A comparison of medetomidine and its active enantiomer ...

Medetomidine, a racemate of the stereoisomers levomedetomidine and dexmedetomidine, is a sedative and analgesic that acts centrally on α2 ... Skiptomaincontent Advertisement SearchallBMCarticles Search DownloadPDF Researcharticle OpenAccess Published:13March2013 Acomparisonofmedetomidineanditsactiveenantiomerdexmedetomidinewhenadministeredwithketamineinmice WesleyMBurnside1,2,PaulAFlecknell1,AngusICameron3&AurélieAThomas1  BMCVeterinaryResearch volume 9,Article number: 48(2013) Citethisarticle 10kAccesses 27Citations Metricsdetails AbstractBackgroundMedetomidine-ketamine(MK)anddexmedetomidine-ketamine(DK)arewidelyusedtoprovidegeneralanaesthesiainlaboratoryanimals,buthavenotbeencompareddirectlyinmanyofthesespecies,includingrodents.Thisstudyaimedtocomparetheonsetanddepthofanaesthesia,andchangesinvitalsigns,afterintraperitoneal(IP)orsubcutaneous(SC)administrationofketamine(75mgkg-1)combinedwithmedetomidine(1mgkg-1)ordexmedetomidine(0.5mgkg-1)usingarandomisedsemi-crossoverdesignwith≥48hoursbetweentreatmentsin10maleand10femalemice.Eachmousewasanaesthetisedtwiceusingthesameadministrationroute(IPorSC):oncewitheachdrug-ketaminecombination.Anaesthetisedmiceweremonitoredonaheatingpadwithoutsupplementaloxygenfor89minutes;atipamezolewasadministeredforreversal.Thetimesthattherightingreflexwaslostpost-injectionandreturnedpost-reversalwereanalysedusinggenerallinearmodels.Tail-pinchandpedalreflexeswereexaminedusingbinomialgeneralizedlinearmodels.Pulserate(PR),respiratoryrate(fr),andarterialhaemoglobinsaturation(SpO2)werecomparedusinggeneralizedadditivemixedmodels.ResultsTherewerenosignificantdifferencesamongtreatmentsforthetimestakenforlossandreturnoftherightingreflex,orresponseofthetail-pinchreflex.ThepedalwithdrawalreflexwasabolishedmorefrequentlywithMKthanDKovertime(P=0.021).TheresponseofPRandSpO2weresimilaramongtreatments,butfrwassignificantlyhigherwithMKthanDK(P≤0.0005).MarkedlylowSpO2concentrationsoccurredwithin5minutespost-injection(83.8±6.7%)inalltreatmentgroupsandweremostsevereafter89minuteslapsed(66.7±7.5%).Nostatisticaldifferencesweredetectedinregardstoadministrationroute(P≤0.94).ConclusionsThisstudyfailedtodemonstrateclinicaladvantagesoftheenantiomerdexmedetomidineovermedetomidinewhencombinedwithketaminetoproducegeneralanaesthesiainmice.Atthedosesadministered,deepsurgicalanaesthesiawasnotconsistentlyproducedwitheithercombination;therefore,anaestheticdepthmustbeassessedbeforeperformingsurgicalprocedures.Supplementaloxygenshouldalwaysbeprovidedduringanaesthesiatopreventhypoxaemia. BackgroundInjectableanaesthesiaisoftenconsideredthemethodofchoiceforexperimentalproceduresinsmallrodents[1].Alpha-2agonistsareroutinelyusedincombinationwithotherdrugstoproduceanaesthesia.Onebenefitofα2agonistsisthattheireffectscanbereversedusingaspecificantagonist,atipamezole[2].Oftheseagents,medetomidineisapopularchoiceinvariousspeciesduetoitshighα2receptorselectivitycomparedtoromifidine,detomidine,andxylazine.Medetomidine,aracemateofthestereoisomerslevomedetomidineanddexmedetomidine,isasedativeandanalgesicthatactscentrallyonα2adrenergicreceptorslargelyconcentratedinthelocuscoeruleusofthebrainstemtodecreasesympathetictone.Peripherally,medetomidineactivatespostsynapticα2adrenergicreceptorsinvascularsmoothmuscletocausevasoconstriction.Itsmainsideeffectsincludebradycardia,hypotension,respiratorydepression,hypothermiaanddiuresis[3–7].Hypotensionisaresultofcentrallymediatedeffectsonsympathetictonethatmaybeapparentaftertheinitialperipheralvasoconstrictiveeffectspass[2,8–10].Thisphenomenonisalsoobservedduringtheadministrationofotherα2agonists[11,12].Dexmedetomidinehasbeenidentifiedastheactiveenantiomerofmedetomidine,yettheeffectsoflevomedetomidinehavebeendebated.Unlikemedetomidineanddexmedetomidine,levomedetomidinealonedoesnotappeartohaveeffectsonthecardiovascularsystemandonlyprovidessedationoranalgesiaathighdosesinratsandmice[3].Itsclearanceisfourtimesmorerapidinthedog[13].Asecondstudyinthedogcomparedahighdoseandlowdoseoflevomedetomidinebyadministrationofaninitialintravenous(IV)bolus(10or80μgkg-1)followedbytwo-hourconstantrateinfusionsoflevomedetomidinealone(25or200μgkg-1h-1)withorwithoutasingledosedexmedetomidine(10μgkg-1);thestudyconcludedthatthecombinedadministrationofahighdoseoflevomedetomidineanddexmedetomidinesignificantlyreducedsedationscoresandincreasedtheincidenceofbradycardia[14].Inhumancellculture,levomedetomidinewasdescribedasan“inverse”agonistbecauseituncoupledactiveα2adrenergicreceptorsbydecreasing[Ca2+]andinhibitingcAMPfunction[15].Ithasbeensuggestedthatthesedativeeffectsofdexmedetomidinealonemaythereforebemorepredictableandthecardiovascularsideeffectsshouldbeminimisedcomparedtotheracemicmixture.However,nosignificantdifferencewasobservedwhenlevomedetomidinewasco-administeredwithdexmedetomidineuntillevomedetomidineexceededeighttimesthenormalracemicpreparation[13].Althoughsomestudieshavesuggestedthatdexmedetomidineissuperiortomedetomidine[13,16],thismaynotbethecase.Ahandfulofstudieshavecomparedthesedativeeffectsofmedetomidineanddexmedetomidineinthemouseandrat[3],dog[13,17,18],cat[16,19,20],andsheep[10].Allofthesestudiesexcepttwoconcludedtherewerenoclinicaladvantagesofdexmedetomidineovermedetomidine[13,16].Althoughtherewerenosignificantdifferences,onestudyconcludedthat“dexmedetomidinetendedtobeslightlymorepotentthantheequivalentdoseofmedetomidine”andmayprovidemorepredictablesedationandanalgesiainthedog[13].Amorerecentcomparisonreportedsignificantlygreatermusclerelaxationinmedetomidine-treatedcats[16].Ketamineincombinationwithmedetomidine(MK)hasbeenwidelyusedasananaestheticforlaboratoryratsandmice[1,7,21–24].KetamineisacentrallyactingNMDA-receptorantagonistthatrapidlyinducesdissociativeanaesthesiawhileprovidinganalgesia.Itssideeffectsincludetachycardia,dysphoria,andmusclerigidity.Whencombinedwithanα2agonist,generalanaesthesiamaybeattained.Themusclerelaxantpropertiesoftheα2agonistoffsettherigidityinducedbyketamineandco-administrationdecreasestheeffectivedoseofeachdrug[5–7].Theintroductionofdexmedetomidineasaveterinaryproducthasbeenaccompaniedbythewithdrawalofmedetomidineinsomecountries(e.g.theUSA).Consequently,useofdexmedetomidineincombinationwithketamine(DK)hasincreased,withdoseratesbasedonassumptionsofpotencyderivedfromtherelativelyfewstudiesinotherspecies.Becausedexmedetomidinewasidentifiedastheactiveenantiomerofmedetomidine,thedoseofdexmedetomidineadministeredisnormallyhalfthatofthemedetomidine;thisisduetotheabsenceoflevomedetomidinethatcomprises50%ofthemedetomidineracemate.Threestudiesinotherspeciesadministeredequalamountsofketaminecombinedwithdosesofmedetomidineordexmedetomidineassumedbytheresearcherstobeequipotent.Astudyofthegolden-headedliontamarinLeontopithecuschrysomelasconcludedthatDKprovidedgreateranaestheticdepthbecausethelengthoftimeittooktamarinstreatedwithDKtowalkafterstandingwassignificantlygreater[25].Similarly,afieldexperimentintheChinesewaterdeerHydropotesinermisalsoobservedamorerapidrecoverywithMK,aswellassignificantlyfasterimmobilisation[26].TherewerenosignificantdifferencesbetweenMKandDKwhenadministeredtotheBennett’swallabyMacropusrufogriseus[27].AlthoughthesestudiessupportinterspeciesvariationinresponsetoMKandDKadministration,currentlythereappeartobenodatadirectlycomparingMKandDKinlaboratoryrodents.Thisstudyaimedtocomparetheonsetanddepthofanaesthesia,andchangesinvitalsigns,afterintraperitoneal(IP)orsubcutaneous(SC)administrationofMKorDKcombinationsinmice.MethodsAnimalsTwentyC57BL/6Nmice,10maleand10femalewereacquiredfromacommercialbreeder(CharlesRiverUKLtd.,Kent,UK).Thesemicewereacclimatedtwoweekspriortothestudyinananimalroommaintainedat22±1°Cand35%humidity,ona12-hourlight-darkcycle(beginningat07:00)with15to20airchangeshour-1;regularserologicalmonitoringensuredthisfacilityisfreefromallrecognisedrespiratorypathogensofrodents.Apositive-pressureindividuallyventilatedcagesystem(Maxiseal,Arrowmight,Hereford,UK)wasusedtohouseamaximumofsixsame-sexmicecage-1.Eachcagecontainedaspenwoodchipbedding(BS&SLtd.,Edinburgh,UK)andnestingmaterial(shreddedpaper,DBMFoodHygieneSuppliesLtd.,Broxburn,UK).Food(CRM(P),SpecialDietsServices,Essex,UK)andtapwaterwereprovidedadlibitum.Atthetimeofthestudy,themicewere6weeksoldandearnotchedforidentification;malesweighed23±1.4gandfemalesweighed19±0.7g.ExperimentaldesignFouranaesthetictreatmentswereevaluatedbyarandomisedsemi-crossoverdesignwith≥48hoursbetweentreatments.Ketamine(75mgkg-1,Ketalar™Injection,PfizerLtd.,Sandwich,UK)wascombinedwithmedetomidine(1mgkg-1,Domitor®,JanssenAnimalHealth,Basingstoke,UK)ordexmedetomidine(0.5mgkg-1,Dexdomitor®,JanssenAnimalHealth).Eachmousewasrandomlyanaesthetisedwithonedrug-ketaminecombination(e.g.medetomidine)administeredbytheIPorSCroute;afteraminimumof48hours,eachmousewasanaesthetisedagainwiththeotherdrug-ketaminecombination(e.g.dexmedetomidine)administeredbythesamerouteasitsfirsttreatment.Datawerecollectedfrom06to17June2011between9:00and13:00dailytoensuretimeofdaydidnotaffectresults.Nomorethanthreemicewereconcurrentlyanesthetisedtoallowenoughtimetomonitoreachindividual;theinjectionofeachmousewasstaggeredby5minutes.Thesameoperatorcollectedallthedataobtainedinthisstudy.ThisstudywascarriedoutinaccordancewithprojectandpersonallicensesgrantedundertheUnitedKingdom’sAnimals(ScientificProcedures)Act(1986)andtheNewcastleUniversityEthicalReviewCommitteespecificallyapprovedthisstudy(PPL60/4126).ProcedureThetimefrominjectiontolossoftherightingreflex(LORR)wasrecordedwhenthemouseappearedimmobileandwasphysicallyrolledintolateralrecumbencybyhandtoverifythattherightingreflexwasabolished.Eachmousewasplacedonadigitalthermoregulatedheatingpad(37°C,507220F,HarvardApparatus,Kent,UK)tobreatheroomair;protectiveeyelubricantwasapplied(Puralube®,Pharmaderm,Melville,NY,USA).Thehairoftherightthighwasclippedandapulseoximeter(MouseOx®,StarrLifeSciencesCorp.,Oakmont,PA,USA)probewasplacedtomonitorpulserate(PR)andarterialhaemoglobinsaturation(SpO2).InadditiontoPRandSpO2,thetail-pinchandpedalwithdrawalreflexes(presenceorabsencedetermined“byhand”),andrespirationrate(fr;determinedbyobservationofchestwallmovement)weremonitoredfor89minutesfrom5minutespost-injectionat7-minuteintervals.ThePRandSpO2wereaveragedfromvaluescollectedevery0.2seconds(MouseOx®)overa30-secondtimeintervalforeachsampletimepoint.Regardlessofanyparameters,theeffectsofmedetomidineordexmedetomidinewereantagonisedat89minutespost-injectionbyatipamezole(5mgkg-1,Antisedan®,JanssenAnimalHealth)administeredbythesamerouteasinduction.Thetimeuntilreturnoftherightingreflex(RORR)wasrecordedasthetimefromatipamezoleadministrationuntilthemouserolledunassistedfromlateraltoventral(sternal)recumbency.Then,micewereplacedinafan-assistedincubator(25°C,MediHeat™,PecoServiesLtd.,Cumbria,UK)untilfullrecovery.StatisticalanalysisGenerallinearmodels(glms)wereusedtoanalysethetimesuntilLORRandRORR.Thefullmodelsincludeddrug,administrationroute,bodyweight,andsexasexplanatoryvariableswithdrugandadministrationrouteincludedasaninteractionterm.TheoptimalmodelwasdeterminedbythestepwiseremovalofvariablestoreachthelowestAkaike’sinformationcriterion(AIC).Areductionof≥5inAICwasconsideredindicativeofasignificantimprovementinmodelfit.Thepresenceoftail-pinchandpedalwithdrawalreflexeswasevaluatedwithgeneralizedlinearmodels(GLMs).Modelsincludedabinomialerrorstructuretoaccountforthebinarynatureoftheresponsevariable.Explanatoryvariablesinthefullmodelincludeddrug,administrationroute,andtimeeachmeasurementwastaken,withdrugandadministrationrouteincludedasaninteractionterm.Stepwiseremovalofvariableswasusedtodeterminetheoptimalmodel.Modelresidualswereexaminedwithanauto-correlationfunction(acf)andshowedthatthepedalwithdrawalreflexmodelsweretemporallyauto-correlated.Pedalwithdrawalreflexwasbetterexplainedwithabinomialgeneralizedadditivemodelwithanauto-regressivecorrelationstructuretoaccountforthetemporaldependencebetweenresiduals.Stepwiseremovalofvariableswasusedtodeterminetheoptimalmodel.ThePR,fr,andSpO2wereexaminedwithgeneralizedadditivemixedeffectsmodels(GAMMs)toallowforpotentialnon-linearrelationshipsamongvariablesaswellasviolationsofindependencewithinthedata.Thefullmodelsforeachresponsevariableincludedtheothertworesponsevariablesasadditionalexplanatoryvariablesforeachmodel(e.g.themodelforPRincludedfr,andSpO2).Drug,administrationroute,time,bodyweight,andsexwerealsoincludedasexplanatoryvariablesforeachofthethreeresponsevariables.Whereanexplanatoryvariableappearedtodemonstratenon-linearrelationshipswiththeresponse(basedonprimaryvisualassessmentofdata),theywereincludedassmoothtermsinthefullmodel(Additionalfile1).Mousewasincludedasanormallydistributedrandomeffecttoaccountforpseudo-replicationinthesemi-crossoverdesign.Optimalmodelswerereachedbythestepwiseremovalofvariables,andreplacementofnon-significantsmoothtermswithlinearones.Finalmodelsweretestedwithacfsforthepresenceoftemporalauto-correlation.OptimalcorrelationstructureswereselectedbyAICtocorrectforthisauto-correlation.Allmodelshadthisbestaccountedforbyauto-regressivemoving-averagecorrelationstructures.Thesewerethenappliedtothefullmodelandstepwiseremovalofexplanatoryvariableswasperformedagain.AllanalyseswereperformedusingRversion2.14.0(RFoundationforStatisticalComputing;http://www.R-project.org).AsignificancelevelofP≤0.05wasusedduringinterpretationoftheseanalysesandallmeansarereportedasthemean±standarddeviationinthetext.ResultsThetimeuntilLORRwasnotsignificantlyaffectedbydrug(glm,F=1.14,P=0.29),administrationroute(glm,F=0.14,P=0.71;Figure 1),orindividualbodyweight(glm,F=3.30,P=0.078).Similarly,thetimeuntilRORRwasnotsignificantlyaffectedbydrug(glm,F=0.26,P=0.61),administrationroute(glm,F=1.86,P=0.18;Figure 1),orindividualbodyweight(glm,F=0.16,P=0.69).Figure1Lossandreturnoftherightingreflex.Meantime(seconds)untillossoftherightingreflex(LORR)andreturnoftherightingreflex(RORR)afteradministrationofmedetomidine-ketamine(MK)ordexmedetomidine-ketamine(DK)bytheintraperitoneal(IP)orsubcutaneous(SC)route.ThetimetoLORRwasnotsignificantlyaffectedbydrug(P=0.29)oradministrationroute(P=0.71).Similarly,thetimeuntilRORRwasnotsignificantlyaffectedbydrug(P=0.61)oradministrationroute(P=0.18).FullsizeimageLossofthetail-pinchreflexoccurredby12minutespost-injectionanddidnotsignificantlydifferbetweenMKandDK(GLM,z=0.92,P=0.36;Figure 2).Neitherdrugconsistentlyachievedlossofthepedalwithdrawalreflexbyeitheradministrationroute,butwasmorefrequentwithMKthanDKovertime(GLM,z=2.3,P=0.021;Figure 2).Figure2Tail-pinchandpedalreflexes.Percentageofindividualswithpresenttail-pinchandpedalwithdrawalreflexesafteradministrationofmedetomidine-ketamine(MK)ordexmedetomidine-ketamine(DK)overtime.Lossofthetail-pinchreflexdidnotsignificantlydifferbetweendrugcombination(P=0.36).Pedalwithdrawalreflexlosswasnotconsistentlyachievedbyeitherdrugcombination,butwasmorefrequentwithMKthanDKovertime(P=0.021).FullsizeimagePulseratewasnotsignificantlydifferentbetweendrug(GAMM,t=0.48,P=0.63;Figure 3)oradministrationroute(GAMM,t=0.47,P=0.64),bodyweight(GAMM,t=0.008,P=0.99)orsex(GAMM,t=1.26,P=0.21).Itwasnegativelycorrelatedwithtimeuntilabout47minutespost-injection,andpositivelycorrelatedthereafter(GAMM,F=16.59,e.d.f.