Rev. Bras. Anestesiol. vol.66 número5

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REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

PublicaçãoOficialdaSociedadeBrasileiradeAnestesiologia

www.sba.com.br

SCIENTIFIC

ARTICLE

Evaluation

of

the

effects

of

intra-arterial

sugammadex

and

dexmedetomidine:

an

experimental

study

Volkan

Hancı

a,∗

,

¸ule

S

Özbilgin

b

,

Seda

Özbal

b

,

Gonca

Kamacı

c

,

Hasan

Ates

¸

d

,

Nilay

Boztas

¸

a

_,

_Bekir

_U˘

_gur

_Ergür

b

_,

_Ahmet

_Arıkano˘

_glu

a

_,

_Osman

_Yılmaz

c

_,

Bülent

Serhan

Yurtlu

a

a_Dokuz_Eylül_University,_School_of_Medicine,_Department_of_{Anesthesiology}_and_{Reanimation, ˙Inciraltı, ˙Izmir,}_Turkey b_Dokuz_Eylül_University,_School_of_Medicine,_Department_of_Histology_and_{Embryology, ˙Inciraltı, ˙Izmir,}_Turkey

c_Dokuz_Eylül_University,_School_of_Medicine,_Department_of_Experienced_Laboratory_Animal_{Science, ˙Inciraltı, ˙Izmir,}_Turkey d_Dokuz_Eylül_University,_School_of_Medicine,_Department_of_Plastic,_{Reconstructive}_and_Aesthetic_{Surgery, ˙Inciraltı, ˙Izmir,}_Turkey

Received20December2014;accepted30January2015 Availableonline1October2015

KEYWORDS

Sugammadex; Dexmedetomidine; Intra-arterial; Rabbit; Experimental

Abstract

Background: Intra-arterialinjectionofmedicationsmaycauseacuteandsevereischemiaand resultinmorbidityandmortality.Thereisnoinformationintheliteratureevaluatingthe arte-rialendothelialeffectsofsugammadexanddexmedetomidine.Thehypothesisofourstudyis thatsugammadexanddexmedetomidinewillcausehistologicalchangesinarterialendothelial structurewhenadministeredintra-arterially.

Methods:Rabbits were randomly dividedinto 4 groups.Group Control (n=7);no interven-tionperformed.GroupCatheter(n=7);acannulainsertedinthecentralarteryoftheear,no medicationwasadministered.GroupSugammadex(n=7);rabbitsweregiven4mg/kg sugam-madexintothecentralarteryoftheear, andGroup Dexmedetomidine(n=7);rabbitswere given1␮g/kgdexmedetomidineintothecentralarteryoftheear.After72h,theearswere amputatedandhistologicallyinvestigated.

Results:Therewasnosignificantdifferencefoundbetweenthecontrolandcathetergroups inhistologicalscores.Theendothelial damage,elasticmembraneandelastic fiberdamage, smooth musclehypertrophy and connective tissueincrease scores inthe dexmedetomidine and sugammadex groups were significantly higher than both the control and the catheter groups (p<0.05).There was nosignificant differencefound between the dexmedetomidine andsugammadexgroupsinhistologicalscores.

Conclusion:Administrationofsugammadexanddexmedetomidinetorabbitsbyintra-arterial routescausedhistologicalarterialdamage.Tounderstandthehistologicalchangescausedby sugammadexanddexmedetomidinemoreclearly,moreexperimentalresearchisneeded. ©2015SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗_{Corresponding}_author.

E-mail:[email protected](V.Hancı).

http://dx.doi.org/10.1016/j.bjane.2015.01.003

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PALAVRAS-CHAVE

Sugamadex; Dexmedetomidina; Intra-arterial; Coelho; Experimental

Avaliac¸ãodosefeitosdesugamadexedexmedetomidinaintra-arterial:estudo

experimental

Resumo

Justificativa: Ainjeçãointra-arterialdemedicamentospodecausarisquemiaagudaegravee resultarem morbidadeemortalidade.Nãoháinformaçõesnaliteraturaavaliando osefeitos endoteliaisarteriaisdesugamadexedexmedetomidina.A hipótese denossoestudofoique dexmedetomidinaesugamadexcausariamalteraçõeshistológicasnaestruturaendotelial arte-rialquandoadministradosporviaintra-arterial.

