Rev. Bras. Anestesiol. vol.65 número5

(1)

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

OfficialPublicationoftheBrazilianSocietyofAnesthesiology

www.sba.com.br

SCIENTIFIC

ARTICLE

Effect

of

low

dose

dexmedetomidine

premedication

on

propofol

consumption

in

geriatric

end

stage

renal

disease

patients

Pinar

Ergenoglu

∗

_,

_Sule

_Akin,

_Cagla

_Bali,

_Hatice

_Evren

_Eker,

_Oya

_Yalcin

_Cok,

_Anis

_Aribogan

BaskentUniversitySchoolofMedicine,AnesthesiologyandReanimationDepartment,Adana,Turkey

Received17September2014;accepted11November2014 Availableonline2May2015

KEYWORDS

Geriatricpatient; Endstagerenal disease;

Dexmedetomidine; Propofol

Abstract

Backgroundandobjective: Sedation in dialysis dependent end-stage renal disease patients requirescautionasaresultofperforminghighdosesofsedativesanditscomplications. Mul-tidrugsedationregimensmightbesuperiorandadvantageonlesserdrugconsumptionandby thewayadverseeventswhichoccureasilyinend-stagerenaldiseasepatients.Weevaluated theeffectsofdexmedetomidinepremedicationonpropofolconsumption,sedationlevelswith Observer’sAssessmentofAlertnessandSedationscoresandthebispectralindexandthe hemo-dynamicchanges,potentialsideeffectsingeriatricpatientswithend-stagerenaldiseasewho underwenthipfracturesurgeryunderspinalanesthesia.

Method: Inthisrandomized,controlled,double-blindstudy60elderlypatients(age≥65years) withend-stagerenaldiseaseandhipfracturescheduledforanterogradefemoralintramedullary nailing were assigned to groups that received either intravenous saline infusion (Group C) ordexmedetomidine0.5␮g/kg/10mininfusionforpremedication(GroupD).Allthepatients

receivedpropofolinfusionaftertheinductionofthespinalanesthesia.

Results:Total propofol consumption, propofol dose required for targeted sedation levels accordingtoObserver’sAssessmentofAlertnessandSedationscoresandbispectralindexlevels, recoverytimesweresignificantlylowerinGroupD(p<0.001).ThetimetoreachtoObserver’s AssessmentofAlertnessandSedationscore4andtoachievebispectralindex≤80was signi-ficantlylowerinGroupCcomparedwithGroupD(p<0.001).Adverseeventsweresimilarin bothgroups.

Conclusion:Dexmedetomidinepremedication lowersintraoperative propofolconsumptionto maintaintargetedlevelofsedation.Thereforelowdosedexmedetomidinepremedicationin additiontopropofolinfusionmightbeanalternativeingeriatricpatientswithend-stagerenal diseaseforsedation.

∗_{Corresponding}_author.

E-mail:pergenoglu@yahoo.com(P.Ergenoglu).

http://dx.doi.org/10.1016/j.bjane.2014.11.002

(2)

PALAVRAS-CHAVE

Pacientegeriátrico; Doenc¸arenalem estágioterminal; Dexmedetomidina; Propofol

Efeitodapré-medicac¸ãocomdosebaixadedexmedetomidinasobreoconsumode propofolempacientesgeriátricoscomdoenc¸arenalemestágioterminal

Resumo

Justificativaeobjetivo: Asedaçãoempacientedependentedediálisecomdoençarenalem estágioterminal(DRET)requercautelacomoresultadodaadministraçãodealtasdosesde seda-tivosesuascomplicações.Osregimesdesedaçãocommúltiplasdrogaspodemsersuperiorese vantajososemrelaçãoaoconsumomenordedrogaseaoseventosadversosqueocorrem facil-menteempacientescomDEET.Avaliamososefeitosdapré-medicaçãocomdexmedetomidina sobreoconsumodepropofol,osníveisdesedaçãocomosescoresdaObserver’sAsssessment ofAlertnessandSedation(OAA/S)edoíndicebispectral(BIS),asalteraçõeshemodinâmicase ospotenciaisefeitoscolateraisempacientesgeriátricoscomDRETsubmetidosàcirurgiapara fraturadequadrilsobraquianestesia.

