Rev. Bras. Anestesiol. vol.64 número5

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REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

Official Publication of the Brazilian Society of Anesthesiology

www.sba.com.br

SCIENTIFIC

ARTICLE

The

comparison

of

the

effects

of

dexmedetomidine,

fentanyl

and

esmolol

on

prevention

of

hemodynamic

response

to

intubation

Nermin

Gogus,

Belgin

Akan

∗

_,

_Nurten

_Serger,

_Mustafa

_Baydar

AnesthesiologyandReanimationClinic,AnkaraNumuneTrainingandResearchHospital,Ankara,Turkey

Received13September2013;accepted30October2013 Availableonline11December2013

KEYWORDS Laryngoscopy; Intubation; Hemodynamic response;

Dexmedetomidine; Fentanyl;

Esmolol

Abstract

Backgroundandobjectives: Laryngoscopy andintubation cancause hemodynamicresponse. Variousmedicationsmay be employed tocontrolthatresponse. In thisstudy,we aimedto comparetheeffectsofdexmedetomidine,fentanylandesmololonhemodynamicresponse. Methods:Ninetyelectivesurgerypatientswhoneededendotrachealintubationwhowerein AmericanSocietyofAnesthesiologyI---IIgroupandagesbetween21and65yearswereincludedin thatprospective,randomized,double-blindstudy.Systolic,diastolic,meanarterialpressures, heart ratesatthe timeofadmittance atoperationroom were recordedasbasal measure-ments. The patients were randomizedinto threegroups: Group I (n=30) received 1␮g/kg dexmedetomidinewithinfusionin10min,Group II(n=30)received2␮g/kgfentanyl,Group IIIreceived2mg/kgesmolol2minbeforeinduction.Thepatientswereintubatedin3min. Sys-tolic,diastolic,meanarterialpressuresandheartratesweremeasuredbeforeinduction,before intubationand1,3,5,10minafterintubation.

Results:Whenbasallevelswerecomparedwiththemeasurementsofthegroups,itwasfound that5and10minafterintubationheartrateinGroupIandsystolic,diastolic,meanarterial pressuresinGroupIIIwerelowerthanothermeasurements(p<0.05).

Conclusions:Dexmedetomidine was superior intheprevention of tachycardia.Esmolol pre-ventedsytolic,diastolic,meanarterialpressureincreasesfollowingintubation.Weconcluded thatfurtherstudiesareneededinordertofindastrategythatpreventstheincreaseinsystemic bloodpressureandheartrateboth.

∗_{Corresponding}_author.

E-mail:belginakan@yahoo.com(B.Akan).

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PALAVRAS-CHAVE Laringoscopia; Intubac¸ão; Resposta hemodinâmica; Dexmedetomidina; Fentanil;

Esmolol

Comparaçãoentreosefeitosdedexmedetomidina,fentanileesmololnaprevenção darespostahemodinâmicaàintubação

Resumo

Justificativaeobjetivos: Laringoscopia e intubac¸ão podem causar resposta hemodinâmica. Vários medicamentos podem ser usados para controlar essa resposta. Neste estudo,nosso objetivo foi comparar os efeitos dedexmedetomidina, fentanile esmololsobre a resposta hemodinâmica.

Métodos: Foramincluídosnoestudoprospectivo,randômicoeduplo-cego90pacientes progra-madosparacirurgiaseletivas,comintubaçãoendotraqueal,estadofísicoASAI-II,entre21e65 anos.Pressõesarteriaismédias,sistólicas,diastólicasefrequênciascardíacasforammedidasao darementradanasaladeoperaçõeseregistradascomovaloresbasais.Ospacientesforam ran-domizadosemtrêsgrupos:GrupoI(n=30)recebeu1␮g/kgdedexmedetomidinacominfusão em10min;GrupoII(n=30)recebeu2␮g/kgdefentanil;GrupoIII(n=30)recebeu2mg/kgde esmolol2minantesdaindução.Ospacientesforamintubadosem3min.Aspressõesmédias, sistólicasediastólicaseasfrequênciascardíacas forammedidasantesdaindução,antesda intubaçãoenosminutos1,3,5e10apósaintubação.

