Rev. Bras. Anestesiol. vol.66 número3

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

Colonoscopy

sedation:

clinical

trial

comparing

propofol

and

fentanyl

with

or

without

midazolam

Jose

Francisco

Nunes

Pereira

das

Neves

_,

Mariana

Moraes

Pereira

das

Neves

Araújo

_,

_Fernando

_de

_Paiva

_Araújo

_,

Clarice

Martins

Ferreira

_,

_Fabiana

_Baeta

_Neves

_Duarte

_,

_Fabio

_Heleno

_Pace

_,

Laura

Cotta

Ornellas

_,

_Todd

_H.

_Baron

_,

Lincoln

Eduardo

Villela

Vieira

de

Castro

Ferreira

a_{UniversidadeFederaldeJuizdeFora(UFJF),JuizdeFora,MG,Brazil}

b_{InstitutoNacionaldeTraumatologiaeOrtopedia(INTO),RiodeJaneiro,RJ,Brazil} c_{UNCSchoolofMedicine,NorthCarolina,USA}

Received27June2014;accepted17September2014 Availableonline12March2016

KEYWORDS

Sedation; Colonoscopy; Propofol; Fentanil; Midazolam

Abstract Colonoscopyisoneofthemostcommonprocedures.Sedationandanalgesiadecrease anxiety anddiscomfort andminimize risks.Therefore, patients preferto be sedatedwhen undergoingexamination,althoughthebestcombinationofdrugshasnotbeendetermined.The combinationofopioidsandbenzodiazepinesisusedtorelievethepatient’spainanddiscomfort. Morerecently,propofolhasassumedaprominentposition.Thisrandomizedprospectivestudy isuniqueinmedicalliteraturethatspecificallycomparedtheuseofpropofolandfentanylwith orwithoutmidazolamforcolonoscopysedationperformedbyanesthesiologists.Theaimofthis studywastoevaluatethesideeffectsofsedation,dischargeconditions,qualityofsedation, andpropofolconsumption duringcolonoscopy,withorwithoutmidazolamaspreanesthetic. Thestudyinvolved140patientswhounderwentcolonoscopyattheUniversityHospitalofthe FederalUniversityofJuizdeFora.Patientsweredividedintotwogroups:GroupIreceived intra-venousmidazolamaspreanesthetic5minbeforesedation,followedbyfentanylandpropofol; GroupIIreceivedintravenousanesthesiawithfentanylandpropofol.PatientsinGroupIIhada higherincidenceofreaction(motororverbal)tothecolonoscopeintroduction,bradycardia, hypotension,andincreasedpropofolconsumption.PatientsatisfactionwashigherinGroupI. Accordingtothemethodologyused,thecombinationofmidazolam,fentanyl,andpropofolfor colonoscopysedationreducespropofolconsumptionandprovidesgreaterpatientsatisfaction. © 2015SociedadeBrasileirade Anestesiologia.Publishedby ElsevierEditoraLtda.Allrights reserved.

∗_{Correspondingauthor.}

E-mail:[email protected](L.E.V.V.C.Ferreira). http://dx.doi.org/10.1016/j.bjane.2014.09.014