Método: Neste estudorandômico, controlado eduplo-cego, 60 pacientesidosos(idade≥65 anos),comDRETefraturadequadril,agendadosparafixaçãointramedulardehastefemoral anterógradaforamdesignadosparagruposparareceberaminfusãointravenosadesoluçãosalina (GrupoC)oupré-medicaçãocominfusãode0,5mgkg/10mindedexmedetomidina(DEX)(Grupo D).Todosospacientesreceberaminfusãodepropofolapósainduçãodaraquianestesia.

Resultados: Oconsumototaldepropofol,adosedepropofolnecessáriaparaosníveis-alvode sedaçãodeacordocomosescoresdaOAA/S,osvaloresdoBISeostemposderecuperação foramsignificativamentemenoresnoGrupoD(p<0,001).Otempoparaatingiroescore4na OAA/SevaloresBIS≤80foisignificativamenteinferiornoGrupoCemcomparaçãocomoGrupo D(p<0,001).Oseventosadversosforamsemelhantesemambososgrupos.

Conclusão:Apré-medicaçãocomdexmedetomidinareduzoconsumodepropofolno intraoper-atórioparamanteronível-alvodesedação.Portanto,apré-medicaçãocomDEXemdosebaixa emcombinaçãocominfusãodepropofolpodeserumaalternativaparasedaçãoempacientes geriátricoscomDRET.

Introduction

Theincidenceofendstagerenaldiseaseanddialysis pop-ulation inthe elderly continuestoincrease universally.1---3 Hip fractures are also major problem and the anesthesia techniqueshouldbeplannedindetailduetopotential alter-ations in volume distribution, protein binding, and drug metabolismandexcretion.4---6_In_an_ideal_anesthesia_regime, themostimportantparametersareprovidinghemodynamic stability withoptimalfluid andelectrolyte balance, using drugs withalowermetabolism, shorter half-lifeand non-renal clearance, targeting early recovery and return of cognitiveandpsychomotorfunctions.7

Neuraxial techniques such as single spinal injection is frequently performed for the intraoperative anesthesia managementofpatientswithchronicrenalfailure.8 Coad-ministration of spinal anesthesia and sedation became a standard protocol for providing patients’ anxiolysis and amnesiaat theintraoperativeperiod.9 _Propofol_is_the fre-quently used agent and combination regimens such as propofol vs alfentanil or midazolam vs fentanyl for seda-tion are commonly used in patients with chronic renal failure.10,11_The_{sedoanalgesia}_drug_doses_should_be_titrated and to reduce dose consumption combination regimens shouldbeperformedinhemodialysispatients.12

Dexmedetomidine (DEX)is aselective␣2receptor

ago-nistagent,mightbeanalternativeofchoiceforcombination regimen with propofol due to its sedative and analgesic

propertieswithminimaleffectsonventilation.13_There_are limitednumber of studies investigating the effectof DEX in patients withend stage renal disease (ESRD),however thesestudies are not specific to geriatric patients at the sametime.14,15

In this study we evaluate the effects of dexmedeto-midine premedication on propofol consumption, sedation levels,hemodynamicchanges,potentialsideeffectsin geri-atricpatientswithESRDwhounderwenthipfracturesurgery underspinalanesthesia.

Materials

and

methods

(3)

whorejectedspinalanesthesia)andhistoryofallergytoany medicationsusedinthisstudy.

The randomization scheme was developed by a com-puter and covered in sealed envelopes. These envelopes werepreparedbyanindependentanesthesiologistwhowas notassociatedwiththestudy.Theenvelopeswereopened bytheanesthesiatechnician,whoalsopreparedthestudy drugs.

Patientswererandomlydividedintotwogroups:

Group control (Group C): Saline infusion for

premedi-cation, midazolam 0.02mg/kg; spinal block (hyperbaric bupivacaine0.5%,12.5mg,n=30).

GroupDEX(GroupD):0.5␮g/kg/10mindexmedetomidine

infusionforpremedication,midazolam0.02mg/kg;spinal block(hyperbaricbupivacaine0.5%,12.5mg,n=30).