=6.13,P≤0.0005).PulseratewasalsopositivelycorrelatedwithSpO2untilabout77%SpO2,afterwhichthecorrelationbecamenegative(GAMM,F=9.20,e.d.f.=2.74,P≤0.0005).Figure3Vitalsigns.Meanpulserate(PR)andrespiratoryrate(fr)afteradministrationofmedetomidine-ketamine(MK)ordexmedetomidine-ketamine(DK),andarterialhaemoglobinsaturation(SpO2)afterdrugadministrationbytheintraperitoneal(IP)orsubcutaneous(SC)routeovertime.Althoughmeanswerenotusedtodeterminestatisticalsignificance,theyeffectivelydisplaydatatrends.FullsizeimageThefrwassignificantlyhigherwithMKthanDK(GAMM,t=4.047,P≤0.0005;Figure 3).Administrationroutedidnotsignificantlyaffectfr(GAMM,t=0.077,P=0.94).ThecorrelationbetweenfrandSpO2wasnegativeuntilapproximately76%SpO2,atwhichpointthecorrelationbecomespositive(GAMM,F=19.19,e.d.f.=1.86,P≤0.0005).TheSpO2wasnotaffectedbydrug(GAMM,t=0.76,P=0.45)oradministrationroute(GAMM,t=1.75,P=0.081;Figure 3),butpositivelycorrelatedwithbodyweight(GAMM,t=2.85,P=0.0046)andwassignificantlylowerinmalesthanfemales(GAMM,t=2.88,P=0.0041).TheSpO2wasnegativelycorrelatedwithPR(GAMM,t=6.87,P=0.0001)andfr(GAMM,t=4.240,P≤0.0005).Itwaspositivelycorrelatedwithtimeuntilabout47minutespost-injectionandnegativelycorrelatedthereafter(GAMM,F=50.87,e.d.f.=2.86,P≤0.0005).DiscussionMedetomidineanddexmedetomidineareroutinelyadministeredaloneorincombinationwithotherdrugsincludingketamine;however,tothebestofourknowledge,onlyahandfulofpeer-reviewedstudieshaveaimedtocomparethesedativeandanalgesicpropertiesofthesedrugsaloneandevenfewercomparedtheiruseinconjunctionwithketamine.OurstudyfoundnosignificantdifferenceinLORRandRORRtimesbasedondrug,administrationroute,orindividualbodyweight.Lossofthetail-pinchreflexoccurredby12minutespost-injectioninalltreatmentsanddidnotsignificantlydifferbetweenMKandDK.Neitherdrugconsistentlyachievedlossofthepedalwithdrawalreflexbyeitheradministrationroute,butlosswasmorefrequentwithMKthanDKovertime.Pulseratewasnotsignificantlydifferentamongtreatments,butfrwassignificantlyhigherwithMKthanDK;administrationroutedidnotsignificantlyaffectfr.TheSpO2wasnotaffectedbydrugoradministrationroute,butpositivelycorrelatedwithbodyweightandwassignificantlylowerinmalesthanfemales.Onaverage,theSpO2ofthemicewasmarkedlylow(<85%)within5minutespost-injectionanddecreasedseverely(to<70%)by89minutes.Manystudiesthatdirectlycomparedmedetomidineanddexmedetomidineasasedativeorpremedicationfoundnoclinicallysignificantdifferencesinvariousspecies[3,15–19].Inacollectionofexperimentsinlaboratoryrodents,IVsedationwithmedetomidineanditsenantiomerswerefoundtoinducesimilarlevelsofhypotension,bradycardiaandlossofthemydriaticresponse;levomedetomidinehadnocardiovascularorpupillaryeffectwhenadministeredIV[3].Intermsofanalgesia,thesamegroupfoundthatallthreedrugs(0.01to1mgkg-1medetomidine;0.01to0.1mgkg-1dexmedetomidine;0.3to10mgkg-1levomedetomidine)appearedtoinhibittheaceticacid-inducedwrithingresponseinmice.Ultimately,thesestudiesconcludedtherewerenomajordifferencesbetweenmedetomidineanddexmedetomidine[3].Basedontheresultsofthewrithingtest,levomedetomidinemayhaveanalgesicproperties.Thislackofdifferencesreportedinthesepreviousstudieswhenmedetomidineanddexmedetomidinewereadministeredalonesupportsourcurrentfindingsthattherewasnoapparentclinicaldifferencebetweenthesedrugsadministeredincombinationwithketamine.ThedrugdosagesusedinthisstudyrepresentcommonlyreportedMKcombinationsadministeredtomice[1,7,22–24].Thedexmedetomidinedose(0.5mgkg-1)usedwascalculatedashalfthemedetomidinedose(1mgkg-1)becauseitlacksthelevomedetomidinecomponentpresentintheracemicmixture.Wethereforeexpectedthedosesofmedetomidineanddexmedetomidinetobeequipotent.Therecommendeddoseofatipamezoletoreversetheeffectsofthesedrugsis5mgkg-1for1mgkg-1ofmedetomidineor0.5mgkg-1ofdexmedetomidine[22],butitsreportedqualityofreversalisinconsistent[21].WeusedthetimeuntilRORRasameasureofMKandDKreversibilitybyatipamezole;therewerenosignificantdifferences,buttherewasawidevariationinrecoverytimes(293±258seconds).Dependingontheproceduretobeperformed,theidealanaestheticdepthmayvary.Inpractice,depthofanaesthesiaisgenerallydefinedbythelossofspecificreflexesasthedepthofanaesthesiaprogressesfromsedationtosurgicalanaesthesia.Sedationisthefirstlevel;inmice,locomotionceases,respirationslows,andtheheadandtailarerelaxed.Next,lightanaesthesiaoccurswhentherightingreflexislost,butthemousewillrespondtopainfulstimuli.Surgicaldepthofanaesthesiaisachievedwhenthetail-pinchandpedalwithdrawalreflexesarelost.Subcutaneousadministrationof0.3mgkg-1ofdexmedetomidineabolishedtherightingreflexinrats,butparadoxicalexcitabilitywasobservedatthe1mgkg-1dose;neithermedetomidinenordexmedetomidineinducedsustainablelossofthepedalwithdrawalreflexindicatinglightanesthesia[3].Similarly,thedosesofMKandDKadministeredinourstudyinducedLORR(89±51seconds),but,basedontheirfailuretoabolishthepedalwithdrawalreflexthroughoutthetimepost-injection,maynotprovideappropriateanaestheticdepthsuitableforsurgicalprocedures(Figure 2).ThesefindingswereconsistentwithotherreportsofMKadministrationinmice[1,22].StudiesthatcompareddepthofanaesthesiabetweenMKandDKsuggestedthatDKproducedagreateranaestheticdepth[25,26];conversely,ourstudyobservedsignificantlydeeperanaesthesiafromMK(Figure 2).Theseinconsistentfindingscouldbeduetospeciesdifferencesamongmice,golden-headedliontamarinsandChinesewaterdeer.Similarly,differencesamongdifferentstrainsofthesamespecies(e.g.aBALB/corC57BL/6Nbackgroundinmice)havebeenreportedinthefieldofanalgesiaandanaesthesia[28–31].NormalrestingPRinthemouserangesfrom350to600beatsminute-1[32].Bradycardiawasapparentforapproximately26minutespost-injectionwhentheaveragePRreachedaminimum(236±35beatsminute-1);thePRsteadilyincreasedthereafter(Figure 3).ThisdramaticdecreaseinPRwasattributedtoreflexbradycardia,abaroreceptorresponsethatcompensatesforinitialα2-inducedperipheralvasoconstrictionandhypertension.OtherstudiesalsofoundnodifferencesinPRwhenMKandDKwerecompared[26,27].Thesewell-understoodphysiologicalmechanismssupportthatthePRrespondedasexpectedwhenanα2agonistisadministered,whilethesestudiessupportthattherearenoclinicaldifferencesbetweenMKorDKadministeredIVorSCinmice.Thenormalrestingfrinthemouserangesfrom80to200breathsminute-1[32].ThemicetreatedwithDK(144±17breathsminute-1)hadsignificantlylowerfrthanthosetreatedwithMK(156±15breathsminute-1;Figure 3),butthedifferencedoesnotappeartobeclinicallysignificantbasedonthenormalrestingrespiratoryrateandthelackofdifferenceamongtreatmentswithregardstoSpO2.Theincreaseinfrovertimecouldbeacombinedresponsetoarapiddecreaseinarterialpartialpressureofoxygen(PaO2)andpotentialincreaseinarterialpartialpressureofcarbondioxide(PaCO2).AlthoughPaCO2istheprimarytriggerstimulatingtherespiratorydrive,abnormallylowPaO2(≤60mmHg)alonecanhavearoleaswell,referredtoasthe“hypoxicventilatoryresponse”[33,34].DirectmeasurementsofPaO2andPaCO2wouldbenecessarytoconfirmthis.Onobservation,respiratorypatternsofindividualmiceappearedshallowerovertime;thismayaccountforthesteadyincreaseinfr,whiletheSpO2continuedtodecrease.Respiratorydepression,alsoknownashypoventilation,causedbyα2agonistswassuspectedinthisstudybecausedepressionofthecentralnervoussystemfollowingtheactivationofα2agonistreceptorsincludesdepressionofrespiratorycentres.