PALAVRAS-CHAVE

Sedac¸ão; Colonoscopia; Propofol; Fentanil; Midazolam

Sedac¸ãoparacolonoscopia:ensaioclínicocomparandopropofolefentanilassociado

ounãoaomidazolam

Resumo Acolonoscopiaéumdosprocedimentosmaisfeitos.Sedac¸ãoeanalgesiadiminuem aansiedadeeodesconfortoeminimizamriscos.Emrazãodisso,ospacientespreferemque oexamesejafeitosobanestesia,emboranão tenhasidodeterminadaamelhorcombinac¸ão defármacos.Aassociac¸ãodebenzodiazepínicoscomopioideséusadaparaaliviaradoreo desconfortodopaciente.Maisrecentemente, opropofolassumiuposic¸ãode destaque.Este estudo,prospectivoerandomizado,éúniconaliteraturamédicaeespecificamentecomparou ousodopropofolefentanilassociadoounãoaomidazolamnasedac¸ãoparacolonoscopiafeita poranestesiologistas.Osobjetivosdoestudoforamavaliarosefeitoscolateraisdasedac¸ão,as condic¸õesdealta,aqualidadedasedac¸ãoeoconsumodepropofolduranteacolonoscopia,com ousemomidazolamcomopré-anestésico.Envolveu140pacientessubmetidosàcolonoscopia, noHospitalUniversitáriodaUniversidadeFederaldeJuizdeFora.Ospacientesforam dividi-dosemdoisgrupos.OGrupoIrecebeu,porviaendovenosa,midazolamcomopré-anestésico, cincominutosantesdasedac¸ão,seguidodofentanilepropofol.OGrupoIIrecebeu,porvia endovenosa,anestesiacomfentanilepropofol.OspacientesdoGrupoIIapresentarammaior incidênciadereac¸ão(motoraouverbal)àintroduc¸ãodocolonoscópio,bradicardia,hipotensão arterialemaiorconsumodepropofol.Asatisfac¸ãodospacientesfoimaiornoGrupoI.Deacordo comametodologiaempregada,aassociac¸ãodemidazolamaopropofolefentanilparasedac¸ão emcolonoscopiareduzoconsumodepropofolecursacommaiorsatisfac¸ãodopaciente. ©2015SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos direitosreservados.

Introduction

Colonoscopyisoneofthemostcommonproceduresinthe world.Sedation andanalgesia areconsidered key compo-nents,astheyreduceanxietyanddiscomfortandtherefore improvetheproceduretolerabilityandpatientsatisfaction, minimize risk of complications and provide better condi-tionsfortheexamination.1,2_{Colonoscopypainresultsfrom}

mesenterictractionmaneuversandcolonicdistensionbygas insufflationandthedevicefrequentwindinginsidethe intes-tine,whichrequires correction maneuvers.3---6 _{As a result,}

manypatientsprefertheexaminationdoneundersedation andanalgesia.7

Althoughthegoalofsedationistofacilitatecolonoscopy, patientsmay havevarying degrees ofimpairment intheir cognitive function, with a consequent delay in discharge andrestrictionsinvariousdailyactivities.Thecombination ofbenzodiazepines withopioidshasbeen usedsince1980 in colonoscopy procedures toalleviate patient’s painand discomfort.Morerecently,propofolhastakenaprominent position.4---7

Propofol may be used alone or in combination with opioids(fentanyl25---75␮g,meperidine25---50mg),and/or

benzodiazepines (midazolam 0.5---2.5mg), but thereis no clearevidencethatthecombinationofpropofolwithother drugsleadstoreductionofsideeffects.8_Theuseof

propo-folalonerequireshigherdoses,whichmayleadtoincreased incidenceof side effects.However, therisks andbenefits of adding analgesic and sedative to propofol are contro-versial, and the selection of drugs is a crucial factor in determiningtheoutcomes.9_{Regardlessofthedrugused,the}

anesthesiaforcolonoscopyisrelatedtocomplicationssuch ashypoxia,respiratorydepression,apnea,hypotension,and cardiacdysrhythmia.6,7,10,11

Based on surveys, only two studies evaluated the use of propofol and fentanyl combined with midazolam for colonoscopy.However,bothstudiesusedpropofolaloneas thebasisforcomparisonwiththeotherthreegroups: fen-tanylandpropofol,midazolamandpropofol,andpropofol with fentanyl and midazolam.9,12 _{In the study by}

Pad-manabhan et al., although sedation has been made by anesthesiologists,theobjectiveofthestudieswasto eval-uateonlythecognitivefunctionofpatientspost-sedation, withoutanymentionoftheparametersrelatedtothe endo-scopicprocedure.9_{Inturn,inthesurveyconductedbyRex}

andVannatta,althoughvariablessimilartoourshavebeen evaluated,thesedationwasmadebyregisterednursesand supervisedbyendoscopists.

Our study is unique in the literature that specifically compared, prospectively, the use of propofol and fen-tanyl associated or not with midazolam in sedation for colonoscopyperformedbyanesthesiologists.

Methods

A prospective, randomized, double-blind study, involving 140patientsundergoingcolonoscopyattheUniversity Hos-pital (HU/CAS) of the Federal University of Juiz de Fora

The study included menandwomen, agedbetween 18 and60years,ASAI-II,referredtotheDigestiveEndoscopy Unit of HU/CAS of UFJF for a diagnostic colonoscopy. Patients invited to participate in the study signed the informedconsent,and the study primaryobjectives were toevaluate theside effects of sedation,discharge condi-tionsfromthepost-anesthesiacareunit(PACU),andquality ofsedation intheopinionof theendoscopistandpatient. Secondarily,weevaluatedthetotalconsumptionof propo-fol.