The study drugs were brought to the operation the-aterbytheanesthesiatechnician.Theanesthesiologistwho performed premedications, spinal anesthesia, intraopera-tivepostoperativefollow-upsanddatarecordingswasalso blindedtothestudydrugsandgroupallocation.

Aperipheralintravenouslinewasplacedusingan18---20 gauge catheter in patients. Patients arrived in the oper-ation theater without premedication. Routine anesthesia monitoringwasperformedwithpulse-oxymeter,5-leadECG, noninvasiveblood pressure measurement,pulse oxymetry andBIS.BISscoresweremeasuredusinganAspectBISVista Monitor(AspectMedicalSystems,Inc).Electroencefalogram (EEG)wasrecordedusingBISQUATROTM_sensor_stuck_to_the preparedforeheadskinasexplainedintheinstructions.All thepatientsreceived0.02mg/kgmidazolam.0.5␮g/kgDEX

in20mLwasadministeredin10minwithaninfusionpump. An equivalent volumeof saline solution was given tothe controlgroupbyusingthesamemethod.Baseline,1-,5-, 10-minuteOAA/Sscores,BIS,peripheraloxygensaturation (SpO2),heartrate(HR),systolicbloodpressure(SBP), dias-tolic blood pressure (DBP) values were recorded. At this period 250mL of 0.9% NaCl was infused. Basal SBP, DBP, HR, SpO2, BIS values were recorded before induction of thespinalblock.Lumbarpuncturewasperformedinlateral decubitis position with a Quincke® ₂₇ _gauge _spinal nee-dleat theL3---L4 interspaces using the midline approach. Patients were promptly rotated to supine position after

blockinduction.Inductionofthespinalblockwasaccepted astimeof0forallintraoperativedatarecordings.All param-eterswere recordedat 1-,5-min andevery 5min for the firsthour and followingthe firsthour every 15min during surgery.

Hypotension was described as ≥25% decrease in SBP fromthebaselineor incaseswhensystolicbloodpressure decreases below 90mmHg. Ephedrine 5mg was adminis-teredintravenouslyandtherateofcrystalloidinfusionwas increased.

Thesensorialblocklevelandthemotorblocklevelwere assessedbypinpricktestandmodifiedBromagescale(0=no motor block, 1=hip flexion with extended leg blocked, 2=kneeflexionblocked,3=completemotorblock), respec-tively.TimetoreachthelevelofT10andtoBromage3was alsonoted.Propofolinfusionwasstartedinallthepatients atadose of50mcg/kg/minafterthelevelofblockarised toT10dermatome level.OAA/S scalewasusedfor evalu-atingthelevelofsedation16 ₍_Table₁_)._Intermittent_0.5_mL bolus doses of propofolwere givenfor reaching totarget OAA/S scores andBISlevelsat thebeginning ofthe seda-tionifnecessary.Sedativeagent(DEXvspropofol)infusion startingtimewasaccepted as0pointfor therecordingof thetimetoreachtoOAA/Sscore4andthetimetoreachto BIS≤80.TargetBISvalueswerebetween70and80.Infusion rate wastitrated according tothe targetedOAA/S scores andBISlevels.IncaseOAA/Sscore<4andBIS<70,propofol infusionratewasreduced.Propofolinfusionwasstoppedat thebeginningofskinsuturing.

Patientsweremonitoredatthepostoperativecareunit and all monitoring parameters were registered at every 5min for 1h. Criteria for transferring the ward were OAA/S=5,BIS>90,Bromage=0---1.

Totalpropofolconsumption,timenecessarytoreachthe targeted level of sedation (OAA/S score 4 and BIS≤80), propofol dose required for targeted OAA/S score and BIS levels,recoverytime(BIS>90),durationofsurgery,amount of bleeding, vasoactive drug need were recorded. Pos-sible side effects and possible complications during the preoperative, intraoperativeperiodand thepostoperative follow-upsuchashypotension(SBP<90mmHg),bradycardia (HR<60min),respiratorydepression(SpO2≤90%),nausea, vomiting,anddeepsedationwerecarefullymonitoredand recorded.

