupEs150(n=39) GroupEs50(n=40)

_{BIS 2.86±2.64}a _2.89±3.53a _9.25±4.84

_{BISmax 4.73±4.37}a _6.17±6.85a _10.80±5.48

a _{p<0.05(comparedtoGroupEs50)}

Table3 Motionresponseinthegroups.

Group GroupEs250(n=38) GroupEs150(n=39) GroupEs50(n=40)

Movement 19(50%)a _22(56.4%)a _35(87.5%)

Nomovement 19(50%)a _17(43.6%)a _5(12.5%)

bolus, placeboor withdifferent druggroups (nicardipine, lidocaine, alfentanil, fentanyl, etc.).18,21---27 _{Additionally,}

no consensus has been reached on the optimum dose, administration method and timing.2,3 _{In a meta-analysis}

studyevaluatingthe effectivenessof esmolol on hemody-namicchangesinducedbytrachealintubationbyFigueredo and Garcia-Fuentes,2 _{esmolol suppressed the adrenergic}

response to tracheal intubation independent of dose and it was reported that after a loading dose of 500␮gkg−1_,

within4min200---300␮gkg−1_min−1_{continuousinfusiondose}

wasthemostefficientprotocol.Johansenetal.12

adminis-teredpropofol/N2O/morphineanesthesiawithesmololand,

reportedadose-independentslightincreaseinHRandblood pressure after tracheal intubation. In this study, similar toprevious studies, after tracheal intubation in all three groupsanincreaseinHRandMAPindependentofdosewas found compared to values before intubation in all three groups.2,12,14

A short-termeffective ␤1 adrenergic receptor blocker,

ONO-1101 in increasing infusion doses, significantly sup-pressed the SAP increase linked to tracheal intubation, however it was reported that it increased the incidence ofhypotension.28 _{Similarly,FigueredoandGarcia-Fuentes}2

inameta-analysisstudy,foundesmolol administeredwith induction agents and especially opioids, caused a dose-linked increase in hypotension and bradycardia incidence beforetrachealintubation.Togetherwiththisintheperiod beforeintubation in the placebo group therewas a 2.6% reduction in MAP while the esmolol group had a 10.1% decreaseinMAP.Similarlyinourstudy,inallthreegroups, thedeclineinMAPfromthebeginningofpropofolinfusion continuedafteradditionofesmololinfusionuntiltheperiod priortotracheal intubation.Although thereis no statisti-callysignificantdifferencebetweengroups;comparedwith baselineinall 3groups beforetrachealintubation (Group Es250:17%,GroupEs150:15%,andGroupEs50:11.2%)there was a significant decrease in MAP. However hypotension (MAP<60mmHg) or bradycardia (HR<50beatsmin−1_{) was}

notobservedinanypatient.

Many studies on the effect of esmolol on the hemo-dynamic response to tracheal intubation have used succinylcholine as a muscle relaxant.21---27 _{Administration}

of propofol with succinylcholine has caused significant bradycardia29_{andfasciculationsduetosuccinylcholinehave}

been suggested to have an adverse affect on monitoring BIS.30 _{Forthesereasonswechoserocuroniuminourstudy.}

Rocuronium’s vagolytic effect31 _{may have prevented the}

expectedbradycardiaandhypotensionduetopropofoland esmololadministrationand contributedtoensuringstable hemodynamics. This situation we believe is additionally affectedbynotusingopioidsforinduction.

As described by Prys Roberts and Kissin, to determine the depth of anesthesia, voluntary movement response to a specific type of painful stimulus is the most appro-priate concept. Anesthesia depth is a pharmacodynamic measurementthatincludestheinteractionofthetwo med-ication groups (hypnotic and analgesic agents) that form thebasisofclinicalanesthesia.32_{Inhibitionofthecerebral}

cortex by hypnotics results in clinical loss of conscious-ness and reduction in BIS values (or on EEG). The basic effectof analgesics is inhibition of the subcortical struc-tures and spinal cord weakening the communication of

painful stimuli to the cortex. As a result clinical con-sciousnesslevelsandmovement responsereduce. Inspite of the sedative effects of opioids suppressing thecortex, ‘‘unconsciousness’’isonlyformedbyhypnoticsatthe corti-callevel.‘‘Lackofresponse’’isformedbytheinteractions ofanalgesicsandhypnoticsatbothcorticalandsubcortical levels.32

Guignard et al.17 _{in patients under propofol}

anesthe-sia in steady-state conditions found that in the absence ofpainfulstimuliremifentanylinfusiondidnotchangeBIS valuesbeforetrachealintubation;howeveritreducedthe increaseinBISvalues(_{BIS),hemodynamicandmovement}

responses totracheal intubation in adose-linked manner. For this reason in evaluating the analgesic component of anesthesiaafterpainfulstimulitheyconcluded_BISvalues

maybeassensitiveashemodynamicchanges.Berkenstadt et al.33 _{reported that bolus administrationof esmolol did}

not change BIS values in the absence of painful stimuli. Menigaux et al.14 _{in patients anesthetized with propofol}

andOdaetal.15_{inanesthesiawith1MACsevofluranewith}

esmololinfusion,similartoopioids,foundtherewasno sig-nificanteffectontheBISvaluesbeforetrachealintubation, howeverincreasein_{BISvalueslinkedtotracheal}