Resultados: Quandoosníveis basaisforamcomparadosentreosgrupos,verificou-sequenos minutos5e10pós-intubac¸ãoasfrequênciascardíacasnoGrupoIeaspressõesarteriaismédias, sistólicasediastólicasnoGrupoIIIestavammaisbaixasdoqueemoutrostemposmensurados (p<0,05).

Conclusões: Dexmedetomidinafoisuperiornaprevenc¸ãodetaquicardia.Esmololpreveniuo aumentodaspressõesarteriaismédias,sistólicasediastólicasapósaintubac¸ão.Concluímosque estudosadicionaissãonecessáriosparadescobrirumaestratégiaqueprevinatantooaumento dapressãoarterialsistêmicaquantodafrequênciacardíaca.

Introduction

During general anesthesia airway control is generally provided by laryngoscopy and intubation. Laryngoscopy and intubation lead to mechanical and chemical stimuli. Mechanical stimulus causes reflex responses in cardiovas-cular and respiratory systems.1 _That _response _reaches _its

maximum level within 1min and ends in 5---10min after intubation. On the other hand, chemical stimulus results withcatecholaminereleaseviaincreasein sympathoadren-ergicactivity.Catecholaminereleaseleadstohypertension, tachycardiaandarrhythmia.Tachycardiageneratesamore powerfulloadontheheartwhencomparedwith hyperten-sionasitincreasesoxygenconsumptionofthemyocardium, decreasesdiastolicfillingandfinallyreducescoronaryblood supply.2

The degree of the reflexresponse oflaryngoscopy and intubation is related with the deepness of anesthesia, patient’sageandthepresenceofdiabetesorheartdisease. Narcotic analgesics,local anesthetics, beta-blockers, cal-ciumcanalblockersandvasodilatorsareemployedinorder tocontrolthatresponse.3_{Dexmedetomidine}_is _a_selective ␣2 adrenergic agonist. Its effects on cardiovascular sys-tem are particularly prominent.4,5 _The _effect _of _fentanyl

on cardiovascular system is not much. The exact reason of bradycardia due to fentanyl use is not clear, but it is considered to be related with central vagal stimulation.6

Amongtheseagents,esmolol isacardioselective␤ adren-ergicblockerthathasaneffectwithrapidonsetandshort duration.While itinhibits ␤1 receptorsof myocardium,it

alsoinhibits ␤2 receptors of smoothmuscles of bronchial andvascularwallsathigherdoses.7

In this study, we aimed to compare the effects of dexmedetomidine,fentanylandesmololoncontrolof hemo-dynamicresponseduetolaryngoscopyandintubation.

Methods

ThestudywasapprovedbyEthicalBoardofAnkaraNumune Training and Research Hospital. Ninety elective surgery patients who were in American Society of Anesthesiol-ogy (ASA) I and II groups and whose ages were between 21 and 65 years were included in that study. The study wasplanned asa prospective, double blind and random-ized study. Those in whom difficulty in intubation was expected, who had coronary artery disease, hyperten-sion, chronic obstructive pulmonary disease or diabetes and who were using any cardiovascular medication were excluded.

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Table1 Patientdemographicsinthegroups.

GroupI(n=30) GroupII(n=30) GroupIII(n=30)

Age(years) 41.2±10.6 41.5±10.0 43.8±12.8

Gender(F/M) 11/19 15/15 15/15

ASA(I/II) 15/15 11/19 15/15

Weight(kg) 77.9±11.0 75.5±12.6 77.0±12.3

(DAP)andmean(MAP)arterialpressuresweremonitoredvia automaticnon-invasive blood pressure measurementsand peripheraloxygensaturation(SpO2)wasmonitoredviapulse oxymetry.