Table1 Theobserver’sassessmentofalertness/sedationscore.

Responsiveness Speech Facialexpression Eyes Compositescore

Respondsreadilytonamespoken innormaltone

Normal Normal Clear;noptosis 5(alert)

Lethargicresponsetoname spokeninnormaltone

Mildslowingor thickening

Mildrelaxation Glazedormildptosis

(lessthanhalfthe eye)

4

Respondsonlyafternameiscalled loudly/orrepeatedly

Slurringorprominent slowing

Markedrelaxation (slackjaw)

Glazedormarked ptosis(halftheeyeor more)

3

Respondsonlyaftermildprodding orshaking

Fewrecognizable words

--- --- 2

Doesnotrespondtomildprodding orshaking

(4)

Statistical

analysis

Statisticalanalysiswasperformedusingthestatistical pack-age SPSS (Version 17.0, SPSS Inc., Chicago, IL, USA). The primary outcome of this study was total propofol con-sumptionduringthehipfracturesurgery.Apoweranalysis indicatedthat26patientspergroupwererequiredtodetect atruedifferenceof40mgbetweengroupswherethe antici-patedstandarddeviationwas43.16.Thestandarddeviation wasbasedonapilotgroupofpatientsundergoinghip frac-ture surgery. The type 1 error was set at 0.05 and type II error at 0.10. We allowed for 4 more patients in each groupstocompensatefordropoutsduringthestudyperiod. For each continuous variable, normality was checked by Kolmogorov---Smirnov and Shapiro---Wilk tests and by his-tograms.Independentsamplest-testandtheMann---Whitney

U-test were performed for between-groups comparisons where appropriate. Pre-post measures were analyzed by RepeatedMeasureAnalyses.Valuesofp<0.05were consid-eredtobestatisticallysignificant.

Results

Sixty-hemodialysisdependentchronicrenalfailurepatient scheduledforhipfracturerepairwereenrolledinthestudy.

Fig. 1 presents the allocation of patients in groups. The groupswerecomparablewithrespecttodemographicdata, durationofsurgery,timetoreachtoT10,toBromage3and toBromage0(Table2).

Total propofol consumption, propofol dose required for targeted sedation levels and recovery time were

Table2 Demographicdataandblockcharacteristics.

GroupC GroupD

Age(yr) 71.70±4.84 70.83±5.18

Height(cm) 163.73±5.89 163.96±5.34

Weight(kg) 64.76±7.02 64.40±6.01

Durationofsurgery(min) 103.63±7.77 102.56±6.40 TimetoreachtoT10

(min)

3.63±0.55 3.60±0.53

Timetoreachto Bromage3(min)

4.63±0.56 4.56±0.54

Timetoreachto Bromage0(min)

180.0±8.51 181.16±7.27

Dataexpressedasmean±SD.

significantlylowerinGroup D whencomparedwithGroup C(p<0.001).Thetimetoachievetotargetedsedation lev-elsaccordingtoOAA/SscoreandBISlevelswassignificantly lowerin Group C comparedwith Group D (p<0.001). All thepatientsin GroupD achievedtargetedsedation levels withonly DEX infusion without propofol infusion require-ment(Table3).

ComparisonofpreoperativeOAA/SandBISscoresshowed that the scores were significantly lower in Group D com-paredwithGroup Cat preoperative5thand10thminutes (p<0.001).Intraoperative OAA/Sscoresat 1-,3-,5-,10th minutesandintraoperativeBISscoresat1-,3-,5-,10-,15th minutesweresignificantlylowerinGroupDcomparedwith GroupC(p<0.05).The scoresweresimilarinboth groups till75thminutesandweresignificantlylowerat75th,90th minutesingroupC(p<0.05)(Figs.2and3).Postoperative

Enrollment

Randomized (n=60)

Allocation

Follow-Up

Analysis

Assessed for eligibility (n=60)

Excluded (n=0)

Allocated to control group (n=30)

♦ Not meeting inclusion criteria (n=0) ♦ Declined to participate (n=0) ♦ Other reasons (n=0)

♦ Received allocated intervention (n=30) ♦ Did not receive allocated intervention (n=0)