Método: Oscoelhosforamrandomicamentedivididosemquatrogrupos:grupocontrole(n=7), semintervenc¸ãorealizada;grupocateter(n=7),umacânulafoiinseridanaartériacentralda orelha emedicamentosnão foramadministrados;gruposugamadex(n=7),oscoelhos rece-beram4mg/kgdesugamadexnaartériacentraldaorelha;grupodexmedetomidina(n=7),os coelhosreceberam1␮g/kgdedexmedetomidinanaartériacentraldaorelha.Após72horas, asorelhasforamamputadasehistologicamenteexaminadas.

Resultados: Nãohouvediferenc¸asignificativaentreosgruposcontroleecateterreferenteaos escoreshistológicos.Osescoresdodanocausadoaoendotélioeàmembranaefibraelásticas, da hipertrofiado músculo liso edoaumento dotecidoconjuntivo foramsignificativamente maioresnosgruposdexmedetomidinaesugamadexqueemambososgruposcontroleecateter (p<0,05).Nãohouvediferenc¸asignificativaentreosgruposdexmedetomidinaesugamadexnos escoreshistológicos.

Conclusão:Aadministraçãodesugamadexedexmedetomidinaacoelhosporviaintra-arterial causoudanosarteriaishistológicos.Paraentenderasalteraçõeshistológicascausadaspor suga-madexedexmedetomidinacommaisclareza,estudosexperimentaisadicionaissãonecessários. ©2015SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Este éum artigo OpenAccess sobumalicençaCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Intra-arterial injection of medications may cause acute

and severe ischemia and result in morbidity and

mortal-ity. The intra-arterialinjection and cannulationincidence

varies from 1/3440 to1/56,000. Medications for sedation

orgeneralanesthesia,mainly,aremistakenlyadministered

intra-arterially.1,2 _{Intra-arterial} _injection _of _medications

maycauseacuteandsevereischemia.Itisdifficulttofully

determine the correct incidence of rare situations such

asthis.1---3 _After_the _intravenous_forms _of _medications_are

giventhroughintra-arterialroutes,localischemiaandlater

tissuenecrosismaydevelopintheartery.The

physiopatho-logical mechanisms of intra-arterial medication injection

anddevelopmentof ischemiaarenotclear.Among

mech-anisms blamedare formation of crystalsof medication in

smallarteries, secondary hemolysis and platelet

aggrega-tionafterintimaldamage,andstasis,thrombosisanddirect

cytotoxicityintheartery.Thetissuedamageisessentially

determined bythe chemical structure andamount of the

medication.1---3

The pathogenesis of formation of necrosis after

intra-arterialinjectionofmedicationisnotclear.1,4_The_rabbit_ear

modelisafrequentlyusedmethodtoresearchthe pathologi-calprocessofintra-arterialinjections.Nomatterhowvisibly

different rabbit and human ears are, they arehelpful to

observethetissueresponsetointra-arterialmedications.4

Sugammadexisamedicationnewlyenteringanesthesia

practice. It is a cyclodextrine-structured medication that

selectivelybindstoaminosteroid-structurenon-depolarizing

musclerelaxants likerocuronium, endingtheir effects. It

showshighselectivityespeciallyforrocuroniumand

vecuro-nium.Itmayenterphysicochemicalreactionswithdifferent

medications.5

There is no information in the literature

evaluat-ing the arterial endothelial effects of sugammadex and

dexmedetomidine, two medications newly entering

anes-theticpractice.Onlyasinglecasereportwasfound about

dexmedetomidinemistakenlyadministeredintra-arterially.6

The hypothesis of our study is that sugammadex and

dexmedetomidine will cause histological changes in

arte-rial structure when administered intra-arterially. To test

this hypothesis in this planned study we used rabbit ear

arteriestointra-arteriallyinject4mg/kgsugammadexand

1␮g/kgdexmedetomidineaimingtoresearchthe

histologi-caleffects.