Thepatientswererandomizedintothreegroups.These groups were determined with closed envelopes. The subjects were blinded to the treatment they received. The anesthesiologists who prepared and administered the medications were provided to be different. Group I (n=30) received 1␮g/kg dexmedetomidine (Precedex®_, Meditera, 200␮g/2mL) with infusion in 10min, Group II (n=30) received 2␮g/kg fentanyl citrate (Fentanyl®_, Janssen-Cilag,0.05mg/mL)andGroupIIIreceived2mg/kg esmolol (Brevibloc®_, _Eczacibasi, ₁₀_mg/mL) ₂_min _before induction.Then6mg/kg thiopentaland0.1mg/kg vecuro-nium were administered intravenously. Three minutes laterlaryngoscopy andintubation were performed by the sameanesthesiologist.The patientsinwhomendotracheal intubationcouldnotbeachievedwithin45swereexcluded fromthestudy.Allpatientsreceived50%O2(2L/min),50% N2O(2L/min)and1.5MACsevoflurane(Sevorane®,Abbott) during maintenance of anesthesia. These parameters were measured and recorded before induction (t0), after induction (t1) before intubation (t2) and 1 (t3), 3(t4), 5 (t5) and 10min (t6) after intubation in all patients. The measurements before induction (t0) were considered as basallevelsandallofothermeasurementswerecompared with these basal levels. Surgical incisions were started following completionof thatdata collectionprocess. The patientswereventilatedinordertomaintainendtidalCO2 levels between 30 and 35mmHg. During the operations HR, SAP, MAP, DAP, and SpO2 levels were recorded with 5min intervals. After the operations, the subjects were monitoredinrecoveryroomfor60minfollowingawakening andthenweretransferredtoinpatientclinics.

Statisticalanalysis

SPSS (Statistical Packagefor Social Sciences)for Windows version10.0wasusedforstatisticalanalysis.One-wayAnova and Student’s ttest wereused for comparisonof quanti-tative databesides descriptivestatisticalmethods (mean, standarddeviation)inevaluationofstudydata.Chi-square testwasemployedforcomparisonofqualitativedata.The comparisons were considered as not significant (p>0.05), significant (p<0.05) or extremely significant (p<0.001) in aconfidenceintervalof95%.Asamplesizeof30achieved 100%powertodetectadifference(P1---P0)of0.2540using atwo-sidedbinomialtest.Thetargetsignificancelevelwas 0.0500.The actual significancelevelachievedbythistest was0.9229(92%).

Results

Therewasnodifferencebetweenthreegroupsaccordingto age,weight,gender andASA physiologicalscores (p>0.05 forall,Table1).

MeanSAPdecreasedatt1,t2,t5,andt6inGroupI,att1, t5andt6inGroupII,att2,t5,andt6inGroupIII(p<0.001 for all).When the groups werecomparedwitheachother, meanSAPwaslowerinGroupIIIthanothergroupsatt1,t2, t5andt6(p<0.05forall,Table2).

MeanDAPdecreasedatt1,t2,andt6inGroupI(p<0.001, p<0.001andp<0.05,respectively),att5andt6inGroupII (p<0.001forboth),att1,t2,t5,andt6inGroupIII(p<0.05, p<0.001,p<0.05andp<0.001,respectively,Table3).

MeanMAPdecreasedatt1,t2,andt6inGroupI(p<0.001, p<0.001andp<0.05,respectively),att5andt6inGroupII (p<0.001forboth),att1,t2,t5andt6inGroupIII(p<0.05, p<0.001, p<0.05 and p<0.001, respectively). When the

Table2 Thecomparisonofthegroupsaccordingtosystolicarterypressuremeasurements(mmHg).

GroupI(n=30) GroupII(n=30) GroupIII(n=30) p

t0 138.63±16.99 141.03±11.87 131.03±16.55 0.066

t1 117.00±18.27a 123.73±17.45a 114.27±20.81 0.040b

t2 115.37±18.47a 132.83±17.76 103.07±17.45a 0.039b

t3 147.13±19.41 156.60±16.87 147.43±21.27 0.079

t4 129.20±20.72 134.63±16.46 125.93±23.70 0.055

t5 119.17±17.10a 116.67±17.43a 111.60±19.91a 0.037b

t6 116.17±17.01a 110.73±18.05a 103.90±22.06a 0.031b

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Table3 Thecomparisonofthegroupsaccordingtodiastolicarterypressuremeasurements(mmHg).

t0 82.03±10.23 82.67±9.87 80.57±10.26 0.055

t1 73.33±12.07a 80.40±9.11 71.03±14.89a 0.040b

t2 72.00±13.40c 83.57±11.93 63.73±11.20c 0.038b

t3 97.73±12.28 99.23±13.01 95.07±13.49 0.080

t4 83.07±14.40 88.50±13.97 80.83±14.68 0.058

t5 76.77±12.15 75.10±12.34 71.67±15.61a 0.040b

t6 74.90±13.60 73.50±12.16a 67.76±16.62c 0.035b

a _Significant_at_the_level_of_p_<_0.05_(inter_group_{comparisons).} b _Significant_at_the_level_of_p_<_0.05.