Allocated to Dexmedetomidine group (n=30)

♦ Received allocated intervention (n=30) ♦ Did not receive allocated intervention (n=0)

♦ Excluded from analysis (n=0)

Lost to follow-up (n=0) Discontinued intervention (n=0) Lost to follow-up (n=0)

Discontinued intervention (n=0)

Analysed (n=30)

♦ Excluded from analysis (n=0)

Analysed (n=30)

(5)

100 90 80 70 60 50 40 30 20 10 0

BIS Scores

Time (minute)

Group D Group C

PRE basal

PRE 1 PRE 5

PRE 10

IO 1 IO 3 IO 5

IO 10 IO 15 IO 20 IO 25 IO 30 IO 45 IO 60 IO 75 IO 90 PO 5

PO 10 PO 15 PO 30 PO 45 PO 60

Figure2 BISvaluesofthepatients.Valuesgivenaremedian(*p<0.001;†_p₌_0.001;‡_p₌_0.002).

Table3 Sedationdata.

GroupC GroupD p

Timetoachieve BIS≤80(min)

5.08±0.51 7.65±1.49 <0.001

Timetoreachto OAA/Sscore4 (min)

4.03±0.45 5.28±0.85 <0.001

Propofoldosefor BIS≤80(mg)

37.17±5.83 0.00±0.00 <0.001

Totalpropofol consumption(mg)

197.0±50.08 82.0±23.03 <0.001

Recoverytime (BIS≥90)(min)

16.73±1.84 7.30±1.52 <0.001

Dataexpressedasmean±SD.

OAA/S scores were similarbetween groups (Fig. 3). Post-operative BIS scores were significantly lower at 5-, 10th minutes in Group C (p<0.001); but was similar between groupsafterthe10thminutes(Fig.2).

Theheartrate,SBP,DBP,SpO2showeddecreaseatGroup D but there were no significant differences among two groups.Hypotensionwasobservedat8patientsinGroupD and9patientsinGroupC;bradycardiaobservedat6patients inGroupDand5patientsinGroupCduringthe intraopera-tiveperiod.Howeverthedifferencebetweenthegroupswas notstatisticallysignificant.None ofthepatientsexhibited respiratorydepression,nauseaandvomiting.

Discussion

In this study we showed that in geriatric patients with chronicrenalfailuresedationregimenwithDEX premedica-tionreducestotalpropofolconsumptionwithrapidrecovery time(GroupC:16.73±1.84min;GroupD:7.30±1.52min). Ontheotherhand,accordingtothepharmacokinetic prop-ertiesthetimerequiredtoattaintheaimedlevelofsedation wassignificantlyshorterwithpropofolinthecontrolgroup (5.08±0.51min)incomparisonwiththeDEXpremedication (7.65±1.49min).

Propofolisanultrafastagentwithapeakeffectwithin 5minofadministrationandisusedforsedationoranesthesia maintenance.17,18_It_has_been_reported_that_the pharmacoki-neticsofbolusorinfusiondosesarenotaffectedmarkedly andcanbeusedsafelyinESRDpatients.19,20_DEX_is_a_highly selective␣2adrenoceptoragonistdrugwithsedative,

sym-patholytic,andanalgesicactions.Itismetabolizedintoits inactivemetabolitesinliveranditseliminationisunaffected byrenaldisease.Byvirtueoftheseproperties,itmayoffer analternativeoptionforsedationinESRDpatients.15,21_It_has also been reportedthat it does not exert any respiratory depressant effectevenin highdoses,anditcanbesafely usedforsedationinveryelderlypeople.22

Dose determination studies for DEX in patients with chronic renal failure have demonstrated that the drug providedsufficientsedationwithanysignificantsideeffect at a dose of 0.6␮g/kg/10min in volunteer patients aged

18to65yearswithcreatinineclearanceof<30.15 _We_also

5

4

3

2

1

0

O

AA/S Scores

Time (minute)

