Rev. Bras. Anestesiol. vol.65 número1

REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

www.sba.com.br

SCIENTIFIC

ARTICLE

Rectal

dexmedetomidine

in

rats:

evaluation

of

sedative

and

mucosal

effects

Volkan

Hanci

_,

_Kanat

_Gülle

_,

_Kemal

_Karakaya

_,

_Serhan

_Yurtlu

_,

_Meryem

_Akpolat

_,

Mehmet

Fatih

Yüce

_,

_Fatma

_Zehra

_Yüce

_,

_Is

_¸ıl

_Özkoc

_¸ak

_Turan

a_{DepartmentofAnesthesiologyandReanimation,DokuzEylulUniversity,SchoolofMedicine,Izmir,Turkey}

b_{DepartmentofHistologyandEmbryology,ZonguldakBulentEcevitUniversity,SchoolofMedicine,Zonguldak,Turkey} c_{DepartmentofGeneralSurgery,ZonguldakBulentEcevitUniversity,SchoolofMedicine,Zonguldak,Turkey}

d_{DepartmentofAnesthesiologyandReanimation,ZonguldakBulentEcevitUniversity,SchoolofMedicine,Zonguldak,Turkey}

Received1July2013;accepted9September2013 Availableonline5November2013

KEYWORDS Dexmedetomidine; Rectum;

Rat; Anesthesia; Mucosa

Abstract

Backgroundandobjectives: Inthisstudy,weinvestigatedtheanestheticandmucosaleffects oftherectalapplicationofdexmedetomidinetorats.

Methods:Male Wistar albino ratsweighing 250---300g were dividedinto four groups: Group S (n=8) wasa sham groupthat served asabaseline for the normalbasal values; Group C (n=8)consistedofratsthatreceivedtherectalapplicationofsalinealone;GroupIPDex(n=8) includedratsthatreceivedtheintraperitonealapplicationofdexmedetomidine(100␮gkg−1);

andGroupRecDex(n=8)includedratsthatreceivedtherectalapplicationofdexmedetomidine (100␮gkg−1).Fortherectaldrugadministration,weused22Gintravenouscannulaswiththe

styletsremoved.Weadministeredthedrugsbyadvancingthecannula1cmintotherectum,and therectaladministrationvolumewas1mLforalltherats.Thelatencyandanesthesiatime(min) weremeasured.Twohoursafterrectaladministration,75mgkg−1_{ketaminewasadministered} forintraperitonealanesthesiainallthegroups,followedbytheremovaloftherats’rectums toadistaldistanceof3cmviaanabdominoperinealsurgicalprocedure.Wehistopathologically examinedandscoredtherectums.

Results:AnesthesiawasachievedinalltheratsintheGroupRecDexfollowingthe adminis-tration ofdexmedetomidine. TheonsetofanesthesiaintheGroup RecDexwassignificantly laterandofashorterdurationthanintheGroupIPDEx(p<0.05).IntheGroupRecDex,the administrationofdexmedetomidineinducedmild---moderatelossesofmucosalarchitecturein thecolonandrectum,2hafterrectalinoculation.

Conclusion: Although100␮gkg−1dexmedetomidine administeredrectallytoratsachieveda

significantlylongerdurationofanesthesiacomparedwiththerectaladministrationofsaline,our

∗_{Correspondingauthor.}

E-mails:[email protected],[email protected](V.Hanci).

histopathologicalevaluationsshowedthattherectaladministrationof100␮gkg−1

dexmedeto-midineledtomild---moderatedamagetothemucosalstructureoftherectum.

©2013SociedadeBrasileiradeAnestesiologia.PublishedbyElsevier EditoraLtda.Allrights reserved.

PALAVRAS-CHAVE Dexmedetomidina; Reto;

Rato; Anestesia; Mucosa

Dexmedetomidinaretalemratos:avaliac¸ãodosefeitossedativosesobreamucosa

Resumo

Justificativaeobjetivos: Nesteestudonósinvestigamososefeitosanestésicosesobreamucosa daaplicac¸ãoretaldedexmedetomidinaaratos.