Method

ThestudywascompletedinDokuzEylülUniverstiyMedical

Facultyexperimentalanimallaboratoryafterreceiving

per-missionfromDokuzEylülUniversityMedicalFacultyAnimal

Experiments Ethics Committee (Meeting date: 08.01.2014

---Decisionnumber:115/2013).Theresearchused28adult

male New Zealand white rabbits weighing from 2.5 to

3kg.ThesubjectsobtainedfromDEUMFExperimental

Ani-mals Laboratory were fed with standard rabbit feed and

water.Therabbitswerehousedintemperature-controlled

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study.Duringtheexperimentinternationalguidelineswere

maintainedforcareoflaboratoryanimals.

Using sterile techniques the rabbits in the

experimen-talgroupweregiven50mg/kgketamineintraperitoneally.

Asthe animalsmay havedifferent responses tothe

anes-theticmedications,depthofanesthesiawasdeterminedby

monitoringpalpebraorcorneareflexes.

Ourstudy usedthe rabbit earmodeldescribed by

Kin-monthandSheppard.7_Rabbits_with_sufficient_anesthesia_had

intra-arterialinterventionwitha24Gcannula.

Rabbitswererandomlydividedinto4groups:

GroupControl(n=7):rabbitsinthisgrouphadno

inter-ventionperformed.

GroupCatheter(n=7):rabbitshadacannulainsertedin

thecentralartery ofthe ear,howevernomedication was

administered.

Group Sugammadex(n=7):rabbits weregiven4mg/kg

(100mg/mL)sugammadexintothecentralarteryoftheear,

givenasboluswithin10sforatotalvolumeof2mL.

Group Dexmedetomidine (n=7): rabbits were given

1␮g/kg (100␮g/mL) dexmedetomidine into the central

arteryof the ear withloadingdose administered withan

infusionpumpover10minforatotalvolumeof2mL.

After 72h, the rabbits in all groups were given

50mg/kg ketamine intraperitoneally and after anesthesia

wasprovided,the earswereamputatedandhistologically

investigated.

Formacroscopicinvestigationsectionsespeciallyto

eval-uate arterial cross-section, samples were fixed in 10%

buffered formaldehyde and then submerged in paraffin.

Then the prepared paraffin blocks were serially cut to

4␮m thicknessusing a rotarymicrotome (Leica RM 2135,

LeicaInstruments,Nussloch,Germany).Thesesectionswere

stainedwithhematoxylin---eosinandMasson’strichrome.

Evaluationofhistomorphologyofarterialtissue

To investigate the images obtained fromthe sections, an

imageanalysismethodusingacomputervideocamerawere

used(UTHSCImagesoftware). Allsectionswereanalyzed,

only sections with clear artifacts linked to staining were

excludedfromtheevaluation.Afterstainingwascompleted

the sections were investigated under a light microscope

(OlympusBX-51,Tokyo,Japan)andimageswereevaluated

afteruploadingtoacomputerwithahighresolutioncamera

(OlympusDP-71,Japan). Allsectionsweredigitally

photo-graphed.

Underthelightmicroscopearterialtissuesectionsofthe

subjectgroupwereevaluatedfor arterialendothelial

reg-ularityand integrity,andregularityof theinternal elastic

membraneandunderlyingsmoothmuscleandelasticfibers.

Thegroupswerescoredsemiquantitativelyforendothelial

damage,elasticmembraneandelasticfiberdamage,smooth

musclehypertrophy,andincreaseinconnectivetissue.The

scoringwas0=none,1=veryslightdamage,2=slight

dam-age,3=moderatedamage,and4=severedamage.8

Statistical

analysis

Statistical analysis was performed by using the

Statisti-calPackagefortheSocial Sciences(SPSS)version16.0for

Windows (SPSS Inc., Chicago, IL, USA). The

Kolmogorov---Smirnov test was used toexamine compatibility between

measuredvariablesandnormaldistribution.Mann---Whitney

Utest wasusedfor statistical analysis.Descriptive

statis-tics included arithmetic median (minimum---maximum). A

p-value<0.05wasconsideredsignificant.

Results

Theeararterycross-sectionsofatotalof 28NewZealand

typewhiterabbitswereevaluated.

After rabbits were given the study medications

intra-arterially until the end of the 72h evaluation period,

macroscopic ischemia and necrosis findings were not

observed intheears ofanyrabbit givensugammadexand

dexmedetomidine.