c _Extremely_significant_at_the_level_of_p_<_0.001_(inter_group_{comparisons).}

Table4 Thecomparisonofthegroupsaccordingtomeanarterypressuremeasurements(mmHg).

t0 100.77±12.23 99.97±11.81 96.43±11.66 0.058

t1 87.10±12.05a 95.60±10.55 84.10±16.43b 0.040c

t2 86.63±14.14a 121.63±17.76 76.83±13.02a 0.037c

t3 114.30±13.65 119.53±16.87 112.33±19.49 0.081

t4 98.63±15.22 102.30±16.46 97.13±16.85 0.056

t5 91.90±13.15 84.80±17.43a 85.63±16.88b 0.039c

t6 90.30±14.38b 85.73±18.05a 80.86±20.35a 0.035c

a _Extremely_significant_at_the_level_of_p_<_0.001_(inter_group_{comparisons).} b _Significant_at_the_level_of_p_<_0.05_(inter_group_{comparisons).}

c _Significant_at_the_level_of_p_<_0.05.

groupswerecomparedwitheachother,meanMAPwaslower inGroupIIIthanothergroupsatt1,t2,t5andt6(p<0.05for all,Table4).

Mean HR decreased at t1, t2, t4, t5 and t6 in Group I (p<0.001forall)att2,t5andt6inGroupII(p<0.001,p<0.05 and p<0.001, respectively) and at t2 and t6 in Group III (p<0.05 for both). When thegroups were comparedwith eachother,meanHRwaslowerinGroupIthanothergroups att1,t2,t5andt6(p<0.001forall,Table5).

Discussion

Pathophysiologic effects of endotracheal intubation may be encountered almost in all systems of the body and

may lead to harmful consequences. The most frequent effects are cardiovascular hemodynamic responses char-acterizedwithhypertension, tachycardia, arrhythmia and increase in sympathoadrenergic activity.Although cardio-vascularhemodynamicresponsescarryriskforallpatients who receive anesthesia that risk is more prominent in those who have cerebrovascular or coronary artery dis-ease.Thuspreventingthe increaseinsympathoadrenergic activity due to endotracheal intubation is an important aspect.8 _{Dexmedetomidine} _that_is _a _selective_␣

2 adrener-gic agonist, fentanyl that is an opioid and esmolol, that is a ␤ adrenergic receptor blockerare generallyused for thatpurpose. When we comparedthesemedications with eachother,weobservedthatdexmedetomidinecontrolled

Table5 Thecomparisonofthegroupsaccordingtoheartratemeasurements(beat/min).

t0 87.7±13.35 90.97±17.40 86.34±11.49 0.062

t1 73.47±6.9a 87.57±14.17 82.00±11.49 0.0048b

t2 69.23±8.19a 79.60±15.16a 78.10±9.49c 0.0035b

t3 82.27±8.25 93.20±12.54 89.38±10.6 0.066

t4 76.17±9.18a 87.53±14.47 89.55±10.8 0.0569

t5 70.17±14.8a 80.00±13.44c 84.48±10.00 0.004b

t6 70.60±9.03a 75.72±12.50a 79.38±11.005c 0.003b

a _Extremely_significant_at_the_level_of_p_<_0.001_(inter_group_{comparisons).} b _Extremely_significant_at_the_level_of_p_<_0.001.

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heart rate and esmolol controlled blood pressure bet-ter.

Gupta etal.6 _compared_the_effects_of ₂_mg/kg _esmolol

and2␮g/kgfentanyl thatwereadministered3min before anesthesia induction in order to prevent hemodynamic responseinpatients inwhomelective surgicalprocedures wereplanned.Theyreportedthatasingledoseofesmolol preventedtheincreaseinbloodpressure.Theyalsofound that,althoughclinicallyinsignificant,theeffectofesmolol on the increase in heart rate was better than fentanyl. Atleeetal.9_compared_the_effects_of₁_mg/kg_esmolol_and

30␮g/kgnicardipinealoneandincombinationandreported thattheydidnotpreventbloodpressurechangewhenthey wereadministered solely, but wereeffective in combina-tion. These drugs did not show any effect on heart rate alone or in combination. Figueredo et al.10 _performed _a

meta-analysisofdifferentesmololdosesandreportedthat infusionwasmoreeffectivethansingledoseadministration topreventcardiovascularstressresponse.Weusedesmolol atadoseof2mg/kginthisstudy.Weobservedthatthislevel wasadequatetopreventtheincreasesinsystolic,diastolic andmeanarterialpressures,butdidnothaveanyeffecton heartrate.