Métodos: RatosmachosalbinosWistar,pesando250-300g,foramdivididosemquatrogrupos: GrupoS(n=8)foium gruposhamqueserviudebasepara osvaloresbasaisnormais; Grupo C(n=8)consistiuemratosquereceberamaaplicac¸ãoretalapenasdesorofisiológico;Grupo IPDex(n=8) consistiuem ratosquereceberamaplicac¸ãointraperitonealde dexmedetomid-ina(100␮gkg−1)eGrupoRecDex(n=8)consistiuemratosquereceberamaaplicac¸ãoretal

dedexmedetomidina(100␮gkg−1).Paraaadministrac¸ãodosfármacosporviaretal,usamos

cânulasintravenosasdecalibre22,comosestiletesremovidos.Aadministrac¸ãoconsistiuem avanc¸aracânula1cmnoreto,eovolumedeadministrac¸ãoretalfoide1mLparatodososratos. Ostempos(min)delatênciaedeanestesiaforamregistrados.Duashorasapósaadministrac¸ão porviaretal,75mgkg−1_{decetaminaforamadministradosatodososgrupospara anestesia} intraperitoneal,seguidoporremoc¸ãodosretosdosratosaumadistância3cmdistalpormeio deprocedimentocirúrgicoabdominoperineal.Osretosforamhistopatologicamenteexaminados eclassificados.

Resultados: AanestesiafoirealizadaemtodososratosdogrupoRecDexapósaadministrac¸ão dedexmedetomidina.OtempodeiníciodaanestesianoGrupoRecDexfoisignificativamente maislongoecomumadurac¸ãomaiscurtaquenoGrupoIPDEx(p<0,05).NoGrupoRecDex,a administrac¸ãodedexmedetomidinainduziuperdaslevesamoderadasdaarquiteturadamucosa docólonereto2hapósainoculac¸ãoretal.

Conclusão:Emboraaadministrac¸ãode100␮gkg−1dedexmedetomidinaporviaretalemratos

tenharesultadoemumadurac¸ãosignificativamentemaiordaanestesia,emcomparac¸ãocom aadministrac¸ãoretaldesorofisiológico,nossasavaliac¸õeshistopatológicasmostraramquea administrac¸ãoretalde100␮gkg−1dedexmedetomidinaocasionoudanoslevesamoderadosà

estruturadamucosaretal.

©2013SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos direitosreservados.

Introduction

Premedicationisthepreoperativenasal,oral,rectal, intra-muscularorintravenousadministrationofsedativedrugsto lower the patient’s fear of surgical intervention, achieve sedationandanxiolysis,anddecreasetheamountof anes-thetics needed.1---6 _{In addition tobenzodiazepines such as}

midazolam,whicharecommonlyusedforthispurpose,the

useof alpha2 agonists suchasclonidine and

dexmedeto-midineisbecomingpopular.3---8_{Forpediatricpatients,itis}

essentialthatpremedicationagentsareadministered

non-invasively,i.e.,transmucosally,nasallyororally.3---5,7,8_Rectal

administrationis also preferred,particularly for the

pre-medicationof young children.2,3,9---11 _{Previousstudies have}

shownthat,similartomidazolamandketamine,clonidine

canbeadministeredrectallyforpremedication.2,9---14

Dexmedetomidine is an alpha adrenergic agonist with

highlevels ofspecificity andselectivity toalpha 2

recep-tors.Dexmedetomidinecanbeusedforsedation,analgesia

and anesthesia in intensive care settings, as well as for

local and regional anesthesia applications.8,15---17 _Research

has also shown that dexmedetomidine can be

adminis-teredorally,nasally,transmucosallyor intramuscularlyfor

premedication.4,8,18---24 _{However, there are no published}

studiesconcerningtherectalapplicationof

dexmedetomi-dineforpremedication.

Ourhypothesiswasthatdexmedetomidineadministered

rectally to rats would produce a sedative effect with no

damagetotherectalmucosa.