Allrabbit’sears arterialtissues had investigated histo-logically.

It was observed that the arterial tissue of the

con-trol group had normal histological structure. The arterial

endotheliumwasregularandtherewasnodisruptionofthe

endothelialcontinuityobserved.Theinternalelastic

mem-branewasregularandtherewasnoirregularityobservedin

theorganizationoftheunderlyingsmoothmuscleandelastic

fibers(Figs.1---3).

The cathetergroupsamples hadsimilarcharacteristics

tothecontrolgroup(Figs.1---3).

Whenthedexmedetomidinegroupwasevaluated,

com-paredtothecontrolgrouptherewereclearareasoftissue

damageobservedinsomesubjects.Endothelialirregularity,

disruptionoftheendothelialintegrityandinplace

endothe-lialhypertrophywasobserved.Therewasirregularityinthe

internalelasticmembrane,anddisorganizationofthe

regu-larityofunderlyingsmoothmuscleandelasticfibers.Inthe

tunicamedia therewassmoothmuscle hypertrophy

iden-tified.When this groupis comparedtothecontrol group,

therewasanincreaseinconnectivetissuefound(Figs.1---3).

Whenthesamplesfromthesugammadexgroupare

eval-uated and compared with the control group, irregularity

in the endothelium and disruptionof the integrity of the

endotheliumwereobserved.Thesugammadexgroupswere

observed to have better preservation of the arterial

tis-suecomparedtothedexmedetomidine group.Endothelial

hypertrophywasnotobserved.Theirregularityofthe

inter-nal elastic membrane and disorganization of underlying

smooth muscle andelastic fibers and increase in

connec-tive tissue were observed to be less compared with the

dexmedetomidinegroup(Figs.1---3).

When the results of the histological evaluation of the

groups is investigated,therewasnosignificantdifference

foundbetweenthecontrolandcathetergroupsintermsof

scoresforendothelialdamage,damagetoelasticmembrane

andelasticfibers,smoothmusclehypertrophyand

connec-tivetissueincrease(p>0.05).

Theendothelial damage,elasticmembrane andelastic

fiberdamage, smoothmusclehypertrophy andconnective

tissueincreasescoresinthedexmedetomidineand

sugam-madexgroupsweresignificantlyhigherthanboththecontrol

group(p<0.05)andthecathetergroup(p<0.05).

Therewasnosignificant differencefound between the

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Figure1 Representativelight-microscopicimagesofH---Estaininginvasculartissueinthecontrolgroup(A),cathetergroup(B), sugammadexgroup(C),anddexmedetomidinegroup(D).( )indicatesmoothmusclehypertrophyand( )indicateendothelial damage.

scoresforendothelialdamage,elasticmembraneandelastic

fiberdamage,smooth musclehypertrophy andconnective

tissue increase (p>0.05). The results of the histological evaluationofthegroupscanbeseeninTable1.

Discussion

This study aimed to research the histological effects

of 4mg/kg sugammadex and 1␮g/kg dexmedetomidine

administeredintra-arteriallyusingrabbiteararteries.After

theadministrationofdexmedetomidineandsugammadexit

wasobservedthatscoresforhistological;endothelial

dam-age, elastic membrane and elastic fiber damage, smooth

musclehypertrophyandincreaseinconnectivetissuewere

significantly higher compared with control and catheter

groups. Additionally in no rabbit was tissue ischemiaand

tissuenecrosisobservedafterintra-arterialadministration

ofdexmedetomidineandsugammadex.

Table1 Histologicalevaluationofthestudygroups[median(minimum---maximum)].