intuba-tionandhemodynamicresponseandmovementdecreased. Kawaguchi et al.34 _{studied short-term effect landiolol, a} ␤1 adrenoreceptor antagonist, during steady state

condi-tions of propofol anesthesia, and similartoremifentanyl, reported a suppressionin the increased entropyresponse (responseentropy=REandsituationentropy=SE,reflective of nociceptiveand hypnotic levels in general anesthesia) totrachealintubationintheformofnociceptiveresponse REand RE---SEresponsereductions.In ourstudysimilarto previousstudies,14,15_{intheabsenceofpainfulstimuliafter}

esmololinfusionandbeforeintubationtherewasno reduc-tion in BIS values in all three groups. This result shows that in the absence of painful stimuli esmolol does not affect BIS during general anesthesia. Thus it can be said that esmolol alone has no anesthetic effect. In contrast, a steady-state conditions study by Johansen35 _on

addi-tionof esmololinfusion topropofol/alfentanilanesthesia, showedBIS decreased whilecerebral cortical activitywas suppressedandburstsuppressionwascaused.Howeverthis studydidnotexaminesurgicalstimuliandalsoopioidswere used.

After esmolol infusion cortical EEG suppression and MACreductionshowsthatesmololinfusionshavedifferent pharmacologiceffects during anesthesia, becausecortical suppressionandMACareanatomicallyseparateinanimals.35

AftertrachealintubationinGroupEs250andGroupEs150,

_{BIS values and incidence of movement response were}

significantly reduced compared to Group Es50. Johansen etal.inastudyonpropofol/N2Oanesthesiawithmorphine

premedication reported propofol’s Cp50 values (minimum

effectiveplasmaconcentrationtosuppressmovement due toskinincisionin 50%ofpatients) reducedlinkedtodose of esmololinfusion.12 _{In thesamegroup, esmololinfusion}

affect movement responsewereused,and themovement response to the more submaximal painful stimuli of skin incision, comparedtotrachealintubation,wasevaluated. It is not possible to definitively comment on the effect of esmolol on the movement response to painful stimuli based on these two studies. The results of the present studyareinaccordancewiththoseofpreviousstudies,14,15

thoughtheeffectofesmololonBISandmovementresponse is shown to be dose linked. During propofol anesthesia in the absence of painful stimuli esmolol does not affect BISandinthepresenceof painfulstimulisuppresses_BIS

values and movement response in a dose-linked manner, affecting BIS value increases and movement response to tracheal intubation in a similar manner to esmolol and opioids.14,15,17

The mechanism behind the effect of esmolol on BIS and movement response is not clear. The first mecha-nism proposed to explain this effect is that esmolol has acentralanti-nociceptiveeffect.Anothermechanismmay bepharmacokineticinteractionswithpropofoland/or opi-oids.

Painful stimuli travel through the spinal cord to the brain stem, reticular formation and thalamus and from therearetransmittedtothecerebralcortexwheretheEEG responseforms.8,14_{␤-Adrenergicreceptorsareknownin}

var-ious regions of the reticular activating system and basal forebrain,especiallyinthemedialseptal.Inthisregion,␤ -adrenoceptoragonistinfusionincreasesEEGactivityandthe behavioralsymptomsofwakefulnessinanimals;incontrast

␤-adrenoceptor antagonist infusion is shown to suppress the EEG response.14 _{Specific ␤}

1-adrenoceptor antagonist,

ONO-1101,wasreportedtoreducethepainbehaviorafter intrathecal injections of formalin.14 _{Clinical studies show}

esmololchangesEEGresponsetopainfulstimuliandreduces the increase in BIS.14,15 _{This brings to mind the}

possibil-ity that esmolol’s effects on BIS may be similar to the reduction in ␤-adrenoceptor block due to pain response increasingcentral catecholamine concentration.However, thefactthatshort-actingesmololishydrophilicandcannot passtheblood---brainbarrierdoesnotfullysupportthisidea. Therefore,furtherstudiesareneededontheroleofesmolol incentralmodulationofpain.

Theothermechanismtoexplaintheeffectofesmololon BISandmovementresponseispharmacokineticinteractions withpropofoland/oropioids.11,12_{Johansen,insteady-state}

conditionspropofol/alfentanilanesthesia,foundthatwhile esmolol infusion didnotaffect the plasmaconcentrations of propofol and alfentanil or pharmacokinetics, BIS val-uesdecreasedandreversibleburstsuppressionsoccurred.35

Orme etal.36 _{found esmolol infusion did not significantly}

reduce propofols Cp50-awake value or change the plasma

concentration of propofol. We did not use opioidsin our study.Howeveraspropofolconcentrationwasnotmeasured wecannoteliminatepotentialpharmacokineticinteractions with esmolol. In light of these data the mechanism for esmolol’seffectsonBISandthemovementresponseisnot fullyunderstood.

In conclusion, in patients anesthetized with propofol 250and 150␮gkg−1_min−1_{esmolol infusion after1mgkg}−1

loading dose reduce the increase in BIS values and the movementresponselinkedtotrachealintubationina dose-linked manner compared to 50␮gkg−1_min−1 _{iv infusion.}

Consideringtheresultsofthisstudy,itisconcludedthatin clinicalpractisetosuppresstheresponsestotracheal intu-bation1mgkg−1_{loadingdosefollowedby150␮gkg}−1_min−1

iv esmolol infusion may be used without increasing dose-linkedsideeffects.37

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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