To test this hypothesis, we compared the anesthetic

effects of equal doses of dexmedetomidine administered

rectally or intraperitoneallytorats. In addition,we

com-pared the histopathological effects on rectal mucosa of

rectallyadministereddexmedetomidine.

Materials

and

methods

This study wasapproved by the Animal EthicsCommittee

oftheBulentEcevitUniversity(formerlyZonguldak

Karael-masUniversity)MedicalSchool.Alltheanimalsweretreated

theuniversity’sanimalcarecommitteeandtheprinciplesof

laboratoryanimal care(NIHpublicationno.85-23,revised

in1985).Theratswerehousedinatemperature-controlled

room(24±1◦_{C)ona12-hlight---12-hdarkcycle,andthey}

werefedstandardratchowandwateruntil12hbeforethe

experimentalprotocol.

Thirty-twomaleWistaralbinoratsweighingbetween250

and300gwererandomlydividedintofourgroups ofeight

rats. Group S (n=8) wasa sham group served asa

base-line forthenormal basalvalues;GroupC (n=8) consisted

of rats that received the rectal application of saline

alone;Group IPDex(n=8)included rats thatreceived the

intraperitonealapplicationofdexmedetomidine;andGroup

RecDex(n=8)includedratsthatreceivedtherectal

appli-cationofdexmedetomidine.

The rats’ weights were measured prior to the

exper-iment. For rectal drug administration, we used 22G

intravenouscannulaswiththestyletsremoved.We

admin-istered the drugs by advancing thecannula 1cm into the

rectum,andtherectaladministrationvolumewas1mLfor

alltherats.25

We identified the onset and duration of anesthesia in

allthe groupsby observingthe righting reflex.26 _We

mea-suredthelatencyofanesthesia(thetimerequiredtolose

therighting reflex)and theanesthesiatime(the duration

of theloss of the righting reflex)in minutes(min).26 _Two hours after rectal study drug’s administration; 75mgkg−1

ketaminewasusedinallthegroupsforintraperitoneal

anes-thesia, followed by the removal of the rats’ rectums to

adistal distanceof 3cmvia an abdominoperinealsurgical

procedure.25 _{We histopathologically examined and scored}

therectums.27

Preliminarystudy

Before the experiment, we evaluated the effectiveness

of different dosesof rectally administered

dexmedetomi-dinefrompreviousstudies.16,17,28_{Weadministered1}

␮gkg−1,

10␮gkg−1, 50␮gkg−1 and 100␮gkg−1 dexmedetomidine

rectallytothetworatsineachgroup.25_{Inthepreliminary}

study,anesthesiawasnotachievedwiththerectal

admin-istration of 1 or 10␮gkg−1 dexmedetomidine; however,

anesthesia wasobtained in one of the rats that received

50␮gkg−1dexmedetomidine rectallyandinbothrats that

received100␮gkg−1dexmedetomidinerectally.Therefore,

100␮gkg−1waschosenasthedoseofdexmedetomidineto

beusedrectallyandintraperitoneally.