Groups Endothelial

damage

Damagetoelastic membraneand elasticfibers

Smooth muscle hypertrophy

Connective tissue increase

GroupControl(n=7) 0.0(0.0---0.0) 0.0(0.0---1.0) 0.0(0.0---1.0) 0.0(0.0---0.0) GroupCatheter(n=7) 0.0(0.0---1.0) 0.0(0.0---1.0) 0.0(0.0---0.0) 0.0(0.0---1.0) GroupDexmedetomidine(n=7) 2.0(2.0---3.0)a,b _2.0_(2.0---3.0)a,b _2.0_(2.0---3.0)a,b _2.0_(1.0---3.0)a,b GroupSugammadex(n=7) 2.0(1.0---2.0)a,b _2.0_(1.0---2.0)a,b _2.0_(1.0---2.0)a,b _2.0_(1.0---2.0)a,b

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Figure2 Representativelight-microscopicimagesofH---Estaining(A1---B1---C140×andA2---B2---C2100×magnification)invascular

tissueinthedexmedetomidine group.( ) indicatesmooth musclehypertrophy, ( )indicate disorderinmembraneelastica interna,and( )indicateendothelialhypertrophy.

As a result of mistaken administration of medications

intra-arterially, serious complications such as endothelial

destruction,tissuenecrosis,thrombosisandlossof extrem-itiesmayoccur.1,2,9,10 _The_majority _of_cases_of_medication

mistakenlyadministeredintra-arteriallyinvolveagentsused

foranesthesiaandsedation.1,2_Various_studies_have_reported

the incidence of iatrogenic intra-arterial cannula

inser-tionandintra-arterialmedicationadministrationashaving

ratesbetween1/56,000and1/3440.2,10_Studies_by_D’Eramo

etal.11 _reported_this_rate_as_2/57,575._However_it_is

diffi-culttodeterminethecorrectincidenceofsituationsthatare

rare,likethisone.1,10_When_confronted_with_this_unwanted

situationthoughitisreportedthatearlyinterventionisof

great importance, thereare no well-describedtreatment

methodsforpatients.12,13

Following intra-arterial injection, discomfort, local

irritationandintensepaindistalfromtheinjectionsiteare

observedasthefirstsymptomsfrequentlywithinseconds.

Painmaybedescribed assimilartoanelectric shockor a

burning sensationinthe fingertips.Ashorttimelater,the

patientmaydescribesensoryproblemsliketingling,burning

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Figure3 Representative light-microscopicimages ofMasson’strichrome staining invascular tissueinthe controlgroup (A), cathetergroup(B),sugammadexgroup(C),anddexmedetomidinegroup(D)( )indicateincreaseinconnectivetissue.

muscle spasms and muscle weakness and skin findings of

rednessandskinrashesmaybeencountered.1,2,10,14

Ghourietal.10 _reported_the_signs_that_may_cause

intra-arterialcannulizationtobeconsideredasbrightredblood

comingfromthecannula,pulsatilemovement ofthe

can-nula,blood flowsbackintotheserumseteventhoughthe

junctionoffluidandcannulaishigher,cannulasinhighrisk

areaswherearteriesandveinsareclosesuchasthe

ante-cubital region, and pressure increase in arterial catheter

previouslyinsertedinthesameextremity. Howeverinour

caseofintra-arterialpheniramineinjection,diagnosis was

onlypossibleafterblood gasanalysis,andifintra-arterial

administrationissuspectedconfirmationtestsofbloodgas

analysis or intra vein pressure measurements should be

performed.1

Themostimportantstageoftreatmentforintra-arterial

injection is to provide anticoagulation with heparin and

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withoutcontraindications.15_An_important_part_of_treatment

is formed by preventing vasospasm in the artery.

Intra-arterial administration of local anesthetics like procaine

andlidocaineandvasodilatatorslikepapaverineareaimed

at preventing vasospasm.1,2,10,15 _Peripheral _nerve _block

administrationis an interventional treatment method for

intra-arterialinjectionsaimingtoreduceorpreventreflex

vasospasm and lengthened vasoconstriction by providing

sympatheticblockage. This interventionmayreduce pain,

provide perfusion and reduce vasospasm and efficiently

achievestherapeuticaims.Continuousadministrationwith

the aid of a catheter increases the benefits of the

tech-nique.Howeverperipheralnerveblocksmaynotbethefirst

choiceofinterventionforsomepatientsduetothe

associ-atedrisks.1,2,10,15

Ascase-controlledhumanstudies ofintra-arterial

med-ication injections cannot be performed, there are very

fewpublicationsabout treatmentpresentingexperimental

studiesandtreatmentalgorithms.16---18 _Using_the_rabbit_ear

modelisagoodalternativetoresearchthepathological pro-cessofintra-arterialinjection.KnillandEvans4_researched

theintra-arterialeffectsofthiopental,chlorpromazineand

amphetamine using the rabbit ear model and found that

medicationdosescausinggangreneinhumanshadthesame

effectonrabbitears.Asaresultwechosetousetherabbit earmodelinthisstudy.