Group D Group C

PRE basal

PRE 1 PRE 5

PRE 10

IO 1 IO 3 IO 5 _{IO 10} _{IO 15} _{IO 20} _{IO 25} _{IO 30} _{IO 45} _{IO 60} _{IO 75} _{IO 90} _{PO 5}

PO 10 PO 15 PO 30 PO 45 PO 60

Figure3 OAA/Sscoresofthepatients.Valuesgivenaremedian(*p<0.001;†_p₌_0.001)._PRE,_{preoperative;}_Io,_{intraoperative;}

(6)

attainedthedesiredsedationlevelwithoutanysignificant hemodynamicresponseorsideeffectwithsimilar premed-icationdosesofDEX(0.5␮gr/kg/10min).Alsoweobserved

thatallthepatientsinGroupDreachedtargetedsedation levels following preoperative DEX infusion without any propofolrequirement.

IthasbeenreportedthatDEXusedasanadditiveagent decreasespropofolconsumption.23_Also_in_our_study_a propo-foldosetitrationwasperformedafterDEXpremedicationfor sedationwiththeguidanceofOAA/SandBISmonitoring.It wasdemonstratedthatpropofolconsumptionwas2.4-fold greaterthanthestudygroup(197.0mgvs82.0mg)andthus the recovery period was2.29 times longerin the control group(16.73minvs7.30min).Accordingtotheseresults,it maybesuggested thatthelowerOAA/S andBIS scoresat 75and90minattheintraoperativeperiodaswellaslower BISscoresandasignificantlylongerrecoverytimeat5and 10minatthepostoperativeperiodobservedinthecontrol groupwereassociatedwithahigherpropofolconsumption, andthusdexmedetomidinehadanimportanteffecton post-operativeearlyrecovery.

One other parameter that should be taken into con-sideration is the hemodynamic response. In addition to sympatholyticeffectsofspinalanesthesia,anadditive inter-actionwithcardiovasculareffectsofDEXandpropofolmay be possible. DEX is known to have some cardiovascular effectsincludinghypotensionandbradycardia owingtoits sympatholyticeffects.However,ithasbeen reportedthat itoffersagoodcardiovascularstabilityandthusitisagood sedativeagent.24,25

In a study comparing sedation application with dexmedetomidine or midazolam in ESRD patients it was reportedthatnoneof thepatientsexperienced prolonged hypotensionor bradycardia,allrespondedsatisfactorilyto thetreatment,andnoneof themwereexcludedfromthe study even with large loading doses of 1␮g/kg/10min of

dex.14 _We_also_did_not_demonstrate_a_{significantly}_different hemodynamicresponsetoDEXloadedatadoseof0.5␮g/kg

compared to the control group. However, both groups developedintraoperativehypotension(GroupC,30%;Group D, 26.7%) and bradycardia (Group C, 16.7%; Group D, 20%) after propofolinfusion, which quickly resolvedupon administrationofsympathomimetics.Thisresponsemaybe an additiveresultofthe venodilatativeeffectof propofol and the sympatholytic effect of spinal anesthesia rather thantheeffectofDEX.

In thepresentstudy wefound thatpremedicationwith DEX at a dose of 0.5␮g/kg for 10min attained sufficient

and aimed sedation levels without propofol requirement during the preoperative period. DEX premedication also reducedintraoperativepropofolconsumption, significantly promoted earlyrecovery andwasnotthe causeofsevere side effects.In conclusion, we believethat low dose DEX premedicationinadditiontopropofolinfusionmightbean alternativeregimeningeriatricpatientswithESRDfor seda-tion.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgement

This study was supported by Baskent University Research Fund(BaskentUniversityInstutionalReviewBoardandEthics Committee,ProjectnumberKA12/166).

Trial registration: Clinicaltrials.gov identifier

NCT01837290.

References

1.IsmailN,HakimRM,OreopoulosDG,etal.Renalreplacement therapiesintheelderly:Part1.Hemodialysisandchronic peri-tonealdialysis.AmJKidneyDis.1993;22:759---82.

2.KeithDS. Transplantationintheelderly patient.ClinGeriatr Med.2013;29:707---19.

3.SasakiY,MarioniR,KasaiM,etal.Chronickidneydisease:a riskfactorfordementiaonset:apopulation-based studyThe Osaki-TajiriProject.JAmGeriatrSoc.2011;59:1175---81.