Groups

Theratsintheshamgroup(n=8)didnotreceive the

rec-taladministrationofanysubstances.Theseratswereused

as controls for the histopathological examination of the

rectum.Theywereadministered75mgkg−1_{i.p.ketamine,}

followedbytheremovaloftherectumtoadistaldistanceof

3cmviaabdominoperinealsurgery.25_{Weexaminedtherats’}

rectumsandscoredthemhistopathologically.27

The rats in the control group (n=8) received 1mL of

saline by the advancementof a 22G intravenous cannula

withnostylet1cmintotherectum.Afterthesaline

admin-istration,wemeasuredtheanesthesiadurationintherats.26

Weremovedtheirrectums toa distaldistanceof 3cmvia

abdominoperinealsurgery.26_{Weexaminedtherectumsand}

scoredthemhistopathologically.27

We administered 100␮gkg−1 dexmedetomidine

intraperitoneally to the rats in group IPDex

(intraperi-tonealdexmedetomidine group,n=8).Weestablishedthe

proper dosage of dexmedetomidine with the help of the

preliminary study and previous research.16,17,28 _{After the}

administration of dexmedetomidine, we measured the

anesthesiadurationintherats.26

In the rectal dexmedetomidine group (Group RecDex,

n=8),salinewasaddedto100␮gkg−1dexmedetomidineto

a total volume of 1mL and was administered rectally by

advancinga22Gintravenouscannulawithnostylet1cminto

therectum.Afteradministeringthedexmedetomidine,we

measuredtheanesthesiadurationintherats.26_Therectums

ofthe ratswere removed toa distaldistance of 3cm via

abdominoperineal surgery.25 _{The rectums were examined}

histopathologicallyandscored.27

Histologicassessmentofcolonicmucosaldamage

Forthe light microscopic observation, distal colon

speci-mens wereembedded in paraffin blocksafter being fixed

ina10%formalinsolution.Five-micrometer(5-␮m)sections

wereobtainedandstainedwithhematoxylin---eosinand

Mas-son’strichromeusingstandardmethods.Ahistologistgraded

thecolonicpathologicalchangesinablindedmannerusing

the histologicinjury scale previously developed by Leung

etal.27 _{Briefly, mucosal damage wasgraded from 0 to 4}

accordingtothefollowingcriteria:grade0,normalmucosa;

grade1,damagetothe surfaceepitheliumonly; grade2,

damagetotheepithelium ofthe upperhalf ofthe gland;

grade3,damage tothe majorityof the glandular

epithe-liumthatdidnotextendtothebaseofthegland;andgrade

4,thedestructionoftheepitheliumoftheentiregland.

Statisticalanalysis

Weperformedthestatisticalanalysiswasusingthe

Statis-tical Package for the Social Sciences (SPSS) version 16.0

for Windows (SPSS,Chicago, IL). Forthe scores and

non-normally distributed variables, we compared the groups

using the Mann---Whitney U and Kruskal---Wallis tests. The

resultswereexpressedasmedians(25th---75thpercentiles). Apvalue<0.05wasconsideredstatisticallysignificant.

Results

Resultsconcerningthedurationofanesthesiaandtherectal

histopathologicalevaluationswereobtained.

Durationofanesthesia

Weachievedanesthesiainalltheratsintheintraperitoneal

andrectal dexmedetomidine groups following the

admin-istrationof dexmedetomidine (p<0.001).Inboth ofthese

groups,thedurationofanesthesiawassignificantlylonger

thanintheshamandcontrolgroups(p<0.001).IntheGroup

Table1 Latencyofanesthesiaandanesthesiatimevaluesaccordingtogroup(median[25th---75thpercentiles]). GroupS

(n=8)

Group C(n=8)

GroupRecDex(n=8) GroupIPDex(n=8) p

Latencyofanesthesia(min) 0(0-0) 0(0-0) 13.50(11.25---15.75)a,b,c _{8.5(5---9.75)}a,b _0.001

Anesthesiatime(min) 0(0-0) 0(0-0) 62.50(47.00---79.00)a,b,c _{111.5(96---115.0)}a,b _0.001

Min:minute.

a_{p<0.001comparedtoGroupS;Mann---WhitneyUtest.} b _{p<0.001comparedtoGroupC;Mann---WhitneyUtest.} c _{p<0.001comparedtoGroupIPDex;Mann---WhitneyUtest.}

Figure1 Representativemicrographsofratcolonsectionsstainedwithhematoxylin---eosin(A,C,E)orMasson’strichrome(B, D,F).NormalcolonicmucosaofGroupSandGroupCrats(A---D).Ratstreatedwithrectaldexmedetomidine,showingthemildto moderatelossofsurfaceandglandularepithelialcells(E,F).Scalebar=20␮m.

rapidlythanintheGroupRecDex(p<0.001).Incontrast,the

durationofanesthesiaintheGroupIPDexwassignificantly

longerthanintheGroupRecDex(p<0.001)(Table1).

Histopathologicalfindings

The histologic featuresof the colonicand rectal walls of

theSham andControl groups weredeterminedtobe

nor-mal (Fig. 1A---D). In the Group RecDex, the drug induced

mildandmoderatelossesofthemucosalarchitectureinthe

colonandrectum,2h afterrectalinoculation(Fig.1E---F).