Adachietal.11 _used₂_␮_g/kg_fentanyl_just_before

induc-tioninordertopreventcardiovascularstress.They found thatfentanyl wasmore effective inprevention of cardio-vascularhemodynamicresponsesecondarytoendotracheal intubation than prevention of hemodynamic response to laryngoscopy. They reported that this effect of fentanyl was related with the interaction with plasma concentra-tions of the anesthetics that were used for induction. Ugur et al.12 _used _1.5_mg/kg _esmolol, ₁_␮_g/kg _fentanyl

and1.5mg/kg lidocain 2min beforeintubation and found that esmolol prevented the increase in heart rate. On the other hand, Hussain et al.7 _compared _the _effects _of

2␮g/kg fentanyl and 2mg/kg esmolol that were admin-istered 2min before laryngoscopy and intubation and reported that fentanyl was inadequate to prevent the increases in heart rate and blood pressure. They also showedthatesmololpreventedtheincreaseinheartrate, but did not have any effect on blood pressure. In our study,we found that 2mg/kg esmolol decreased systolic, diastolic and mean arterial pressures more than 2␮g/kg fentanyl, but there was not any difference between two groups according to prevention of the increase in heart rate.

Dexmedetomidinedecreasesarterialbloodpressureand heart rate by reducing serum noradrenalin levels. Talke el al.13 _performed _a _placebo _controlled _study _in

vascu-larsurgeryandshowedthatdexmedetomidine causedless increaseinheartratesandnoradrenalinlevelswhen admin-istered at a dose of 0.8␮g/kg via intravenous infusion. Hall et al.14 _used _0.2 _and _0.6_␮_g/kg _{dexmedetomidine}

via intravenousinfusion and reportedthat although heart rate decreased prominently, there was not any change in mean arterial pressure. Similarly, Yildiz et al.15 _found

thatasingledose of1␮g/kgdexmedetomidine prevented cardiovascular hemodynamic response and decreased the need for additionalopioid during laryngoscopy and endo-tracheal intubation in elective minor surgery patients. It was noticed that infusion doses of dexmedetomidine used in these studies were between 0.2 and 0.8␮g/kg.

Alternatively, Ozkose et al.16 _administered _a _single _dose

of1␮g/kgdexmedetomidine10minbeforeinduction.They reportedthatwhencomparedwithcontrolmeasurements, meanarterialpressuresdecreasedupto20%andheartrates decreasedupto15%1and3minfollowingintubation.They observedbradycardiathatnecessitatedatropin administra-tioninfourof their20patients. Weadministered1␮g/kg dexmedetomidine before induction via infusion in 10min. Wedidnotdemonstrateanydifferenceinsystolic,diastolic andmeanarterialpressuresbetweengroups,butfoundthat itwaseffectiveinpreventingtheincreaseinheartrate.

Themostcommonsideeffectsofdexmedetomidineare hypotension and bradycardia that occur more frequently during loading period. We suggest that reducing loading dose and slowing infusion rate may prevent cardiovascu-lar side effects. We administered dexmedetomidine with slowinfusioninourstudyandobservedbradycardia neces-sitating atropinuse in only one of our patients. Similarly Venn et al.17 _reported _that _these _side _effects _were _not

observedwhen2.5␮g/kgloadingdoseofdexmedetomidine wasadministeredin10minandfollowedbyaninfusionrate of0.2---0.5␮g/kg/min.

We concluded that esmolol was more effective than dexmedetomidine and fentanyl in prevention of the increasesinsystolic, diastolicandmeanarterial pressures following endotracheal intubation. On the other hand, dexmedetomidinewasmoreeffectivethanesmololand fen-tanyl in preventingtheincrease inheart rate.To prevent the increases in blood pressure and heart rate is partic-ularly important fromthe aspect of myocardial ischemia. Weconsideredthatfurtherstudieswillbesuitableinwhich theseagentsareusedincombinationinordertopreventthe increaseinsystemicbloodpressureandheartrateboth.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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