[4,6,35].Measurementsoftidalvolumeandend-tidalcarbondioxideofthemicewouldbenecessarytoconfirmthis.TheeffectofMKandDKonfrinotherstudieswasinconsistent[25–27].Thislackofconsistencycouldbealsoattributedtovariationamongspecies,ormayrequirefurtherexaminationtoverifythephysiologicalprocessthatoccurredinourstudy.AlthoughSpO2wasnotsignificantlydifferentamongtreatmentgroups,therewasaninterestingrelationshipbetweensexandbodyweight.AlthoughasignificantpositivecorrelationexistedbetweenSpO2andbodyweight,malemicehadasignificantlylowerSpO2thanfemales.Anautocorrelationexistsbetweensexandweight:undernormalcircumstancesinmiceofagivenage,maleshaveapredictablygreaterbodyweightthanfemales;however,anunknowncomponentofsexsetstheaverageSpO2ofmalemicelowerthanfemales.Astudyinratssuggestedthatfemalesmayhaveamoreefficientoxygentransportsystemthanmalesrelatedtoahigherpulmonarycompliance[36],whileanotherfoundthatvirginfemaleratsattheonsetofsexualmaturityhaveagreatergas-exchangesurfaceareathanmalerats[37].Inourstudy,agreaterpulmonarycomplianceofprepubescentfemalemicecouldcontributetothesignificantdifferencesobservedbetweensexes.Aspecificstudywouldberequiredtofurtherexplaintherelationshipweobservedinmiceanddetermineifmalesandfemaleshavedifferentrequirementsforoxygenunderanaesthesia.Hypoxaemiaisasignificantcauseofmortalityinanesthetisedmice,yetsupplementaloxygenisnotcommonlyused[7].Inordertomimiccommonlaboratorypractice,supplementaloxygenwasnotsuppliedinthisstudy.TheSpO2wasmarkedlylowwithin5minutespost-injection(83.8±6.7%)anddecreasedseverelyto66.7±7.5%by89minutes(Figure 3).Althoughhypoxaemiawasanticipatedbasedonpreviousstudies,SpO2levelswerelowerthanexpected[25–27].ThislargedecreaseinSpO2couldbeduethemonitoringmethodemployedinourstudy:pulseoximetry.Pulseoximetrywasusedinthisstudybecauseitprovidesasimple,non-invasivemeansofmonitoringrespiratoryfunction;however,pulseoximetryhaslimitations.Readingsbecomelessreliableatloweroxygensaturationlevels(<70to75%)[38,39].Thisisnotusuallyasignificantproblembecauselevelslessthan80%requirecorrectiveactionwhensupplementaloxygenisnotsupplied;thisthresholdincreasesto90%forindividualsreceivingsupplementaloxygen.Additionally,peripheralvasoconstrictionandhypothermia,sideeffectsofmedetomidine,couldhavepreventedaccuratereadingsduetoalackofperfusioninthelocationoftheprobe[4–7].Althoughwedidnotmonitorcoretemperature,theheatingpadusedthroughouttheexperimentshouldhavehelpedtopreventhypothermia.Inapreviousstudyinrats,thepulseoximeterreadingswerecomparabletoarterialbloodgasvalues[40].Othersourcesoferrorcouldincludemechanicalartifactsfromimproperprobeplacementandelectromagneticinterference,butarelesslikely[39].TherewerenosignificantdifferencesbetweenIPandSCadministrationasthetimesofonsetandanaestheticdepthsweresimilar.ThiswasunexpectedbecauseIPadministrationwasanticipatedtoresultinamorerapidonset,greaterfirstpassextractionoftheanaestheticagentsbytheliver,andpossibleconsequentreductioninefficacybasedonpreviouswork[41].Despitethispotentialuncertaintyastodoseequivalence,SCdosingmaybeconsideredpreferabletopreventadditionalstresstotheanimal,aswellaspotentialdamagetointernalorgansthatmayoccurbyIPdelivery;itmayalsobemoreamorereliableroutebecauseIPinjectionshavebeenassociatedwithahighpartialfailurerate[42].Therigorousstatisticalmodelselectionemployedensuredthatadynamicandflexibleco-variancestructurewasappropriatelyappliedtotheerrorstructuresoftime-seriesmodels.Mousewasincludedasarandomeffecttoaccountforthelackofindependencethatresultedfromsubjectingeachmousetobothdrugcombinations(thesemi-crossoverdesign).Appropriatemodelerrorstructuresaccountedfortherepeatedmeasurestakensequentiallyfromeachmouse.Thesemi-crossoverdesignallowedustoreducethenumberofanimalsrequiredforthestudy,reusemiceformultipletreatments,andaccountforphysiologicaldifferencesamongindividuals.Becauseofthelackofindependencebetweentimepointswithinthesedata(asforanyanalysisofatime-series),displayingmeanvaluesforeachtime-pointcanonlybeusedtodemonstrateoveralldatatrends(Figure 