4.Le-WendlingL,BihoracA,BaslantiTO,etal.Regional anesthe-siaascomparedwithgeneralanesthesiaforsurgeryingeriatric patientswithhipfracture:doesitdecreasemorbidity, mortal-ity,andhealthcarecosts?Resultsofasingle-centeredstudy. PainMed.2012;13:948---56.

5.Jørgensen TSH, Hansen AH, Sahlberg M, et al. Falls and comorbidity:thepathwaytofractures.ScandJPublicHealth. 2014;42:287---94.

6.TrainorD,BorthwickE,FergusonA.Perioperativemanagement ofthehemodialysispatient.SeminDial.2011;24:314---26.

7.ByrickRJ.Anesthesiaand endstagerenal failure:isTIVAan advance?CanJAnaesth.1999;46:621---2.

8.Hadimioglu N, Ulugol H, Akbas H, et al. Combination of epidural anesthesia andgeneral anesthesia attenuatesstress response to renal transplantation surgery. Transplant Proc. 2012;44:2949---54.

9.BrownDL.Spinal,epidural,andcaudal anesthesia.In:Miller RD,editor.Miller’sanesthesia.ElsevierHealthSciences;2010. p.1612---27.

10.EddlestonJM,PollardBJ,BladesJF,etal.Theuseofpropofolfor sedationofcriticallyillpatientsundergoinghaemodiafiltration. IntensiveCareMed.1995;21:342---7.

11.LeeSM,KimGH,LeeJJ,etal.Doespropofoland alfentanil-inducedsedationcauseperiodicapnoeainchronicrenalfailure patients?IntJClinPract.2010;64:1---5.

12.Beathard GA, Urbanes A, Litchfield T, et al. The risk of sedation/analgesiainhemodialysispatientsundergoing inter-ventionalprocedures.SeminDial.2011;24:97---103.

13.OkHG,BaekSH,BaikSW,etal.Optimaldoseof dexmedetomi-dineforsedationduringspinalanesthesia.KoreanJAnesthesiol. 2013;64:426---31.

14.RutkowskaK,KnapikP,MisiolekH.Theeffectof dexmedeto-midine sedation on brachial plexus block in patients with end-stagerenaldisease.EurJAnaesthesiol.2009;26:851---5.

15.DeWolfAM,FragenRJ,AvramMJ,etal.Thepharmacokinetics of dexmedetomidinein volunteers withsevererenal impair-ment.AnesthAnalg.2001;93:1205---9.

16.BagchiD,MandalMC,DasS,etal.Bispectralindexscoreand observer’sassessmentofawareness/sedationscoremay mani-festdivergenceduringonsetofsedation:studywithmidazolam andpropofol.IndianJAnaesth.2013;57:351---7.

17.Lundström S, TwycrossR, MihalyoM, et al. Propofol.J Pain SymptomManage.2010;40:466---70.

(7)

19.IckxB,CockshottID,BarvaisL,etal.Propofolinfusionfor induc-tionandmaintenanceofanaesthesiainpatientswithend-stage renaldisease.BrJAnaesth.1998;81:854---60.

20.Kakinohana M, Tokumine J, Kawashima S, et al. Patient-controlled sedation using propofol in eight patients with endstagerenalfailure.JAnesth.2004;18:39---42.

21.Gertler R, BrownHC, Mitchell DH,et al. Dexmedetomidine: anovelsedative-analgesic agent.Proc(BaylUnivMedCent). 2001;14:13---21.

22.Kunisawa T, HanadaS, Kurosawa A, etal. Dexmedetomidine wassafelyusedforsedationduringspinalanesthesiainavery elderlypatient.JAnesth.2010;24:938---41.

23.SenS,ChakrabortyJ,SantraS,etal.Theeffectof dexmedeto-midine infusionon propofolrequirementfor maintenance of optimumdepthof anaesthesiaduringelectivespine surgery. IndianJAnaesth.2013;57:358---63.

24.HallJE,UhrichTD,BarneyJA,etal.Sedative,amnestic,and analgesicpropertiesofsmall-dosedexmedetomidineinfusions. AnesthAnalg.2000;90:699---705.