Thoughtheclinicaltableauofintra-arterialinjectionsis

well described, the underlying physiopathological

mecha-nisms are not clear. Studies have mentioned mechanisms

such as norepinephrine-moderated vasoconstriction,

cre-ation of platelet aggregation and intra-arterial thrombus

linked to medication or cannula, endothelial

inflamma-tion, direct cytotoxic effects, liphophilic characteristics

of the medication and osmolarity characteristics of the

medication.1,2,10,15 _The _common _result _of _these _studies _is

that all medications do not cause ischemia by the same

pathway, thatthe last commonpoint in thepathogenesis

of all intra-arterial injections independent of the variety

of mechanisms is thrombosis and asit is not suitable for

broad prospective human studies, clear understanding of

thepathogenesis is necessary for development of correct

treatmentmodels.1,2,10,15

Intheliteraturetherearemanycasesreportedof

seri-ouscomplicationsobservedafterintra-arterialmedication

injection.Itisreportedthatasaresultofiatrogenic

admin-istration of local anesthetic agent through intra-arterial

routes, rhabdomyolysis occurred.19 _In _the _{benzodiazepin}

group, after diazempam and temazepam, fasciotomyand

amputation were performed due to the occurrence of

phlebitis, vascular disorders, and arterial and venous

thrombosis.20---23_After_phenytoin_was_given_by_arterial_route

ischemia,necrosis and death was reported,24 _while _after

promazine,promethazineandchlorpromazinefromthe

phe-nothiazine group necrosis and extremity loss have been

reported.25,26 _After _thiopenthal, _a _barbiturate,

endoar-teritis, vasoconstriction, thrombosis and tissue necrosis

occurred.27---30_Similar_results_were_encountered_as_a_result

of antibiotics given by arterial route. There are cases of

necrosis and tissue loss found with penicilin, floxacillin

and clindamycin, frequently used in daily practice.31---33

Clear ischemic appearance and gangrene have been

reported after intra-arterial administration of atracurium

and tubocurarine, used in anesthesia as neuromuscular

blockers.34,35

Inaddition tothese catastrophicresults, more

moder-ateprogressionafterintra-arterialadministrationsisfound.

Different results are reported for different paracetemol

preparations.A7yearoldcaseundergoingcraniotomyfor

medulloblastoma was given 350mg paracetemol into the

radial artery by mistakeduring the postoperative period.

The case was monitored but asymptomatic and on the

7th day postoperative doppler ultrasonography revealed

radial artery pulsation was normal. However a 42 year

oldcaseundergoinglaparoscopiccholecystectomywas

mis-takenly given 900mg benzyl alcohol-based paracetemol

intra-arteriallyattheendofsurgeryforpostoperative

anal-gesia.Whenthepatientcomplainedintherecoveryunitof

painin the right hand,this painwasthoughttobe

possi-blyduetomistakeninjectioninthecannulainsertedinthe

rightradialartery.Fortyminuteslaterasaresultof notic-ingbluecolorchangesin2fingersrespondingtoradialartery

distribution,treatmentwasbegun;howeverinspiteofthis

theaffected fingershadtobeamputated.As aresultthe

authorsstatedthatmedicationspreparedwithpreservatives

like water-insoluble benzyl alcohol may lead to

endothe-lial edema and capillary endothelial dysfunction causing

vasospasm.36

Intra-arterialcomplications of water-insoluble

medica-tions like propofol, etomidate and diazepam,24,35---37 _and

high alkali medications like thiopental and phenytoin24,27

have been known for years. Contrary to this there

are no unwanted effects of intra-arterial injection of

medications like atropine, succinylcholine, pancuronium,

midazolam and fentanyl.24 _The _side _effects _of

medica-tionlikeadenosine,neostigmine---atropinecombinationand

neostigmine---glycopyrrolatehavenotbeen reported.38,39 _It

isknownthatmorecomplicationsarecausedby

membrane-solublemedications.4

Babacanetal.30 _in_a_study _researching_the

histopatho-logical criteria of intra-arterial effects of thiopental

and propofol in rabbits found that intra-arterial

admin-istration of 2.5% thiopental may be responsible for

gangrenous changesandthough this effectwasnotfound

with 1% propofol, they concluded it could cause clear

edema.