Theexclusioncriteriawerepatientswithchronicuseof drugs suchasbenzodiazepines, neuroleptics, and anticon-vulsantsfor morethan 30 days;hypersensitivityreactions to drugs used in the study; those undergoing abdominal laparotomy; bodymass indexabove35kgm−2_;psychiatric

patients; inadequate preparation conditions, defined as those preventing or hindering the examination; patients withclinicalsuspicionofintestinalsubocclusionorstenotic colon tumors; using drugs that interfere with the heart rate; requiring complex therapeutic procedures set dur-ingdiagnostic colonoscopy, suchas polypectomyof larger polyps,flatlesionmucosectomy,andmultiplepolypectomy (>3).

Intotal,140patientswereallocatedrandomlyintotwo groups.Athirddoctor,responsibleforrandomization, pre-pared the syringe with premedication (midazolam) and placebo(distilledwater),sothatboththeendoscopistand theanesthesiologistinchargeofsedationwereblindtothe allocationofpatients.

Allpatientsweremonitoredwithpulseoximetry, contin-uous ECG, andnoninvasive blood pressure assessed every 5min. The groups consisted of 70 patients each (Group I andGroupII).InGroupI,patientsreceivedintravenous(IV) midazolam(0.05mgkg−1_{)asapre-anesthetic5minbefore}

sedation, followedby IVfentanyl (1␮gkg−1)and propofol

(1mgkg−1_).

InGroupII,patientsreceivedanesthesiawithIVfentanyl (1␮gkg−1)and propofol(1mgkg−1).In both groups,

anes-thesiawasinducedwithpropofol,andthetotalloadingdose wasappliedslowly,within60s, orlimitedtothedrooping eyelid with loss of corneal-palpebral reflex. The mainte-nance dose of 0.5mgkg−1_{, was repeatedwhenever there}

weresignsof discomfort(motororverbalreaction, tachy-cardiaand/orhypertension).Inbothgroups,supplementary oxygenwasofferedwithnasalcatheter(3Lmin−1_).

Endoscopic examinationwas performed by two experi-encedendoscopistsusingaFujinon4400videosystem and colonoscopytubesoftheseries490.

Duringprocedures,age,weight,andheightofpatients; indication for colonoscopy; reactions (motor or verbal) to the introduction of the colonoscope; time to colono-scopeintroductionintothececum;totalexaminationtime; dose of propofol induction; total propofol consumption; cardiovascular disorders: hypertension and tachycardia, defined as elevated blood pressure and heart rate levels greater than 20% above preanesthetic values; hypoten-sion and bradycardia, defined as a loss greater than 20% above preanesthetic values, and changes in the levelsof peripheral hemoglobin oxygen saturation. In cases where hypoxia lasted for more than 30s or the drop reached levels below 80%, ventilation was started with a face mask.

After30minutesinthePACU,thepatientswithascore

≥9 according tothe Aldrete---Kroulik modified indexwere consideredfitfordischarge.13_{Finally,weevaluatedthe}

sat-isfactionoftheendoscopistandpatientusingavisualanalog scale(0=dissatisfiedand10=extremelysatisfied).

Statisticalanalysiswasperformedandinitiallywe evalu-atedthedatanormalityusingtheKolmogorov-Sminorvtest. Thenwechosetousenon-parametrictestsbecausethedata didnotreachnormaldistribution.Tocomparethemeansof the twogroups, we used the Mann---Whitney test, and to compareproportionsweusedthechi-squaretest.All ana-lyzeswereperformedusingtheGraphPadPrismversion5.01 software,anda p-value <0.05wasconsideredstatistically significant.

Results

Table1showsasummaryof alltheresearchdata, includ-inggeneraldatarelatedtocolonoscopy,cardiovascularand hemoglobin saturation changes, sedation, and anesthetic recovery.

Allpatientsunderwentacompletecolonoscopy examina-tion.Regardingtheexamination,patientsinGroupIIhada higherincidenceofreaction(motororverbal)tothe colono-scopeintroduction(p<0.04).