The histological examinationsdemonstrated the presence

ofmucosaldamagewiththe lossofsurface andglandular

epithelialcells.AsshowninTable1,themicroscopicscore

(2[2-2])of thecolonsfromtheGroupRecDexwas

signifi-cantlyhigherthanthat ofthecolonand rectumsegments

fromtheshamandcontrolrats(p<0.001)(Table2).

Discussion

In this study, rectaldexmedetomidine administrationwas

showntohaveanestheticactivity buttoalsocause

signif-icantmucosaldamagetoratrectalmucosacomparedwith

theshamandcontrolgroups.

Alpha2agonists constitutea groupof drugscommonly

used in anesthesia for the purposes of sedation,

analge-sia and anesthesia.11---14,18---24 _{Clonidine, a member of this}

group, can also be used for premedication.11---14 _Rectal

Table2 Histopathologicalevaluationscoresaccordingtogroup(median[25th---75thpercentiles]).

GroupS(n=8) GroupC(n=8) GroupRecDex(n=8) p

Microscopicscore 0(0-0) 0(0-0) 2(2-2)a,b _0.001

premedication administration is particularly preferredfor youngchildrenduetotheeaseofadministration.2,3,9---11

Previous studies have reported that clonidine can be

usedeffectively rectally.11---14 _{Comparing the effectiveness}

of rectally administered clonidine to that of midazolam,

Bergendahletal.11_{foundthattheuseoftheformeras}

pre-medication resulted in lowerpain scores than midazolam

intheearlypostoperativestage.Theauthorsalsoreported

thatchildrenwhowererectallyadministeredketaminewere

more sedated in first 24 postoperative hours than those

whoreceivedmidazolam.11 _{In a study comparingthe}

rec-tal administrationof 2.5␮gkg−1 clonidine and300␮gkg−1

midazolamtopreventtheincreaseinneuropeptideYcaused

bytracheal intubationinchildren, Bergendaletal.13

con-cluded that there was no significant difference between

the two groups. A study that investigated the

pharma-cokineticcharacteristicsofrectallyadministeredclonidine

demonstratedthatitsmaximum plasmaconcentrationwas

0.77ngmL−1 _{and that the time required to reach this}

concentrationwas51min.14 _{Thesamestudyfoundthatthe}

half-lifeofrectalclonidinewas12.5handthebioavailability

was95%.Theauthorsreportedthattheplasma

concentra-tionof clonidinereached clinicallyeffective levels10min afterrectal administration.14 _{Theystated that2.5}

␮gkg−1

clonidine rectally administered to children approximately

20minbeforeanesthesiainductioncouldachieveaclinically effectiveplasmaconcentration.14

Dexmedetomidine is a highly specific and sensitive

alpha adrenergic agonist, and it can be administered

orally, nasally, transmucosally or intramuscularly for

premedication.4,8,18---24

Özcengiz et al.20 _{showed that oral dexmedetomidine}

could preventpost-sevolurane agitation in children. Yuen

etal.4_{reportedthat1}

␮gkg−1intranasaldexmedetomidine

producedsignificantlyhighersedationinchildrenaged2---12

yearscomparedwithoral midazolam.Theauthors

empha-sizedthatdexmedetomidineandmidazolamcreatedsimilar

premedicationconditionsandthatbothwereacceptable.4

In anotherstudy, Yuenetal.29 _{found that sedation began}

anaverageof25minafterintranasaldexmedetomidineand

that the mean duration of sedation was 85min. Sakurai

etal.21_{reportedthat3---4}

␮gkg−1dexmedetomidine

admin-isteredtochildrenbuccally1hbeforesurgerywasreliable

andeffective.