Though there is much literature information on the

intra-arterial effects of many agents used in

anesthe-sia, the studies on sugammadex and dexmedetomidine

which have newly entered clinical application are very

limited.

Sugammadexisamodifiedgammacyclodextrinmolecule

which has newly entered trade use. The unique

molecu-lar structure of sugammadex encapsulates rocuronium, a

neuromuscularblocker,removingitfromthemuscle---nerve

junction and it is used to selectively and rapidly reverse

neuromuscular blockage. Cyclodextrins are empty cut-off

cone-shaped or ring-shaped ‘‘donut-like’’ molecules with

hydrophobiccavityandhydrophilicouterstructure

contain-ing sugar rings (d-glucopyranose units) in a 3-dimensional

structure, frequently used in food and pharmaceutical

industries to transform lipophobic agents into lipophilic

types. The negatively charged hydroxyl groups make the

molecule soluble in water. The carbon atoms together

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cavity. Thus the water-soluble molecule surrounds a lipophiliccore.Thisstructureisofasuitablesizeto encap-sulatelipophilicmedicationsandincreasewatersolubility.

Non-covalentthermodynamic interactions can form

inclu-sioncomplexes.Thecavitysizeislargerthanalphaandbeta

gamma cyclodextrin and is 0.8mm. Thermodynamic, Van

derWaals, hydrophobicinteractions,hydrogenandcharge

transferinteractionscontributetotheformationofinclusion complexes(host---guestcomplexes).Theinclusioncomplexis

anencapsulatedlipophilicmolecule.Thesugammadexvial

contains injection water prepared with hydrochloric acid

andsodiumhydroxidetoadjustpH.5,40

Inourliteratureanalysiswedidnotencounterany clini-calorexperimentaldatarelatedtotheintra-arterialeffects

of sugammadex. In our study,after 4mg/kg intra-arterial

sugammadexadministration, histologicalendothelial

musclehypertrophywereobserved.Inaddition,connective

tissuescoresweresignificantlyhighercomparedtothe

con-trolandcathetergroups.

A selective ␣-2 adrenoreceptoragonist,

dexmedetomi-dine has gained a place in anesthesia practice due to

its sedative and analgesic effects. Though

dexmedeto-midine has sedative, analgesic, and anxiolytic effects,

it does not cause respiratory depression. When given

as continuous IV infusion it provides predictable stable

hemodynamics. Dexmedetomidine is widely used across

a variable spectrum from neuroanesthesia, the intensive

care patient population, gastrointestinal endoscopy, and

conscious fiberoptic intubation.41,42 _We _found _one _case

study ofintra-arterial administrationofdexmedetomidine

in the literature. This case study emphasized that after

dexmedetomidinewasmistakenlyadministeredtotheradial

artery no ischemic complications were encountered.6 _In

ourstudy thoughtissueischemia andtissuenecrosiswere

notobservedafterintra-arterialadministrationof1␮g/kg

dexmedetomidine asinfusion over 10min usingrabbit ear

arteries,histologicalevaluationobservedendothelial

musclehypertrophy and connectivetissueincrease scores

weresignificantly higherthan in thecontrol andcatheter

groups.

Themostimportantlimitationofourstudyisthatweonly

usedasingledose ofsugammadexanddexmedetomidine.

Our study wasonly ableto obtain ethics committee

per-missionforsingledoses(4mg/kgsugammadexand1␮g/kg

dexmedetomidine).To researchwhethersugammadexand

dexmedetomidine cause vein damage related to dose,

advancedstudieswithdifferentdosesarerequired.

In conclusion, administration of sugammadex and

dexmedetomidine, newly entered anesthesiapracticeand

with increasing popularity, to rabbits by intra-arterial

routes caused histological arterial damage. To

under-stand the histological changes caused by sugammadex

and dexmedetomidine more clearly, more experimental

researchisneeded.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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