3).Moredifficulttointerpretgraphicallyandbeyondthescopeofthisstudy,theappropriateplotsdemonstratingthestatisticalnatureoftheserelationshipsrequiredindividualplotsforeachmouse(Additionalfile2).Thestatisticalanalysesofrelatedpreviousworkhavereliedheavilyonrepeatedmeasuresanalysisofvariance(ANOVA)[13,14,19,25–27,43].Whilethesetestsaccountforadegreeofdependencebetweendatapoints,themixedeffectsmodelingapproachweutilisedismoreflexibleandrobustthanmorecommonanalyses.WhereasarepeatedmeasuresANOVAcanbeusedtodetectlineardependenciesbetweenresponseandexplanatoryvariables,themodelsusedherecanbeusedtoexplainnon-linearautocorrelation(e.g.adecayindependenceastimebetweendatapointsincreases)[44,45].Moderndataanalysistechniquescouldbeusedtorefineexperimentalprotocolandmorepowerfulmethodologiescouldbeencouragedinlaboratoryanimalmedicinetoreducethenumbersofindividualsusedinstudies.OurstudyfailedtodemonstrateclinicaldifferencesintheuseofMKorDKadministeredeitherIPorSCinthemouse.Wealsodemonstratedtheneedforappropriateoxygensupplementation,evenduringshortorminorprocedures.FurtherresearchshouldexaminetheeffectsofMKandDKindifferentmousestrains.Bloodpressuremonitoringmayhavedemonstratedtherelationshipbetweentheinitialhypertensionexpectedfromtheperipheralvasoconstrictioninducedbyα2agonistsandtheinitialbradycardiaobserved.Then,thecentrallymediateddecreaseinbloodpressurereportedtofollowmaycorrelatewiththesteadyincreaseinPRwhichoccurredafter26minutespost-injection[2,8–12].Ameasureofrectaltemperaturewouldensuretheheatingpadwasappropriatelymaintainingbodytemperature.ConclusionsOurstudyfailedtodemonstrateclinicaladvantagesoftheactiveenantiomerdexmedetomidineovertheracemicmixturemedetomidinewhencombinedwithketamineforgeneralanaesthesiainmice.Theseresultsreassurecolleaguesworkinginlocationswheremedetomidineisnolongeravailablethatdexmedetomidinecanbeusedwitha50%reductionindoserate.ThedosesofMKandDKadministeredinthisstudydidnotconsistentlyproducedeepsurgicalanaesthesia,soanaestheticdepthmustbeassessedbeforeperformingsurgicalprocedures.TherewasnoadvantageoftheIPadministrationroutecomparedtotheSCinjection,buttheSCroutemaybesuggestedbasedonpreviousreportsofreducedinjury,stressandpartialfailurerates[42].BecausetheSpO2levelsofallanaesthetisedmiceweremarkedlyorseverelylowthroughoutthisstudy,supplementaloxygenshouldalwaysbeprovidedregardlessofthelengthoftheprocedure. 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ReprintsandPermissionsAboutthisarticleCitethisarticleBurnside,W.M.,Flecknell,P.A.,Cameron,A.I.etal.Acomparisonofmedetomidineanditsactiveenantiomerdexmedetomidinewhenadministeredwithketamineinmice. BMCVetRes9,48(2013).https://doi.org/10.1186/1746-6148-9-48DownloadcitationReceived:24September2012Accepted:06March2013Published:13March2013DOI:https://doi.org/10.1186/1746-6148-9-48SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsAlpha-2agonistsDexmedetomidineDrugadministrationrouteGeneralanaesthesiaHypoxaemiaKetamineMouseMedetomidineSubcutaneousinjectionSupplementaloxygen DownloadPDF AssociatedContent Section Pharmacologyandtoxicology Advertisement BMCVeterinaryResearch ISSN:1746-6148 Contactus Submissionenquiries:[email protected] Generalenquiries:[email protected]