Regardingcardiovascularchanges,GroupIIhadahigher frequencyofhypotension,althoughthisdifferencedidnot reachstatisticalsignificance(p=0.121),andagreater num-berofepisodesofbradycardia(p=0.04).Onlyoneepisode ofmildhypoxemiawasseenineachgroup.

Themeandoseofpropofolusedforinductionwassimilar between both groups. However, the total consumption of propofolwashigherinGroupII,andthisdifferencereached statisticalsignificance(p<0.001).

TheassessmentofpatientsinthePACUwiththeuseof Aldrete---Kroulikmodifiedscaleandthesatisfactionof endo-scopistsandpatientsareshownattheendofTable1.When comparingthesethreevariables,onlypacient satisfaction wassignificantlyhigherinGroupI(p=0.006).

Discussion

Colonoscopy is a procedure often performed for preven-tion, diagnosis, and treatment of a variety of symptoms anddiseasesof thelowerdigestivetract,9,14 _andsedation

oranesthesiashouldbeconsideredasanimportanttoolto increaseitseffectiveness.15

Sedation oranesthesia isintended todecrease anxiety anddiscomfort,increasetoleranceandsatisfactionwiththe procedure,reducerisksofcomplications,andpromote sat-isfactoryconditionsfortheexamination.2,5,15

The dose and the depth of sedation should be indi-vidualized according to the needs of each patient.2

Gastrointestinalendoscopicproceduresareoften complex and require endoscopist’s attention. Patient cooperation and anesthesiologist participation help to improve the procedure,2,16,17_{increasethedetectionofpolyps,and}

facil-itatetherapeuticprocedures.7,16

There are several anesthetic techniques available for colonoscopy.2 _{Traditionally, the combination of narcotics}

Table1 Studydata.

GroupI GroupII p

n 70 70

---Sex(male/female) 35.7/64.3 38.5/61.4

---Meanage(years) 48.4±9.7 48±10.8 0.996

Weight(kg) 71.1±13.2 69.8±13.2 0.670

Height(m) 1.7±0.1 1.7±0.1 0.849

Colonoscopydata

RCI 3/70(4.3%) 14/70(20%) <0.04

MTIC 6.9±3.5 6.3±3.0 0.590

TET 19.4±6.4 20.2±5.6 0.191

CardiovascularandSpO2data

Arterialhypertension 1/70(1.4%) 0/70(0%) 0.315

Arterialhypotension 14/70(20%) 22/70(31%) 0.121

Tachycardia 0/70(0%) 0/70(0%) 1.000

Bradycardia 0/70(0%) 4/70(5.6%) 0.04

SpO2 1/70(1.4%) 1/70(1.4%) 1.000

Sedationdata

MDI(mg) 70.6±13.4 71±14.6 0.890

TCP(mg) 153±60.3 206±79.2 <0.001

Anestheticrecoverydata

AKI>9 70/70(100%) 70/70(100%) >0.05

ESR 9.7±0.7 9.6±0.7 0.432

PSR 9.8±0.5 9.4±1.0 0.006

Sex,dataexpressedasapercentage;age,weightandheight:dataexpressedasmeanandstandarddeviation;RCI,reactiontocolonoscope introduction;n,noofcases/noofpatients(%);MTIC,meantimeofdeviceintroductiontothececuminminutes;TET,totalexamination time(meanin minutes);MDI,mean dose ofpropofolinduction;TCP, totalconsumptionofpropofol;AKI,post-anestheticrecovery accordingto themodifiedAldrete---Kroulikindex; ESR,endoscopistsatisfactionratings (meanand standarddeviation);PSR,patient satisfactionratings(meanandstandarddeviation).

propofol occupies a prominent place.1,2,7,16---18 _The

phar-macokinetic model of propofol presents a safe agent for colonoscopybecauseithasan amnesiceffectanda4-min half-life,whichprovidesfastrecoveryandawakeevenafter prolongedadministration.19_{However,theanalgesiceffectof}

propofolislimitedand,whenusedasasingleagent,higher dosesarerequiredwhichincreasestheriskofdeepsedation. Thebolusadministrationassociatedwithashorthalf-lifeof propofolfacilitates the occurrence of ‘‘sedation waves’’, in which deep sedation peaks and respiratory depression mayalternatewithepisodesofsuperficialityandriskof agi-tationduringcolonoscopy.9 _{Theuseof continuousinfusion}

pumpminimizesthisproblem,butincreasesthecostofthe procedure.