In a comparison of the effects of 2␮gkg−1 intranasal

dexmedetomidine and 0.5mgkg−1 _{midazolam for}

preme-dication in pediatric patients, Talon et al.22 _{found that}

thetwodrugshadsimilaranesthesiainduction and

recov-ery characteristics. However, the authors reported that

dexmedetomidinewasmoreeffectiveininducingsleepand

thatitwasausefulalternativetooralmidazolam.22

Althoughtherectaluseofclonidineandtheoral,nasal

and transmucosal use of dexmedetomidine for

premedi-cationhavebeendefined,thereisnoliteratureontherectal

useofdexmedetomidine.

In our study, the rectal administration of 100␮gkg−1

dexmedetomidine achieved anesthesia in all the rats in

thatgroup. Thedurationof anesthesiainboth thegroups

thatreceivedintraperitonealandrectaldexmedetomidine

was significantly longer than in the sham and control

groups.However,theonsetofanesthesiawassignificantly

later in the rectal dexmedetomidine group than in the

intraperitonealdexmedetomidine group,and theduration

ofanesthesiawassignificantlyshorterthaninthe intraperi-tonealgroup.

Rectal administrationis an alternative method of

pre-medication,particularlyforyoungchildren.Theabsorption

mechanisms of rectally administered drugs resemble the

uppergastrointestinalsystem.Passivetransportisthemain

mechanismofrectaldrugabsorption.Theabsorptionspeed

ofrectallyadministereddrugsisinfluencedbyfactorssuch

as the molecular weight, lipid solubility and ionization

degreeof thedrug.However,therectaladministrationof

drugshasbeenreportedtocausesideeffectssuchaslocal

inflammation, rectal mucosal damage, rectal ulceration,

rectalbleedingandpain.30

Therectaladministrationofanestheticagentsmayalso

causerectalmucosaldamage.25_{Previousstudieshaveshown}

thatrectallyadministered10%methohexitonecausesrectal

mucosaldamageinratsthatbeginswithinminutes,becomes

noticeableat60min,andcontinues24h.25

However,therehavebeenonlyafewstudiesofthe

rec-talmucosaleffectsofalpha2agonists.31,32_Maxsonetal.31

reportedclonidineadministrationtoratstodecreasemucus

productioninanintestinalischemia/reperfusionmodel.In

acase study,thelong-termuse ofclonidine wasreported

tocause cicatricialpemphigoidin theanus,vulvamucosa

andperianalskin.32_{Inthatcase,thedirect} immunofloures-centexaminationofthelesionsindicatedthepossibilityof

complement-mediated tissue damage between epidermal

basalcellsandthebasalmembrane.32

Inourliteraturereview,wewerenotabletofindastudy

thatevaluated the effectsof rectally administered

cloni-dine on rectal mucosa cells. We found in our study that

rectallyadministered100␮gkg−1dexmedetomidinecaused

themoderatelossoftherectalmucosalsurfaceand

glandu-larepithelialcells.Weareoftheopinionthatthemucosal

damage caused by dexmedetomidine may have a

mecha-nismsimilartothatofclonidine.31,32 _{However,wedidnot}

investigatethemechanisms ofmucosal damageformation

inthepresentstudy.Thesepreliminaryfindingsinratsmay

not be observed in rectal mucosa of humans due to the

highdose andresultinghigh concentration appliedtothe

rectalmucosainthisstudy.Webelievethatfuturestudies

shouldinvestigatetheeffectsofdexmedetomidineonrectal

mucosaandthereversibilityofthedamage.

Thedexmedetomidinedosageusedinourstudywas

iden-tifiedasthemosteffectiveinrectaluseinthepreliminary

study.Severalother studies have demonstrated

neuropro-tectiveeffects of dexmedetomidine,albeit onlyat higher

doses(upto100␮gkg−1).33---35

In conclusion, although the rectal administration

of dexmedetomidine to rats achieved a significantly

longer duration of anesthesia compared with saline, our

histopathologicalevaluationshowedthattheformer

treat-ment led to moderate damage in the mucosal structure

of the rectum. Therefore, for the rectally safe use of

dexmedetomidineaspremedication,webelievethatfuture

studiesareneededtorevealtheeffectsofthedrugonrectal mucosa.

Conflicts

of

interest

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