Italsoshouldbeconsideringthat,becausepropofolhasa verynarrowtherapeuticwindow,whichleadseasilyfroma stateofmoderatetodeepsedationorgeneralanesthesia,2

andbecausethereisnoreversalagent,propofolshouldonly beadministeredbyananesthesiologistordoctorwithproven experienceinairwaymanagement.9

To reduce thesementioned risks, sedation with propo-fol in colonoscopy hasits administrationoften associated withfentanyland/ormidazolam,which,insmalldoses, usu-allyproducemoderatesedation.4,16,18_{Somestudiesreported}

thatpatientsreceivingcombinedsedationweredischarged morequicklyandreportedgreatersatisfaction.4,20,21

Our results showed that patients who did not receive midazolam (Group II) had a higher frequency of reaction tothecolonoscopeintroduction(Table1).Webelievethat theadditionofmidazolamtopropofolandfentanyl,atthe dosesusedintheresearch(minimumrecommendeddoses), providesa moreadequate level of sedationtothe device introduction.

The similarity between the two groups regarding the rectum-cecumtimeandthetotalexaminationtime(Table1) shows that procedures were technically similar in both groups,andthuscomparable.

Another important finding in our study was the total consumption of propofol significantly lower in Group I. This findingisconsistent withtheliterature,inwhich the reduced propofol dose is associated with the combined use of opioids and benzodiazepines.4,6,9,21 _The

combina-tion of propofol and fentanyl and/or midazolam reduces the consumption of propofol and decreases the risk of deepsedation,withoutprolongingtherecovery.22_Asmaller

consumption of propofol is usually expected in combined sedation.12,16 _{Similarly to our study, two other studies}

midazolam and fentanyl.12,16 _{Reduction in propofol}

con-sumptionisanimportanttechnicalaspectbecausethedrug hasnospecificantidotesorantagonists,whichcanbe con-sideredalimitingfactorforitsuse.14,19

Sedation can prolong recovery and discharge time and increase costs and the possibility of cardiopulmonary complications.Heartrate,bloodpressure,andpulse oxime-try should be routinely monitored, and some protocols suggestsupplementaloxygenadministration,8_becausethe

practice of sedation for colonoscopy exposes patients to increasedmortalityand morbidity.Inourstudy,we found a higher frequency of hypotension in Group II (Table 1). Although this difference did not reach statistical signif-icance, the higher frequency of hypotension in Group II patientsislikelyduetotheincreasedconsumptionof propo-folinthisgroup,aknownhypotensiveagent.AlsoinGroup II,wenoticedanincreasedfrequencyofbradycardia,which maybeexplainedbythe possibilityof myocardial depres-sion.Theinteractionofpropofolwithmuscariniccholinergic receptors is concentration-dependent and may induce bradycardia.23

Regardingtheperipheralhemoglobinoxygensaturation, weobservedinbothgroupsonlyonepatientwithtemporary reductionofSpO2,withoutrequirementforventilationwith

afacemask.Ourdatasupportthefactthatbothtechniques are safe and have small risk of cardiopulmonary adverse events,asreportedintheliterature.12,16

ThepossibilityofearlydischargefromPACUisan impor-tant aspect in the care of outpatients, and it generates improvedserviceandlowercosts.1_{Althoughourstudydoes}

notfocusonPACUdischargetime,ourresultsshowedthat regardlessofthesedationtechniqueused,all140patients weredischargedwithanAldrete---Kroulikmodifiedindex>9 after30min.

The endoscopist assessment showed no difference between the groups, demonstrating that anesthesia, regardless of the combination of drugs used, facilitates colonoscopy. Patients in Group II had a higher incidence of reaction to the colonoscope introduction, which may be related to the decreased satisfaction with the tech-niqueandconfirmsthattheadditionofmidazolamimproves comfort.

Conclusion

According to the methodology used, the combination of midazolam, propofol, and fentanyl for sedation in colonoscopyreducesthetotalconsumptionofpropofoland isassociatedwithgreaterpatientsatisfaction.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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